Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Department of Food Science, Ishikawa Prefectural University, Nonoichi 921-8836, Japan.
World J Gastroenterol. 2021 May 14;27(18):2160-2176. doi: 10.3748/wjg.v27.i18.2160.
The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis. Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease (NAFLD) by modulating gut microbiota. Partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber, has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes. However, its effects on NAFLD remain to be fully elucidated.
To determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis.
Seven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic (Ath) diet (a mouse model of NAFLD) for 8 wk, with or without 5% PHGG. Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium. Body weight, liver weight, macroscopic findings in the liver, blood biochemistry [aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total cholesterol, triglyceride, free fatty acids, and glucose levels], liver histology, myeloperoxidase activity in liver tissue, mRNA expression in the liver and intestine, serum endotoxin levels in the portal vein, intestinal permeability, and microbiota and short-chain fatty acid (SCFA) profiles in the cecal samples were investigated.
Mice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels, liver fat accumulation, liver inflammatory (tumor necrosis factor-α and monocyte chemotactic protein-1) and fibrogenic (collagen 1a1 and α smooth muscle actin) marker levels, and liver myeloperoxidase activity, which were significantly attenuated by PHGG treatment. Furthermore, the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor (TLR) 4 and TLR9 expression, confirming that intestinal permeability was significantly elevated, as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran. PHGG treatment did not affect fatty acid metabolism in the liver. However, it decreased lipopolysaccharide signaling through the gut-liver axis. In addition, it significantly increased the abundance of cecal and subcluster XIVa. Treatment with PHGG markedly increased the levels of SCFAs, particularly, butyric acid, acetic acid, propionic acid, and formic acid, in the cecal samples.
PHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.
在慢性肝病发病机制的背景下，肠道-肝脏轴引起了广泛关注。研究表明，膳食纤维等益生元可以通过调节肠道微生物群来减轻非酒精性脂肪性肝病（NAFLD）。部分水解瓜尔胶（PHGG）是一种水溶性膳食纤维，已被报道可缓解各种肠道疾病和代谢综合征的症状。然而，其对 NAFLD 的影响仍有待充分阐明。
确定 PHGG 通过肠道-肝脏轴治疗是否可以减轻小鼠的 NAFLD 发展。
给 7 周龄雄性 C57BL/6J 小鼠给予小剂量的葡聚糖硫酸钠进行慢性间歇性给药，以诱导肠道通透性增加，然后用对照或动脉粥样硬化（Ath）饮食（NAFLD 的小鼠模型）喂养 8 周，同时给予或不给予 5%的 PHGG。肠道通透性增加。体重、肝重、肝脏大体观察、血液生化[天门冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）、总胆固醇、甘油三酯、游离脂肪酸和葡萄糖水平]、肝脏组织学、肝组织髓过氧化物酶活性、肝脏和肠道中的 mRNA 表达、门静脉血清内毒素水平、肠道通透性以及盲肠样本中的微生物群和短链脂肪酸（SCFA）谱。
肠道通透性增加的 Ath 饮食小鼠血清 AST 和 ALT 水平显著升高，肝脂肪堆积，肝炎症（肿瘤坏死因子-α和单核细胞趋化蛋白-1）和纤维化（胶原 1a1 和α平滑肌肌动蛋白）标志物水平以及肝髓过氧化物酶活性均显著降低，PHGG 治疗可显著减轻。此外，Ath 饮食联合肠道通透性增加导致门脉内毒素水平升高，并激活 toll 样受体（TLR）4 和 TLR9 表达，证实通过评估荧光素异硫氰酸酯结合的葡聚糖的腔到血液清除率，肠道通透性显著增加。PHGG 治疗不影响肝脏的脂肪酸代谢。然而，它通过肠道-肝脏轴降低了脂多糖信号。此外，它显著增加了盲肠和亚群 XIVa 的丰度。PHGG 治疗显著增加了盲肠样本中 SCFA 的水平，特别是丁酸、乙酸、丙酸和甲酸。
PHGG 通过调节微生物群和下游 SCFA 谱部分通过肠道-肝脏轴预防小鼠的 NAFLD 发展。
