The liver-gut-brain axis in metabolic dysfunction-associated steatotic liver disease: bidirectional communication, clinical implications, and future perspectives.

BACKGROUND

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of adults worldwide and is increasingly recognized as a multisystem disorder. In addition to hepatic and cardiometabolic complications, many patients report fatigue, depression, anxiety, sleep disturbance, and subjective cognitive complaints. These manifestations are clinically important but correlate inconsistently with liver histology and may arise from several interacting mechanisms.

AIM: To critically synthesize evidence on the liver-gut-brain axis in MASLD, distinguish established pathways from indirect or preclinical hypotheses, and evaluate implications for biomarkers, patient assessment, and treatment.

METHODS

PubMed was searched through July 15, 2026 using combinations of terms related to MASLD/MASH, intestinal barrier function, gut microbiota, autonomic and stress signaling, hepatic inflammation and fibrosis, neuroinflammation, cognition, biomarkers, and treatment. Guidelines, randomized trials, prospective human studies, systematic reviews, and mechanistically informative experimental studies were prioritized. Evidence derived from cirrhosis, hepatic encephalopathy, other diseases, or animal models is explicitly identified.

RESULTS

The axis comprises neural, endocrine, immune, and metabolic communication. Stress-related hypothalamic-pituitary-adrenal and sympathetic activation may influence behavior, adipose tissue, intestinal motility, mucosal immunity, and epithelial integrity. Barrier dysfunction can increase portal exposure to microbial products that activate hepatic inflammatory pathways and aggravate insulin resistance. Conversely, hepatic and intestinal cytokines, bile acids, hepatokines, and microbial metabolites may signal at vascular and neural interfaces, although direct causal evidence for brain effects in noncirrhotic MASLD remains limited. Lifestyle and cardiometabolic risk management remain foundational. Resmetirom and semaglutide have regulatory indications for selected adults with noncirrhotic MASH and moderate-to-advanced fibrosis, whereas microbiota-directed therapies and neuromodulation remain investigational.

CONCLUSION

The liver-gut-brain axis is a useful integrative framework, but its component pathways have unequal evidentiary support. Longitudinal human studies using standardized hepatic, microbial, inflammatory, autonomic, and neurobehavioral outcomes are required before axis-based biomarkers or endotypes can guide routine care.