Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis

Area of Science:

• Hepatology
• Gastroenterology
• Microbiology

Background:

• Transmembrane-6 superfamily member 2 (TM6SF2) influences hepatic fat metabolism and is linked to steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH).
• The interplay between host genetics, gut microbiota, and MASH pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of TM6SF2 in intestinal epithelial cells (IECs) in MASH development.
• To elucidate the mechanisms linking TM6SF2 deficiency, gut microbiota, and liver pathology.

Main Methods:

• Generated mice with IEC-specific TM6SF2 knockout (Tm6sf2^ΔIEC).
• Utilized fecal microbiota transplantation and co-housing experiments.
• Analyzed intestinal barrier function, microbial composition, and lysophosphatidic acid (LPA) levels.
• Assessed MASH development and therapeutic potential of LPA receptor inhibition.

Main Results:

• Tm6sf2^ΔIEC mice spontaneously developed MASH, characterized by impaired intestinal barrier and gut dysbiosis.
• Fecal microbiota from Tm6sf2^ΔIEC mice induced MASH in germ-free recipients.
• TM6SF2 deficiency increased intestinal free fatty acid secretion, leading to barrier dysfunction, pathobiont enrichment, and elevated LPA.
• LPA translocation from gut to liver promoted lipid accumulation and inflammation, which was suppressed by LPA receptor inhibition.

Conclusions:

• TM6SF2 in IECs is crucial for maintaining intestinal homeostasis and preventing MASH.
• Gut microbiota dysbiosis and elevated LPA are key mediators in TM6SF2 deficiency-induced MASH.
• Modulating gut microbiota or blocking LPA signaling represents a potential therapeutic strategy for MASH associated with TM6SF2 deficiency.