A recent study explores the role of TM6SF2 in metabolic dysfunction-associated steatotic liver disease (MASLD) through the gut-liver axis. By constructing a gut-specific TM6SF2 knockout mouse model and comparing it with wild-type mice under high-fat diet (HFD) conditions, researchers have identified significant differences in lipid deposition, gut microbiota composition, and serum metabolites. These findings suggest that TM6SF2 plays a crucial role in regulating intestinal flora and the progression of MASLD.

In this investigation, scientists utilized CRISPR/Cas9 technology to create a TM6SF2 gut-specific knockout (GKO) mouse model. Both GKO and wild-type mice were subjected to either a HFD or a control diet for 16 weeks. Subsequent analyses revealed that GKO mice on a HFD exhibited increased liver and intestinal lipid accumulation compared to their wild-type counterparts. Furthermore, the gut microbiota of these GKO mice displayed a notable reduction in the Firmicutes/Bacteroidetes ratio when exposed to a HFD. This dietary intervention also led to diminished diversity and abundance of the microbiota, alongside alterations in its overall composition.

Additionally, biochemical markers such as aspartate aminotransferase, alanineaminotransferase, and total cholesterol levels were elevated in HFD-fed GKO mice relative to control mice, while triglyceride levels were observed to be lower. Serum metabolite profiling uncovered an increase in the expression of 17 metabolites, including LPC [18:0/0-0], and a decrease in 22 others, such as benzene sulfate. Notably, LPC (18:0/0-0) differential metabolites may serve as potential biomarkers for HFD-induced MASLD exacerbation in GKO mice.

The study concludes that the absence of TM6SF2 in the gut intensifies liver lipid accumulation and injury in MASLD models. This research underscores the importance of TM6SF2 in modulating intestinal flora and influencing the development of MASLD through the gut-liver axis. Such insights could pave the way for novel therapeutic strategies targeting TM6SF2 to mitigate MASLD progression.