Investigating the Role of Intestinal TM6SF2 Knockout in Metabolic Dysfunction-associated Steatohepatitis
Metabolic dysfunction-associated steatohepatitis (MASH)is a complex disease involving genetic predisposition and gut microbiota. However, how such host gene-microbiota interactions contribute to MASH remains unclear. Transmembrane-6 superfamily member 2 (Tm6sf2) is regulator of hepatic fat metabolism. Here, we discovered that mice lacking Tm6sf2 systematically exhibited more pronounced steatohepatitis than mice with liver-specific Tm6sf2-knockout. Intestine epithelial cell-specific Tm6sf2-knockout (Tm6sf2-IKO) mice spontaneously developed MASH accompanied with impaired gut barrier and gut microbiota dysbiosis. Transplanting stools from Tm6sf2-IKO mice induced steatohepatitis in recipient germ-free mice, whereas co-housing Tm6sf2-IKO mice with Tm6sf2flox controls improved MASH. Mechanistically, intestinal cells of Tm6sf2-IKO mice secreted increased arachidic acid through direct binding of Tm6sf2 and fatty acid-binding protein 5 (Fabp5), which induced intestinal barrier dysfunction, pathobiont enrichment, and elevated lysophosphatidic acid (LPA). LPA translocated to the liver via portal vein, leading to hepatic lipid accumulation and inflammation. Pharmacological inhibition of LPA receptor suppressed MASH in both Tm6sf2-IKO and WT mice. Thus, intestinal TM6SF2 deficiency interrupts intestinal homeostasis, promoting MASH through increased LPA translocation. Modulating microbiota or blocking metabolite receptor may prevent TM6SF2 deficiency-induced MASH.