Gut microbiota-derived metabolite trimethylamine N-oxide alters the host epigenome through inhibition of S-adenosylhomocysteine hydrolase.

The gut microbiota profoundly influences host metabolism through the production of bioactive metabolites that modulate cellular pathways. Among these, trimethylamine N-oxide (TMAO) has emerged as an enigmatic molecule linking dietary factors to cellular dysfunction in cardiovascular, neurological, and oncologic disorders. Here, we investigate the cellular and systemic impact of TMAO on metabolic pathways and epigenetic landscapes. Using cultured cells and a mouse model that simulates endogenous TMAO production, we demonstrate that TMAO disrupts the methionine cycle and dynamically remodels chromatin states via histone posttranslational methylation and acetylation. Compared to liver, brain cortex and hippocampus show greater sensitivity to TMAO levels. Mechanistically, TMAO noncompetitively inhibits S-adenosylhomocysteine hydrolase, leading to accumulation of SAH and subsequent reduction in global methylation capacity. In vitro overexpression of SAM synthase, methionine adenosyltransferase 2A, rescues many of these epigenetic defects by boosting SAM/SAH, highlighting the tissue/cell-specific importance of balancing SAM synthesis and SAH clearance. These mechanistic findings reveal that TMAO targets S-adenosylhomocysteine hydrolase and disrupts the methionine cycle, expanding our understanding of how gut-derived metabolites modulate chromatin states and identifying potential avenues to mitigate TMAO-associated disease.