The multifaceted roles of gut microbiota and their metabolites in metabolic dysfunction-associated steatotic liver disease
image: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health concern and encompasses a spectrum ranging from hepatic steatosis and metabolic dysfunction-associated steatohepatitis to liver fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Insulin resistance, the pathogenic cornerstone of MASLD, drives enhanced peripheral lipolysis and increased hepatic de novo lipogenesis, thereby overloading the liver with lipids and inducing steatosis. Subsequent lipotoxicity, inflammation, and gut microbiota dysbiosis further exacerbate disease progression. The gut microbiota and their metabolites communicate with the liver via the gut-liver axis, forming a complex signaling network that directly or indirectly modulates hepatic metabolism, systemic immune responses, oxidative stress, and intestinal barrier integrity. In this review, we synthesize evidence for the beneficial and detrimental effects of the major human gut microbial communities and their metabolites during the course of MASLD. We delineate how these gut-derived factors regulate hepatic function through an integrated tripartite “gut-liver axis–oxidative stress–metabolic reprogramming” mechanism. These insights may inform microbiome-based precision interventions and accelerate the development of therapeutic strategies targeting MASLD.
Credit: Qianqian Zhang, Jing Zhang
Metabolic dysfunction‑associated steatotic liver disease (MASLD) is a major global health concern progressing from steatosis to MASH, fibrosis, cirrhosis, and HCC. Insulin resistance drives lipid overload, while lipotoxicity, inflammation, and gut dysbiosis accelerate progression. The gut microbiota and their metabolites communicate with the liver via the gut‑liver axis, modulating metabolism, immunity, oxidative stress, and barrier integrity. This review synthesises evidence on microbial taxa and metabolites in MASLD, delineating a tripartite "gut‑liver axis‑oxidative stress‑metabolic reprogramming" mechanism.
Introduction
MASLD affects over 30% of the global population, progressing from steatosis to MASH, fibrosis, and HCC (annual incidence 0.5–2.6% in MASH cirrhosis). The "multiple hits" model involves insulin resistance, lipotoxicity, inflammation, and gut dysbiosis. Microbiota alterations include increased Escherichia, Prevotella, and Streptococcus, with decreased Coprococcus and Ruminococcus.
Key Microbiota in MASLD
Escherichia coli: Barrier disruption allows E. coli translocation via the portal vein. The NF73‑1 strain from MASH patients signals via TLR2/TLR6, promoting NLRP3 activation and M1 macrophage polarisation. Flagellin induces endothelial‑to‑mesenchymal transition via TLR5/MyD88/NF‑κB/TWIST1, promoting fibrosis.
Prevotella: Its role is strain‑dependent. A Prevotella‑dominated enterotype associates with MASLD progression, especially in Asians, correlating with LPS biosynthesis. However, selected strains increase GLP‑1 secretion and improve glucose metabolism, while others aggravate obesity and insulin resistance. Prevotella is better considered a risk stratification marker than a universal target.
Akkermansia muciniphila: This beneficial commensal ameliorates MASLD through four mechanisms: (1) repairing intestinal barrier (upregulating occludin, ZO‑1); (2) suppressing inflammation via TLR2/γδT17 axis inhibition; (3) reprogramming lipid metabolism (reducing SREBP, activating AMPK, increasing CPT1β); and (4) improving insulin resistance (enhancing GLP‑1/PYY, restoring PI3K/Akt signaling).
Microbial Metabolites in MASLD
Endogenous Ethanol: High‑ethanol‑producing strains (K. pneumoniae, E. coli) generate ethanol via glycolysis. Portal vein ethanol is ~187‑fold higher than peripheral levels in MASLD. It promotes disease through: (1) acetaldehyde disrupting tight junctions; (2) CYP2E1‑mediated ROS production; (3) NADH/NAD+ imbalance activating SREBP‑1c lipogenesis and suppressing PPAR‑α oxidation.
Bile Acids: MASLD shows DCA enrichment and FXR desensitisation. DCA activates P2X7, suppresses mitophagy, and promotes pyroptosis via TXNIP/NLRP3. Secondary bile acids activate TGR5/cAMP, suppressing NLRP3. FXR activation reduces SREBP‑1c and improves insulin sensitivity but carries pro‑fibrotic risks. Therapeutic candidates (aldafermin, tropifexor) show benefits in liver enzymes and fat, with class effects (diarrhoea, pruritus). Benefit is most likely in F2‑F3 MASH patients.
Short‑Chain Fatty Acids (SCFAs): Butyrate enhances barrier function by inhibiting prolyl hydroxylase (stabilising HIF‑1α), promoting mucus repair, and restoring tight junctions via HDAC8/NF‑κB. It suppresses hepatic inflammation, promotes M2 macrophage polarisation, and improves lipid profiles. A butyrate‑based formula in a 12‑week trial reduced cholesterol and triglycerides. A prodrug strategy extends liver retention to 72h and shows anti‑fibrotic effects.
Choline and TMAO: Choline deficiency promotes lipid accumulation. Gut microbiota convert choline to TMA, then hepatic FMO3 produces TMAO. TMAO levels are higher in MASLD (OR 2.02). TMAO activates PERK/eIF2α, inducing ER stress and lipid accumulation, and increases miR‑34a/miR‑122. TMAO shows potential as a quantifiable biomarker.
Conclusions
Gut microbiota and metabolites are integral to MASLD pathogenesis through barrier integrity, inflammation, and metabolic reprogramming. Key players include E. coli (pro‑inflammatory), Prevotella (strain‑dependent), A. muciniphila (protective), endogenous ethanol, bile acids (dual roles), SCFAs (protective), and TMAO (pro‑inflammatory). Interventions should be guided by disease stage and dominant dysregulated pathways. Future studies should combine multi‑omics with spatial technologies to link metabolite signals to local inflammation and fibrosis, enabling pathway‑oriented stratification. Stratification of MASLD, MetALD, and cryptogenic SLD is essential to improve patient selection for microbiome‑based interventions.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00605
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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