biostudies-literatureZhang XFood and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (HMRF)Research Grants Council, University Grants Committee (RGC, UGC)National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)102-119https://www.ebi.ac.uk/biostudies/studies/S-EPMC11774752biostudies-literatureUnknown7(1)Transmembrane-6 superfamily member 2 (TM6SF2) regulates hepatic fat metabolism and is associated with metabolic dysfunction-associated steatohepatitis (MASH). TM6SF2 genetic variants are associated with steatotic liver disease. The pathogenesis of MASH involves genetic factors and gut microbiota alteration, yet the role of host-microbe interactions in MASH development remains unclear. Here, we discover that mice with intestinal epithelial cell-specific knockout of Tm6sf2 (Tm6sf2^ΔIEC) develop MASH, accompanied by impaired intestinal barrier and microbial dysbiosis. Transplanting stools from Tm6sf2^ΔIEC mice induces steatohepatitis in germ-free recipient mice, whereas MASH is alleviated in Tm6sf2^ΔIEC mice co-housed with wild-type mice. Mechanistically, Tm6sf2-Nature metabolismIntestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis.PMC1177475214117422 and 1411712308191336T12-703/19-R82222901, 82103355 and 82272619Wu JPan YJi FLau HCWong CCZhou YXu HYu JHa SLee HWZhao YLiang CLi XWong VWZhang YZhang XNg QWCheung AHKLiu CSong YLo JCYfalseIntestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis.Transmembrane-6 superfamily member 2 (TM6SF2) regulates hepatic fat metabolism and is associated with metabolic dysfunction-associated steatohepatitis (MASH). TM6SF2 genetic variants are associated with steatotic liver disease. The pathogenesis of MASH involves genetic factors and gut microbiota alteration, yet the role of host-microbe interactions in MASH development remains unclear. Here, we discover that mice with intestinal epithelial cell-specific knockout of Tm6sf2 (Tm6sf2^ΔIEC) develop MASH, accompanied by impaired intestinal barrier and microbial dysbiosis. Transplanting stools from Tm6sf2^ΔIEC mice induces steatohepatitis in germ-free recipient mice, whereas MASH is alleviated in Tm6sf2^ΔIEC mice co-housed with wild-type mice. Mechanistically, Tm6sf2-2025-01-01T00:00:00Z2025 Jan2026-06-02T01:52:20.89Z2025-04-07T04:18:27.058ZS-EPMC117747523977988910.1038/s42255-024-01177-7