Jing Menghui, Jiang Yuanye
Department of Clinical Development, Sunshine Guojian Pharmaceutical (Shanghai) Co. Ltd, Shanghai, China.
Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Endocrinol (Lausanne). 2025 Nov 17;16:1677175. doi: 10.3389/fendo.2025.1677175. eCollection 2025.
Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) frequently co-occur and aggravate one another through shared pathways of insulin resistance, low-grade inflammation and disordered lipid handling. Framing their interaction through the gut-liver-pancreas axis, this review synthesizes recent progress with a function-first emphasis, moving beyond taxonomic lists to the microbial outputs most consistently linked to dual metabolic-hepatic endpoints. We summarize how short-chain fatty acids (SCFAs), bile acids (BAs), lipopolysaccharide (LPS) and other microbe-associated molecular patterns, branched-chain amino-acid (BCAA) catabolites, trimethylamine N-oxide (TMAO) and endogenous ethanol reach the liver via portal inflow or the enterohepatic BA cycle and act on epithelial, immune and endocrine interfaces, including the farnesoid X receptor (FXR), G-protein-coupled BA receptor 1 (TGR5) and fibroblast growth factor 19/15 signaling. Mechanistic routes-barrier dysfunction and endotoxaemia; SCFA signaling with effects on enteroendocrine tone and substrate flux; BA remodeling that resets hepatic and pancreatic set-points; and nitrogen/choline and ethanol pathways that promote lipotoxic injury-offer biologically coherent explanations for parallel trajectories of hyperglycemia and steatosis/inflammation. We appraise therapeutic modulation spanning diet and fermentable substrates, live biotherapeutics/postbiotics, BA-targeting drugs, fecal microbiota transplantation and metabolic/bariatric surgery, and we outline clinically actionable biomarker opportunities using function-based panels (fermentative capacity, BA transformation, inflammatory ligands, nitrogen/methyl flux) integrated with host metabolites and genetics for diagnosis, risk stratification and response prediction. By advocating standardized reporting, careful control of diet/medications and composite metabolic-hepatic endpoints in prospective trials, this review provides a practical framework to accelerate translation from association to targeted prevention and therapy that improves glycemic control and MASLD activity in parallel.
2型糖尿病（T2DM）与代谢功能障碍相关脂肪性肝病（MASLD）经常同时出现，并通过胰岛素抵抗、低度炎症和脂质代谢紊乱等共同途径相互加重。本综述通过肠-肝-胰轴来阐述它们之间的相互作用，以功能优先为重点总结了近期的进展，超越了分类列表，关注与代谢-肝脏双重终点最密切相关的微生物产物。我们总结了短链脂肪酸（SCFAs）、胆汁酸（BAs）、脂多糖（LPS）和其他微生物相关分子模式、支链氨基酸（BCAAs）分解代谢产物、氧化三甲胺（TMAO）和内源性乙醇如何通过门静脉流入或肠肝胆汁酸循环到达肝脏，并作用于上皮、免疫和内分泌界面，包括法尼醇X受体（FXR）、G蛋白偶联胆汁酸受体1（TGR5）和成纤维细胞生长因子19/15信号通路。其机制途径包括屏障功能障碍和内毒素血症；SCFA信号传导对肠内分泌张力和底物通量的影响；胆汁酸重塑重置肝脏和胰腺的设定点；以及促进脂毒性损伤的氮/胆碱和乙醇途径，这些为高血糖和脂肪变性/炎症的平行轨迹提供了生物学上连贯的解释。我们评估了从饮食和可发酵底物、活生物治疗剂/后生元、靶向胆汁酸的药物、粪便微生物群移植到代谢/减重手术等治疗性调节方法，并概述了基于功能的检测指标（发酵能力、胆汁酸转化、炎症配体、氮/甲基通量）结合宿主代谢物和遗传学用于诊断、风险分层和反应预测的临床可行生物标志物机会。通过倡导标准化报告、在前瞻性试验中仔细控制饮食/药物以及综合代谢-肝脏终点，本综述提供了一个实用框架，以加速从关联研究到靶向预防和治疗的转化，从而同时改善血糖控制和MASLD病情。
