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肠道菌群与代谢健康近五年有哪些值得做医学科普或产品研究的选题？请整理6个方向，覆盖肥胖、糖尿病、脂肪肝、饮食干预、益生菌或后生元，并说明证据成熟度和不宜夸大的边界。要求有引用。
在过去的五年中，肠道菌群与代谢健康领域涌现出许多值得医学科普和产品研究的选题。以下将从肥胖、糖尿病、脂肪肝、饮食干预以及益生菌/后生元这几个方面，整理出6个主要方向，并说明其证据成熟度和科普/产品推广时应注意的边界。
1. 肠道菌群在肥胖发生发展中的作用及干预策略
选题方向： 探索肠道菌群失调如何通过影响能量代谢、食欲调节和炎症反应，从而促进肥胖的发生发展，并研究通过调节肠道菌群实现体重管理和预防肥胖的策略。
具体内容： 肥胖是全球性的主要健康问题，与多种生理和精神疾病相关，包括糖尿病和中风。肠道菌群被证实与多种器官相互作用，包括大脑。肠道菌群及其代谢产物可以通过迷走神经刺激直接或通过免疫-神经内分泌机制间接作用于大脑，从而调节代谢、脂肪堆积、体内平衡、能量平衡以及中枢食欲和食物奖励信号，这些都在肥胖中起着关键作用。肠道-大脑轴（GBA）是肠道菌群与大脑之间的双向连接，通过代谢、内分泌、神经和免疫系统机制影响生理功能和行为，其在肥胖的病理生理学中发挥作用。肠道微生物群的几种改变可以通过调节宿主的代谢途径和饮食行为，导致肥胖。例如，肥胖患者的肠道菌群失调与胰岛素抵抗、慢性炎症和脂肪积累增加有关。
在预测体重减轻和反弹方面，多组学和表型数据，尤其是基线肠道微生物和粪便代谢产物，如N-乙酰-L-天冬氨酸、瘤胃球菌（Ruminococcus callidus）和青春双歧杆菌（Bifidobacterium adolescentis），被证明是有效的预测因子，这为个性化体重管理提供了见解。
证据成熟度： 较高。大量研究已证实肠道菌群与肥胖的密切关联，并通过动物模型和人体研究揭示了多种潜在机制。关于个性化预测和干预的研究正在深入。
不宜夸大的边界：
- 虽然肠道菌群在肥胖中扮演重要角色，但它并非导致肥胖的唯一因素。遗传、生活方式、饮食习惯、社会经济因素等也至关重要。
- 肠道菌群干预（如益生菌、益生元）的效果可能因个体差异而异，并且需要结合全面的饮食和生活方式改变才能达到最佳效果。不应宣传单一菌群干预能“治愈”肥胖。
- 尽管一些研究显示了益生菌和后生元在改善肠道健康和荷尔蒙调节方面的作用，但对体重和体脂的直接影响仍在研究中，不应过度承诺立竿见影的减肥效果。
2. 肠道菌群与糖尿病（特别是2型糖尿病和胰岛素抵抗）的相互作用及干预方案
选题方向： 探讨肠道菌群失调如何影响葡萄糖耐受和胰岛素抵抗，进而导致2型糖尿病的发生发展，并研究通过饮食、益生菌、益生元等手段调节肠道菌群，以改善血糖控制和预防糖尿病并发症。
具体内容： 肠道菌群已被证实与肥胖、代谢综合征以及2型糖尿病的发生发展有关，主要表现为葡萄糖耐受下降和胰岛素抵抗。墨西哥的肥胖和糖尿病高发与生活方式、遗传易感性以及肠道微生物组成改变有关。肠道微生物在代谢调节中发挥重要作用，其失调与胰岛素抵抗、慢性炎症和脂肪积累增加相关。在2型糖尿病及其并发症（如糖尿病肾病、糖尿病视网膜病变、糖尿病神经病变、脑血管疾病、冠心病和外周动脉疾病）患者中，观察到与健康对照组相比，肠道菌群组成存在差异。肠道菌群失调的严重程度与疾病严重程度相关，而动物模型和患者中的益生菌干预已被证实能改善症状和疾病进展。
一些膳食干预措施也显示出对胰岛素抵抗的益处。例如，坚果中的纤维和多酚可能通过改变肠道菌群来发挥抗糖尿病作用。一种含有菊粉、β-葡聚糖、蓝莓花青素和蓝莓多酚的胃肠道微生物调节剂（GIMM）在超重或肥胖个体中被证实能改善血糖耐受并增加饱腹感。多囊卵巢综合征（PCOS）是一种常见的内分泌疾病，其特征是胰岛素抵抗和荷尔蒙失衡。近期研究表明，益生菌和合生制剂通过调节肠道微生物群，可以改善PCOS女性的胰岛素抵抗和荷尔蒙参数，如降低HOMA-IR、空腹血糖和胰岛素，并改善血脂谱和荷尔蒙平衡（增加SHBG，降低总睾酮）。合生制剂的效果比单独使用益生菌或益生元更显著。
证据成熟度： 较高。肠道菌群与2型糖尿病和胰岛素抵抗的关系已得到广泛研究，并有动物模型和人体临床试验支持。特定干预措施的有效性正在累积证据。
不宜夸大的边界：
- 肠道菌群的调节是糖尿病管理的一个有前景的辅助策略，但不能替代传统的药物治疗和医生指导下的生活方式干预。
- 益生菌或益生元的具体效果可能因菌株、剂量、个体生理状态和原有菌群组成而异。不应宣传其为糖尿病的“治愈”方法。
- 非营养性甜味剂（NNSs）如糖精和三氯蔗糖被广泛用作糖替代品，但新兴证据表明，即使低剂量的NNSs也可能通过改变肠道微生物群，对代谢健康产生不利影响，损害血糖调节。因此，在推荐此类产品时需谨慎，并等待更多研究结果。
3. 肠道菌群与脂肪肝（MASLD/MASH）的关系及肝肠轴干预
选题方向： 阐明肠道菌群失调如何通过肝肠轴影响肝脏脂质代谢、炎症和氧化应激，从而促进代谢功能障碍相关脂肪性肝病（MASLD）及代谢功能障碍相关脂肪性肝炎（MASH）的发生发展，并开发靶向肝肠轴的治疗策略。
具体内容： 代谢功能障碍相关脂肪性肝病（MASLD），以前称为非酒精性脂肪肝病（NAFLD），在全球范围内受到广泛关注，其患病率不断上升，通常伴随肥胖并与代谢综合征密切相关。肝脏脂质积累通常会引发脂毒性，并通过介导内质网应激、氧化应激、细胞器功能障碍和铁死亡，导致MASLD或进展为代谢功能障碍相关脂肪性肝炎（MASH）。
近年来，肠道微生物失调在MASLD发展中的作用受到极大关注，这为MASLD提供了新的治疗靶点。肝脏作为代谢中心，整合来自胃肠道和脂肪组织的信号，调节碳水化合物、脂质和氨基酸代谢。肠道来源的代谢产物（如乙酸盐和乙醇）和白色脂肪组织中的非酯化脂肪酸会影响肝脏过程，而这些过程依赖于线粒体功能来维持全身能量平衡。肥胖、胰岛素抵抗和2型糖尿病引起的代谢失调会破坏这些途径，导致MASLD和MASH。
胆汁酸，特别是肠道微生物修饰的胆汁酸（如猪去氧胆酸，HDCA），在NAFLD的发生发展中发挥重要作用。研究表明，HDCA水平与NAFLD的存在和严重程度呈负相关。HDCA治疗通过抑制肠道法尼醇X受体（FXR）和上调肝脏CYP7B1，在多种小鼠模型中减轻了NAFLD。此外，HDCA显著增加了益生菌物种如Parabacteroides distasonis的丰度，这些益生菌通过脂肪酸-肝脏过氧化物酶体增殖物激活受体α（PPARα）信号传导增强脂质分解代谢，进而上调肝脏FXR。这些发现表明HDCA通过同时激活肝脏CYP7B1和PPARα，具有治疗NAFLD的潜力。
证据成熟度： 较高。肠道菌群和肝肠轴在MASLD/MASH中的作用已成为研究热点，并取得显著进展。新的治疗靶点如HDCA及其机制正在被深入探索。
不宜夸大的边界：
- MASLD/MASH的机制复杂多样，涉及脂毒性、铁死亡、氧化应激、内质网应激、线粒体功能障碍以及肠道微生物失调等多个方面。单一的肠道菌群干预可能不足以完全解决所有病理过程。
- 目前，由于机制多样性和临床试验难度，MASLD尚无公认的药理学疗法，潜在靶点仍难以捉摸。因此，在产品研究和科普中，应强调肠道菌群干预作为辅助和预防手段，而非替代标准治疗。
- 尽管HDCA显示出治疗潜力，但仍需更多人体临床试验来证实其疗效和安全性。
4. 饮食干预对肠道菌群的调节及其代谢益处
选题方向： 研究不同饮食模式（如地中海饮食、高膳食纤维饮食、特定植物提取物等）如何重塑肠道菌群组成和功能，以及这些改变如何介导其对肥胖、糖尿病和脂肪肝等代谢疾病的预防和管理作用。
具体内容： 饮食是调节肠道菌群的关键因素，从而影响代谢健康。
- 膳食纤维和多酚： 膳食纤维和多酚在坚果中可以改变肠道菌群，具有抗糖尿病作用。同样，红酒多酚能调节肠道菌群，在肥胖患者中减少代谢综合征的标志物。红酒多酚显著增加了粪便双歧杆菌（Bifidobacteria）和乳酸杆菌（Lactobacillus）（肠道屏障保护剂）以及丁酸产生菌（如Faecalibacterium prausnitzii和Roseburia）的数量，同时减少了如LPS产生菌（大肠杆菌和阴沟肠杆菌）等不良细菌群。这些肠道菌群的改变可能与代谢综合征标志物的改善有关。
- 石榴提取物： 一项针对代谢综合征患者的随机临床试验发现，石榴提取物（PE）的益生元作用取决于药物治疗，主要受抗高血压治疗的影响。PE后，乳酸杆菌在抗糖尿病、降脂和抗高血压患者中增加，双歧杆菌在降脂和抗糖尿病患者中增加，而艰难梭菌XIVa在非降脂和非抗高血压患者中减少。这表明在代谢综合征治疗中，靶向肠道菌群可以作为补充，但需考虑患者的个体药物治疗情况。
- 个性化饮食： 任何肥胖管理方法的有效性都依赖于成功的行为改变，特别是饮食行为。饮食策略应根据患者的个体需求量身定制，并应从整体角度评估其对健康的益处，包括对肠道微生物群的滋养。膳食选择可以促进微生物组成和代谢产物，从而改善或损害代谢综合征和睡眠稳态。
证据成熟度： 较高。多种饮食成分和模式对肠道菌群的影响及其代谢益处已有大量研究支持，但个性化饮食干预的效果和机制仍在深入研究中。
不宜夸大的边界：
- 饮食干预的效果并非普适，需要考虑个体差异、基因、现有药物治疗以及肠道菌群的基线状态。
- 强调均衡饮食和健康生活方式是根本，不应过度宣传某种单一食物或补充剂的“奇效”。
- 在产品研究方面，需要更精确地确定特定饮食成分对特定菌群的调节作用以及其对代谢指标的具体影响，避免泛化。
5. 益生菌和后生元在代谢健康中的应用与机制
选题方向： 研究特定益生菌菌株或后生元（如热灭活菌体、代谢产物）如何通过调节肠道菌群、改善肠道屏障功能、产生有益代谢产物（如短链脂肪酸），从而改善肥胖、糖尿病、脂肪肝和胰岛素抵抗等代谢紊乱。
具体内容： 益生菌和后生元作为功能性成分，其受欢迎程度日益增加，因为宠物主人寻求改善宠物健康和寿命的方法。针对狗的研究显示，日常补充活的益生菌（PRO）和热灭活的后生元（POST）形式的Bifidobacterium animalis subsp. lactis CECT 8145，能够降低粪便pH值，并增加粪便丙酸盐浓度。虽然对肠道微生物组的整体丰富度和多样性没有显著影响，但PRO和POST补充与细菌组成在科和属水平上的变化相关，并可能诱导致病性、氨基酸生物合成和DNA修复相关途径的潜在有益变化。
在人体研究中，益生菌和合生制剂显示出改善PCOS女性胰岛素抵抗和荷尔蒙参数的潜力。益生菌和益生元已被认为是糖尿病管理的一种有前景的新方法，而粪便微生物移植也是其中之一。在动物模型和人体患者中，益生菌干预已被证实与症状改善和疾病进展相关。
证据成熟度： 中等偏高。益生菌和后生元在调节肠道菌群和改善代谢健康方面显示出潜力，特别是在动物模型和一些小型人体试验中取得了积极结果。然而，大规模、多中心、长期的临床试验仍在进行中，以确认其广泛适用性和长期效果。
不宜夸大的边界：
- 益生菌和后生元的效果具有菌株特异性，不同菌株的作用机制和效果可能大相径庭。不应将所有益生菌或后生元一概而论。
- 尽管研究显示益生菌和后生元可以安全地用于狗，并支持它们在肠道健康和荷尔蒙调节方面的作用，但对人体的长期效果和最佳剂量仍需进一步研究。
- 对于特定代谢疾病，益生菌/后生元是辅助疗法，不能替代药物治疗。在产品推广时，必须明确其定位，避免夸大疗效。
6. 肠道菌群与代谢综合征共病的综合管理
选题方向： 针对代谢综合征患者常伴随的多种共病（如肥胖、糖尿病、脂肪肝、睡眠障碍、心血管风险），研究肠道菌群在这些共病间的“串扰”机制，并开发针对肠道菌群的多靶点综合干预方案，以实现对代谢综合征的整体管理。
具体内容： 代谢综合征是一组相互关联的危险因素，包括肥胖、胰岛素抵抗、血脂异常和高血压，这些都显著增加了心血管疾病和2型糖尿病的风险。肠道菌群失调在代谢综合征的发展中扮演关键角色。
- 睡眠障碍与代谢综合征： 近年来，越来越多的证据表明肠道微生物的组成与睡眠调节之间存在关联。有趣的是，睡眠障碍的患病率通常与心脏代谢共病（如糖尿病、血脂异常和代谢综合征）相关。在这个复杂的场景中，肠道-大脑轴作为肠道微生物群和大脑睡眠调节途径之间的主要沟通路径，揭示了睡眠障碍和代谢综合征之间一些共同的宿主-微生物生物标志物。膳食选择可以促进微生物组成和代谢产物，从而改善或损害代谢综合征和睡眠稳态。
- 心血管风险： 坚果中的不饱和脂肪酸、纤维、多酚、精氨酸和镁等成分可能通过改善肠道菌群、降低胆固醇吸收、抑制炎症和氧化应激、改善内皮功能和血压，从而降低2型糖尿病和心血管疾病的风险。红酒多酚通过调节肠道菌群，可以改善肥胖代谢综合征患者的标志物。
- 多重药物治疗的影响： 代谢综合征患者的多重药物治疗会影响肠道菌群。例如，石榴提取物的益生元作用取决于药物治疗，主要受抗高血压治疗的影响。这提示我们在设计肠道菌群干预方案时，需考虑患者正在接受的药物治疗。
证据成熟度： 较高。肠道菌群在代谢综合征及其多种共病（如肥胖、糖尿病、心血管风险、睡眠障碍）中的作用已得到证实。但针对多重共病的综合干预方案，尤其是结合药物治疗的个性化方案，仍需更多研究。
不宜夸大的边界：
- 代谢综合征的综合管理是一个复杂的过程，涉及多学科协作。肠道菌群干预应被视为全面管理计划的一部分，而非独立解决方案。
- 强调肠道菌群干预可以改善多种代谢指标，但不能承诺其能完全替代现有药物治疗或解决所有共病问题。
- 在产品研究中，需要更精细地评估干预措施在多重共病背景下的综合效果，并考虑潜在的药物-微生物相互作用。
总结： 上述6个方向在近五年的研究中都取得了显著进展，为医学科普和产品研究提供了丰富的素材。在进行科普宣讲或产品推广时，应始终坚持科学严谨的态度，清晰界定证据的成熟度，避免过度宣传和不切实际的承诺。强调肠道菌群干预是辅助性、个性化和长期性的健康管理策略，应在专业人士指导下进行，并结合健康饮食和生活方式的全面改变。
References
1Updated mechanisms of MASLD pathogenesis.PubMed
Yuxuan Li, Peipei Yang, Jialu Ye, et al.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.
2Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis.PubMed
Junliang Kuang, Jieyi Wang, Yitao Li, et al.
Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1. Additionally, HDCA significantly increased abundances of probiotic species such as Parabacteroides distasonis, which enhances lipid catabolism through fatty acid-hepatic peroxisome proliferator-activated receptor alpha (PPARα) signaling, which in turn upregulates hepatic FXR. These findings suggest that HDCA has therapeutic potential for treating NAFLD, with a unique mechanism of simultaneously activating hepatic CYP7B1 and PPARα.
3Pharmacological Therapy Determines the Gut Microbiota Modulation by a Pomegranate Extract Nutraceutical in Metabolic Syndrome: A Randomized Clinical Trial.PubMed
Adrián Cortés-Martín, Carlos Eduardo Iglesias-Aguirre, Amparo Meoro, et al.
SCOPE: Poly-pharmacological therapy shapes the gut microbiota (GM) in metabolic syndrome (MetS) patients. The effects of polyphenols in poly-medicated MetS patients are unknown. METHODS AND RESULTS: A randomized, placebo-controlled, double-blinded, and crossover trial in poly-medicated MetS patients (n=50) explored whether the effects of a pomegranate extract nutraceutical (PE, 320 mg phenolics/day for 1 month) are affected by the drug therapy. Considering the lipid-lowering (LL-), anti-hypertensive (HP-) and(or) anti-diabetic (AD-) treatments: GM (16S rRNA sequencing), short-chain fatty acids, 40 inflammatory-metabolic and endotoxemia-related biomarkers, associations between biomarkers and GM with 53 cardiometabolic dysfunctions-related single-nucleotide polymorphisms (SNPs), and urolithin metabotypes (UMs) influence are evaluated. Representative SNPs-GM associations after PE include Lactococcus and ClostridiumXIVa with rs5443-GNB3 (G-protein-β-polypeptide-3) and ClostridiumXIVa with rs7903146-TCF7L2 (transcription-factor-7-like-2) and rs1137101-LEPR (leptin-receptor). PE decreases sICAM-1 in LL-patients and the lipopolysaccharide-binding protein in all the patients. PE does not affect the other patients' markers as a group or stratifying by UMs. After PE, Lactococcus increases in AD-, LL-, and HP-patients, Bifidobacterium increases in LL- and AD-, while Clostridium XIVa decreases in non-LL- and non-HP-patients. CONCLUSION: The prebiotic effect of PE depends on the medication, mainly on HP-treatments. Targeting GM can complement MetS therapy, but the patients' drug therapy should be considered individually.
4Effects of supplementation of live and heat-treated Bifidobacterium animalis subspecies lactis CECT 8145 on glycemic and insulinemic response, fecal microbiota, systemic biomarkers of inflammation, and white blood cell gene expression of adult dogs.PubMed
Emanuela Kayser, Fei He, Sophie Nixon, et al.
The popularity of functional ingredients such as probiotics and postbiotics has increased as pet owners seek ways to improve the health quality and longevity of their pets. Limited research has been conducted regarding the use of probiotics and postbiotics and their effects on canine health. The objective of this study was to evaluate the effects of daily supplementation of Bifidobacterium animalis subsp. lactis CECT 8145, in both live probiotic (PRO) and heat-treated postbiotic (POST) forms, on fecal fermentative end-products and microbiome, insulin sensitivity, serum gut hormones, oxidative stress, inflammatory biomarkers, and white blood cell gene expression of adult dogs. Eighteen adult beagles and 18 adult English pointers were used in a double-blinded placebo-controlled parallel group design, with 12 animals per group (6 English pointers and 6 beagles). The study began with a 60 d adaptation period followed by a 90 d period of daily supplementation with either PRO, POST, or placebo (maltodextrin; CON). Longitudinal assessment of body weight, body condition score, and pelvic circumference did not differ among dietary supplements (P > 0.05). Throughout the experimental period, fecal scores did not differ (P > 0.05); however, fecal pH was lower (P = 0.0049) in the dogs fed POST compared with CON. A higher fecal concentration of propionate (P = 0.043) was observed in dogs fed PRO and POST when compared with CON. While PRO and POST supplementation were associated with changes in bacterial composition at the family and genus level, the overall richness and diversity of the microbiome were not significantly affected. Functional analysis of the metagenome also suggests that PRO and POST supplementation induced potentially beneficial changes in the abundance of pathways involved in pathogenicity, amino acid biosynthesis, and DNA repair. No differences in glycemic or insulinemic responses were observed among the groups (P > 0.05). Dogs supplemented with PRO had a higher (P < 0.05) mean white blood cell leptin relative fold gene expression compared with groups POST and CON. Serum metabolites and complete blood cell counts were within normal ranges and all dogs remained healthy throughout the study. Together, these data suggest that the PRO and POST can safely be supplemented for dogs. Moreover, the results of this study support further investigation of the role of PRO and POST in supporting parameters related to gut health and hormonal regulation.
5Dietary and Lifestyle Strategies for Obesity.PubMed
Thomas M Barber, Stefan Kabisch, Andreas F H Pfeiffer, et al.
The prevalence of obesity globally has tripled over the last half century, and currently affects around 650 million adults and 340 million children and adolescents (ages 5-19 years). Obesity contributes towards >50 co-morbidities and premature mortality. Obesity is a highly stigmatised condition that is associated with much mental and emotional distress and dysfunction. Thus, obesity is a major contributor to healthcare expenditure globally. Traditionally, the management of obesity stratifies into three major groups that include metabolic (bariatric) surgery, pharmacotherapies, and lifestyle (primarily dietary) strategies. Although listed as a separate category, dietary strategies for obesity remain a central component of any management plan, and often complement other surgical and pharmacotherapeutic options. Indeed, the effectiveness of any management approach for obesity relies upon successful behavioural changes, particularly relating to eating behaviours. In this concise review, we explore the foundational pillars of dietary strategies for obesity: sleep, listening, routine, de-stressing and optimisation of social conditions. We then discuss the importance of balancing dietary macronutrients (including dietary fibre, carbohydrates, protein and ultra-processed foods [UPFs]) as a key dietary strategy for obesity. Although we focus on general principles, we should provide bespoke dietary strategies for our patients, tailored to their individual needs. Rather than judging the utility of a diet based simply on its associated magnitude of weight loss, we should adopt a more holistic perspective in which a dietary strategy is valued for its overall health benefits, including the nurturing of our gut microbiota, to enable them to nurture and protect us.
6Gut Microbiota and Complications of Type-2 Diabetes.PubMed
Camelia Oana Iatcu, Aimee Steen, Mihai Covasa
The gut microbiota has been linked to the emergence of obesity, metabolic syndrome and the onset of type 2 diabetes through decreased glucose tolerance and insulin resistance. Uncontrolled diabetes can lead to serious health consequences such as impaired kidney function, blindness, stroke, myocardial infarction and lower limb amputation. Despite a variety of treatments currently available, cases of diabetes and resulting complications are on the rise. One promising new approach to diabetes focuses on modulating the gut microbiota with probiotics, prebiotics, synbiotics and fecal microbial transplantation. Differences in gut microbiota composition have been observed in preclinical animal models as well as patients with type 2 diabetes and complications such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cerebrovascular disease, coronary heart disease and peripheral artery disease compared to healthy controls. Severity of gut microbiota dysbiosis was associated with disease severity and restoration with probiotic administration in animal models and human patients has been associated with improvement of symptoms and disease progression. Characterizing the gut microbiota dysbiosis in different diseases and determining a causal relationship between the gut microbiota and disease can be beneficial in formulating therapeutic interventions for type 2 diabetes and associated complications. In this review, we present the most important findings regarding the role of the gut microbiota in type 2 diabetes and chronic complications as well as their underlying mechanisms.
7Integrative metabolism in MASLD and MASH: Pathophysiology and emerging mechanisms.PubMed
Gregory R Steinberg, Celina M Valvano, William De Nardo, et al.
The liver acts as a central metabolic hub, integrating signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, and amino acid metabolism. Gut-derived metabolites, such as acetate and ethanol, and non-esterified fatty acids from white adipose tissue influence hepatic processes, which rely on mitochondrial function to maintain systemic energy balance. Metabolic dysregulation caused by obesity, insulin resistance, and type 2 diabetes disrupts these pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). In this review, we explore the metabolic fluxes within the gut-adipose tissue-liver axis, focusing on the pivotal role of de novo lipogenesis, dietary substrates like glucose and fructose, and changes in mitochondrial function during MASLD progression. We also highlight the contributions of white adipose tissue insulin resistance and impaired mitochondrial dynamics to hepatic lipid accumulation. Further understanding how the interplay between substrate flux from the gastro-intestinal tract integrates with adipose tissue and intersects with structural and functional alterations to liver mitochondria will be important to identify novel therapeutic targets and advance the treatment of MASLD and MASH.
8Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients.PubMed
Isabel Moreno-Indias, Lidia Sánchez-Alcoholado, Pablo Pérez-Martínez, et al.
This study evaluated the possible prebiotic effect of a moderate intake of red wine polyphenols on the modulation of the gut microbiota composition and the improvement in the risk factors for the metabolic syndrome in obese patients. Ten metabolic syndrome patients and ten healthy subjects were included in a randomized, crossover, controlled intervention study. After a washout period, the subjects consumed red wine and de-alcoholized red wine over a 30 day period for each. The dominant bacterial composition did not differ significantly between the study groups after the two red wine intake periods. In the metabolic syndrome patients, red wine polyphenols significantly increased the number of fecal bifidobacteria and Lactobacillus (intestinal barrier protectors) and butyrate-producing bacteria (Faecalibacterium prausnitzii and Roseburia) at the expense of less desirable groups of bacteria such as LPS producers (Escherichia coli and Enterobacter cloacae). The changes in gut microbiota in these patients could be responsible for the improvement in the metabolic syndrome markers. Modulation of the gut microbiota by using red wine could be an effective strategy for managing metabolic diseases associated with obesity.
9The Microbiota-Gut-Brain Axis in Metabolic Syndrome and Sleep Disorders: A Systematic Review.PubMed
Adriano Dos Santos, Serena Galiè
BACKGROUND: Over recent decades, a growing body of evidence has emerged linking the composition of the gut microbiota to sleep regulation. Interestingly, the prevalence of sleep disorders is commonly related to cardiometabolic comorbidities such as diabetes, impaired lipid metabolism, and metabolic syndrome (MetS). In this complex scenario, the role of the gut-brain axis as the main communicating pathway between gut microbiota and sleep regulation pathways in the brain reveals some common host-microbial biomarkers in both sleep disturbances and MetS. As the biological mechanisms behind this complex interacting network of neuroendocrine, immune, and metabolic pathways are not fully understood yet, the present systematic review aims to describe common microbial features between these two unrelated chronic conditions. RESULTS: This systematic review highlights a total of 36 articles associating the gut microbial signature with MetS or sleep disorders. Specific emphasis is given to studies evaluating the effect of dietary patterns, dietary supplementation, and probiotics on MetS or sleep disturbances. CONCLUSIONS: Dietary choices promote microbial composition and metabolites, causing both the amelioration and impairment of MetS and sleep homeostasis.
10Prediction of Weight Loss and Regain Based on Multiomic and Phenotypic Features: Results From a Calorie-Restricted Feeding Trial.PubMed
Lin Li, Ruyi Li, Zixin Qiu, et al.
OBJECTIVE: To identify baseline multiomic and phenotypic predictors and develop prediction models for weight and body composition loss and regain in the Low-Carbohydrate Diet and Time-Restricted Eating (LEAN-TIME) trial. RESEARCH DESIGN AND METHODS: A post hoc analysis was conducted of the LEAN-TIME feeding trial using data from 88 adults with overweight/obesity completing a 12-week calorie-restricted weight-loss phase and 79 completing a 28-week weight-regain phase. Baseline dietary, metabolic, fecal metabolome, and gut microbiome data were candidate predictors of changes in weight, body fat mass (BFM), and soft lean mass (SLM). Multivariable regression and the least absolute shrinkage and selection operator model were used to identify predictors and develop weighted-sum prediction models. RESULTS: Multiomic and phenotypic models significantly outperformed phenotype-only models (P < 0.05), demonstrating strong predictive performance during both phases. During weight loss, the multiomic and phenotypic model yielded R2 values of 0.49, 0.61, and 0.54 for changes in weight, BFM, and SLM, respectively, with corresponding root mean square errors (RMSEs) of 1.59, 1.41, and 0.98 kg. For binary classification of clinically meaningful weight loss (≥5%), the model achieved an area under the curve of 0.95 (sensitivity 94.12%; specificity 86.79%). During weight regain, R2 values reached 0.72, 0.73, and 0.66 for weight, BFM, and SLM (RMSEs 1.40, 1.62, and 0.73 kg), respectively. Several key baseline predictors, primarily gut microbes and fecal metabolites, such as N-acetyl-l-aspartic acid, Ruminococcus callidus, and Bifidobacterium adolescentis, were shared for weight and body composition changes during both phases. CONCLUSIONS: Baseline multiomic and phenotypic data effectively predict weight and body composition loss and regain, offering insights for personalized weight management.
11The human microbiome in disease and pathology.PubMed
Jim Manos
This narrative review seeks to examine the relationships between bacterial microbiomes and infectious disease. This is achieved by detailing how different human host microbiomes develop and function, from the earliest infant acquisitions of maternal and environmental species through to the full development of microbiomes by adulthood. Communication between bacterial species or communities of species within and outside of the microbiome is a factor in both maintenance of homeostasis and management of threats from the external environment. Dysbiosis of this homeostasis is key to understanding the development of disease states. Several microbiomes and the microbiota within are used as prime examples of how changes in species composition, particularly at the phylum level, leads to such diverse conditions as inflammatory bowel disease (IBD), type 2 diabetes, psoriasis, Parkinson's disease, reflux oesophagitis and others. The review examines spatial relationships between microbiomes to understand how dysbiosis in the gut microbiome in particular can influence diseases in distant host sites via routes such as the gut-lung, gut-skin and gut-brain axes. Microbiome interaction with host processes such as adaptive immunity is increasingly identified as critical to developing the capacity of the immune system to react to pathogens. Dysbiosis of essential bacteria involved in modification of host substrates such as bile acid components can result in development of Crohn's disease, small intestine bacterial overgrowth, hepatic cancer and obesity. Interactions between microbiomes in distantly located sites are being increasingly being identified, resulting in a 'whole of body' effect by the combined host microbiome.
12Hepatic inflammatory responses in liver fibrosis.PubMed
Linda Hammerich, Frank Tacke
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
13Benefits of Nut Consumption on Insulin Resistance and Cardiovascular Risk Factors: Multiple Potential Mechanisms of Actions.PubMed
Yoona Kim, Jennifer B Keogh, Peter M Clifton
Epidemiological and clinical studies have indicated that nut consumption could be a healthy dietary strategy to prevent and treat type 2 diabetes (T2DM) and related cardiovascular disease (CVD). The objective of this review is to examine the potential mechanisms of action of nuts addressing effects on glycemic control, weight management, energy balance, appetite, gut microbiota modification, lipid metabolism, oxidative stress, inflammation, endothelial function and blood pressure with a focus on data from both animal and human studies. The favourable effects of nuts could be explained by the unique nutrient composition and bioactive compounds in nuts. Unsaturated fatty acids (monounsaturated fatty acids and polyunsaturated fatty acids) present in nuts may play a role in glucose control and appetite suppression. Fiber and polyphenols in nuts may also have an anti-diabetic effect by altering gut microbiota. Nuts lower serum cholesterol by reduced cholesterol absorption, inhibition of HMG-CoA reductase and increased bile acid production by stimulation of 7-α hydroxylase. Arginine and magnesium improve inflammation, oxidative stress, endothelial function and blood pressure. In conclusion, nuts contain compounds that favourably influence glucose homeostasis, weight control and vascular health. Further investigations are required to identify the most important mechanisms by which nuts decrease the risk of T2DM and CVD.
14Effectiveness of Probiotics, Prebiotics, and Synbiotics in Managing Insulin Resistance and Hormonal Imbalance in Women with Polycystic Ovary Syndrome (PCOS): A Systematic Review of Randomized Clinical Trials.PubMed
Darly Martinez Guevara, Sinthia Vidal Cañas, Isabela Palacios, et al.
Polycystic ovary syndrome is a common endocrine disorder in women of reproductive age characterized by insulin resistance and hormonal imbalances. Recent research suggests that probiotics and synbiotics may improve these parameters by modulating the gut microbiota. This study systematically reviewed randomized clinical trials evaluating the impact of probiotic, prebiotic, and synbiotic supplementation on insulin resistance and hormonal parameters in women with PCOS. Exhaustive searches were conducted in PubMed, Cochrane CENTRAL, Scopus, Web of Science, and Embase, following PRISMA guidelines. Randomized trials assessing supplementation with probiotics, prebiotics, or synbiotics for at least 8 weeks in women diagnosed with PCOS according to the Rotterdam criteria were included. Data on participants, interventions, and outcomes related to insulin resistance and hormones were extracted. Eleven studies from Iran involving overweight or obese women aged 15 to 48 were included. Probiotic and synbiotic supplementation showed significant improvements in insulin resistance (reductions in HOMA-IR, fasting glucose, and insulin), lipid profiles (decreased LDL and triglycerides; increased HDL), and hormonal balance (increased SHBG, decreased total testosterone). Synbiotics had more pronounced effects than probiotics or prebiotics alone. Adherence was high, and side effects were minimal. Despite promising results, limitations such as small sample sizes, homogeneous populations, and short intervention durations limit the generalization of the findings. Larger, longer, multicenter trials with diverse populations and standardized methodologies are needed to confirm the efficacy and safety of synbiotics in managing PCOS. Integrating these interventions could improve clinical management and quality of life for affected women, but additional evidence is required to support widespread use.
15Short-Term Effects of Nonnutritive Sweetener (Sucralose and Saccharin) Consumption on Glycemic Control and Gut Microbiota in Patients With Type 2 Diabetes: Protocol for a Double-Blind, Randomized, Placebo-Controlled, Crossover Trial.PubMed
Huey Shin Tan, Harvinder Kaur Gilcharan Singh, Vanitha Mariappan, et al.
BACKGROUND: Nonnutritive sweeteners (NNSs) are widely used as sugar substitutes to help individuals with diabetes manage glycemic control. However, emerging evidence suggests that even low doses of NNSs, such as saccharin and sucralose, may adversely affect metabolic health by impairing glycemic regulation, potentially through alterations in the gut microbiota. In Malaysia, where gut microbiome research is still limited, particularly among individuals with type 2 diabetes mellitus (T2DM), further investigation is warranted to inform safe and evidence-based use of NNSs. OBJECTIVE: This study aims to evaluate the short-term effects of saccharin and sucralose consumption on glycemic control and gut microbiota composition in adults with T2DM. METHODS: This is a double-blind, randomized, placebo-controlled, crossover trial. A total of 33 adults with T2DM will consume sucralose (5 mg/kg body weight), saccharin (2 mg/kg body weight), or a placebo (calcium carbonate) in capsule form daily for 7 days per intervention arm, with a 4-week washout period. Data collection will include anthropometric measurements, biochemical assessments for glycemic control, dietary records, physical activity levels, and stool samples. The homeostatic model assessment for insulin resistance will be used to assess insulin sensitivity, while 16S rRNA V3-V4 region sequencing will be conducted to profile gut microbiota composition. RESULTS: Recruitment is planned to begin in January 2026 and is expected to conclude by September 2026, with study completion anticipated by March 2027. As of December 2025, no participants have been enrolled. CONCLUSIONS: This trial will contribute novel insights into the effects of short-term NNS consumption on glycemic control and gut microbiota composition in individuals with T2DM. These findings may support evidence-based recommendations for NNS use in diabetes management and enhance understanding of microbiome-diet interactions in an ethnically diverse Asian population. TRIAL REGISTRATION: ClinicalTrials.gov NCT07124585; https://clinicaltrials.gov/study/NCT07124585. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/82695.
16Obesity and gut-microbiota-brain axis: A narrative review.PubMed
Arezoo Asadi, Negar Shadab Mehr, Mohamad Hosein Mohamadi, et al.
INTRODUCTION: Obesity is a major health problem that is associated with many physiological and mental disorders, such as diabetes, stroke, and depression. Gut microbiota has been affirmed to interact with various organs, including the brain. Intestinal microbiota and their metabolites might target the brain directly via vagal stimulation or indirectly through immune-neuroendocrine mechanisms, and they can regulate metabolism, adiposity, homoeostasis and energy balance, and central appetite and food reward signaling, which together have crucial roles in obesity. Studies support the concept of bidirectional signaling within the gut-brain axis (GBA) in the pathophysiology of obesity, mediated by metabolic, endocrine, neural, and immune system mechanisms. MATERIALS AND METHODS: Scopus, PubMed, Google Scholar, and Web of Science databases were searched to find relevant studies. RESULTS: The gut-brain axis (GBA), a bidirectional connection between the gut microbiota and brain, influences physiological function and behavior through three different pathways. Neural pathway mainly consists of the enteric nervous system (ENS) and vagus nerve. Endocrine pathway, however, affects the neuroendocrine system of the brain, particularly the hypothalamus-pituitary-adrenal (HPA) axis and immunological pathway. Several alterations in the gut microbiome can lead to obesity, by modulating metabolic pathways and eating behaviors of the host through GBA. Therefore, novel therapies targeting the gut microbiome, i.e., fecal microbiota transplantation and supplementation with probiotics and prebiotics, can be a potential treatment for obesity. CONCLUSION: This study corroborates the effect of gut microbiome on physiological function and body weight. The results show that the gut microbiota is becoming a target for new antiobesity therapies.
17Metabolic Dysfunction-Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options.PubMed
Piero Portincasa, Mohamad Khalil, Laura Mahdi, et al.
The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from "nonalcoholic fatty liver disease" (NAFLD) to "metabolic dysfunction-associated fatty liver disease" (MAFLD) and, finally, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut-liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH.
18Gastrointestinal microbiome modulator improves glucose tolerance in overweight and obese subjects: A randomized controlled pilot trial.PubMed
Candida J Rebello, Jeffrey Burton, Mark Heiman, et al.
OBJECTIVE: The objective of this study was to examine the effects of a gastrointestinal microbiome modulator (GIMM) containing inulin, β-glucan, blueberry anthocyanins, and blueberry polyphenols on metabolic parameters, fecal markers of gut microbiota, and satiety. DESIGN AND METHODS: Thirty overweight or obese individuals aged 18 to 70years, were enrolled in a randomized controlled trial. Participants consumed the test product or placebo daily for four weeks. Stool samples were collected and blood was drawn at baseline and week four for assessments of gut microbiota, satiety hormones, glucose control, and lipid measures. Subjective satiety was assessed weekly. Linear models were used to compare differences from baseline to week four. RESULTS: GIMM consumption improved blood glucose tolerance (p=0.008), and increased satiety (p=0.03). There were no statistically significant differences in insulin sensitivity, fecal markers of gut microbiota, plasma satiety hormones, or serum lipid concentrations between the groups. However, plasma satiety hormones and fecal short chain fatty acid concentrations increased in the test group compared to the placebo. CONCLUSIONS: GIMM consumption for four weeks, increases satiety, and improves glucose tolerance possibly through insulin-independent pathways.
19Gut microbiome and bone health: update on mechanisms, clinical correlations, and possible treatment strategies.PubMed
Andrea Ticinesi, Carmine Siniscalchi, Tiziana Meschi, et al.
The intestinal microbiome is increasingly regarded as a relevant modulator of the pathophysiology of several age-related conditions, including frailty, sarcopenia, and cognitive decline. Aging is in fact associated with alteration of the equilibrium between symbiotic bacteria and opportunistic pathogens, leading to dysbiosis. The microbiome is able to regulate intestinal permeability and systemic inflammation, has a central role in intestinal amino acid metabolism, and produces a large number of metabolites and byproducts, with either beneficial or detrimental consequences for the host physiology. Recent evidence, from both preclinical animal models and clinical studies, suggests that these microbiome-centered pathways could contribute to bone homeostasis, regulating the balance between osteoblast and osteoclast function. In this systematic review, we provide an overview of the mechanisms involved in the gut-bone axis, with a particular focus on microbiome function and microbiome-derived mediators including short-chain fatty acids. We also review the current evidence linking gut microbiota dysbiosis with osteopenia and osteoporosis, and the results of the intervention studies on pre-, pro-, or post-biotics targeting bone mineral density loss in both animal models and human beings, indicating knowledge gaps and highlighting possible avenues for future research.
20Obesity and Diabetes in Mexico: An Approach to the Intestinal Microbiota.PubMed
Ruth Michelle Acosta-Meneses, Esther Ramírez-Moreno, Laura Berenice Olvera-Rosales, et al.
Obesity and diabetes have reached alarming prevalence rates globally, with Mexico being one of the most affected countries. This review explores the epidemiology of these metabolic disorders and analyzes their prevalence and risk factors, as well as the crucial role of the intestinal microbiota in their development. Obesity and diabetes in Mexico have been linked to lifestyle factors, genetic predispositions, and alterations in the gut microbial composition. The intestinal microbiota plays a significant role in metabolic regulation, and its dysbiosis has been associated with insulin resistance, chronic inflammation, and increased fat accumulation. Studies in Mexico have highlighted specific microbial patterns in individuals with obesity and diabetes, suggesting a unique interplay between diet, microbiota composition, and metabolic health. Strategies to restore microbial balance, such as dietary modifications and probiotic interventions, have shown promising results in improving metabolic parameters and reducing disease progression. However, challenges remain in understanding the long-term effects of microbiota-targeted therapies and their individual variability. This review underscores the need for further research to develop personalized interventions aimed at modulating the gut microbiota for obesity and diabetes management. Future directions should focus on integrative approaches combining nutrition, prebiotics, and microbiome-based therapeutics to combat the increasing burden of metabolic diseases in Mexico.