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 ER alpha 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.
