Microbiome‑Mediated Crosstalk Between T2DM and MASLD: A Translational Review Focused on Function

Menghui Jing¹Yuanye Jiang^2*

• ¹Sunshine Guojian Pharmaceutical Shanghai Co Ltd, Shanghai, China
• ²Putuo District Central Hospital, Shanghai, China

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 synthesises recent progress with a function-first emphasis, moving beyond taxonomic lists to the microbial outputs most consistently linked to dual metabolic–hepatic endpoints. We summarise 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 remodelling 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 hyperglycaemia and steatosis/inflammation. We appraise therapeutic modulation spanning diet and fermentable substrates, live biotherapeutics/postbiotics, BA-targeting drugs, faecal 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 standardised 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 glycaemic control and MASLD activity in parallel.