Gut microbiota and metabolomics in metabolic dysfunction-associated fatty liver disease: interaction, mechanism, and therapeutic value

Abstract

The global epidemic of Metabolic dysfunction-associated fatty liver disease (MAFLD) urgently demands breakthroughs in precision medicine strategies. Its pathogenesis centers on the cascade dysregulation of the gut microbiota-metabolite-liver axis: microbial dysbiosis drives hepatic lipid accumulation and fibrosis by suppressing short-chain fatty acid synthesis, activating the TLR4/NF-κB inflammatory pathway, and disrupting bile acid signaling. Metabolomics further reveals characteristic disturbances including free fatty acid accumulation, aberrantly elevated branched-chain amino acids (independently predictive of hepatic steatosis), and mitochondrial dysfunction, providing a molecular basis for disease stratification. The field of precision diagnosis is undergoing transformative innovation-multi-omics integration combined with AI-driven analysis of liver enzymes and metabolic biomarkers enables non-invasive, ultra-high-accuracy staging of fibrosis. Therapeutic strategies are shifting towards personalization: microbial interventions require matching to patient-specific microbial ecology, drug selection necessitates efficacy and safety prediction, and synthetically engineered "artificial microbial ecosystems" represent a cutting-edge direction. Future efforts must establish a "multi-omics profiling-AI-powered dynamic modeling-clinical validation" closed-loop framework to precisely halt MAFLD progression to cirrhosis and hepatocellular carcinoma by deciphering patient-specific mechanisms.

Keywords: gut microbiota; gut-liver axis; metabolic dysfunction-associated fatty liver disease (MAFLD); metabolomics; precision medicine.

Figure 1

Flowchart of literature selection process in this study.

Figure 2

Mechanisms of the gut-liver axis and bile acid metabolism in MAFLD. Bile acids (e.g., CA, cholic acid) derived from hepatic cholesterol (CHO) metabolism are synthesized via CYP7A1 (cholesterol 7α-hydroxylase). They enter intestinal circulation and activate the Farnesoid X Receptor (FXR), inducing fibroblast growth factor 15/19 (FGF15/19). This suppresses hepatic CYP7A1 via portal feedback, completing the enterohepatic loop. The axis interacts with gut microbiota metabolites and influences intestinal barrier integrity. Dysregulation of this pathway (highlighted in MAFLD-condition) links gut-liver crosstalk, microbial metabolites, and barrier dysfunction to disease progression.

Figure 3

Integrated metabolic network of glucose transport, lipid synthesis, and insulin signaling. Cellular glucose uptake, facilitated by Glucose Transporters (GLUT), fuels glycolysis to generate pyruvate and also regulates the transport of Branched-Chain Amino Acids (BCAAs), creating a fundamental link between carbohydrate and amino acid metabolism. Glucose-derived metabolites, notably acetyl-CoA, activate the Carbohydrate-Responsive Element-Binding Protein (ChREBP), which drives de novo lipogenesis by upregulating key enzymes: Acetyl-CoA Carboxylase (ACC) and Fatty Acid Synthase (FAS) for palmitic acid synthesis, and Diacylglycerol Acyltransferase (DGAT) for Triacylglycerol (TAG) assembly. Concurrently, lipid metabolism involves the release of free fatty acids via lipolysis, their cellular transport via specific transporters, and their utilization in pathways like β-oxidation or modulation of membrane fluidity. The Insulin Signaling Pathway is central to coordinating this metabolic network; insulin receptor activation promotes glucose uptake and anabolic processes, but impaired signaling disrupts critical functions including membrane fluidity, receptor efficacy, and overall metabolic homeostasis. This network features significant cross-talk, particularly where BCAA metabolism intersects with glucose flux and lipid synthesis pathways. Additionally, catecholamines (e.g., adrenaline) influence energy balance by activating β3-adrenergic receptors, which modulate lipolysis and energy expenditure, further integrating hormonal control with core metabolic processes.