Intestinal TM6SF2 Protects Against Metabolic Dysfunction-associated Steatohepatitis through the Gut-Liver Axis

Transmembrane-6 superfamily member 2 (TM6SF2) regulates hepatic fat metabolism and is closely associated with metabolic dysfunction-associated steatohepatitis (MASH). MASH involves genetic predisposition and gut microbiota alteration, yet the role of host-microbes interaction in disease development remains unclear. Here, we discover that mice with Tm6sf2 specific knockout in intestinal epithelial cells (Tm6sf2ΔIEC) developed MASH, accompanied by impaired intestinal barrier and microbial dysbiosis. Transplanting stools from Tm6sf2ΔIEC mice induce steatohepatitis in recipient germ-free mice, whereas MASH is alleviated in Tm6sf2ΔIEC mice cohoused with wildtype mice. Mechanistically, Tm6sf2-deficient intestinal cells secrete increased free fatty acids by interplaying with fatty acid-binding protein 5 to induce intestinal barrier dysfunction, pathobiont enrichment and elevated lysophosphatidic acid (LPA). LPA is further translocated to the liver, causing lipid accumulation and inflammation. Pharmacological inhibition of LPA receptor suppresses MASH in both Tm6sf2ΔIEC and wildtype mice. Hence, modulating microbiota or blocking metabolite receptor is potential therapeutics against TM6SF2 deficiency-induced MASH.