Angptl4 integrates dietary and microbial signals to disrupt gut barrier function in MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver morbidity, yet mechanisms linking gut barrier dysfunction to early progression remains poorly defined. We identify intestinal angiopoietin-like 4 (Angptl4) as a central integrator of dietary and microbial signals that governs barrier integrity and hepatic oxidative stress, key early MASLD features. Using intestinal-specific Angptl4 knockout mice, mechanistic in vitro systems, humanized microbiota models, and multi-cohort human studies, we show that intestinal Angptl4 expression is regulated by dietary fatty acids via PPARα signaling and microbiota-derived pattern-recognition pathways, including flagellin-activated-TLR5-EGR1 activation, alongside diet-associated shifts in TLR signaling. These signals destabilize epithelial barriers, amplifying gut-to-liver metabolic and microbial flux. In human cohorts, fecal Angptl4 increases with dysbiosis and metabolic dysfunction, capturing a gut barrier-related dimension distinct from endotoxemia or acute injury. Thus, intestinal Angptl4 emerges as a mechanistic hub linking diet, microbiota, and gut-liver dysfunction, supporting precision barrier-targeted strategies in MASLD.