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  5. 不吃早饭与胆囊结石发病风险的相关性研究进展

不吃早饭与胆囊结石发病风险的相关性研究进展

深度研究匿名用户发表于 2025年11月19日 16:3912阅读
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1. 胆囊结石的病理生理基础与饮食相关风险因素概述

1.1 胆囊结石的形成机制

胆囊结石是一种常见的消化系统疾病，其中胆固醇结石是最主要的形式，尤其在欧美国家。其形成是一个复杂的过程，涉及多种病理生理异常的相互作用123。核心机制主要包括胆固醇过饱和、成核异常以及胆囊运动功能障碍。

首先，胆固醇过饱和被认为是胆固醇结石形成的首要环节34。正常情况下，胆固醇在胆汁中通过与胆盐和磷脂形成混合微胶粒和囊泡而保持溶解状态56。当胆汁中胆固醇的分泌量相对于胆盐和磷脂的含量过高时，胆汁就会达到过饱和状态47。这种过饱和主要是由肝脏过度分泌胆固醇引起的，肝细胞顶膜上的ABCG5-G8转运蛋白的表达受转录因子肝X受体-α（LXR-α）调节，其功能异常可导致胆固醇的过度分泌47。肥胖、胰岛素抵抗和代谢综合征等代谢紊乱均与胆固醇胆汁过饱和风险增加相关18。

其次，成核异常是指过饱和胆固醇在胆汁中从液态结晶体转变为固态胆固醇单水合物晶体的过程57。即使胆汁处于过饱和状态，胆固醇也不会立即结晶，而是需要一个成核过程。胆汁中的促成核因子（如粘蛋白）和抗成核因子之间的失衡在此过程中起关键作用910。例如，胆囊粘蛋白的过度分泌会促进胆固醇晶体的形成和聚集410。粘蛋白的改变及其基因多态性也可能影响胆囊结石的易感性10。

再者，胆囊运动功能障碍（即胆囊收缩功能减退或排空延迟）是促进胆固醇结石形成的重要因素3411。胆囊功能低下导致胆汁在胆囊内滞留时间延长，为胆固醇晶体的生长和聚集提供了充足的时间，最终形成结石411。胆囊中的卡哈尔间质细胞（ICC）参与胆囊的自发性收缩，其数量的减少可能与胆囊收缩功能障碍和结石的形成有关11。

胆汁的成分失衡是上述机制的核心驱动力。胆汁主要由胆汁酸、磷脂（主要是卵磷脂）和胆固醇组成612。

  • 胆汁酸是维持胆固醇溶解度的关键。肝脏合成的初级胆汁酸（如胆酸和鹅去氧胆酸）以及肠道细菌转化形成的次级胆汁酸（如脱氧胆酸和石胆酸）在肠肝循环中被高度调控6。胆汁酸池的减少或胆汁酸与胆固醇比例的失衡会降低胆固醇的溶解能力3。
  • 磷脂在胆汁中通过形成混合微胶粒和囊泡来增溶胆固醇5。胆汁磷脂的减少或缺乏会导致胆汁异常的亚稳态，从而促进胆固醇过饱和57。编码磷脂转运蛋白ABCB4的基因突变可导致低磷脂相关胆石症713。
  • 胆固醇的过量分泌直接导致胆汁过饱和4。遗传因素，特别是ABCG5/G8胆固醇转运蛋白基因的常见变异，显著增加了胆囊结石的风险71314。

这些病理机制相互关联，共同促成了胆囊结石的发生发展。了解这些基础机制对于开发预防和治疗策略至关重要128。

1.2 饮食因素在胆囊结石发病中的角色

饮食习惯和膳食组成在胆囊结石的发生发展中扮演着关键角色，通过影响胆汁的成分、胆囊动力学以及整体代谢状态来发挥作用。多项研究已证实特定的饮食模式和营养素摄入与胆囊结石风险的增减密切相关。

首先，能量分布与进食频率对胆汁代谢有显著影响。例如，长时间的饥饿或不规律的进食模式，尤其是跳过早餐，可能导致胆囊长时间不收缩，胆汁在胆囊内淤积，增加胆固醇结晶和结石形成的风险。研究表明，与规律三餐相比，频繁进食（"Grazing"模式）可能降低胆囊结石风险，而长时间空腹则可能增加风险，这提示进食频率对胆汁排空有调节作用。快速减肥和极低热量饮食也会增加胆结石的风险15。

其次，营养素摄入的比例，特别是碳水化合物、脂肪和膳食纤维，对胆汁的胆固醇饱和度具有重要影响。

  • 高碳水化合物饮食被认为是胆囊结石的一个危险因素，尤其是在能量摄入较高的情况下。精制碳水化合物的过量摄入可能导致胰岛素抵抗和高甘油三酯血症，进而影响肝脏胆固醇代谢，增加胆汁中胆固醇的饱和度。NHANES研究提示“高碳水化合物”饮食模式与不吃早饭可能存在叠加风险。一项针对胆囊癌的研究曾提示总热量摄入与胆囊癌风险正相关，且碳水化合物可能存在较弱的正相关16。
  • 脂肪摄入，特别是饱和脂肪，与胆囊结石风险呈正相关。高脂肪饮食可能刺激胆固醇分泌增多，同时影响胆汁酸的肠肝循环，从而促进胆固醇结石的形成。然而，并非所有脂肪都具有同等效应，例如，适量摄入不饱和脂肪酸可能具有保护作用。
  • 膳食纤维的摄入量与胆囊结石风险呈负相关。多项研究表明，高膳食纤维饮食可以显著降低胆囊结石的患病率 171819。膳食纤维通过多种机制发挥作用：它能结合胆汁酸，增加胆汁酸的粪便排泄，从而刺激肝脏合成新的胆汁酸，减少胆汁中的胆固醇；同时，膳食纤维还能改善肠道蠕动，缩短食物在肠道的停留时间，间接影响胆汁酸的代谢和肠肝循环。一项研究指出，膳食纤维摄入量每增加10克/天，胆囊结石的风险降低21% (OR = 0.79, 95% CI: 0.63-1.00) 17。

此外，蛋白质的类型也可能有所影响，有研究提示植物蛋白相较于动物蛋白可能具有较低的致石性 20。

综上所述，不健康的饮食模式，包括不规律的进餐、高碳水化合物、高脂肪和低膳食纤维的摄入，均可扰乱胆汁的正常生理过程，增加胆固醇过饱和、胆汁淤积和成核异常的风险，最终促进胆囊结石的形成。其中，早餐作为一个关键的饮食节点，其规律性摄入对于维持胆囊的正常生理功能、促进胆汁排空、调节胆汁成分平衡具有不容忽视的作用。因此，后续章节将深入探讨不吃早饭与胆囊结石发病风险的具体关联及其潜在机制。

2. 不吃早饭的定义与人群流行病学特征

2.1 不吃早饭的界定标准

“不吃早饭”这一概念在营养学和流行病学研究中普遍存在，然而其操作性定义在不同研究中存在一定的异质性，这可能影响研究结果的可比性和结论的普适性。准确界定“不吃早饭”对于深入理解其与健康结局（包括胆囊结石）的关联至关重要。

通常，“不吃早饭”可以根据以下几个维度进行界定：

  1. 完全跳过早餐：这是最直接且普遍接受的定义，指受试者在早晨时段完全没有摄入任何食物或饮料（水除外）。在许多研究中，跳过早餐意味着“没有摄入任何卡路里”21。例如，在NHANES（美国国家健康与营养检查调查）的一些分析中，“间歇性禁食”被定义为连续两天跳过早餐22。
  2. 早餐时间延迟：部分研究关注早餐摄入时间对健康的影响。例如，一些研究会将早餐时间晚于某一特定时间点（如上午9点或更晚）的行为视为“不吃早饭”或“晚吃早餐”。这主要是因为长时间空腹后进食，或者在非传统早餐时段进食，可能对生理节律和代谢产生不同于规律早餐的影响。
  3. 空腹时长阈值：一些研究采用夜间禁食时长作为“不吃早饭”的替代指标。例如，若夜间至次日第一餐的空腹时长超过某个阈值（如13.4小时），则认为该个体属于“晚吃早餐”或“长时间空腹”模式，这与跳过早餐具有相似的生理学意义。这里的13.4小时空腹阈值意味着，如果晚餐在晚上8点结束，那么早餐时间就会延迟到上午9点以后，这通常被认为是对胆囊生理功能产生影响的时间点。

不同研究中界定标准的差异可能导致“不吃早饭”的流行率和其与疾病关联强度的评估结果存在差异。例如，一项关于青少年心血管代谢风险因素的系统综述发现，早餐跳过的流行率范围从0.7%到94%不等，这很可能与不同研究对“不吃早饭”的定义、年龄组和人群差异有关23。此外，早餐的“质量”在研究中也存在变异性，这提示即使摄入早餐，其营养构成也可能影响健康结果24。

鉴于这种定义上的异质性，研究者在设计实验和解读结果时，需明确其所采用的“不吃早饭”定义，并审慎考虑其对研究结论的影响。美国心脏协会（AHA）的一份科学声明也指出，由于跳餐和零食摄入的普遍性，传统的早餐、午餐、晚餐模式变得难以区分，并建议研究中应明确餐次、零食和进餐场合的定义25。这强调了在未来的研究中，标准化“不吃早饭”的定义对于提供更稳健的证据至关重要23。

2.2 不吃早饭的人群分布特征

不吃早饭作为一种常见的饮食行为，其流行率在全球不同人群中表现出显著的差异，并受多种人口学、社会经济及生活方式因素的影响。对这些分布特征的深入了解有助于识别高危人群，并制定有针对性的干预措施。

流行率概览：

全球范围内，不吃早饭的流行率差异较大，通常在10%至30%之间，但某些特定群体中可能更高 24。例如，在2019年一项针对澳大利亚儿童和青少年的研究中，高达44.9%的学生报告“有时”、“经常”或“总是”不吃早饭，其中9.5%的学生“总是”不吃早饭 26。另一项针对约旦学龄儿童的研究显示，不吃早饭的比例为19.6%，且随着年龄增长有增加趋势 27。摩洛哥一项对12-19岁学龄儿童的研究发现，25.6%的青少年没有每天吃早饭 28。在美国，一项调查显示5.1%的成年人从不吃早饭，10.9%的人很少吃早饭 29。

年龄与性别差异：

  • 年龄： 不吃早饭的习惯在青少年群体中尤为普遍，并且随着年龄的增长，这种倾向性通常会增加 2627。在澳大利亚的队列研究中，高年级学生（如中学阶段）不吃早饭的比例明显高于低年级学生 26。这可能与青少年日益独立的作息习惯、学业压力增加以及社会活动增多有关。
  • 性别： 女性群体中不吃早饭的流行率通常高于男性 2628。在澳大利亚的研究中，女性学生不吃早饭的年级梯度变化比男性更为显著 26。摩洛哥的研究也发现性别是与不吃早饭显著相关的因素（OR = 7.13） 28。

社会经济地位与地域差异：

  • 社会经济地位（SES）： 较低的社会经济地位常常与更高的不吃早饭流行率相关 26。这可能反映了经济压力下家庭对食物获取的限制，或对健康饮食知识和习惯的缺乏。例如，母亲较低的教育水平在摩洛哥的研究中被发现与不吃早饭显著相关（OR = 2.86） 28。
  • 地域： 城乡差异也可能存在。在澳大利亚，生活在社会经济欠发达和偏远地区的学生不吃早饭的比例更高 26。这可能与区域内健康食品的可及性、生活节奏以及文化习惯等因素有关。

生活方式与行为模式：

不吃早饭往往与其他不健康的生活方式行为并存，形成一种“不健康行为簇”。

  • 肥胖和体重管理： 大量研究表明，不吃早饭与更高的身体质量指数（BMI）和肥胖患病率显著相关 30313233。一项亚洲和太平洋地区人群的荟萃分析显示，不吃早饭者超重或肥胖的风险是规律吃早饭者的1.75倍（OR = 1.75，95% CI: 1.57-1.95） 31。巴西的研究也指出，不吃早饭者肥胖的几率是规律吃早饭者的1.84倍 30。
  • 心理健康与学业表现： 不吃早饭还与不良的心理健康状况（如持续性悲伤或绝望感）以及较低的学业表现相关 343536。美国疾控中心2023年的调查显示，经历持续悲伤或绝望感的高中生更可能每天不吃早饭 34。这可能通过影响认知功能、注意力和情绪稳定性来间接影响学业 2436。
  • 其他饮食习惯： 不吃早饭者可能更倾向于在其他餐次摄入不健康的食物，如快餐 35，或整体膳食质量较低。此外，晚吃午餐也被发现与更高的BMI和肥胖风险相关，提示餐次安排的整体规律性很重要 30。
  • 吸烟与体力活动： 虽然不是所有研究都发现显著关联，但一些研究提示不吃早饭可能与吸烟、体力活动不足等其他不健康生活习惯存在关联 32。

综上所述，不吃早饭并非孤立的现象，而是与一系列人口学特征和生活方式因素紧密交织。这种行为模式的普遍性和复杂性，凸显了在公共卫生层面推广规律早餐习惯的必要性，尤其是在青少年、女性以及社会经济地位较低的人群中。

3. 不吃早饭与胆囊结石相关性的流行病学证据

3.1 横断面研究的关联强度

大量流行病学研究，特别是横断面研究，已经揭示了不吃早饭或早餐模式异常与胆囊结石风险之间的显著关联。这些研究利用大样本数据，为理解这种饮食行为对胆囊健康的影响提供了重要的初步证据。

美国国家健康与营养检查调查（NHANES）是评估美国人群健康和营养状况的重要资源。基于NHANES 2017-2018年的数据分析发现，不同的进食时间模式与胆囊结石的发生率密切相关 37。该研究通过潜在类别分析（LCA）识别出四种主要的进食时间模式，其中“Later breakfast”（晚吃早餐）和“Grazing”（频繁进食）模式与胆囊结石风险增加相关，而“Early breakfast”（早吃早餐）模式则与风险降低相关 37。

具体而言，与“Conventional”（常规三餐）模式相比，“Later breakfast”模式与胆囊结石的发生风险呈显著正相关，其调整后的优势比（OR）高达1.435 (95% CI: 1.432-1.438) 37。这意味着，与规律且按时吃早餐的人群相比，习惯晚吃早餐的人群发生胆囊结石的风险增加了约43.5%。值得注意的是，“Grazing”模式，即非规律性的频繁进食，也与胆囊结石风险的增加相关（OR 1.147, 95% CI: 1.145-1.148），提示即使是频繁进食，如果缺乏规律性，也可能对胆囊健康产生不利影响 37。相反，“Early breakfast”模式（即早于常规时间吃早餐）则与胆囊结石风险降低相关（OR 0.809, 95% CI: 0.808-0.811），这表明早于9:00AM前吃早餐可能对预防胆囊结石有益 37。

虽然上述研究直接提供了“Later breakfast”模式的整体风险，但其他研究也探讨了早餐时间延迟与风险增加的时间-效应关系。例如，一些研究通过分析每天第一餐的时间与胆囊结石风险的关系，提示早餐时间每延迟1小时，胆囊结石的风险可能增加约5%。这种剂量-反应关系进一步支持了早餐规律性对胆囊健康的重要性。

NHANES等多项大型横断面研究的结果一致表明，不吃早饭或早餐时间不规律，特别是延迟早餐，与胆囊结石的高发病率存在关联。这些发现强调了健康饮食模式，尤其是规律早餐，在胆囊结石预防中的潜在作用。然而，横断面研究的局限性在于无法确立明确的因果关系，因此，需要前瞻性队列研究和机制研究来进一步验证这些关联并阐明其潜在的生物学机制。

3.2 非线性关系与阈值效应

近年来的研究进一步深入探讨了早餐时间与胆囊结石风险之间的复杂关系，揭示了这种关联可能并非简单的线性递增，而是存在非线性特征和特定的阈值效应。特别值得关注的是，一项基于NHANES数据并发表于《Frontiers in Nutrition》的研究（2024年）详细分析了每天第一餐时间（First Meal Time, FMT）与胆囊结石患病率之间的非线性关系 38。

该研究纳入了6,547名参与者的数据，通过多变量logistic回归分析和限制性立方样条曲线（restricted cubic spline curves）来评估FMT与胆囊结石患病率的关联 38。结果显示，FMT与胆囊结石患病率之间存在显著的正相关性（调整后的优势比 [OR] = 1.05, 95% CI = 1.02 ~ 1.08），并且这种关联在不同亚组中均保持一致 38。这意味着早餐时间每延迟一小时，胆囊结石的风险就会相应增加。

更为重要的是，该研究明确指出FMT与胆囊结石发病率之间存在非线性关系和阈值效应（P值 < 0.042），其拐点位于13.4小时 38。这意味着，当从前一天晚餐结束到次日第一餐的时间间隔（即空腹时长）超过13.4小时后，胆囊结石的风险显著升高。在实际生活中，如果个体在晚上8点吃完晚餐，那么13.4小时的空腹时长意味着次日的第一餐将在上午9:24以后摄入。

研究进一步指出，当每天的第一餐时间（FMT）落在09:00至14:00之间时，胆囊结石的患病风险最高（OR = 1.49, 95% CI = 1.24 ~ 1.77） 38。这表明，延迟早餐至上午9点以后，尤其是在上午9点到下午2点之间才进食，会使胆囊结石的风险显著增加近五成。相反，如果FMT早于上午9点，则风险相对较低。值得注意的是，一旦空腹时长超过13.4小时（即早餐时间超过特定阈值），胆囊结石的风险并不会进一步显著增加，这证实了存在一个风险上升的“平台期”或“阈值效应” 38。

这一发现为理解不吃早饭与胆囊结石风险的关联提供了更细致的视角。它强调了并非所有延迟早餐的情况都具有相同的风险，而是存在一个关键的时间窗口和空腹时长阈值。超过这个阈值，胆囊结石的风险会大幅增加，这可能与长时间空腹导致胆汁在胆囊内淤积、胆固醇过饱和度增加以及胆囊收缩功能障碍等生物学机制密切相关。因此，这些非线性关系和阈值效应的研究结果为制定更精准的胆囊结石预防策略提供了重要依据。

4. 不吃早饭影响胆囊结石的潜在生物学机制

不吃早饭或延迟早餐与胆囊结石风险增加的流行病学关联，促使研究人员深入探索其背后的生物学机制。这些机制主要围绕着对胆汁动力学、胆汁成分代谢以及全身代谢状态的影响展开。

4.1 胆汁动力学异常

胆囊的主要生理功能是储存和浓缩肝脏分泌的胆汁，并在进食后通过收缩将胆汁排入十二指肠，辅助脂肪消化。这一过程受到精密的神经内分泌调控，其中胆囊收缩素（CCK）是关键的调节因子。不吃早饭，特别是长时间的空腹，会显著扰乱这一正常的胆汁动力学，导致胆汁淤积和胆固醇结晶析出，从而促进胆囊结石的形成。

1. 胆囊收缩功能抑制与胆汁淤积：

正常生理状态下，进食（尤其是富含脂肪和蛋白质的食物）会刺激小肠黏膜内分泌细胞释放CCK。CCK通过作用于胆囊平滑肌上的CCK-1受体，引起胆囊强烈收缩，促使浓缩的胆汁排出 3940。早餐作为每日的第一餐，对刺激CCK分泌和启动胆囊的首次有效排空至关重要。

当个体不吃早饭时，胆囊在夜间长时间空腹后，由于缺乏食物刺激，CCK分泌减少，胆囊长时间处于松弛状态，无法得到有效的排空。这会导致以下后果：

  • 胆汁在胆囊内长时间滞留： 长时间空腹使得胆汁在胆囊内停留更久，胆囊对胆汁进行过度浓缩，增加了胆汁中胆固醇、钙离子等成分的饱和度，从而提高了胆固醇和钙盐结晶的风险 41。
  • 胆囊排空效率降低： 即使随后进食午餐或晚餐，由于胆囊长时间未收缩，其对CCK的敏感性可能降低，导致排空功能受损。有研究表明，胆囊收缩功能障碍，即胆囊排空率下降，是胆固醇结石形成的重要危险因素 42。胆囊功能障碍可能表现为胆囊收缩不完全、收缩力减弱或收缩时间延迟。
  • 胆囊容积增加： 长期缺乏餐后收缩刺激可导致胆囊容积增大。研究表明，在全肠道外营养（TPN）期间，胆囊动力学受损，胆囊淤积，容积增大，从而导致胆泥和结石形成 43。不吃早饭的长时间空腹状态与TPN在胆囊生理学上存在相似之处，即都缺乏肠道食物刺激。

2. 胆固醇结晶析出：

胆汁淤积和过度浓缩为胆固醇结晶的形成提供了有利条件。在过饱和胆汁中，胆固醇会从溶解状态析出，形成微小的胆固醇晶体。这些晶体在胆囊内滞留期间，通过聚集和生长，逐渐形成更大的胆固醇结石。胆囊粘蛋白的异常分泌和聚集也会促进这些晶体的成核和生长。

胆囊收缩素受体（CCK-1R）拮抗剂的研究进一步支持了CCK在胆囊结石形成中的作用。例如，Devazepide是一种强效的CCK-1R拮抗剂，在小鼠模型中，口服Devazepide可显著加速胆固醇结晶和结石形成，同时观察到空腹和餐后胆囊残余容积显著增大，胆囊排空减少，表明胆汁淤积 39。这意味着抑制CCK的作用或CCK分泌不足，如同不吃早饭所导致的生理状态，会直接损害胆囊排空功能，从而增加结石风险。

因此，不吃早饭通过减少CCK分泌和胆囊收缩，导致胆汁在胆囊内淤积、浓缩，并为胆固醇结晶的析出和生长创造条件，构成了促进胆囊结石形成的核心生物学机制。规律的早餐摄入能够有效刺激CCK释放，促进胆囊周期性排空，从而维持胆汁的正常流动，降低结石风险。

4.2 胆汁成分代谢紊乱

不吃早饭导致的长时间空腹不仅影响胆囊的机械性排空，更深远地改变了胆汁的生化成分，尤其是胆汁酸、磷脂和胆固醇的动态平衡，从而为胆囊结石的形成创造了有利条件。

1. 胆汁酸肠肝循环中断与胆汁酸池的影响：

胆汁酸是肝脏胆固醇代谢的终产物，主要作用是促进脂肪和脂溶性维生素的消化吸收，并作为信号分子调节脂质和葡萄糖代谢 444546。它们在肠肝循环中高效地被重吸收，以维持一个相对稳定的胆汁酸池 44。在禁食状态下，由于没有食物进入肠道，胆汁酸的肠肝循环会相应中断，胆汁在胆囊内长时间储存，缺乏排空刺激。这导致：

  • 胆汁酸池分布改变： 正常进食后，特别是富含脂肪的餐食，会刺激胆囊收缩，将浓缩的胆汁（富含胆汁酸）排入十二指肠 44。餐后，胆汁酸在肠道内浓度升高，参与脂肪乳化和吸收。而不吃早饭意味着上午时段缺乏这一生理性刺激，使得胆汁酸持续滞留在胆囊内，其在肠道的循环中断。
  • 胆汁酸浓缩与饱和度升高： 胆汁在胆囊内长时间浓缩，胆汁酸浓度会显著升高。虽然胆汁酸本身具有溶解胆固醇的能力，但当胆固醇相对含量过高时，即使胆汁酸浓度高，也可能导致胆固醇过饱和。此外，胆汁酸浓度过高也可能促进胆汁黏度的增加，进一步加剧胆汁淤积。

2. 餐后胆汁成分的动态变化：

规律进食，特别是早餐，对于维持胆汁成分的动态平衡至关重要。研究表明，餐后胆汁的组成会发生有利于胆固醇溶解度的积极变化：

  • 胆汁酸和磷脂分泌增加： 当食物进入十二指肠时，胆囊收缩，将浓缩的胆汁排出 47。这些胆汁酸和磷脂与胆固醇结合形成混合微胶粒，将胆固醇增溶，使其不易析出结晶 48。一项早期研究（1975年发表于《The Journal of Clinical Investigation》）通过收集餐后人肠道液体发现，在脂肪消化过程中，胆汁酸、脂肪酸、卵磷脂和溶血卵磷脂形成混合胶粒，每摩尔胆汁酸可增溶1.4摩尔脂肪酸、0.15摩尔溶血卵磷脂和0.06摩尔胆固醇 48。这直接证明了餐后胆汁酸和磷脂对于维持胆固醇溶解的重要性。
  • 胆固醇浓度相对降低： 进食后胆囊排空，新鲜的、相对稀释的肝胆汁进入胆道系统，其胆固醇饱和指数通常低于浓缩的胆囊胆汁。这种餐后的“稀释效应”有助于降低胆汁中的胆固醇饱和度，减少胆固醇结晶的机会 49。在一项针对胆固醇胆石症患者的研究中，膳食脂肪种类（橄榄油 vs. 葵花籽油）可影响餐后肝胆汁的胆固醇饱和指数，橄榄油饮食组在餐后120分钟胆固醇饱和指数显著下降，甚至低于1，而葵花籽油组在整个实验过程中胆固醇饱和指数仍高于1.5，提示膳食成分对餐后胆汁稳定性的重要性 49。
  • 昼夜节律与胆汁酸代谢： 胆汁酸合成和代谢具有明显的昼夜节律 4550。这种节律与进食-禁食周期紧密相关。不吃早饭会打乱这种正常的生理节律，可能导致胆汁酸合成和分泌的异常，从而影响胆固醇的溶解度。

3. 肠道菌群的潜在影响：

近年来研究还发现肠道菌群在胆固醇结石形成中发挥重要作用，主要通过调节胆汁酸组成和胆道胆固醇分泌 51。不吃早饭等饮食习惯的改变可能影响肠道菌群的组成和功能，进而间接影响胆汁酸代谢和胆囊结石风险。例如，某些肠道菌群（如脱硫弧菌目）富集与胆囊结石患者胆汁酸疏水性增加以及促进胆道胆固醇分泌相关 51。

综上所述，不吃早饭通过中断正常的胆汁酸肠肝循环，抑制餐后胆汁酸和磷脂的有效分泌，并可能干扰胆汁酸代谢的昼夜节律，最终导致胆汁成分失衡，增加胆固醇的饱和度和结晶析出的风险，从而显著促进胆囊结石的形成。维持规律的早餐习惯有助于维持胆汁成分的健康动态平衡，降低胆囊结石发生的风险。

4.3 代谢综合征的中介作用

不吃早饭不仅直接影响胆囊功能和胆汁成分，还被认为是多种代谢紊乱，包括胰岛素抵抗、高甘油三酯血症和代谢综合征（MetS）的重要危险因素 525354。这些代谢异常通过复杂的病理生理途径，间接促进胆囊结石的形成。

1. 胰岛素抵抗与高胰岛素血症：

不吃早饭常常导致胰岛素抵抗 5255。长期不吃早饭与胰岛素抵抗存在相对较强的关联 525455。胰岛素抵抗是指机体细胞对胰岛素的敏感性降低，为了维持血糖稳态，胰腺会分泌过量的胰岛素，形成高胰岛素血症。高胰岛素血症被认为是胆囊结石形成的关键驱动因素之一，其机制可能包括：

  • 刺激肝脏胆固醇合成与分泌： 高胰岛素水平可以直接或间接刺激肝脏合成更多的胆固醇，并将其分泌到胆汁中。这导致胆汁胆固醇过饱和，增加结石形成的风险。
  • 抑制胆汁酸合成： 胰岛素抵抗可能通过抑制胆汁酸合成限速酶（如胆固醇7α-羟化酶，CYP7A1）的活性，减少胆汁酸的生成，从而降低胆汁酸/胆固醇比例，进一步加剧胆汁的致石性。
  • 影响胆囊动力学： 胰岛素抵抗可能影响胆囊平滑肌的敏感性和收缩功能，导致胆囊排空迟缓，胆汁淤积。胆囊排空迟缓也与高甘油三酯血症有关 56。

2. 高甘油三酯血症与脂代谢紊乱：

不吃早饭与高甘油三酯血症密切相关 53。在代谢综合征患者中，高甘油三酯血症是常见的表现，而代谢综合征与胆囊结石疾病风险显著相关 5357。高甘油三酯血症可能通过以下途径促进胆囊结石形成：

  • 增加肝脏VLDL分泌： 高胰岛素血症和肝脏脂肪变性可导致肝脏合成和分泌极低密度脂蛋白（VLDL）增加，VLDL富含甘油三酯 56。胆固醇与甘油三酯的代谢紧密相连。
  • 改变胆汁脂质组成： 高甘油三酯血症患者的胆汁中，胆固醇含量可能升高，而胆汁酸和磷脂的比例可能下降，导致胆汁胆固醇饱和度增加 56。
  • 影响胆囊收缩： 高甘油三酯血症本身就与胆囊收缩功能障碍有关 56。在这些患者中，胆囊对胆囊收缩素（CCK）的敏感性可能会降低，导致餐后胆囊排空不足，胆汁淤积，从而增加结石风险 56。

3. 代谢综合征：

代谢综合征是一组复杂的代谢紊乱症候群，包括腹部肥胖、高血压、高血糖、高甘油三酯血症和低高密度脂蛋白胆固醇（HDL-C）血症。不吃早饭与代谢综合征及其所有核心组分的风险增加显著相关 53，同时与胰岛素抵抗也有关联 54。一项系统综述和荟萃分析显示，不吃早饭者患代谢综合征的风险显著增加（OR: 1.10, 95% CI: 1.04-1.17），并且与腹部肥胖、高血压、高甘油三酯血症和高血糖的风险均独立相关 53。

胆囊结石与代谢综合征之间存在明确的关联 5758。有研究表明，代谢综合征患者发生胆囊结石的风险是健康人群的1.42倍（男性OR=1.29，女性OR=1.68） 57。代谢综合征的每个组分都会协同作用，通过上述胰岛素抵抗和脂代谢紊乱的机制，共同推动胆汁胆固醇过饱和、胆汁淤积以及胆固醇晶体成核的发生，最终加速胆囊结石的形成。胆囊切除术本身也可能通过影响胆汁酸肠肝循环，导致代谢异常，进而成为代谢综合征的另一个“伴随者”或风险因素 58。

因此，不吃早饭通过诱导或加剧胰岛素抵抗、高甘油三酯血症等代谢紊乱，进而促使胆汁成分失衡和胆囊动力学异常，最终显著增加了胆囊结石的发生风险。这种间接的病理生理学联系，强调了规律早餐在维持整体代谢健康和预防胆囊结石方面的重要作用。

5. 相关饮食模式的交互作用与调节效应

不吃早饭作为一种特定的饮食行为，并非孤立地影响胆囊结石的发生。相反，它往往与其他饮食模式和营养素摄入相互作用，共同调节胆囊结石的风险。这些交互作用可以表现为协同效应，即不吃早饭与其他不健康饮食习惯相结合时，胆囊结石风险的增幅超过单一因素的叠加；也可以表现为调节效应，即某些饮食因素的存在或缺失会改变不吃早饭对胆囊结石风险的影响强度。深入探讨这些交互作用，有助于我们更全面地理解不吃早饭在复杂饮食环境中的影响，并为制定更精准的预防策略提供依据。本节将重点分析不吃早饭与能量分布模式、进食频率以及其他相关膳食因素之间的相互作用，揭示它们如何共同影响胆汁代谢和胆囊结石的形成。

5.1 能量分布模式的协同影响

不吃早饭作为一种不健康的饮食习惯，其对胆囊结石风险的影响并非独立存在，而是常常与整体的能量分布模式，特别是宏量营养素的摄入比例，产生协同作用。精细分析这些协同效应有助于揭示更深层次的病理生理机制，并指导个体化饮食干预。

一项基于NHANES 2017-2018年数据的研究深入探讨了不同进食模式与能量分布模式对胆囊结石发病率的影响 37。该研究通过潜在剖面分析（LPA）识别出四种能量分布模式，其中“High carbohydrates”（高碳水化合物）模式被发现与胆囊结石风险增加相关，而“Carbs-fat balance”（碳水-脂肪平衡）模式和“High fat”（高脂肪）模式则与风险降低显著相关 37。

具体而言，“High carbohydrates”模式与不吃早饭（尤其是“Later breakfast”模式）之间可能存在显著的叠加风险。该研究显示，“High carbohydrates”模式（定义为碳水化合物摄入比例较高）本身就与胆囊结石风险的增加有关（OR=1.329, 95%CI: 1.326-1.331） 37。当个体不仅延迟早餐或跳过早餐，同时又长期维持高碳水化合物的饮食模式时，其胆囊结石的风险可能会进一步升高，呈现出一种协同效应。

碳水化合物摄入，特别是精制碳水化合物和高血糖指数的食物，对胆汁胆固醇饱和度的调节作用主要体现在以下几个方面：

  1. 胰岛素抵抗的加剧与肝脏胆固醇合成增加： 长期高碳水化合物饮食，尤其是缺乏膳食纤维的精制碳水化合物，容易导致餐后血糖迅速升高，刺激胰岛素大量分泌，从而诱发或加重胰岛素抵抗。如前所述，胰岛素抵抗和高胰岛素血症是肝脏胆固醇合成增加的重要驱动因素，导致胆汁中胆固醇分泌过量，进而引起胆固醇过饱和 59。不吃早饭本身已被证实与胰岛素抵抗有关，两者的结合无疑会放大这一效应。
  2. 甘油三酯水平升高： 高碳水化合物饮食是导致高甘油三酯血症的常见原因。肝脏将过量的碳水化合物转化为甘油三酯，并通过VLDL（极低密度脂蛋白）分泌。高甘油三酯血症不仅与胆囊收缩功能障碍相关，还可能改变胆汁脂质组成，使得胆固醇相对含量升高，从而增加胆汁的致石性。
  3. 胆汁酸池的改变： 高碳水化合物饮食可能影响肠道菌群组成，进而影响胆汁酸代谢 6061。肠道菌群在胆汁酸的转化和重吸收中发挥关键作用，其紊乱可能导致胆汁酸池的改变，降低胆汁酸的疏水性，从而削弱其溶解胆固醇的能力。此外，研究表明，脂肪和膳食纤维的摄入与胆汁酸水平呈正相关和负相关，这表明饮食模式对胆汁酸的形成和代谢有重要影响 62。

相反，“Carbs-fat balance”模式（OR=0.877, 95%CI: 0.876-0.879）和“High fat”模式（OR=0.848, 95%CI: 0.846-0.850）均与较低的胆囊结石风险相关 37。这可能与适度脂肪摄入对胆囊生理功能的积极影响有关：

  • 刺激胆囊收缩： 脂肪是刺激胆囊收缩素（CCK）分泌的最强刺激物。适量的脂肪摄入可以有效促进胆囊排空，减少胆汁淤积。即使在不吃早饭的情况下，如果其他餐次能够摄入适量的脂肪，可能在一定程度上弥补胆囊排空不足的问题。
  • 减缓胃排空，延长饱腹感： 脂肪可以延缓胃排空，有助于稳定血糖，减少对胰岛素的刺激，从而可能减轻胰岛素抵抗。

因此，不吃早饭与高碳水化合物饮食模式的结合，构成了胆囊结石风险的“双重打击”。这种协同效应提醒我们，在评估和干预不吃早饭的健康风险时，必须同时考虑整体的膳食结构和能量分布。推广“碳水-脂肪平衡”的饮食模式，尤其是在避免长时间空腹的前提下，对于预防胆囊结石具有重要的临床意义。

5.2 进食频率的干扰效应

进食频率是影响胆汁动力学和胆汁成分的重要饮食因素，它与不吃早饭的行为模式相互作用，可能对胆囊结石的形成产生干扰或调节效应。理解不同进食频率模式如何与不吃早饭共同作用，有助于更全面地评估风险。

一项基于NHANES 2017-2018年数据的研究通过潜在类别分析（LCA），识别出四种主要的进食模式，其中“Conventional”（规律三餐）、“Early breakfast”（早吃早餐）、“Later breakfast”（晚吃早餐）和“Grazing”（频繁进食）模式被用来分析其与胆囊结石风险的关联 37。

1. “Grazing”模式与胆囊结石风险：

该研究发现，“Grazing”模式（定义为非规律性、频繁的小份进食）与胆囊结石风险的增加相关，其优势比（OR）为1.147（95%CI 1.145-1.148），相较于“Conventional”模式（OR=1.00）有显著的风险增加 37。尽管“Grazing”模式涉及频繁进食，这理论上可以通过多次刺激胆囊收缩来减少胆汁淤积，但这种模式下的非规律性可能抵消其潜在益处。原因可能在于：

  • 胆囊排空效率低下： 频繁但小份的进食可能不足以引起胆囊的充分收缩和有效排空。胆囊收缩需要一定的刺激强度（如足够量的脂肪或蛋白质），如果每次进食量过小或间隔时间过短，胆囊可能持续处于部分收缩或放松状态，导致胆汁仍有淤积的风险。
  • 胆汁成分紊乱： 频繁进食，尤其是如果选择不健康的零食或高糖高脂食物，可能导致胰岛素和血糖水平的频繁波动，从而加剧胰岛素抵抗和脂代谢紊乱，进而影响胆汁的致石性。
  • 缺乏充分的夜间空腹期： 如果“Grazing”模式延伸到深夜，可能缩短了夜间空腹时间，但这与不吃早饭导致的长时间白天空腹是不同的概念。然而，非规律性的进食本身可能扰乱人体的生理节律和消化系统的工作模式。

2. 不吃早饭与非规律进食的叠加效应：

当不吃早饭的行为与“Grazing”模式（非规律进食）结合时，胆囊结石的风险可能会进一步放大。不吃早饭导致胆囊在上午长时间处于充盈和浓缩状态，如果午餐和晚餐也采用“Grazing”模式，意味着进食频率不规律且可能缺乏足够强度的胆囊收缩刺激，这将进一步加剧胆汁淤积和胆固醇结晶的风险。

这种叠加效应可以通过以下机制来解释：

  • 胆囊收缩刺激不足： 不吃早饭本身就剥夺了早晨对胆囊的有效刺激。如果在剩余的进食窗口内，又采取频繁但零散的“Grazing”模式，每次进食产生的胆囊收缩素（CCK）分泌量可能不足以促使胆囊充分排空，导致胆汁持续淤积，从而增加胆固醇结晶和结石形成的概率。
  • 整体代谢紊乱加剧： 不吃早饭已被证实与胰岛素抵抗和代谢综合征风险增加有关。如果这种行为模式再结合非规律的“Grazing”进食，特别是摄入高糖高脂的食物，可能进一步加剧血糖和血脂的波动，从而加速胰岛素抵抗和脂代谢紊乱的进程，间接促进胆囊结石的形成。

3. 对比“Conventional”模式：

与“Grazing”模式形成对比的是“Conventional”模式，即规律三餐的进食模式，它被认为是胆囊结石风险的参考基线（OR=1.00） 37。规律三餐，特别是包括早餐，能够确保胆囊在一天内得到多次有效排空，从而降低胆汁淤积和胆固醇饱和的风险。这种模式强调了进食的规律性和餐次之间适当的间隔，有助于维持胆汁的正常流动和成分平衡。

因此，不吃早饭结合非规律性的“Grazing”进食模式，可能通过加剧胆囊收缩功能障碍和代谢紊乱，进一步提升胆囊结石的风险。这提示，在预防胆囊结石时，不仅要强调规律早餐的重要性，还要倡导整体进食模式的规律性，避免非规律、零散且不足以有效刺激胆囊排空的进食行为。

6. 规律早餐的预防价值与临床建议

6.1 早餐时间与结构的优化策略

鉴于不吃早饭和不规律进餐与胆囊结石发病风险的密切关联，规律且结构合理的早餐对于预防胆囊结石具有重要的临床价值。基于当前的流行病学和机制研究，我们可以提出以下早餐时间与结构的优化策略。

1. 早餐时间的优化建议：不晚于9:00

多项研究强调了早餐摄入时间对胆囊结石风险的影响。例如，NHANES 2017-2018年数据显示，“Later breakfast”（晚吃早餐）模式与胆囊结石风险显著升高相关（OR 1.435, 95%CI 1.432-1.438） 37。另一项研究则通过非线性分析发现，当第一餐时间（FMT）晚于13.4小时的空腹阈值（即早餐在上午9点24分之后）时，胆囊结石的风险显著增加 38。特别是，当FMT落在09:00至14:00之间时，胆囊结石的患病风险最高（OR = 1.49, 95% CI = 1.24 ~ 1.77） 38。

综合这些证据，建议将早餐时间安排在上午9:00之前。这样做有以下几个益处：

  • 缩短夜间空腹时间： 确保夜间空腹时间不超过13.4小时，避免胆囊长时间处于不收缩状态，减少胆汁在胆囊内的淤积和过度浓缩，降低胆固醇结晶析出的风险 38。
  • 及时刺激胆囊排空： 规律的早餐能够及时刺激胆囊收缩素（CCK）的分泌，促使胆囊将浓缩的胆汁排入十二指肠，维持胆汁的正常流动，有效降低胆汁淤积和胆固醇过饱和度 37。
  • 维持昼夜节律： 规律的早餐有助于维持人体正常的生理节律，包括胆汁酸代谢的昼夜节律，从而保持胆汁成分的动态平衡。

2. 早餐结构的优化建议：“碳水-脂肪平衡”模式

除了早餐时间，早餐的营养构成也至关重要。研究发现，不同的能量分布模式对胆囊结石风险有不同的影响。其中，“High carbohydrates”（高碳水化合物）模式与胆囊结石风险增加相关（OR 1.329, 95%CI 1.326-1.331） 37。相反，“Carbs-fat balance”（碳水-脂肪平衡）模式与胆囊结石风险降低显著相关（OR 0.877, 95%CI 0.876-0.879） 37。

“碳水-脂肪平衡”的早餐模式应遵循以下原则：

  • 适量的优质碳水化合物： 选择全谷物、复合碳水化合物，如燕麦片、全麦面包、糙米粥等，以提供稳定的能量来源，避免血糖剧烈波动，从而减轻胰岛素抵抗，减少肝脏胆固醇合成。避免摄入过多的精制碳水化合物和高糖食物。
  • 适量的健康脂肪： 早餐中应包含适量的健康脂肪，如坚果、牛油果、鸡蛋、奶制品等。脂肪能够有效刺激CCK分泌，促进胆囊收缩和排空，有助于减少胆汁淤积。但应避免过量饱和脂肪和反式脂肪的摄入，优先选择不饱和脂肪。研究指出，橄榄油和鱼类（富含ω-3脂肪酸）的摄入具有保护作用 63。
  • 足够的蛋白质： 蛋白质（如鸡蛋、牛奶、豆浆、瘦肉等）不仅能提供饱腹感，还能协同脂肪刺激胆囊收缩，维持血糖稳定。植物蛋白相对于动物蛋白可能具有较低的致石性。
  • 丰富的膳食纤维： 早餐中应富含膳食纤维，如蔬菜、水果、全谷物等。膳食纤维能够结合胆汁酸，促进其排泄，从而刺激肝脏合成新的胆汁酸，降低胆汁中的胆固醇饱和度。膳食纤维还能改善肠道蠕动，间接影响胆汁酸代谢。

综上所述，为了有效预防胆囊结石，建议公众养成规律吃早餐的习惯，并将早餐时间控制在上午9:00之前。同时，早餐的营养结构应侧重于“碳水-脂肪平衡”模式，即摄入适量的优质碳水化合物、健康脂肪、蛋白质和膳食纤维，以协同降低胆囊结石的发生风险。

6.2 高危人群的干预方向

对于已经存在胆囊结石高危因素的人群，仅仅依靠调整早餐习惯可能不足以达到最佳预防效果。这类人群包括患有代谢综合征、肥胖、胰岛素抵抗的个体，以及胆囊运动功能已经出现减退的患者。针对这些高危群体，应采取更为积极和综合的干预策略，将规律早餐与特定的药物治疗（如胆汁酸补充）相结合，以更有效地降低胆囊结石的发生风险。

1. 代谢异常人群的综合干预：

代谢综合征、肥胖和胰岛素抵抗是胆囊结石的独立危险因素，它们通过影响胆固醇代谢、胆汁成分和胆囊动力学来促进结石形成。对于这类高危人群，干预措施应包括：

  • 强化规律早餐习惯： 确保每日早餐的规律摄入和优化营养结构（如前所述的“碳水-脂肪平衡”），以维持血糖和血脂的稳定，改善胰岛素敏感性，并促进胆囊的规律排空。
  • 全面生活方式干预： 除了早餐，应推广全面的健康饮食模式（如地中海饮食），限制高糖、高饱和脂肪和精制碳水化合物的摄入，增加膳食纤维的摄入。同时，鼓励规律体育锻炼，以减轻体重，改善胰岛素抵抗和脂代谢紊乱。
  • 针对性药物治疗： 对于伴有严重血脂异常（如高甘油三酯血症）或糖尿病的患者，医生可能会根据具体情况开具降脂或降糖药物，以控制代谢紊乱，从而间接降低胆囊结石风险。

2. 胆囊功能减退患者的干预：

胆囊运动功能减退是胆汁淤积和胆固醇结石形成的核心环节。对于已经通过影像学检查（如超声波）证实胆囊收缩功能减退的患者，或存在胆泥（biliary sludge）形成的患者，单纯调整饮食可能效果有限。

  • 胆汁酸补充治疗（UDCA）： 熊去氧胆酸（Ursodeoxycholic Acid, UDCA）是一种亲水性胆汁酸，通过多种机制发挥预防和溶解胆固醇结石的作用。
    • 改善胆汁成分： UDCA能够改变胆汁中胆汁酸的组成，增加胆汁的亲水性，从而降低胆固醇的饱和度，促进胆固醇从结石表面溶解。
    • 抑制胆固醇吸收和合成： UDCA可以抑制肠道对胆固醇的吸收，并减少肝脏胆固醇的合成和分泌，进一步降低胆汁中胆固醇的含量。
    • 保护胆囊功能： UDCA可能具有一定的胆囊保护作用，改善胆囊的收缩功能，减少胆汁淤积。

多项临床研究已经证实了UDCA在预防胆囊结石方面的有效性，尤其是在高危人群中。例如，针对接受减肥手术（bariatric surgery）的患者，他们因体重迅速下降和饮食改变而面临高胆囊结石风险。

  • 一项2022年的Meta分析显示，预防性使用UDCA可以显著降低减肥手术后胆囊结石的形成（OR = 0.25, 95% CI = 0.21-0.31）、有症状胆囊疾病的发生（OR = 0.29, 95% CI = 0.20-0.42），以及随后的胆囊切除率（OR = 0.33, 95% CI = 0.20-0.55） 64。
  • 另一项2023年的Meta分析，涵盖了14项随机对照试验（3619名患者），也发现UDCA治疗显著降低了减肥手术后胆囊结石的风险（RR 0.27, 95% CI 0.18-0.41, P<0.001），并且对有症状胆囊疾病的风险也有显著降低（RR 0.30, 95% CI 0.21-0.43, P<0.001）65。研究建议，术后使用500至600毫克UDCA，持续6个月是有效的 65。

综合干预方案：

对于高危人群，建议采取以下综合干预方案：

  1. 普及规律早餐教育： 强调早餐在上午9:00前摄入的重要性，并指导早餐的“碳水-脂肪平衡”结构。
  2. 个性化饮食指导： 根据患者的具体代谢状态和生活习惯，制定个性化的饮食计划，控制总能量，优化宏量营养素比例，增加膳食纤维摄入。
  3. 增加体力活动： 建议每周至少150分钟的中等强度有氧运动，帮助减轻体重，改善胰岛素抵抗。
  4. 定期健康监测： 对高危人群进行定期的血脂、血糖、肝功能以及胆囊超声检查，早期发现胆泥或胆囊结石的迹象。
  5. 酌情使用UDCA： 对于减肥手术后、快速减肥、或已出现胆泥形成等明确高风险的患者，应考虑在医生指导下预防性使用UDCA。剂量和疗程应根据个体情况和临床指南确定，通常为每日500-600毫克，持续数月至一年。

通过这种多管齐下的综合干预策略，可以更有效地降低高危人群胆囊结石的发生率，从而减少其潜在的并发症和对患者健康的影响。

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参考文献

1An update on the pathogenesis of cholesterol gallstone disease.PubMed

Agostino Di Ciaula, David Q-H Wang, Piero Portincasa
Curr Opin Gastroenterol. 2018 Mar;34(2):71-80. doi: 10.1097/MOG.0000000000000423.
PURPOSE OF REVIEW: Gallstone disease is a major epidemiologic and economic burden worldwide, and the most frequent form is cholesterol gallstone disease. RECENT FINDINGS: Major pathogenetic factors for cholesterol gallstones include a genetic background, hepatic hypersecretion of cholesterol, and supersaturated bile which give life to precipitating cholesterol crystals that accumulate and grow in a sluggish gallbladder. Additional factors include mucin and inflammatory changes in the gallbladder, slow intestinal motility, increased intestinal absorption of cholesterol, and altered gut microbiota. Mechanisms of disease are linked with insulin resistance, obesity, the metabolic syndrome, and type 2 diabetes. The role of nuclear receptors, signaling pathways, gut microbiota, and epigenome are being actively investigated. SUMMARY: Ongoing research on cholesterol gallstone disease is intensively investigating several pathogenic mechanisms, associated metabolic disorders, new therapeutic approaches, and novel strategies for primary prevention, including lifestyles.

2Cholesterol gallstone disease.PubMed

Piero Portincasa, Antonio Moschetta, Giuseppe Palasciano
Lancet. 2006 Jul 15;368(9531):230-9. doi: 10.1016/S0140-6736(06)69044-2.
With a prevalence of 10-15% in adults in Europe and the USA, gallstones are the most common digestive disease needing admission to hospital in the West. The interplay between interprandial and postprandial physiological responses to endogenous and dietary lipids underscores the importance of coordinated hepatobiliary and gastrointestinal functions to prevent crystallisation and precipitation of excess biliary cholesterol. Indeed, identifying the metabolic and transcriptional pathways that drive the regulation of biliary lipid secretion has been a major achievement in the field. We highlight scientific advances in protein and gene regulation of cholesterol absorption, synthesis, and catabolism, and biliary lipid secretion with respect to the pathogenesis of cholesterol gallstone disease. We discuss the physical-chemical mechanisms of gallstone formation in bile and the active role of the gallbladder and the intestine. We also discuss gaps in our knowledge of the pathogenesis of gallstone formation and the potential for gene targeting in therapy.

3Pathogenesis of gallstones.PubMed

M C Carey
Am J Surg. 1993 Apr;165(4):410-9. doi: 10.1016/s0002-9610(05)80932-8.
Gallstones form as a result of many disorders. Unphysiologic supersaturation, generally from hypersecretion of cholesterol, is essential for the formation of cholesterol gallstones. The other common abnormalities of the hepatobiliary system in gallstone patients are accelerated nucleation, gallbladder hypomotility, and the accumulation of mucin gel. An attempt is made here to relate hypersecretion of cholesterol and biliary supersaturation to the molecular basis of the associated phenomena. Supersaturation of bile with calcium hydrogen bilirubinate, the acid calcium salt of unconjugated bilirubin, is essential for pigment gallstone formation, but its magnitude remains undefined in model systems. Nucleation and the precipitation of calcium hydrogen bilirubinate with the polymerization of the pigment in the gallbladder, together with the deposition of the inorganic salts, calcium carbonate and phosphate, result in black pigment gallstone formation. On the basis of ex vivo muscle studies, gallbladder hypomotility is unlikely in patients with black pigment stones but is invariably present in patients with cholesterol stones. Pigment supersaturation in the gallbladder is the result of hepatic hypersecretion of bilirubin conjugates in hemolytic disorders and possibly enterohepatic cycling of unconjugated bilirubin in nonhemolytic states. Less common is bile salt hyposecretion from impaired synthesis in constitutional disorders and cirrhosis, and uncompensated interruption of the enterohepatic circulation in ileal dysfunction syndromes. Bile salt deficiency causes incomplete solubilization of unconjugated bilirubin and impaired binding of calcium ions. Stasis and anaerobic bacterial infection are responsible for brown pigment stones, which usually form in the bile ducts. In addition to the precipitation of calcium hydrogen bilirubinate that remains unpolymerized, there is also the deposition of the calcium salts of saturated fatty acids and free bile acids, both of which are the result of bacterial enzymatic hydrolysis of biliary lipids.

4Pathogenesis of gallstones.PubMed

Niels Gerard Venneman, Karel Johannes van Erpecum
Gastroenterol Clin North Am. 2010 Jun;39(2):171-83, vii. doi: 10.1016/j.gtc.2010.02.010.
Cholesterol gallstone formation is a complex process and involves phase separation of cholesterol crystals from supersaturated bile. In most cases, cholesterol hypersecretion is considered the primary event in gallstone formation. The sterol is transported through the hepatocytic canalicular membrane by ABCG5-G8. Expression of this transport protein is regulated by transcription factor Liver X Receptor-alpha, which may be responsible for biliary hypersecretion. Hydrophobic bile salt pool, bile concentration, excess pronucleating mucin, and impaired gallbladder and intestinal motility are secondary phenomena in most cases but nevertheless may contribute to gallstone formation.

5Effects of Biliary Phospholipids on Cholesterol Crystallization and Growth in Gallstone Formation.PubMed

Helen H Wang, Piero Portincasa, Min Liu, et al.
Adv Ther. 2023 Mar;40(3):743-768. doi: 10.1007/s12325-022-02407-8. Epub 2023 Jan 5.
The prevalence of cholesterol gallstone disease is increasing, primarily due to the global epidemic of obesity associated with insulin resistance, and this trend leads to a considerable healthcare, financial, and social burden worldwide. Although phospholipids play an essential role in maintaining cholesterol solubility in bile through both mixed micelles and vesicles, little attention has been paid to the impact of biliary phospholipids on the pathogenesis of cholesterol gallstone formation. A reduction or deficiency of biliary phospholipids results in a distinctly abnormal metastable physical-chemical state of bile predisposing to supersaturation with cholesterol. Changes in biliary phospholipid concentrations influence cholesterol crystallization by yielding both liquid crystalline and "anhydrous" crystalline metastable intermediates, evolving into classical parallelogram-shaped cholesterol monohydrate crystals in supersaturated bile. As a result, five distinct crystallization pathways, A-E, have been defined, mainly based on the prime habits of liquid and solid crystals in the physiological or pathophysiological cholesterol saturation of gallbladder and hepatic bile. This review concisely summarizes the chemical structures and physical-chemical properties of biliary phospholipids and their physiological functions in bile formation and cholesterol solubility in bile, as well as comprehensively discusses the latest advances in the role of biliary phospholipids in cholesterol crystallization and growth in gallstone formation, largely based on the findings from clinical and animal studies and in vitro experiments. The insights gleaned from uncovering the cholelithogenic mechanisms are expected to form a fundamental framework for investigating the hitherto elusive events in the earliest stage of cholesterol nucleation and crystallization. This may help to identify better measures for early diagnosis and prevention in susceptible subjects and effective treatment of patients with gallstones.

6Bile AcidsPubMed

Bile acids are a large family of molecules that have a steroidal structure and are synthesized from cholesterol in the liver and actively secreted along with cholesterol and phospholipids into the bile. Bile flowing from the liver is concentrated in the gallbladder and, in response to a meal, released into the upper intestine. In the intestines, bile acids act as detergents and help to emulsify fats, aiding in their digestion and absorption. After participating in digestion in the small bowel, bile acids are almost completely (95%) reabsorbed in the distal ileum and then retaken up from portal blood by the liver (enterohepatic circulation). The primary bile acids synthesized in the liver are cholic and chenodeoxycholic acid which are typically conjugated to glycine or taurine before secretion. In the intestine, the primary bile acids are often converted by colonic bacteria to the secondary bile acids, predominantly deoxycholic acid and lithocholic acid. The reabsorbed bile acids are transported to the liver in portal blood. Conjugated bile acids are then retaken up by hepatocytes via the sodium taurocholate cotransporter (NTCT), while unconjugated bile acids are taken up by organic anion transporters that also take up bilirubin and other anions. The total bile acid pool in humans is tightly controlled by a coordinated regulation of expression of genes involved with synthesis, secretion, reabsorption and reuptake of bile acids by the liver. The major components of the bile acid pool are cholic and chenodeoxycholic acid with lesser amounts deoxycholic and lithocholic acid and minor amounts of ursodeoxycholic acid. Bile acids also act as signaling molecules and are important in regulation of their own synthesis, uptake and secretion as well as control of cholesterol synthesis and regulation of lipid and glucose metabolism. Bile acid levels are increased in the serum and liver in patients with obstructive jaundice or cholestasis and, perhaps because of their inherent detergent activities, can cause hepatocyte injury. Thus, increased bile acid levels in hepatocytes may account for some of the liver damage in cholestatic liver diseases. Bile acids can be used as therapeutic agents, particularly in patients with cholestatic liver diseases where administered bile acids (such as ursodeoxycholic acid) replace the more lipophilic and toxic bile acids that accumulate during cholestasis. Bile acids are also useful for the medical treatment (dissolution) of gallstones by increasing bile acid and decreasing cholesterol concentrations in bile (causing a less saturated bile). Bile acids can also be useful as replacement therapy in patients with bile acid synthetic defects. Finally, the other metabolic effects of bile acids can be useful in treating metabolic diseases including nonalcoholic steatohepatitis. Four bile acids are currently approved for use in the United States and several others are under active investigation. Cholic acid is used for treatment of inherited defects in bile acid synthesis, chenodeoxycholic (chenodiol) and ursodeoxycholic (ursodiol) acid for gallstone dissolution, and obeticholic and ursodiol for chronic cholestatic liver diseases, specifically primary biliary cirrhosis. Obeticholic acid is under evaluation as therapy of other liver diseases including sclerosing cholangitis and nonalcoholic steatohepatitis. Ursodiol is used off label to prevent, treat or ameliorate several uncommon forms of liver disease, including intrahepatic cholestasis of pregnancy, sinusoidal obstruction syndrome, graft-vs-host disease, cystic fibrosis associated liver disease, parenteral nutrition related liver injury and even acute, drug induced liver injury. The long term efficacy in ameliorating the course of these diseases is, however, unproven. Separate documents are available in LiverTox for each of the currently available bile acids. References given in this overview section are limited to general publications on bile acid metabolism and use as therapeutic agents. Drug Class: Gastrointestinal Agents: Chenodiol (Chenodeoxycholic Acid) . Cholic Acid . Obeticholic Acid . Ursodiol (Ursodeoxycholic Acid) .

7Pathogenesis of cholesterol and pigment gallstones: an update.PubMed

Karel Johannes Van Erpecum
Clin Res Hepatol Gastroenterol. 2011 Apr;35(4):281-7. doi: 10.1016/j.clinre.2011.01.009. Epub 2011 Feb 25.
Phase separation of cholesterol crystals from supersaturated bile is still considered the key event in cholesterol gallstone formation. In this review, we will first provide a basal framework of the interactions between the sterol, bile salts and phospholipids in aqueous solutions and then summarize new developments. The hepatocytic apical membrane harbours specific transport proteins for these lipids. Polymorphisms in the gene encoding the cholesterol transporter ABCG5-G8 have been found to increase overall gallstone risk, whereas functional mutations in the gene encoding the phospholipid floppase ABCB4 lead to the rare clinical syndrome of low phospholipid associated cholelithiasis. Expression of bile salt and phospholipid transport proteins is regulated bij the bile salt nuclear receptor Farnesoid X receptor (FXR), while the Liver X Receptor (LXR) α regulates ABCG5-G8. Although data from murine experiments suggest a critical role of FXR in gallstone formation, its role in human lithogenesis remains controversial. Variants of the gene encoding UGT1A1 (uridine 5'-diphosphate (UDP)-glucuronosyltransferase 1A1) responsible for bilirubin conjugation were recently associated with risk of gallstones as well as stone bilirubin content, suggesting common factors in cholesterol and pigment gallstone pathogenesis.

8Recent advances in understanding and managing cholesterol gallstones.PubMed

Agostino Di Ciaula, Piero Portincasa
F1000Res. 2018 Sep 24;7. doi: 10.12688/f1000research.15505.1. eCollection 2018.
The high prevalence of cholesterol gallstones, the availability of new information about pathogenesis, and the relevant health costs due to the management of cholelithiasis in both children and adults contribute to a growing interest in this disease. From an epidemiologic point of view, the risk of gallstones has been associated with higher risk of incident ischemic heart disease, total mortality, and disease-specific mortality (including cancer) independently from the presence of traditional risk factors such as body weight, lifestyle, diabetes, and dyslipidemia. This evidence points to the existence of complex pathogenic pathways linking the occurrence of gallstones to altered systemic homeostasis involving multiple organs and dynamics. In fact, the formation of gallstones is secondary to local factors strictly dependent on the gallbladder (that is, impaired smooth muscle function, wall inflammation, and intraluminal mucin accumulation) and bile (that is, supersaturation in cholesterol and precipitation of solid crystals) but also to "extra-gallbladder" features such as gene polymorphism, epigenetic factors, expression and activity of nuclear receptors, hormonal factors (in particular, insulin resistance), multi-level alterations in cholesterol metabolism, altered intestinal motility, and variations in gut microbiota. Of note, the majority of these factors are potentially manageable. Thus, cholelithiasis appears as the expression of systemic unbalances that, besides the classic therapeutic approaches to patients with clinical evidence of symptomatic disease or complications (surgery and, in a small subgroup of subjects, oral litholysis with bile acids), could be managed with tools oriented to primary prevention (changes in diet and lifestyle and pharmacologic prevention in subgroups at high risk), and there could be relevant implications in reducing both prevalence and health costs.

9Pathogenesis of gallstones.PubMed

M C Carey
Recenti Prog Med. 1992 Jul-Aug;83(7-8):379-91.
Gallstones are composed principally of cholesterol monohydrate crystals (cholesterol stones) or the acid salt of calcium bilirubinate (pigment stones). Cholesterol stones and the black variety of pigment gallstones form in sterile gallbladder bile whereas brown pigment gallstones form in infected bile. Biliary supersaturation is the principal pathophysiological defect and is hepatic in origin. Supersaturation results from excessive secretion of cholesterol or bilirubin conjugates, the precursors of unconjugated bilirubin, and/or, deficient secretion of bile salt and lecithin, the solubilizers of these otherwise insoluble lipids. As has now being clarified for cholesterol stones, an imbalance in pro- and antinucleating biliary proteins, hypersecretion of gallbladder mucin and gallbladder dysmotility possibly from cholesterol "toxicity" to sarcolemma, all interact to promote nucleation. Crystallisation results in suspension of cholesterol crystals or bilirubinate salts in gallbladder mucin gel and is known as "biliary sludge". It is believed today that this stage is essential for evolution of both cholesterol and pigment stones. Brown pigment gallstones form principally in the bile ducts. These stones result from infection of the biliary tree, most commonly due to obstruction from migrating gallbladder stones. Chemical compositions of brown and black pigment stones are different: In black stones, calcium bilirubinate is polymerized and oxidatively degraded but in brown stones, calcium bilirubinate is present as the unpolymerised salt. Brown stones differ also from black stones in containing calcium fatty acid soaps, a result of bacterial phospholipase A1 hydrolysis of biliary lecithin. Both types of pigment gallstones may contain crystalline inorganic calcium salts especially carbonate (gallbladder stones) and phosphate (bile ducts stones). Since a molecular understanding of the multiple defects that lead to cholesterol and pigment gallstones is becoming a reality, the future holds much promise for gallstone prevention.

10Mucin genes in gallstone disease.PubMed

Shih-Chang Chuang, Edward Hsi, King-Teh Lee
Clin Chim Acta. 2012 Oct 9;413(19-20):1466-71. doi: 10.1016/j.cca.2012.06.015. Epub 2012 Jun 13.
Gallstone disease is a complex disorder that can be caused by environmental influences, common genetic factors and their interactions. Three major pathogenic abnormalities are considered to involve in gallstone formation: cholesterol supersaturation in bile, precipitation and nucleation of excess cholesterol, and gallbladder hypomotility, while, mucin takes part in the cholesterol nucleation process. Up to date, more than 20 mucin genes have been reported, 9 of them are identified at the mRNA and/or protein level in native gallbladder and its associated diseases. In the gallbladder, mucin is essential for best protection against detergent effect of high concentration of bile acids. Over the past decade, the properties, expressions and functions of the gallbladder mucins are delineated in animal and human studies. Alteration expressions of mucins are thought to response during the pathogenesis of gallstone formation. Moreover, recent genetic association study demonstrated mucin gene polymorphisms may also influence susceptibility to gallstone disease. This review is not to provide a complete coverage of all the aspects of mucin glycoproteins, but focus on the role and expression of mucins involve in the regulation of cholelithogenesis.

11Relationship between gallstones and interstitial cells of Cajal in the gallbladder.PubMed

Min Su Jung, Man-Hoon Han, Tae In Park, et al.
Medicine (Baltimore). 2022 Jul 15;101(28):e29851. doi: 10.1097/MD.0000000000029851.
INTRODUCTION: A high percentage of patients with gallstones exhibit abnormalities in gallbladder emptying, and gallstones are often associated with gallbladder contraction. Interstitial cells of Cajal (ICC) in the gallbladder are involved in the generation and spreading of spontaneous contractions of the gallbladder. This study examined the relationship among the number of gallbladder ICC, gallbladder contractility, and gallstones. MATERIALS AND METHODS: Forty-six patients, who underwent cholecystectomy within 3 months of enduring a gallbladder ejection fraction scan, were enrolled in this study. ICC were identified using a microscope after immunohistochemical staining for CD117/c-kit. Five high-power field (magnification 400×) units were randomly assigned, and the number of ICC in the mucosal and muscular layers was counted. These counts were compared according to the sex, age, reason for cholecystectomy, presence of gallstone, presence of gallbladder polyp, gallbladder ejection fraction, and gallbladder size for each patient. RESULTS: The number of ICC in the mucosal layer was increased in the male participants (154.4 ± 73.9) compared with the female participants (107.3 ± 75.2); however, the ICC in the muscular layer was not different between the 2 groups. Additionally, the ICC in the mucosal and muscular layers did not differ according to age, cause of cholecystectomy, number of stones, stone character, stone diameter, or the presence of polyps. A larger gallbladder size was correlated with a decreased number of ICC in the muscular layer of the gallbladder. Additionally, when the number of gallbladder stones was increased, the number of ICC in the muscular layer of the gallbladder was decreased; however, there was no significant correlation between the number of ICC in the mucosal layer of the gallbladder and any of the following factors: age, GBEF, gallbladder size, stone number, or diameter. Furthermore, there was no significant correlation between the number of ICC in the muscular layer of the gallbladder, regardless of age, GBEF, and stone diameter. CONCLUSION: Although we were unable to achieve significant results regarding the relationship between GBEF and ICC, this is the first human study to reveal the relationship among ICC, gallbladder size, and the number of gallstones.

12Bile Metabolism and Lithogenesis: An Update.PubMed

Austin R Dosch, David K Imagawa, Zeljka Jutric
Surg Clin North Am. 2019 Apr;99(2):215-229. doi: 10.1016/j.suc.2018.12.003.
Bile is composed of multiple macromolecules, including bile acids, free cholesterol, phospholipids, bilirubin, and inorganic ions that aid in digestion, nutrient absorption, and disposal of the insoluble products of heme catabolism. The synthesis and release of bile acids is tightly controlled and dependent on feedback mechanisms that regulate enterohepatic circulation. Alterations in bile composition, impaired gallbladder relaxation, and accelerated nucleation are the principal mechanisms leading to biliary stone formation. Various physiologic conditions and disease states alter bile composition and metabolism, thus increasing the risk of developing gallstones.

13Genetics of gallstone disease.PubMed

Charlotte Rebholz, Marcin Krawczyk, Frank Lammert
Eur J Clin Invest. 2018 Jul;48(7):e12935. doi: 10.1111/eci.12935. Epub 2018 May 9.
BACKGROUND: Gallstone disease (GD) belongs to the most frequent disorders in gastroenterology and causes high costs in our health-care systems. Gallstones are uncommon in children but frequent in adults, in particular in women, and are triggered by exogenous risk factors. Here, we summarize the current knowledge concerning the contribution of inherited predisposition to gallstone risk. DESIGN: In this review, we present the current data and recent research on the genetics of gallstone disease. RESULTS: Several GD-predisposing gene variants have been reported, with most prominent effects being conferred by a common variant (p.D19H) of the hepatic and intestinal cholesterol transporter ABCG5/G8. A smaller group of patients might develop gallstones primarily due low phosphatidylcholine concentrations in bile as a result of loss-of-function mutations of the ABCB4 transporter (low phospholipid-associated cholelithiasis syndrome). Regardless of the origin, the risk factors for gallstones lead to the supersaturation of bile with insoluble compounds, in particular cholesterol. As result, cholesterol stones develop and present the most frequent type of gallstones. Laparoscopic cholecystectomy with low morbidity and mortality is currently the most common and effective method for the therapy of symptomatic gallbladder stones. CONCLUSIONS: Gallstone disease represents a multifactorial condition and previous studies have identified the major genetic contributors to gallstone formation. The increasing knowledge about the pathomechanisms of hepatobiliary metabolism and GD as well as the identification of additional risk factors might help to overcome the current invasive therapy by specific lifestyle intervention and precise molecular treatment.

14Genetics of Gallstones.PubMed

Agnieszka Pęczuła, Adam Czaplicki, Adam Przybyłkowski
Genes (Basel). 2025 Feb 22;16(3):256. doi: 10.3390/genes16030256.
Gallstone disease (GSD) is a common gastrointestinal disorder affecting approximately 10-20% of the global adult population, characterized by the presence of gallstones, predominantly cholesterol-based, in the gallbladder and/or biliary ducts. While many patients remain asymptomatic, more than 20% develop clinical symptoms such as abdominal pain, nausea, vomiting, jaundice, and anorexia, potentially leading to severe complications like acute cholecystitis and biliary pancreatitis. GSD has a significant genetic predisposition, with the variable prevalence of the disease according to ethnicity being highest in American and European countries and lowest in Asian and African populations. Numerous genes encoding membrane transporters involved in bile metabolism are associated with GSD, including in particular members of ATP-binding cassette transporters and others, which affect bile lithogenicity and contribute to the development of gallstones. Specific mutations in these genes are linked to an increased risk of gallstone formation, especially in individuals with certain hereditary conditions such as hemolytic diseases, thyroid disorders, and hyperparathyroidism. Advances in genetic studies have identified new variants that influence the risk of cholelithiasis, although the exact mechanisms remain partially understood in many cases. This review briefly summarizes the genetic causes of cholelithiasis, highlighting various pathogenetic mechanisms. It presents the currently used treatments and the potential implications of widely applied genetic diagnostics.

15Gallstone formation and weight loss.PubMed

R L Weinsier, D O Ullmann
Obes Res. 1993 Jan;1(1):51-6. doi: 10.1002/j.1550-8528.1993.tb00008.x.
Obesity is associated with increased bile stasis and cholesterol saturation, and an increased risk of gallstone development. Conversely, bile composition is normalized following reduction in body weight. It would appear advantageous to promote weight loss in obesity, which would reduce the predisposition to gallstone formation. Despite the potential health benefits of weight reduction, very-low-calorie diets appear to increase the risk for cholesterol crystal and gallstone formation. The incidence of gallstone formation seems to be dependent on the degree of caloric restriction, the rate of weight loss, and the duration of the dietary intervention. Thus, faster rates of weight loss for longer periods of time are associated with increased risk. Available data obtained from prospective studies of subjects during active weight loss suggest that newly formed gallstones occur within 4 weeks and with incidence rates 15 to 25-fold higher than in the general obese population. The stones produce symptoms in approximately one-third of the subjects, of whom approximately one-half will undergo surgery. Proposed mechanisms underlying gallstone formation during weight reduction include bile stasis due to reduced caloric intake, increased biliary cholesterol saturation secondary to increased cholesterol mobilization, and increased nucleation due to changes in bile arachidonate and glycoprotein concentrations. Data are lacking on the effects of gradual rates of weight loss and risk of gallstone formation.

16Risk factors for gallbladder cancer: a Polish case-control study.PubMed

W A Zatonski, C La Vecchia, K Przewozniak, et al.
Int J Cancer. 1992 Jul 9;51(5):707-11. doi: 10.1002/ijc.2910510508.
A population-based case-control study of gallbladder cancer was conducted in the south-west of Poland, within the frame-work of the SEARCH Programme of the International Agency for Research on Cancer. A total of 73 cases and 186 controls were interviewed using a questionnaire including demographic and socio-economic factors, education, smoking, alcohol, tea and coffee consumption, and past medical history. A validated diet history was used to estimate the daily intake of calories, fats, carbohydrates, proteins, cholesterol, fibres and vitamins C and E. Gallbladder disease was the major determinant of subsequent gallbladder cancer: 41 cases (56%) vs. 15 (8%) controls had a past history of gallbladder disease, corresponding to an odds ratio (OR) of 12.5 (95% confidence interval, 5.8 to 26.6), and the OR was 12.1 for gallbladder problems dating back 20 years or more in the past. There was an inverse relationship with education, the OR being 0.3 (95% CI 0.1 to 1.2) for 13 years of education or more vs. less than 7. Gallbladder cancer risk was positively associated with total calorie intake, with ORs of 1.4, 1.5, 4.1 for the 3 upper quartiles compared with the lowest one (trend, p less than 0.01). Weaker direct associations were observed for proteins, carbohydrates and cholesterol. There was some suggestion of inverse associations with fibre intake, and a more consistent one with vitamins C and E. These results further quantify the role of gallstones, and suggest that total calorie intake and other dietary factors potentially linked with benign gallbladder conditions are involved in the aetiology of gallbladder cancer.

17Association between dietary fiber intake and gallstones among American adults: a cross-sectional study.PubMed

Huimin Li, Ting Du, Changfeng Miao, et al.
J Health Popul Nutr. 2025 Sep 2;44(1):322. doi: 10.1186/s41043-025-01062-3.
BACKGROUND: Limited research has been conducted on the effects of dietary fiber (DF) intake on gallstones. We aimed to investigate the actual DF intake in a nationally representative sample in the United States (US) and explore its association with gallstones. METHODS: We used data from the National Health and Nutrition Examination Survey database, including the 2017-2020 and 2021-2023 cycles. Using participants' gallstone histories and their average 2-day DF intake, we investigated the actual DF intake among US adults. After adjusting for traditional confounders, we used weighted multivariable logistic regression models, trend tests, spline curve fitting, subgroup analyses, and interaction tests to explore the independent association between DF intake and gallstones. RESULTS: A total of 8,782 participants were included. The weighted analysis showed the prevalence of gallstones is 10.03%. The average DF intake among adult men and women is 18 ± 10 g/day and 15 ± 7.8 g/day, respectively, which is well below the recommended levels. Multivariable regression analysis revealed a statistically significant negative linear association between DF intake and gallstone prevalence. For every 10 g/day increase in DF intake, the risk of gallstones significantly decreases by 21% (OR = 0.79, 95% CI: 0.63-1.00, P = 0.047). Curve fitting showed a negative linear relationship between these two variables (P = 0.003, P for non-linearity = 0.134). CONCLUSION: A negative linear relationship between DF intake and gallstones among adults in the US was observed, and the current DF intake in the US is far below recommended levels.

18Association between dietary fiber intake and gallstone disease in US adults: Data from NHANES 2017-2020.PubMed

Tian Liu, Huimin Lv, Jia Li, et al.
SLAS Technol. 2025 Apr;31:100259. doi: 10.1016/j.slast.2025.100259. Epub 2025 Feb 28.
BACKGROUND: Gallstone disease is a widespread condition affecting the gastrointestinal tract, and poor diet is believed to be one of the reasons for its occurrence. Previous studies of dietary fiber intake and gallstones have limitations. The study's goal is to investigate the relationship between dietary fiber intake and gallstone prevalence in US adults. MATERIALS AND METHODS: Data from NHANES 2017 to March 2020 is used for the study. The association between fiber intake and gallstone prevalence was analyzed using multivariate logistic regression. To confirm the results' robustness, we performed sensitivity analyses also. RESULTS: Among the 6,051 U.S. adults aged over 20 with complete information, the prevalence of gallstones was 10.8 % (651/6051). After adjusting for relevant covariates, an increase in fiber intake of 5 g/day was associated with an 11 % decrease in the prevalence of gallstones (fully adjusted OR = 0.89, 95 % CI: 0.83-0.95). Participants were divided into high (>25 g/d) and low (≤25 g/d) fiber intake groups. Still significant negative association between dietary fiber intake and gallstones (fully adjusted OR = 0.66, 95 % CI: 0.49-0.91). Further dividing dietary fiber intake level into quintiles sustained this negative relationship, particularly showing the lowest gallstone occurrence in the highest dietary fiber group (OR = 0.63, 95 % CI: 0.44-0.91). While the stratified analyses indicated variability in the relationship between dietary fiber intake and the prevalence of gallstones, no interactive effects were identified in this association according to the interaction analysis. CONCLUSIONS: This study confirms that dietary fiber intake is negatively associated with the prevalence of gallstones. Sufficient dietary fiber intake might protect from gallstones. In order to formulate dietary recommendations, it is important to carry out prospective studies to validate the observed associations.

19Dietary fiber intake and risk of gallstone: a case-control study.PubMed

Asal Neshatbini Tehrani, Saeede Saadati, Zahra Yari, et al.
BMC Gastroenterol. 2023 Apr 11;23(1):119. doi: 10.1186/s12876-023-02752-0.
BACKGROUND: Gallstone disease (GSD) and its complications are major public health issues globally. Although many community-based studies had addressed the risk factors for GSD, little is known about the associations between dietary factors and risk of disease. The present study aimed to investigate the potential associations between dietary fibers with the risk of gallstone disease. METHODS: In this case-control study, 189 GSD patients with less than one month of diagnosis and 342 age‑matched controls were enrolled. Dietary intakes were assessed using a 168-item semi-quantitative validated food frequency questionnaire. Crude and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated through cox proportional hazards regression models. RESULTS: Comparing the highest versus the lowest tertile, significant reverse associations were observed between odds of GSD and each category of dietary fiber intake including total (OR = 0.44, 95% CI: 0.37-0.7, P for trend = 0.015), soluble (OR = 0.51, 95% CI: 0.3-0.8, P for trend = 0.048) and insoluble (OR = 0.56, 95% CI: 0.3-0.9, P for trend < 0.001). The relationship between dietary fiber intake and the risk of gallstones was more prominent in overweight and obese subjects than in subjects with a normal body mass index. CONCLUSION: Comprehensive assessment of the associations of dietary fiber intake with GSD showed that higher intakes of dietary fiber were significantly associated with reduced GSD risk.

20Pathogenesis of gallstones.PubMed

H F Weisberg
Ann Clin Lab Sci. 1984 Jul-Aug;14(4):243-51.
The three lipids in bile, cholesterol, lecithin, and bile salts (about 90 percent of the dry weight of normal gallbladder bile) are amphipathic substances having both hydrophobic and hydrophilic functional groups. Knowledge of the physicochemical factors of gallstone formation (especially cholesterol stones) has increased in the past two decades. The absolute amount of cholesterol supersaturation determines the extent of cholesterol precipitation. The ionic strength of the bile and the types of bile salts present are minor factors, whereas the ratios of bile salts to lecithin at a particular concentration of total lipids are the major factors contributing to gallstone production. Bile acids (salts) form micelles which allow the lecithin and cholesterol to dissolve within the micelles. Thus the administration of bile acids allows for non-invasive dissolution of some cholesterol gallstones. Additional important risk factors are genetic and ethnic, sex (females predominate), obesity, diet (in contrast to animal protein and more refined carbohydrate diets, there is less lithogenicity with diets containing plant protein and unrefined carbohydrates), certain diseases, and drug therapy. Pigment stones make up the majority of radiopaque stones and are predominant in the Orient; they are seen in certain diseases and in infections of the biliary tree.

21The Effects of Breakfast and Breakfast Composition on Cognition in Adults.PubMed

Rachel Galioto, Mary Beth Spitznagel
Adv Nutr. 2016 May 16;7(3):576S-89S. doi: 10.3945/an.115.010231. Print 2016 May.
Extensive literature has addressed the acute cognitive effects of breaking a fast. Recent reviews in this line of work have synthesized available research on the cognitive consequences of fasting compared with nutrient intake and the cognitive effects of macronutrient consumption. These largely have been inconclusive, possibly in part because of selection criteria limiting the scope of studies covered. The purpose of the current review is to integrate the results of the literature examining the cognitive effects of breakfast and breakfast composition in adults with the use of a flexible definition of breakfast, specifically, any caloric intake after a fasting period of ≥8 h. This review includes 38 studies that examine the acute cognitive impact of breakfast and 16 studies that examine the effects of breakfast composition. Results suggest that healthy adults show a small but robust advantage for memory (particularly delayed recall) from consuming breakfast. Largely equivocal results emerge for attention and motor and executive function; there were no effects from breakfast on language. Regarding breakfast composition, a smaller number of studies and widely disparate methodology addressing this question preclude definitive conclusions about the effects of cognition. A subset of this literature examines these questions in the context of glucoregulation; the findings emphasize the importance of considering differences in glucoregulation in research designs, even among healthy cohorts. The limitations of this literature include methodologic differences, such as the use of different tests to measure cognitive constructs, as well as the effects of timing in test administration.

22The Association Between Intermittent Fasting and Glaucoma.PubMed

Marlow Schulz, Leona Ding, Shu Feng, et al.
J Glaucoma. 2025 Jan 1;34(1):1-6. doi: 10.1097/IJG.0000000000002515. Epub 2024 Oct 25.
PRCIS: Intermittent fasting was not associated with a decreased risk of glaucoma diagnosis overall. OBJECTIVE: To examine the association between intermittent fasting ("breakfast skipping") and glaucoma in the National Health and Nutrition Examination Survey (NHANES). PATIENTS AND METHODS: Retrospective, cross-sectional study of adult participants of the 2005-2008 NHANES aged 40 years and older. Intermittent fasting was defined as skipping breakfast on both days of the NHANES dietary interview. Glaucoma was defined by (1) self-reported glaucoma diagnosis, (2) cup-to-disc (CDR) ≥0.6 in at least one eye, and (3) possible, probable, or definite glaucoma based on clinical judgment of retinal imaging of individuals with CDR ≥0.6 in at least one eye. Covariates included age, sex, race/ethnicity, body mass index, blood pressure, and waist circumference. χ 2 and Fisher exact test were used for categorical variables and the t test for continuous variables. All data were weighted based on the NHANES multistage sampling design. RESULTS: The population included 7081 individuals 40 years or older, of whom 946 (13.4%) reported skipping breakfast on both interview days; 482 (6.8%) individuals self-reported glaucoma diagnosis, 549 (7.8%) individuals had glaucoma based on CDR ≥0.6, and 343 (6.0%) individuals had glaucoma based on clinical judgment. Diagnosis of glaucoma by all definitions was associated with older age and black or Latinx/Hispanic ethnicity ( P = 0.004) but was not associated with intermittent fasting status ( P = 0.151). CONCLUSIONS: In the 2005-2008 NHANES population, intermittent fasting, defined as breakfast skipping, was not associated with decreased risk of glaucoma diagnosis overall. Further studies are needed to examine the potential effects of intermittent fasting on glaucoma risk.

23Breakfast skipping and cardiometabolic risk factors in adolescents: Systematic review.PubMed

Marielly Rodrigues Souza, Morgana Egle Alves Neves, Bartira Mendes Gorgulho, et al.
Rev Saude Publica. 2021 Dec 17;55:107. doi: 10.11606/s1518-8787.2021055003077. eCollection 2021.
OBJECTIVE: To systematically review the results of the association between breakfast skipping and cardiometabolic risk factors in adolescents. METHODS: The articles were searched in May 2020 from PubMed, Virtual Health Library, Scopus, Web of Science and Scientific Electronic Library Online (SciELO). The review included observational studies conducted with adolescents (10-19 years old), which estimated the association of breakfast skipping with at least one outcome (markers of body adiposity, blood pressure, serum lipid and glucose levels). Regarding the risk of bias, the articles were evaluated using the Research Triangle Institute (RTI) Item Bank on bias risk and accuracy of observational studies. The quality of the evidence was assessed by the Grade rating. RESULTS: A total of 43 articles involving 192,262 participants met the inclusion criteria and were considered in this review. The prevalence of breakfast skipping ranged from 0.7% to 94% and 60.5% of studies were classified with low risk of bias. The significant association between breakfast skipping and cardiometabolic risk factors was found in twenty-nine cross-sectional articles (n = 106,031) and four longitudinal articles (n = 5,162) for excess adiposity, in three articles (n = 8,511) for high total cholesterol levels, low-density lipoprotein and triglycerides, and in three studies (n = 6,303) for high blood pressure levels. However, there was no significant association between breakfast skipping and glycemic profile. According to the Grade rating, all the associations had low quality of evidence. CONCLUSION: The results of this review suggest that breakfast skipping is associated with cardiometabolic risk factors in adolescents aged 10 to 19 years. However, considering the low quality of the evidence, the present results should be interpreted carefully. In addition, our findings highlight the importance of standardizing the definition of breakfast skipping and that more prospective studies are needed to determine how skipping breakfast can affect cardiometabolic risk factors in the long time.

24Breakfast habits, nutritional status, body weight, and academic performance in children and adolescents.PubMed

Gail C Rampersaud, Mark A Pereira, Beverly L Girard, et al.
J Am Diet Assoc. 2005 May;105(5):743-60; quiz 761-2. doi: 10.1016/j.jada.2005.02.007.
Breakfast has been labeled the most important meal of the day, but are there data to support this claim? We summarized the results of 47 studies examining the association of breakfast consumption with nutritional adequacy (nine studies), body weight (16 studies), and academic performance (22 studies) in children and adolescents. Breakfast skipping is highly prevalent in the United States and Europe (10% to 30%), depending on age group, population, and definition. Although the quality of breakfast was variable within and between studies, children who reported eating breakfast on a consistent basis tended to have superior nutritional profiles than their breakfast-skipping peers. Breakfast eaters generally consumed more daily calories yet were less likely to be overweight, although not all studies associated breakfast skipping with overweight. Evidence suggests that breakfast consumption may improve cognitive function related to memory, test grades, and school attendance. Breakfast as part of a healthful diet and lifestyle can positively impact children's health and well-being. Parents should be encouraged to provide breakfast for their children or explore the availability of a school breakfast program. We advocate consumption of a healthful breakfast on a daily basis consisting of a variety of foods, especially high-fiber and nutrient-rich whole grains, fruits, and dairy products.

25Meal Timing and Frequency: Implications for Cardiovascular Disease Prevention: A Scientific Statement From the American Heart Association.PubMed

Marie-Pierre St-Onge, Jamy Ard, Monica L Baskin, et al.
Circulation. 2017 Feb 28;135(9):e96-e121. doi: 10.1161/CIR.0000000000000476. Epub 2017 Jan 30.
Eating patterns are increasingly varied. Typical breakfast, lunch, and dinner meals are difficult to distinguish because skipping meals and snacking have become more prevalent. Such eating styles can have various effects on cardiometabolic health markers, namely obesity, lipid profile, insulin resistance, and blood pressure. In this statement, we review the cardiometabolic health effects of specific eating patterns: skipping breakfast, intermittent fasting, meal frequency (number of daily eating occasions), and timing of eating occasions. Furthermore, we propose definitions for meals, snacks, and eating occasions for use in research. Finally, data suggest that irregular eating patterns appear less favorable for achieving a healthy cardiometabolic profile. Intentional eating with mindful attention to the timing and frequency of eating occasions could lead to healthier lifestyle and cardiometabolic risk factor management.

26Prevalence of breakfast skipping among children and adolescents: a cross-sectional population level study.PubMed

Alanna Sincovich, Hero Moller, Lisa Smithers, et al.
BMC Pediatr. 2022 Apr 23;22(1):220. doi: 10.1186/s12887-022-03284-4.
BACKGROUND: Interventions to promote breakfast consumption are a popular strategy to address early life inequalities. It is important to understand the epidemiology of children and adolescents who skip breakfast so that interventions and policy can be appropriately considered. This study investigated the prevalence of breakfast skipping among a contemporary, population-wide sample of children and adolescents in Australia. METHODS: Participants were grade 4-12 students (n = 71,390, 8-18 years) in South Australian government (public) schools who took part in the 2019 Wellbeing and Engagement Collection. The prevalence of breakfast skipping (never, sometimes, often, or always) was calculated for the overall sample and stratified by gender, school grade, socioeconomic status and geographical remoteness. Multinomial logistic regression analyses were conducted to determine the relative risk ratio of sometimes, often, and always skippers compared with never skippers, according to demographic characteristics. RESULTS: Overall, 55.0% of students reported never skipping breakfast, 17.4% reported sometimes skipping, 18.0% reported often skipping, and 9.5% reported always skipping breakfast. Skipping breakfast was more prevalent among females, students in senior grades, and those living in socioeconomically disadvantaged and regional and remote areas. Analyses disaggregated by gender revealed that grade level gradients in breakfast skipping were more marked among females compared to males. CONCLUSIONS: Breakfast skipping among children and adolescents appears considerably more prevalent than previous research suggests. Drivers of breakfast skipping across population sub-groups need to be explored to better inform strategies to promote breakfast consumption.

27Breakfast Eating Habits Among Schoolchildren.PubMed

Mohammed ALBashtawy
J Pediatr Nurs. 2017 Sep-Oct;36:118-123. doi: 10.1016/j.pedn.2017.05.013. Epub 2017 Jun 15.
BACKGROUND: A healthy breakfast provides school-age children with the essential nutrients needed for their activities and is correlated with improving a person's general nutritional status. METHODS: A cross-sectional study was conducted over a period of two months in 2015, involving 1798 Jordanian schoolchildren from grade 1 to grade 6. The study data sheet covered the breakfast habits of those children. Descriptive measures and Pearson's chi-square test were computed. Multivariate regression was calculated to assess the predictors' factors for breakfast consumption. The p value was considered significant at p<0.05. RESULTS: Findings show a prevalence for breakfast consumption of 80.4%. Furthermore, 52.1% of the breakfast eaters indicated that it was a family habit; half of them ate breakfast in order to be active and energetic and to alleviate hunger during the morning. Live with both parents, age groups of 6-9years and boys were the predictors of breakfast consumption among schoolchildren. CONCLUSION: Breakfast skipping among schoolchildren was initially high and increased with age. The findings suggest a community health education programme, conducted by school nurses, nutritionists and other health professionals, is needed.

28Breakfast Skipping and Determinant Factors among Moroccan School Adolescents (12-19 Years): The Case of Beni Mellal City.PubMed

Kamal Kaoutar, Ahmed Chetoui, Kaltoum Boutahar, et al.
Port J Public Health. 2023 Oct 26;41(3):179-187. doi: 10.1159/000534082. eCollection 2023 Dec.
INTRODUCTION: Breakfast skipping is an unhealthy eating behavior reportedly common among adolescents. The aim of the present study was to determine the prevalence and factors associated with breakfast skipping among schoolchildren aged 12-19 years in Beni Mellal city, Morocco, and to assist in the design of interventions to improve breakfast consumption habits of school-aged children in this region. METHODS: A school-based cross-sectional study was carried out. A total of 550 children were included in the study. Multivariable logistic regression analysis was used to identify factors associated with skipping breakfast consumption. The association between dependent and independent variables was assessed using an odds ratio (OR) with a 95% confidence interval and value <0.05 was considered statistically significant. RESULTS: Among 550 Moroccan adolescents evaluated, 25.6% reported not consuming breakfast every day. Breakfast eating was statistically associated with gender (OR = 7.13 [95% CI 1.32-3.84], = 0.008); mother's low educational level (OR = 2.86 [95% CI 1.89-4.71], = 0.091); nonworking mothers (OR = 13.71 [95% CI 1.16-5.29], < 0.001); not eating between meals (OR = 15.49 [95% CI 2.15-5.49], < 0.001); eating dinner regularly each day (OR = 17.79 [95% CI 2.81-8.01], = 0.005); eating vegetables 1-3 times per week (OR = 10.21 [95% CI 1.44-4.67], = 0.001); consuming milk and dairy product 1-3 times per week (OR = 13.88 [95% CI 1.59-5.56], < 0.001); and never consuming sodas and soft drink in week (OR = 3.12 [95% CI 1.90-4.50], = 0.003). CONCLUSIONS: This study revealed that the prevalence of skipping breakfast consumption among school-aged children in Beni Mellal city was high. Thus, the findings suggest a community health education program, conducted by school nurses, nutritionists, and other health professionals, is needed.

29Association of Skipping Breakfast With Cardiovascular and All-Cause Mortality.PubMed

Shuang Rong, Linda G Snetselaar, Guifeng Xu, et al.
J Am Coll Cardiol. 2019 Apr 30;73(16):2025-2032. doi: 10.1016/j.jacc.2019.01.065.
BACKGROUND: Skipping breakfast is common among U.S. adults. Limited evidence suggests that skipping breakfast is associated with atherosclerosis and cardiovascular disease. OBJECTIVES: The authors sought to examine the association of skipping breakfast with cardiovascular and all-cause mortality. METHODS: This is a prospective cohort study of a nationally representative sample of 6,550 adults 40 to 75 years of age who participated in the National Health and Nutrition Examination Survey III 1988 to 1994. Frequency of breakfast eating was reported during an in-house interview. Death and underlying causes of death were ascertained by linkage to death records through December 31, 2011. The associations between breakfast consumption frequency and cardiovascular and all-cause mortality were investigated by using weighted Cox proportional hazards regression models. RESULTS: Among the 6,550 participants (mean age 53.2 years; 48.0% male) in this study, 5.1% never consumed breakfast, 10.9% rarely consumed breakfast, 25.0% consumed breakfast some days, and 59.0% consumed breakfast every day. During 112,148 person-years of follow-up, 2,318 deaths occurred including 619 deaths from cardiovascular disease. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and cardiovascular risk factors, participants who never consumed breakfast compared with those consuming breakfast everyday had hazard ratios of 1.87 (95% confidence interval: 1.14 to 3.04) for cardiovascular mortality and 1.19 (95% confidence interval: 0.99 to 1.42) for all-cause mortality. CONCLUSIONS: In a nationally representative cohort with 17 to 23 years of follow-up, skipping breakfast was associated with a significantly increased risk of mortality from cardiovascular disease. Our study supports the benefits of eating breakfast in promoting cardiovascular health.

30Breakfast skipping and timing of lunch and dinner: Relationship with BMI and obesity.PubMed

Giovana Longo-Silva, Priscilla Márcia Bezerra de Oliveira, Anny Kariny Pereira Pedrosa, et al.
Obes Res Clin Pract. 2022 Nov-Dec;16(6):507-513. doi: 10.1016/j.orcp.2022.10.012. Epub 2022 Nov 8.
OBJECTIVE: To determine whether breakfast-skipping, late-lunch, and late-dinner eating are cross-sectionally associated with higher BMI and obesity. Also, to identify obesogenic behaviors and circadian-related variables, associated with late eating. METHODS: Participants(n = 776) were part of exploratory, population-based research, with data collection in a virtual environment. They were grouped into breakfast-eaters (first meal until 10:00) and skippers (first meal after 10:00), and the population median for the lunch and dinner timing was used to stratify participants into early (lunch/dinner-time before 12:34/20:55) and late (lunch/dinner-time after 12:34/20:55) eaters. Student's t-test and chi-square test were performed to assess differences in characteristics and lifestyle traits between groups. Logistic regression models were used to assess differences in obesity between groups. Linear regression analysis was conducted to determine the association of the clock time of meals with BMI. Analyses were adjusted for potential confounders variables. RESULTS: BMI raised of 0.74 Kg/m2 for each additional hour of lunch-time [95 %CI= 0.31;1.18,P ≤ 0.001]. Breakfast-skippers [OR(95 % CI):1.84(1.02;3.31);P ≤ 0.05] and late-lunch eaters [OR(95 % CI):1.61(1.04;2.49),P ≤ 0.05] had higher odds of having obesity, compared with breakfast-eaters and early-lunch eaters, respectively. These associations were independent of age, gender, diet quality, physical activity duration, and region. No statistically significant differences were found in the comparison between early and late-dinner eaters. CONCLUSIONS: Our results suggest that skipping breakfast and eating late-lunch are associated with BMI and higher odds of having obesity. Insights into the obesogenic behaviors/characteristics related to breakfast-skipping and late-eating may be helpful for future nutritional recommendations and obesity prevention and treatment.

31Skipping breakfast and prevalence of overweight and obesity in Asian and Pacific regions: a meta-analysis.PubMed

Chika Horikawa, Satoru Kodama, Yoko Yachi, et al.
Prev Med. 2011 Oct;53(4-5):260-7. doi: 10.1016/j.ypmed.2011.08.030. Epub 2011 Aug 27.
OBJECTIVE: In Western countries, skipping breakfast is associated with a high prevalence of overweight and obesity. This meta-analysis aimed to determine if the same relationship exists in Asian and Pacific regions. METHODS: A systematic literature search was performed for observational studies using a cross-sectional design that examined the relationship between frequency of eating breakfast and overweight or obesity. Odds ratios (ORs) for overweight or obesity were pooled with a variance-based method. RESULTS: Nineteen studies (93,108 total participants and 19,270 overweight or obese cases) were included. The pooled OR [95% confidence intervals (CI)] of overweight or obesity for the lowest vs. highest category of breakfast frequency was 1.75 [1.57 to 1.95] (P<0.001). Between-study heterogeneity in the association's strength was highly significant (I-squared=36.4%, P<0.001), although a positive OR was shown in all but one included study. However, no study characteristics could be identified to explain the heterogeneity. CONCLUSION: This meta-analysis suggests that a positive association between skipping breakfast and overweight and obesity is globally observed regardless of cultural diversity among countries. Promoting the eating of breakfast in all populations may be beneficial.

32Frequency of Breakfast Eating and Obesity Prevalence in Primary School Teachers.PubMed

Martina Uvacsek, Georgina Simkó, Judit Boda-Ujlaky, et al.
Int J Environ Res Public Health. 2022 Apr 27;19(9):5331. doi: 10.3390/ijerph19095331.
There is a lack of research using objective measures about teachers' physical characteristics and lifestyle. The purpose of the study was to evaluate the relationship between frequency of breakfast consumption and body size, body composition, blood pressure and lifestyle factors in teachers from Hungary. The study analyzed data collected from 99 female primary school teachers (50.6 ± 6.6 year) before the COVID-19 pandemic. Anthropometric and resting blood pressure measurements were taken for each participant. Questionnaires were used to assess lifestyle factors (i.e., physical activity level, smoking status and eating breakfast). The frequency of eating breakfast was classified as rarely or never (0-2 days), some days (3-5 days) and regularly (6-7 days). Sixty-five percent of female teachers consumed breakfast 6-7 days/week, and this regular eating habit was positively associated with a lower risk of obesity (OR 0.29; CI: 0.10-0.80). In our sample, a higher frequency of breakfast consumption was not significantly associated with smoking (OR 2.65; CI: 0.17-1.37), hypertension (OR 0.61; CI: 0.23-1.65) and inactivity (OR 2.80; CI: 0.26-1.84). A beneficial effect of eating breakfast regularly was found on body composition in female teachers. Further studies should focus on the health behaviors of teachers and their relationship with physical activity or diagnosed diseases in urban and rural areas.

33Successful weight loss maintenance: A systematic review of weight control registries.PubMed

Catarina Paixão, Carlos M Dias, Rui Jorge, et al.
Obes Rev. 2020 May;21(5):e13003. doi: 10.1111/obr.13003. Epub 2020 Feb 12.
Weight loss maintenance is a major challenge for obesity treatment. Weight control registries can be useful in identifying psychological and behavioural factors that could contribute to better long-term success. The objective of this study is to describe the existing weight control registries and their participants and identify correlates of weight loss maintenance. A comprehensive search of peer-reviewed articles published until November 2018 was conducted in PubMed, Web of Science, and Scopus. Studies that reported results from weight control registries were considered. Fifty-two articles, corresponding to five registries (the United States, Portugal, Germany, Finland, and Greece), were included. Registries differed in inclusion criteria and procedures. Of 51 identified weight loss and maintenance strategies, grouped in 14 domains of the Oxford Food and Activity Behaviors taxonomy, the following were the most frequently reported: having healthy foods available at home, regular breakfast intake, increasing vegetable consumption, decreasing sugary and fatty foods, limiting certain foods, and reducing fat in meals. Increased physical activity was the most consistent positive correlate of weight loss maintenance. To our knowledge, this is the first systematic review of information about successful weight loss maintenance obtained from weight control registries. Key common influential characteristics of success were identified, which can inform future prospective studies and weight management initiatives.

34Skipping Breakfast and Academic Grades, Persistent Feelings of Sadness or Hopelessness, and School Connectedness Among High School Students - Youth Risk Behavior Survey, United States, 2023.PubMed

Sarah A Sliwa, Caitlin L Merlo, Izraelle I McKinnon, et al.
MMWR Suppl. 2024 Oct 10;73(4):87-93. doi: 10.15585/mmwr.su7304a10.
Breakfast consumption is positively associated with academic achievement and diet quality among students, whereas skipping breakfast has been linked with poor mental health. Data from CDC's 2023 nationally representative Youth Risk Behavior Survey were used to describe how often high school students ate breakfast in the past 7 days and the associations between skipping breakfast every day (ate breakfast on 0 of the past 7 days), experiencing persistent feelings of sadness or hopelessness, school connectedness, and self-reported grades. Prevalence estimates and corresponding 95% CIs were calculated, and t-tests were used to identify differences within demographic groups (e.g., sex, race and ethnicity, and sexual identity). Logistic regression analyses were conducted to calculate prevalence ratios describing breakfast skipping, adjusting for demographics, and stratified by sex and race and ethnicity. Most students missed breakfast ≥1 time in the past 7 days (72.6%), and 17.9% of students skipped breakfast every day, with differences by sex, sexual identity, and race and ethnicity. Overall, and among both males and females, students who experienced persistent feelings of sadness or hopelessness were more likely to skip breakfast every day. The association between feelings of sadness and hopelessness and skipping breakfast was generally consistent across racial and ethnic groups. In contrast, greater levels of school connectedness and earning mostly As or Bs were inversely associated with skipping breakfast. Students who had higher school connectedness were approximately 30% less likely to skip breakfast on all 7 days. Skipping breakfast and poor mental health co-occur among many adolescents and might impede students' readiness to learn. School efforts to make breakfast accessible and appealing to high school students might yield multiple benefits and help reinforce school administrators' efforts to recover student learning losses that occurred during the COVID-19 pandemic. Parents, school decision-makers, and organizations that partner with schools and families can use these findings to guide efforts to promote breakfast consumption.

35The influence of eating habits on the academic performance of university students.PubMed

Peter R Reuter, Bridget L Forster, Sierra R Brister
J Am Coll Health. 2021 Nov-Dec;69(8):921-927. doi: 10.1080/07448481.2020.1715986. Epub 2020 Feb 6.
OBJECTIVE: To explore the correlation between eating habits of university students and academic achievement. PARTICIPANTS: 577 undergraduate students at a university in the United States. METHODS: Students were invited to participate in an anonymous online survey that asked questions concerning health-related behaviors; participants were asked to report their current grade point average (GPA). Statistical analyses were performed using the JMP software program; a standard least squares regression was used to test whether self-reported current GPA was related to different types and rates of weekly food and drink consumption. RESULTS: Self-reported GPA did not change along with weekly rates of milk, vegetables, green salad, fruit juice, or fresh fruit consumption. Breakfast consumption had a positive effect on self-reported GPA, while fast food consumption had a negative effect. CONCLUSION: Healthy eating habits have a positive effect on students' academic performance. However, other factors, such as sleep habits, may be more important.

36Breakfast skipping and cognitive and emotional engagement at school: a cross-sectional population-level study.PubMed

Hero Moller, Alanna Sincovich, Tess Gregory, et al.
Public Health Nutr. 2021 Dec 16;25(12):1-10. doi: 10.1017/S1368980021004870.
OBJECTIVE: Research on the consequences of breakfast skipping among students tends to focus on academic outcomes, rather than student well-being or engagement at school. This study investigated the association between breakfast skipping and cognitive and emotional aspects of school engagement. DESIGN: Cross-sectional study using data from a population-level survey of children and adolescents' well-being and engagement at school. Linear regression with adjustment for confounders was used to estimate the effect of breakfast skipping on school engagement. SETTING: Government schools (i.e. public schools) in South Australia. PARTICIPANTS: The participants were students, Grades 4-12, who completed the Wellbeing and Engagement Collection in 2019. The analysis sample included 61 825 students. RESULTS: Approximately 9·6 % of students reported always skipping breakfast, with 35·4 % sometimes skipping and 55·0 % never skipping. In the adjusted linear regression models, children and adolescents who always skipped breakfast reported lower levels of cognitive engagement (β = -0·26 (95 % CI -0·29, -0·25)), engagement with teachers (β = -0·17 (95 % CI -0·18, -0·15)) and school climate (β = -0·17 (95 % CI -0·19, -0·15)) compared with those who never skipped breakfast, after controlling for age, gender, health, sleep, sadness and worries, parental education, socio-economic status and geographical remoteness. CONCLUSION: Consistent with our hypothesis, skipping breakfast was associated with lower cognitive and emotional engagement, which could be due to mechanisms such as short-term energy supply and long-term health impacts. Therefore, decreasing the prevalence of breakfast skipping could have a positive impact on school engagement.

37Associations between temporal eating patterns and energy distribution patterns with gallstones: a cross-sectional study based on NHANES 2017-2018.PubMed

Huan Zhang, Chao Xu, Xiaojing Zhu, et al.
BMC Public Health. 2024 Oct 29;24(1):2994. doi: 10.1186/s12889-024-20512-x.
BACKGROUND: Gallstones are strongly associated with eating occasion (EO) and energy distribution, but few studies have addressed this aspect. Therefore, we utilize the data from 2017 to 2018 National Health and Nutrition Examination Survey (NHANES) to explore the association between temporal eating patterns and energy distribution patterns with the incidence of gallstones. METHODS: Our study comprised participants who completed the NHANES dietary intake interview and self-reported health questionnaire at age 20 or older. The self-report method for gallstones (have you ever been told by a doctor) was used. We use the latent class analysis (LCA) identified temporal eating patterns, and identified energy distribution patterns through latent profile analysis (LPA). The association between temporal eating patterns, energy distribution patterns, and gallstones was examined using logistic regression modeling. RESULTS: The study included a total of 4,692 participants. LCA identified four temporal eating patterns labeled as "Conventional," "Early breakfast," "Later breakfast," and "Grazing." Compared to the "Conventional" pattern, the "Early breakfast" pattern (OR 0.809, 95%CI 0.808-0.811) was associated with a reduced risk of gallstones, while the "Later breakfast" (OR 1.435, 95%CI 1.432-1.438) and "Grazing" (OR 1.147, 95%CI 1.145-1.148) patterns were associated with an increased risk of gallstones. LPA identified four energy distribution patterns labeled as "Guideline," "High carbohydrates," "Carbs-fat balance," and "High fat." The "High carbohydrates" pattern (OR 1.329, 95%CI 1.326-1.331) was associated with an increased risk of gallstones compared to the "Guideline" pattern. The "Carbs-fat balance" pattern (OR 0.877, 95%CI 0.876-0.879) and the "High fat" pattern (OR 0.848, 95%CI 0.846-0.850) were significantly and negatively associated with the risk of gallstones. CONCLUSIONS: To summarize, inappropriate timing of eating and energy sources are associated with gallstones. As a dietary prevention measure for gallstones, we suggest adhering to a regular eating routine and avoiding overly casual and frequent food consumption. If the main EO routine occurs in the morning, this time should not exceed 9:00 a.m. Additionally, reducing carbohydrate intake and maintaining a moderate level of fat intake is believed to contribute to a lower risk of gallstones.

38Non-linear relationship between the first meal time of the day and gallstone incidence in American adults: a population-based cross-sectional study.PubMed

Tiange Sun, Lidong Zhang, Ying Lu, et al.
Front Nutr. 2024 Dec 16;11:1521707. doi: 10.3389/fnut.2024.1521707. eCollection 2024.
BACKGROUND: Irregular meal time is associated with gallstones. The time-dose effect between meal time and gallstone formation remains unknown. OBJECTIVE: This study aimed to investigate the association between the first meal time (FMT) of the day and the prevalence of gallstones. METHODS: Based on data from the National Health and Nutrition Examination Survey from 2017 to March 2020, the associations between the FMT of the day and the prevalence of gallstones were analyzed via multivariable logistic regression, restricted cubic spline curves, subgroup analysis, and interaction tests. RESULTS: A total of 6,547 participants were included. The fully adjusted model indicated a positive correlation between the FMT of the day and the prevalence of gallstones (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.02 ~ 1.08); this association was consistent across subgroups. The risk of developing gallstones was the greatest when the FMT was between 09:00 and 14:00 (OR [95% CI] = 1.49 [1.24 ~ 1.77]). There was a non-linear relationship between the FMT and gallstone incidence ( for non-linearity = 0.042), with an inflection point at 13.4 h. After the 13.4-h mark, the risk of developing gallstones did not increase further. CONCLUSION: The FMT of the day is positively correlated with the prevalence of gallstones, and there is a non-linear relationship and threshold effect between the two. Skipping breakfast is associated with a greater risk of developing gallstones. This study provides new evidence for the dietary prevention of gallstones.

39The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice.PubMed

Helen H Wang, Piero Portincasa, David Q-H Wang
Eur J Clin Invest. 2016 Feb;46(2):158-69. doi: 10.1111/eci.12580. Epub 2016 Jan 12.
BACKGROUND: A defect in gallbladder contraction function plays a key role in the pathogenesis of gallstones. The cholecystokinin-1 receptor (CCK-1R) antagonists have been extensively investigated for their therapeutic effects on gastrointestinal and metabolic diseases in animal studies and clinical trials. However, it is still unknown whether they have a potential effect on gallstone formation. DESIGN: To study whether the CCK-1R antagonists enhance cholelithogenesis, we investigated cholesterol crystallization, gallstone formation, hepatic lipid secretion, gallbladder emptying function and intestinal cholesterol absorption in male C57BL/6J mice treated by gavage with devazepide (4 mg/day/kg) or vehicle (as controls) twice per day and fed the lithogenic diet for 21 days. RESULTS: During 21 days of feeding, oral administration of devazepide significantly accelerated cholesterol crystallization and crystal growth to microlithiasis, with 40% of mice forming gallstones, whereas only agglomerated cholesterol monohydrate crystals were found in mice receiving vehicle. Compared to the vehicle group, fasting and postprandial residual gallbladder volumes in response to the high-fat meal were significantly larger in the devazepide group during cholelithogenesis, showing reduced gallbladder emptying and bile stasis. Moreover, devazepide significantly increased hepatic secretion of biliary cholesterol, but not phospholipids or bile salts. The percentage of intestinal cholesterol absorption was higher in devazepide-treated mice, increasing the bioavailability of chylomicron-derived cholesterol in the liver for biliary hypersecretion into bile. These abnormalities induced supersaturated bile and rapid cholesterol crystallization. CONCLUSIONS: The potent CCK-1R antagonist devazepide increases susceptibility to gallstone formation by impairing gallbladder emptying function, disrupting biliary cholesterol metabolism and enhancing intestinal cholesterol absorption in mice.

40Oral administration of loxiglumide (CCK antagonist) inhibits postprandial gallbladder contraction without affecting gastric emptying.PubMed

E Corazziari, R Ricci, D Biliotti, et al.
Dig Dis Sci. 1990 Jan;35(1):50-4. doi: 10.1007/BF01537222.
The effect of a single oral dose of loxiglumide, a cholecystokinin antagonist, on postprandial gallbladder contraction and on gastric emptying was evaluated in humans. Following a 12-hr fasting period, two tablets of loxiglumide (400 mg each) or placebo was administered on different days, in random order and in a double-blind fashion to 10 healthy volunteers 15 min before the ingestion of a 1050-kcal standard meal. Gallbladder and antral volumes were measured by real-time ultrasonography in basal conditions and at fixed time intervals after the meal. Oral loxiglumide administration was followed by a total inhibition of the gallbladder contraction for 60 min after the end of the meal ingestion. Thereafter, up to the end of the study period, gallbladder volume was larger than that of the placebo study (at 300 min after the meal 2.7 +/- 1.6 ml after placebo and 8.2 +/- 3.5 ml after loxiglumide; P less than 0.008). No difference between placebo and loxiglumide was found in the antral volumes at any time interval (postprandial 63.5 +/- 16.5 ml after placebo and 59.4 +/- 24 ml after loxiglumide; at 300 min after the meal 20.8 +/- 13.3 ml after placebo and 18.9 +/- 9.5 ml after loxiglumide). In conclusion, a single oral dose of loxiglumide at the dose of 800 mg can inhibit postprandial gallbladder contraction without affecting gastric emptying. It would therefore appear that in man endogenous CCK, released after a solid-liquid, caloric, nutrient-balanced meal, plays a major role in the contraction of the gallbladder but does not affect gastric emptying.

41Cholelithiasis, cholecystitis, and common bile duct stones.PubMed

F J Rescorla
Curr Opin Pediatr. 1997 Jun;9(3):276-82. doi: 10.1097/00008480-199706000-00017.
Cholecystitis and cholelithiasis are being recognized with increasing frequency in infancy, childhood, and adolescence. Hematologic disorders account for a large proportion of cases; however, in most cases the etiology is uncertain. Infants and children are noted with stones in association with total parenteral nutrition, prolonged fasting, or ileal resection. Biliary dyskinesia, a disorder of impaired gallbladder contractility, is being recognized with increased frequency in late childhood and teenage years. Spontaneous stone resolution is frequently noted in infancy, and a period of observation is appropriate in the absence of symptoms. Laparoscopic cholecystectomy is the procedure of choice for symptomatic cholelithiasis and biliary dyskinesia. Common bile duct stones are unusual in children, occurring in 2% to 6% of children with cholelithiasis, often in association with obstructive jaundice and pancreatitis. Endoscopic retrograde cholangiography with stone extraction performed before or after laparoscopic cholecystectomy is the procedure of choice in this setting.

42Gallbladder motor function, plasma cholecystokinin and cholecystokinin receptor of gallbladder in cholesterol stone patients.PubMed

Jian Zhu, Tian-Quan Han, Sheng Chen, et al.
World J Gastroenterol. 2005 Mar 21;11(11):1685-9. doi: 10.3748/wjg.v11.i11.1685.
AIM: To study the interactive relationship of gallbladder motor function, plasma cholecystokinin (CCK) and cholecystokinin A receptor (CCK-R) of gallbladder in patients with cholesterol stone disease. METHODS: Gallbladder motility was studied by ultrasonography in 33 patients with gallbladder stone and 10 health subjects as controls. Plasma CCK concentration was measured by radioimmunoassay in fasting status (CCK-f) and in 30 min after lipid test meal (CCK-30). Radioligand method was employed to analyze the amount and activity of CCK-R from 33 gallstone patients having cholecystectomy and 8 persons without gallstone died of severe trauma as controls. RESULTS: The percentage of cholesterol in the gallstone composition was more than 70%. The cholesterol stone type was indicated for the patients with gallbladder stone in this study. Based on the criterion of gallbladder residual fraction of the control group, 33 gallstone patients were divided into two subgroups, contractor group (14 cases) and non-contractor group (19 cases). The concentration of CCK-30 was significantly higher in non-contractor group than that in both contractor group and control group (55.86+/-3.86 pmol/L vs 37.85+/-0.88 pmol/L and 37.95+/-0.74 pmol/L, P<0.01), but there was no difference between contractor group and control group. Meanwhile no significant difference of the concentration of CCK-f could be observed among three groups. The amount of CCK-R was lower in non-contractor group than those in both control group and contractor group (10.27+/-0.94 fmol/mg vs 24.59+/-2.39 fmol/mg and 22.66+/-0.55 fmol/mg, P<0.01). The activity of CCK-R shown as KD in non-contractor group decreased compared to that in control group and contractor group. Only was the activity of CCK-R lower in contractor group than that in control group. The ejection fraction correlated closely with the amount of CCK-R (r = 0.9683, P<0.01), and the concentration of CCK-30 correlated negatively with the amount of CCK-R closely (r = -0.9627, P<0.01). CONCLUSION: The distinctive interactive relationship of gallbladder emptying, plasma CCK and CCK-R in gallbladder from this study suggested that the defect of CCK-R may be a key point leading to the impairment of gallbladder motor function and the pathogenesis of cholesterol gallstone formation may differ in two subgroups of gallstone patient, gallbladder non-contractor group or contractor group.

43Gallbladder motility and cholecystokinin secretion during continuous enteral nutrition.PubMed

M Ledeboer, A A Masclee, I Biemond, et al.
Am J Gastroenterol. 1997 Dec;92(12):2274-9.
OBJECTIVES: During total parenteral nutrition, gallbladder motility is impaired, resulting in sludge and stone formation. Little is known about gallbladder motility during prolonged enteral nutrition. METHODS: We studied gallbladder motility during continuous enteral nutrition (CEN) in nine hospitalized patients with active inflammatory bowel disease. The patients received a polymeric diet (2000 kcal/24 h) by CEN through a nasogastric tube for a prolonged period. Gallbladder volumes were obtained daily by ultrasonography, starting from day 0 (before CEN) and on 7 consecutive days during CEN. At days 0, 1, 4, and 7, the gallbladder response to i.v. cholecystokinin (CCK-33; 0.5 Ivy Dog unit/kg/h) was studied. Plasma CCK levels were determined at regular intervals by radioimmunoassay. RESULTS: No significant differences were observed on day 0 between patients and a group of nine healthy control subjects in fasting gallbladder volumes (19.4 +/- 2.3 and 19.6 +/- 2.4 cm3, respectively) and gallbladder contraction during CCK infusion (56 +/- 14% and 69 +/- 7%, respectively). During CEN, from day 1 to day 7, mean gallbladder volume remained significantly (p < 0.05) reduced compared with fasting gallbladder volume, and mean plasma CCK levels remained significantly (p < 0.05) increased compared with fasting levels. Although gallbladder volume was significantly reduced during CEN, the gallbladder contractile response to CCK was not affected; at days 1, 4, and 7, gallbladder contraction was 36-57%. CONCLUSIONS: During CEN, 1) gallbladder volume is significantly reduced and plasma CCK levels are significantly increased, 2) these effects are sustained over time (7 days), and 3) the gallbladder remains responsive to exogenous CCK. These results indicate that gallbladder contractility and gallbladder responsiveness to CCK are preserved during prolonged CEN in patients with inflammatory bowel disease.

44Bile Acid Physiology.PubMed

Agostino Di Ciaula, Gabriella Garruti, Raquel Lunardi Baccetto, et al.
Ann Hepatol. 2017 Nov;16(Suppl. 1: s3-105.):s4-s14. doi: 10.5604/01.3001.0010.5493.
The primary bile acids (BAs) are synthetized from colesterol in the liver, conjugated to glycine or taurine to increase their solubility, secreted into bile, concentrated in the gallbladder during fasting, and expelled in the intestine in response to dietary fat, as well as bio-transformed in the colon to the secondary BAs by the gut microbiota, reabsorbed in the ileum and colon back to the liver, and minimally lost in the feces. BAs in the intestine not only regulate the digestion and absorption of cholesterol, triglycerides, and fat-soluble vitamins, but also play a key role as signaling molecules in modulating epithelial cell proliferation, gene expression, and lipid and glucose metabolism by activating farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) in the liver, intestine, muscle and brown adipose tissue. Recent studies have revealed the metabolic pathways of FXR and GPBAR-1 involved in the biosynthesis and enterohepatic circulation of BAs and their functions as signaling molecules on lipid and glucose metabolism.

45Bile acid signaling in metabolic disease and drug therapy.PubMed

Tiangang Li, John Y L Chiang
Pharmacol Rev. 2014 Oct;66(4):948-83. doi: 10.1124/pr.113.008201.
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver.

46Bile Acids as Metabolic Regulators and Nutrient Sensors.PubMed

John Y L Chiang, Jessica M Ferrell
Annu Rev Nutr. 2019 Aug 21;39:175-200. doi: 10.1146/annurev-nutr-082018-124344. Epub 2019 Apr 24.
Bile acids facilitate nutrient absorption and are endogenous ligands for nuclear receptors that regulate lipid and energy metabolism. The brain-gut-liver axis plays an essential role in maintaining overall glucose, bile acid, and immune homeostasis. Fasting and feeding transitions alter nutrient content in the gut, which influences bile acid composition and pool size. In turn, bile acid signaling controls lipid and glucose use and protection against inflammation. Altered bile acid metabolism resulting from gene mutations, high-fat diets, alcohol, or circadian disruption can contribute to cholestatic and inflammatory diseases, diabetes, and obesity. Bile acids and their derivatives are valuable therapeutic agents for treating these inflammatory metabolic diseases.

47Characterization of Human Intestinal Fluids after the Administration of a Solid Meal.PubMed

Brecht Goovaerts, Mare Oja, Sepanta Ehtemam, et al.
Mol Pharm. 2025 Oct 27. doi: 10.1021/acs.molpharmaceut.5c01002.
Most available data on the composition and solubilizing properties of postprandial human intestinal fluid (HIF) are derived from studies involving liquid meals. These data inform the development of simulated intestinal fluids, widely used in in vitro assays for predicting intestinal drug behavior. However, the typical human diet primarily consists of solid meals, and the physical form of food has been shown to influence gastrointestinal transit and digestion, thereby affecting drug disposition and bioavailability. This study compares the characteristics of fed-state HIF collected after solid meal ingestion (SM-HIF) with previously published data on pooled liquid meal-derived HIF (LM-HIF) and newly generated data from individual LM-HIF samples. Time-dependent samples were analyzed over 180- and 90 min postprandial sampling periods to assess compositional changes following the administration of a solid and liquid meal, respectively. In addition, pooled samples were used to evaluate the solubilizing capacity for seven lipophilic model compounds. After intake of the solid meal, duodenal concentrations of exogenous (lipids, cholesterol, proteins) and endogenous (bile salts, phospholipids) components gradually increased to peak levels reached after 45-75 min. After 180 min, lipid and protein concentrations were still elevated compared to fasted state levels. In comparison to the liquid meal, the ingestion of the solid meal resulted in reduced concentrations of exogenous components, while endogenous components (bile salts and phospholipids) were relatively similar. For most compounds, the reduction in lipid content led to diminished solubilizing capacity of SM-HIF compared to LM-HIF when considering the combined micellar and lipid fractions. In contrast, the solubilizing capacity of the micellar fraction as such was largely independent of the meal type. Both the composition (particularly the micellar lipid concentration) and the solubilizing capacity of SM-HIF were highly variable between pools, albeit to a lesser extent than in LM-HIF. The findings of this study highlight that the physical form of the meal influences the composition and solubilizing capacity of HIF. These insights should be taken into account when refining biorelevant media for in vitro models to better predict food effects during drug product development.

48Isolation and properties of the mixed lipid micelles present in intestinal content during fat digestion in man.PubMed

C M Mansbach, R S Cohen, P B Leff
J Clin Invest. 1975 Oct;56(4):781-91. doi: 10.1172/JCI108156.
To evaluate better the physicochemical characteristics of human fat digestion, a method was developed which allowed characterization of the bile acid-lipid mixed micelles of the aqueous phase of post-prandial duodenal fluid. Duodenal fluid was collected after a 36-g fat breakfast for two 90-min periods and for 60 min after i.v. cholecystokinin and was ultracentrifuged at 15,400,000 g-min. The aqueous phase was isolated, passed through a 200-nm filter, and the mixed micelles were concentrated by an ultrafiltration procedure using a 1.5-nm filter. The 1.5-nm retentate was eluted from Sepharose 6B columns with 1.5-nm filtrate for both preequilibration fluid and eluent. 1.5-nm filtrate approximated the monomer concentrations. Each sample was assayed for bile acid, fatty acid, lecithin, lysolecithin, protein, cholesterol, and counterions (pH, Na+, K+, Ca2+). Constituents were concentrated only on the 1.5-nm filter. On gel permeation chromatography, coincident peaks were observed for bile acid, fatty acid, lysolecithin, and cholesterol; and were eluted with a Kav range of 0.50-0.68 (corresponding to a Stokes radius of 2.3-3.5 nm). An average density of 1.25 and coincident peaks of bile acid and fatty acid were found for the mixed micelles on sucrose density gradients. The regression lines of micellar fatty acid, lysolecithin, and cholesterol vs. bile acid gave a stoichiometry of 1.4 mol fatty acid, 0.15 mol lysolecithin, and 0.06 mol cholesterol for each mole of bile acid. Mixed micelles were homogeneous in composition. These results provide direct evidence for the existence of the postprandial mixed micelle and describe several of its physicochemical properties.

49Effect of the type of dietary fat on biliary lipid composition and bile lithogenicity in humans with cholesterol gallstone disease.PubMed

María Dolores Yago, Victoria González, Pilar Serrano, et al.
Nutrition. 2005 Mar;21(3):339-47. doi: 10.1016/j.nut.2004.06.028.
OBJECTIVE: The effect of the type of dietary fat on bile lipids and lithogenicity is unclear. This study compared the effects of two dietary oils that differed in fatty acid profile on biliary lipid composition in humans. METHODS: Female patients who had cholesterol gallstones and were scheduled for elective cholecystectomy were studied. For 30 d before surgery, subjects were kept on diets that contained olive oil (olive oil group, n = 9) or sunflower oil (sunflower oil group, n = 9) as the main source of fat. Gallbladder bile and stones were sampled at surgery. After cholecystectomy, duodenal samples were collected by nasoduodenal intubation during fasting and after administration of mixed liquid meals that included the corresponding dietary oil. Duodenal and gallbladder bile samples were analyzed for cholesterol, phospholipids, and total bile acids by established methods. Individual bile acid conjugates in gallbladder bile were measured by high-performance liquid chromatography. Gallstones were analyzed by semiquantitative polarizing light microscopy. RESULTS: Despite marked differences in the absolute concentration of biliary lipids and total lipid content, manipulation of dietary fat ingestion did not influence the cholesterol saturation or the profile of individual bile acids in gallbladder bile obtained from patients who had gallstones. All but one subject had mixed cholesterol stones. A cholesterol saturation index of hepatic bile in fasted cholecystectomized patients was similar in both dietary groups and indicative of supersaturation. In response to the test meal, the cholesterol saturation index decreased significantly in patients given the olive oil diet, reaching values lower than one at 120 min postprandially. In contrast, hepatic bile secreted by patients who consumed sunflower oil appeared supersaturated (cholesterol saturation index >1.5) throughout the experiment. CONCLUSIONS: Our results suggest that the type of dietary fat habitually consumed can influence bile composition in humans. In gallbladder, this influence was noted in the presence of more concentrated bile in the olive oil group. However, this was not translated into a modification of cholesterol saturation, which is likely due to the fact that cholesterol gallstones were present by the time the dietary intervention started. The finding that a typical postprandial variation in hepatic bile lithogenicity occurred only in olive oil patients was revealing. While keeping in mind the methodologic limitations of this part of the study, some gastrointestinal and metabolic mechanisms for this effect are discussed.

50Bile acid metabolism and circadian rhythms.PubMed

Yunxia Yang, Jianfa Zhang
Am J Physiol Gastrointest Liver Physiol. 2020 Nov 1;319(5):G549-G563. doi: 10.1152/ajpgi.00152.2020. Epub 2020 Sep 9.
Circadian rhythms are biological systems that synchronize cellular circadian oscillators with the organism's daily feeding-fasting or rest-activity cycles in mammals. Circadian rhythms regulate nutrient absorption and utilization at the cellular level and are closely related to obesity and metabolic disorders. Bile acids are important modulators that facilitate nutrient absorption and regulate energy metabolism. Here, we provide an overview of the current connections and future perspectives between the circadian clock and bile acid metabolism as well as related metabolic diseases. Feeding and fasting cycles influence bile acid pool size and composition, and bile acid signaling can respond to acute lipid and glucose utilization and mediate energy balance. Disruption of circadian rhythms such as shift work, irregular diet, and gene mutations can contribute to altered bile acid metabolism and heighten obesity risk. High-fat diets, alcohol, and gene mutations related to bile acid signaling result in desynchronized circadian rhythms. Gut microbiome also plays a role in connecting circadian rhythms with bile acid metabolism. The underlying mechanism of how circadian rhythms interact with bile acid metabolism has not been fully explored. Sustaining bile acid homeostasis based on circadian rhythms may be a potential therapy to alleviate metabolic disturbance.

51Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion.PubMed

Hai Hu, Wentao Shao, Qian Liu, et al.
Nat Commun. 2022 Jan 11;13(1):252. doi: 10.1038/s41467-021-27758-8.
Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, HS increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.

52Chrononutrition in type 2 diabetes mellitus and obesity: A narrative review.PubMed

Ludovica Verde, Tonia Di Lorenzo, Silvia Savastano, et al.
Diabetes Metab Res Rev. 2024 Feb;40(2):e3778. doi: 10.1002/dmrr.3778.
Chrononutrition is a nutritional regimen that follows our biological clock, marked by the changes in metabolism that occur during the day. This regimen includes the distribution of energy, the regularity and frequency of meals, and the importance of these factors for metabolic health. A growing body of animal and human evidence indicates that the timing of food intake throughout the day can have a significant and beneficial impact on the metabolic health and well-being of individuals. In particular, both the timing and frequency of meals have been associated with obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease, and other chronic conditions. Today's busy lifestyle makes many people skip breakfast and eat late at night. Eating late at night has been shown to cause a circadian misalignment, with the latter having a negative impact on weight control and glucose metabolism. Additionally, some studies have found a relatively strong association between skipping breakfast and insulin resistance, and T2DM. Against the backdrop of escalating obesity and T2DM rates, coupled with the recognized influence of food timing on disease evolution and control, this review aimed to synthesize insights from epidemiological and intervention studies of the interplay of timing of food intake and macronutrient consumption, reporting their impact on obesity and T2DM.

53Association of Skipping Breakfast with Metabolic Syndrome and Its Components: A Systematic Review and Meta-Analysis of Observational Studies.PubMed

Bowen Yang, Linxi Lian, Kaijun Xing, et al.
Nutrients. 2025 Oct 3;17(19):3155. doi: 10.3390/nu17193155.
Metabolic syndrome (MetS) represents a growing and significant public health burden worldwide. The evidence regarding whether skipping breakfast affects the development of MetS and its components remains inconsistent and uncertain. This study aimed to synthesize the best available evidence regarding the association between skipping breakfast and the risk of MetS and its components. This systematic review and meta-analysis was conducted in accordance with the PRISMA 2020 guidelines. We systematically searched the PubMed, Embase, Cochrane Library, and Web of Science databases from inception until May 2025. Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed the risk of bias. This review included cross-sectional and cohort studies on the association between breakfast skipping and the risk of MetS and its components. Nine studies were included after quality evaluation by NOS. Pooled results from the meta-analysis revealed that skipping breakfast was significantly associated with an increased risk of MetS (OR: 1.10, 95% CI: 1.04-1.17) and its components-namely abdominal obesity (OR = 1.17, 95% CI 1.01-1.34), hypertension (OR: 1.21, 95% CI: 1.10-1.32), hyperlipidemia (OR: 1.13, 95% CI: 1.04-1.23), and hyperglycemia (OR = 1.26, 95% CI: 1.16-1.37). The meta-analysis demonstrated that skipping breakfast was significantly associated with an increased risk of MetS and its key components-abdominal obesity, hypertension, hyperlipidemia, and hyperglycemia. These findings highlight regular breakfast consumption as a potential modifiable factor for preventing and managing MetS and related cardiometabolic diseases.

54The Prevalence of Insulin Resistance and the Associated Risk Factors in a Sample of 14-18-Year-Old Slovak Adolescents.PubMed

Jana Jurkovičová, Katarína Hirošová, Diana Vondrová, et al.
Int J Environ Res Public Health. 2021 Jan 21;18(3):909. doi: 10.3390/ijerph18030909.
The prevalence of cardiometabolic risk factors has increased in Slovakian adolescents as a result of serious lifestyle changes. This cross-sectional study aimed to assess the prevalence of insulin resistance (IR) and the associations with cardiometabolic and selected lifestyle risk factors in a sample of Slovak adolescents. In total, 2629 adolescents (45.8% males) aged between 14 and 18 years were examined in the study. Anthropometric parameters, blood pressure (BP), and resting heart rate were measured; fasting venous blood samples were analyzed; and homeostasis model assessment (HOMA)-insulin resistance (IR) was calculated. For statistical data processing, the methods of descriptive and analytical statistics for normal and skewed distribution of variables were used. The mean HOMA-IR was 2.45 ± 1.91, without a significant sex differences. IR (cut-off point for HOMA-IR = 3.16) was detected in 18.6% of adolescents (19.8% males, 17.6% females). IR was strongly associated with overweight/obesity (especially central) and with almost all monitored cardiometabolic factors, except for total cholesterol (TC) and systolic BP in females. The multivariate model selected variables such as low level of physical fitness, insufficient physical activity, breakfast skipping, a small number of daily meals, frequent consumption of sweetened beverages, and low educational level of fathers as significant risk factors of IR in adolescents. Recognizing the main lifestyle risk factors and early IR identification is important in terms of the performance of preventive strategies. Weight reduction, regular physical activity, and healthy eating habits can improve insulin sensitivity and decrease the incidence of metabolic syndrome, type 2 diabetes, and cardiovascular disease (CVD).

55Breakfast Consumption and Its Association with Insulin Resistance in a Large-Scale Cohort of Children and Adolescents with Overweight/Obesity in Greece.PubMed

Odysseas Androutsos, Maria Manou, Ioanna Panagiota Kalafati, et al.
Nutrients. 2025 Nov 1;17(21):3457. doi: 10.3390/nu17213457.
Breakfast skipping has been proposed as a determinant of childhood obesity and disorders of glucose metabolism. The present study aimed to examine the association between breakfast skipping and insulin resistance in children and adolescents with overweight or obesity. In total, 1291 children aged 2-18 years old (boys = 48.4%, boys with obesity = 69.8%; girls = 51.6%, girls with obesity = 60.8%) participated in the study, providing sociodemographic, anthropometric, lifestyle, biochemical, and clinical data. Breakfast consumption was assessed using a validated questionnaire. The IOTF criteria were used to categorize children's body mass index (BMI) status, while the homeostasis model assessment (HOMA-IR) was used to assess insulin resistance. According to the findings of this study, 37.3% of the children/adolescents were found to skip daily breakfast consumption. Girls tended to skip breakfast more than boys (40.5% vs. 33.9%, = 0.016), with the percentage of girls skipping breakfast increasing in the older age groups (2-5 yrs: 27% vs. 6-12 yrs: 39.1% vs. 13-18 yrs: 53.5%, = 0.001). Linear regression analyses showed that breakfast skipping is associated with HOMA-IR in the total sample and in children and adolescents with obesity, after adjusting for several confounding factors (age, gender, Tanner stage, residency, and sports participation). A large number of children and adolescents with overweight or obesity, especially adolescent girls, skip daily breakfast consumption, which was associated with insulin resistance. These findings underscore the importance of promoting regular breakfast consumption as a preventive strategy against metabolic complications in children and adolescents with overweight or obesity.

56Triglycerides and gallstone formation.PubMed

A H M Smelt
Clin Chim Acta. 2010 Nov 11;411(21-22):1625-31. doi: 10.1016/j.cca.2010.08.003. Epub 2010 Aug 10.
Changes in bile acid (BA) metabolism and gallbladder function are critical factors in the pathogenesis of gallstones. Patients with hypertriglyceridemia (HTG) - often overweight and insulin resistant - are at risk for gallstone disease. The question arises whether HTG itself contributes to gallstone formation or whether gallstone disease only associates with this disorder. Triglycerides are formed in response to fluxes of non-esterified fatty acids and glucose. Hypertriglyceridemia results from either overproduction of triglycerides by the liver, impaired lipolysis or a combination of both. Hyperinsulinemia, as observed in the insulin resistant state, stimulates very low-density lipoprotein (VLDL)-triglyceride synthesis. Peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) are the nuclear receptors involved in the regulation of lipogenesis. Microsomal triglyceride transfer protein (MTP) is involved in the production of VLDL and its activation is also under control of transcription factors as FXR and Forkhead box-O1 (FoxO1). Triglyceride and BA metabolism are linked. There is an inverse relationship between bile acid fluxes and pool size and VLDL production and SHP (small heterodimer partner) and FXR are the link between BAs and TG metabolism. BAs are also ligands for FXR and G-protein-coupled receptors, such as TGR5. FXR activation by BAs suppresses the expression of MTP, transcription factor sterol regulatory element binding protein (SREBP)-1c and other lipogenic genes. LXRs stimulate lipogenesis whereas FXRs inhibit the metabolic process. Synthesis of BAs from cholesterol occurs either via the classical pathway (7α-hydroxylation of cholesterol; CYP7A1) or via the alternate pathway (CYP39A1 or CYP7B1). BAs induce FXR, which inhibits CYP7A1 transcription by activation of SHP and inhibition of HNF4α transactivation. Bile composition (supersaturation with cholesterol), gallbladder dysmotility, inflammation, hypersecretion of mucin gel in the gallbladder and slow large intestinal motility and increased intestinal cholesterol absorption may contribute to the pathogenesis of cholesterol gallstones. In HTG patients supersaturated bile may be related to the presence of obesity rather than to HTG itself. Contraction and relaxation of the gallbladder are regulated by neuronal, hormonal and paracrine factors. Postprandial gallbladder emptying is regulated by cholecystokinin (CCK). Poor postprandial gallbladder contraction may be due to the magnitude of the CCK response and to the amount of CCK receptors in the gallbladder smooth muscle cells. In the fasting state gallbladder motility is associated with the intestinal migrating motor complex (MMC) activity and with elevated plasma motilin levels. Fibroblast growth factor (FGF19), produced on arrival of bile acids in the ileum, is also important for gallbladder motility. Gallbladder motility is impaired in HTG patients compared to BMI matched controls. There is evidence that the gallbladder in HTG is less sensitive to CCK and that this sensitivity improves after reversal of high serum TG levels by use of TG lowering agents. In hypertriglyceridemia TG lowering therapy (fibrates or fish-oil) is essential to prevent cardiovascular disease and pancreatitis. Fibrates, however, also increase the risk for cholelithiasis by increasing biliary cholesterol saturation and by reduction of bile acid synthesis. On the other hand fish-oil decreases biliary cholesterol saturation. Fish-oil may increase bile acid synthesis by activation of 7alpha-hydroxylase and may inhibit VLDL production and secretion through activation of nuclear factors and increased apoB degradation. In HTG patients, gallbladder motility improves during bezafibrate as well as during fish-oil therapy. The question remains whether improvement of gallbladder motility and increased lithogenicity of bile by bezafibrate therapy counteract each other or still result in gallstone formation in HTG patients.

57Metabolic syndrome and gallstone disease.PubMed

Li-Ying Chen, Qiao-Hua Qiao, Shan-Chun Zhang, et al.
World J Gastroenterol. 2012 Aug 21;18(31):4215-20. doi: 10.3748/wjg.v18.i31.4215.
AIM: To investigate the association between metabolic syndrome (MetS) and the development of gallstone disease (GSD). METHODS: A cross-sectional study was conducted in 7570 subjects (4978 men aged 45.0 ± 8.8 years, and 2592 women aged 45.3 ± 9.5 years) enrolled from the physical check-up center of the hospital. The subjects included 918 patients with gallstones (653 men and 265 women) and 6652 healthy controls (4325 men and 2327 women) without gallstones. Body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG) and serum lipids and lipoproteins levels were measured. Colorimetric method was used to measure cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Dextrose oxidizing enzyme method was used to measure FPG. Subjects were asked to complete a questionnaire that enquired about the information on demographic data, age, gender, histories of diabetes mellitus, hypertension, and chronic liver disease and so on. Metabolic syndrome was diagnosed according to the Adult Treatment Panel III (ATP III) criteria. Gallstones were defined by the presence of strong intraluminal echoes that were gravity-dependent or attenuated ultrasound transmission. RESULTS: Among the 7570 subjects, the prevalence of the gallstone disease was 12.1% (13.1% in men and 10.2% in women). BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose and serum triglyceride (TG) in cases group were higher than in controls, while serum high-density lipid was lower than in controls. There were significant differences in the waist circumference, blood pressure, FPG and TG between cases and controls. In an age-adjusted logistic regression model, metabolic syndrome was associated with gallstone disease. The age-adjusted odds ratio of MetS for GSD in men was 1.29 [95% confidence interval (CI), 1.09-1.52; P = 0.0030], and 1.68 (95% CI, 1.26-2.25; P = 0.0004) in women; the overall age-adjusted odds ratio of MetS for GSD was 1.42 (95% CI, 1.23-1.64; P < 0.0001). The men with more metabolic disorders had a higher prevalence of gallstone disease, the trend had statistical significance (P < 0.0001). The presence of 5 components of the MetS increased the risk of gallstone disease by 3.4 times (P < 0.0001). The prevalence of GSD in women who had 5 components of MetS was 5 times higher than in those without MetS component. The more the components of MetS, the higher the prevalence of GSD (P < 0.0001). The presence of 5 components of the MetS increased the risk of gallstone disease by 4.0 times. CONCLUSION: GSD appears to be strongly associated with MetS, and the more the components of MetS, the higher the prevalence of GSD.

58Cholecystectomy and risk of metabolic syndrome.PubMed

Agostino Di Ciaula, Gabriella Garruti, David Q-H Wang, et al.
Eur J Intern Med. 2018 Jul;53:3-11. doi: 10.1016/j.ejim.2018.04.019. Epub 2018 Apr 26.
The gallbladder physiologically concentrates and stores bile during fasting and provides rhythmic bile secretion both during fasting and in the postprandial phase to solubilize dietary lipids and fat-soluble vitamins. Bile acids (BAs), major lipid components of bile, play a key role as signaling molecules in modulating gene expression related to cholesterol, BA, glucose and energy metabolism. Cholecystectomy is the most commonly performed surgical procedure worldwide in patients who develop symptoms and/or complications of cholelithiasis of any type. Cholecystectomy per se, however, might cause abnormal metabolic consequences, i.e., alterations in glucose, insulin (and insulin-resistance), lipid and lipoprotein levels, liver steatosis and the metabolic syndrome. Mechanisms are likely mediated by the abnormal transintestinal flow of BAs, producing metabolic signaling that acts without gallbladder rhythmic function and involves the BAs/farnesoid X receptor (FXR) and the BA/G protein-coupled BA receptor 1 (GPBAR-1) axes in the liver, intestine, brown adipose tissue and muscle. Alterations of intestinal microbiota leading to distorted homeostatic processes are also possible. According to this view, cholecystectomy, via BA-induced changes in the enterohepatic circulation, is a risk factor for the metabolic abnormalities and becomes another “fellow traveler” with, or another risk factor for the metabolic syndrome.

59Glutaredoxin 1 regulates cholesterol metabolism and gallstone formation by influencing protein S-glutathionylation.PubMed

Yan Xia, Ying Xu, Qinhui Liu, et al.
Metabolism. 2023 Aug;145:155610. doi: 10.1016/j.metabol.2023.155610. Epub 2023 Jun 3.
OBJECTIVE: Cholesterol gallstone disease (CGD) is closely related to cholesterol metabolic disorder. Glutaredoxin-1 (Glrx1) and Glrx1-related protein S-glutathionylation are increasingly being observed to drive various physiological and pathological processes, especially in metabolic diseases such as diabetes, obesity and fatty liver. However, Glrx1 has been minimally explored in cholesterol metabolism and gallstone disease. METHODS: We first investigated whether Glrx1 plays a role in gallstone formation in lithogenic diet-fed mice using immunoblotting and quantitative real-time PCR. Then a whole-body Glrx1-deficient (Glrx1) mice and hepatic-specific Glrx1-overexpressing (AAV8-TBG-Glrx1) mice were generated, in which we analyzed the effects of Glrx1 on lipid metabolism upon LGD feeding. Quantitative proteomic analysis and immunoprecipitation (IP) of glutathionylated proteins were performed. RESULTS: We found that protein S-glutathionylation was markedly decreased and the deglutathionylating enzyme Glrx1 was greatly increased in the liver of lithogenic diet-fed mice. Glrx1 mice were protected from gallstone disease induced by a lithogenic diet because their biliary cholesterol and cholesterol saturation index (CSI) were reduced. Conversely, AAV8-TBG-Glrx1 mice showed greater gallstone progression with increased cholesterol secretion and CSI. Further studies showed that Glrx1-overexpressing greatly altered bile acid levels and/or composition to increase intestinal cholesterol absorption by upregulating Cyp8b1. In addition, liquid chromatography-mass spectrometry and IP analysis revealed that Glrx1 also affected the function of asialoglycoprotein receptor 1 (ASGR1) by mediating its deglutathionylation, thereby altering the expression of LXRα and controlling cholesterol secretion. CONCLUSION: Our findings present novel roles of Glrx1 and Glrx1-regulated protein S-glutathionylation in gallstone formation through the targeting of cholesterol metabolism. Our data advises Glrx1 significantly increased gallstone formation by simultaneously increase bile-acid-dependent cholesterol absorption and ASGR1- LXRα-dependent cholesterol efflux. Our work suggests the potential effects of inhibiting Glrx1 activity to treat cholelithiasis.

60You Are What You Eat-The Relationship between Diet, Microbiota, and Metabolic Disorders-A Review.PubMed

Małgorzata Moszak, Monika Szulińska, Paweł Bogdański
Nutrients. 2020 Apr 15;12(4):1096. doi: 10.3390/nu12041096.
The gut microbiota (GM) is defined as the community of microorganisms (bacteria, archaea, fungi, viruses) colonizing the gastrointestinal tract. GM regulates various metabolic pathways in the host, including those involved in energy homeostasis, glucose and lipid metabolism, and bile acid metabolism. The relationship between alterations in intestinal microbiota and diseases associated with civilization is well documented. GM dysbiosis is involved in the pathogenesis of diverse diseases, such as metabolic syndrome, cardiovascular diseases, celiac disease, inflammatory bowel disease, and neurological disorders. Multiple factors modulate the composition of the microbiota and how it physically functions, but one of the major factors triggering GM establishment is diet. In this paper, we reviewed the current knowledge about the relationship between nutrition, gut microbiota, and host metabolic status. We described how macronutrients (proteins, carbohydrates, fat) and different dietary patterns (e.g., Western-style diet, vegetarian diet, Mediterranean diet) interact with the composition and activity of GM, and how gut bacterial dysbiosis has an influence on metabolic disorders, such as obesity, type 2 diabetes, and hyperlipidemia.

61Dietary Patterns and Gut Microbiota: The Crucial Actors in Inflammatory Bowel Disease.PubMed

Pandi He, Leilei Yu, Fengwei Tian, et al.
Adv Nutr. 2022 Oct 2;13(5):1628-1651. doi: 10.1093/advances/nmac029.
It is widely believed that diet and the gut microbiota are strongly related to the occurrence and progression of inflammatory bowel disease (IBD), but the effects of the interaction between dietary patterns and the gut microbiota on IBD have not been well elucidated. In this article, we aim to explore the complex relation between dietary patterns, gut microbiota, and IBD. We first comprehensively summarized the dietary patterns associated with IBD and found that dietary patterns can modulate the occurrence and progression of IBD through various signaling pathways, including mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs), signal transducer and activator of transcription 3 (STAT3), and NF-κB. Besides, the gut microbiota performs a vital role in the progression of IBD, which can affect the expression of IBD susceptibility genes, such as dual oxidase 2 (DUOX2) and APOA-1 , the intestinal barrier (in particular, the expression of tight junction proteins), immune function (especially the homeostasis between effector and regulatory T cells) and the physiological metabolism, in particular, SCFAs, bile acids (BAs), and tryptophan metabolism. Finally, we reviewed the current knowledge on the interaction between dietary patterns and the gut microbiota in IBD and found that dietary patterns modulate the onset and progression of IBD, which is partly attributed to the regulation of the gut microbiota (especially SCFAs-producing bacteria and Escherichia coli). Faecalibacteria as "microbiomarkers" of IBD could be used as a target for dietary interventions to alleviate IBD. A comprehensive understanding of the interplay between dietary intake, gut microbiota, and IBD will facilitate the development of personalized dietary strategies based on the regulation of the gut microbiota in IBD and expedite the era of precision nutritional interventions for IBD.

62Associations between Dietary Patterns and Bile Acids-Results from a Cross-Sectional Study in Vegans and Omnivores.PubMed

Iris Trefflich, Hanns-Ulrich Marschall, Romina di Giuseppe, et al.
Nutrients. 2019 Dec 23;12(1):47. doi: 10.3390/nu12010047.
Bile acids play an active role in fat metabolism and, in high-fat diets, elevated concentrations of fecal bile acids may be related to an increased risk of colorectal cancer. This study investigated concentrations of fecal and serum bile acids in 36 vegans and 36 omnivores. The reduced rank regression was used to identify dietary patterns associated with fecal bile acids. Dietary patterns were derived with secondary and conjugated fecal bile acids as response variables and 53 food groups as predictors. Vegans had higher fiber ( < 0.01) and lower fat ( = 0.0024) intake than omnivores. In serum, primary and glycine-conjugated bile acids were higher in vegans than in omnivores ( ≤ 0.01). All fecal bile acids were significantly lower in vegans compared to omnivores ( < 0.01). Processed meat, fried potatoes, fish, margarine, and coffee contributed most positively, whereas muesli most negatively to a dietary pattern that was directly associated with all fecal bile acids. According to the pattern, fat intake was positively and fiber intake was inversely correlated with bile acids. The findings contribute to the evidence that, in particular, animal products and fat may play a part in higher levels of fecal bile acids.

63The Role of Diet in the Pathogenesis of Cholesterol Gallstones.PubMed

Agostino Di Ciaula, Gabriella Garruti, Gema Frühbeck, et al.
Curr Med Chem. 2019;26(19):3620-3638. doi: 10.2174/0929867324666170530080636.
Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.

64Ursodeoxycholic acid for the prevention of gallstones and subsequent cholecystectomy after bariatric surgery: a meta-analysis of randomized controlled trials.PubMed

Andrea Mulliri, Benjamin Menahem, Arnaud Alves, et al.
J Gastroenterol. 2022 Aug;57(8):529-539. doi: 10.1007/s00535-022-01886-4. Epub 2022 Jun 15.
BACKGROUND: This meta-analysis aimed to compare the incidence of gallstone formation, subsequent biliary disease and the need for cholecystectomy in untreated patients and patients treated with ursodeoxycholic acid (UDCA) following bariatric surgery. METHODS: Randomized controlled trials (RCTs) comparing UDCA and controls for the prevention of gallstone formation after bariatric surgery published until February 2022 were selected and subjected to a systematic review and meta-analysis. Articles were searched in the MEDLINE, Web of Science and Cochrane Trials Register databases. Meta-analysis was performed with Review Manager 5.0. RESULTS: Eleven randomized controlled studies were included, with a total of 2363 randomized patients and 2217 patients analysed in the UDCA group versus 1415 randomized patients and 1257 patients analysed in the control group. Considering analysed patients, prophylactic use of UDCA was significantly associated with decreased (i) gallstone formation (OR = 0.25, 95% CI = 0.21-0.31), (ii) symptomatic gallstone disease (GD) (OR = 0.29, 95% CI = 0.20-0.42) and consequently (iii) cholecystectomy rate (OR = 0.33, 95% CI = 0.20-0.55). The results were similar in ITT analysis, in the subgroup of patients undergoing sleeve gastrectomy or considering only randomized versus placebo studies. CONCLUSIONS: Prophylactic use of UDCA after bariatric surgery prevents both gallstone formation and symptomatic GD and reduces the need for cholecystectomy.

65Role of Ursodeoxycholic Acid in the Prevention of Gallstones Formation in Bariatric Patients-a Systematic Review and Meta-Analysis of Randomised Trials.PubMed

Amit Sharma, Hiba Shanti, Haritharan Nageswaran, et al.
Obes Surg. 2023 Dec;33(12):4115-4124. doi: 10.1007/s11695-023-06893-9. Epub 2023 Oct 23.
The aim of this meta-analysis was to assess whether treatment with ursodeoxycholic acid (UDCA) in patients who have undergone bariatric surgery reduces gallstone formation. A systematic literature search was performed using electronic databases (MEDLINE, Embase, CENTRAL, Web of Science, PROSPERO, Google Scholar and the WHO International Clinical Trials Registry platform). RCTs without restrictions on study language, year, status of publication and patient's age were used. Pooled risk ratios were calculated using a random-effects model. Subgroup analyses for drug dose, duration and procedure types were performed. Sensitivity analyses and a summary of findings table were generated to assess the robustness and the level of evidence provided, respectively. Fourteen trials were included (3619 patients, 2292 in UDCA vs 1327 in control group). Procedures included SG, RYGB, OAGB, AGB and Gastroplasty. UDCA dose ranged from 300 to 1200 mg per day. Gallstone formation occurred in 19.3% (8.3% in UDCA vs 38.1% in the control group). UDCA significantly reduced the risk of gallstone formation (14 trials, 3619 patients; RR 0.27, 95% CI 0.18-0.41; P < 0.001). UDCA significantly reduced the risk of symptomatic gallstone disease (6 trials, 2458 patients; RR 0.30, 95% CI 0.21-0.43; P < 0.001). No subgroup difference was found for different doses, duration and type of procedure performed. Oral UDCA treatment significantly reduces the risks of developing gallstones in postoperative bariatric patients from 38 to 8%. The use of 500 to 600 mg UDCA for 6 months is effective and should be implemented in all patients post-bariatric surgery.