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Microbiome−mediated crosstalk between T2DM and MASLD: a translational review focused on function

Jing, Menghui, Jiang, Yuanye·2025·Frontiers in Endocrinology
DOI 10.3389/fendo.2025.1677175PMC PMC12665569
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Abstract

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.

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Figure 1 Mechanistic overview of gut microbiome-driven pathways linking T2DM and MASLD.
Figure 1 Mechanistic overview of gut microbiome-driven pathways linking T2DM and MASLD.CC BY · PubMed Central
Figure 2 The gut–liver–pancreas axis integrates anatomical conduits (portal inflow and enterohepatic bile−acid cycling) with signaling interfaces.
Figure 2 The gut–liver–pancreas axis integrates anatomical conduits (portal inflow and enterohepatic bile−acid cycling) with signaling interfaces.CC BY · PubMed Central
Figure 3 Clinical integration workflow of microbiome biomarkers in T2DM–MASLD comorbidity.
Figure 3 Clinical integration workflow of microbiome biomarkers in T2DM–MASLD comorbidity.CC BY · PubMed Central

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Metadata

Authors
Jing, M., & Jiang, Y.
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2025-11-17
Volume
16
ISSN
1664-2392
DOI
10.3389/fendo.2025.1677175
PMC
PMC12665569
Cited by
24
References
13
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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