Antibiotic-Induced Gut Microbiota Dysbiosis Modulates Host Transcriptome and m⁶A Epitranscriptome via Bile Acid...

Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N⁶-methyladenosine (m⁶A), the most abundant mammalian mRNA modification. However, which and how gut microbiota-derived metabolites reprogram host transcriptome and m⁶A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota-derived metabolites impact host transcriptome and m⁶A epitranscriptome using multiple mouse models and multi-omics approaches. Various antibiotics-induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ-free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid-producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m⁶A epitranscriptome in multiple tissues. Mechanistically, the expression of m⁶A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m⁶A biology. Collectively, these results demonstrate that antibiotic-induced gut dysbiosis regulates the landscape of host transcriptome and m⁶A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression.