Maladaptive inflammatory and immune responses are responsible for intestinal barrier integrity and function dysregulation.
Proline/
serine-rich coiled-coil
protein 1 (PSRC1) critically contributes to the immune system, but direct data on the gut microbiota and the microbial metabolite
trimethylamine N-oxide (
TMAO) are lacking. Here, we investigated the impact of PSRC1 deletion on
TMAO generation and
atherosclerosis. We first found that PSRC1 deletion in
apoE-/- mice accelerated
atherosclerotic plaque formation, and then the gut microbiota and metabolites were detected using metagenomics and untargeted metabolomics. Our results showed that PSRC1 deficiency enriched
trimethylamine (TMA)-producing bacteria and functional potential for TMA synthesis and accordingly enhanced plasma
betaine and
TMAO production. Furthermore, PSRC1 deficiency resulted in a proinflammatory colonic phenotype that was significantly associated with the dysregulated bacteria. Unexpectedly, hepatic
RNA-seq indicated upregulated
flavin monooxygenase 3 (
FMO3) expression following PSRC1 knockout. Mechanistically, PSRC1 overexpression inhibited
FMO3 expression in vitro, while an ERα inhibitor rescued the downregulation. Consistently, PSRC1-knockout mice exhibited higher plasma
TMAO levels with a
choline-supplemented diet, which was gut microbiota dependent, as evidenced by
antibiotic treatment. To investigate the role of
dysbiosis induced by PSRC1 deletion in
atherogenesis,
apoE-/- mice were transplanted with the fecal microbiota from either
apoE-/- or PSRC1-/-
apoE-/- donor mice. Mice that received PSRC1-knockout mouse feces showed an elevation in
TMAO levels, as well as plaque
lipid deposition and macrophage accumulation, which were accompanied by increased plasma
lipid levels and impaired hepatic
cholesterol transport. Overall, we identified PSRC1 as an
atherosclerosis-protective factor, at least in part, attributable to its regulation of
TMAO generation via a multistep pathway. Thus, PSRC1 holds great potential for manipulating the gut microbiome and alleviating
atherosclerosis.