Abstract
Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolic diseases, including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of this efficacy has remained elusive. Here, we show that TRF improves MASLD, which is associated with a significant enrichment of Ruminococcus torques (R.torques). Mechanistically, R.torques suppresses the intestinal HIF-2α-ceramide pathway via the production of 2-hydroxy-4-methylpentanoic acid (HMP). We identify rtMor as a 4-methyl-2-oxopentanoate reductase that synthesizes HMP in R.torques. Finally, we show that either the colonization of R.torques or oral HMP supplementation can ameliorate inflammation and fibrosis in a MASH mouse model. These findings identify R.torques and HMP as potential TRF mimetics for the treatment of metabolic disorders.
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