Rifaximin improves anxiety- and depression-like behaviors in rats by regulating NPY in the colon and mPFC.

Growing evidence implicates the brain-gut axis in depression pathogenesis, though the underlying mechanisms remain elusive. This study investigated the antidepressant potential of rifaximin, a non-absorbable antibiotic, and its mechanisms via the brain-gut axis in a rat chronic unpredictable mild stress (CUMS) model. We found that CUMS induced anxiety- and depression-like behaviors, impaired colonic endocrine cell function, and downregulated neuropeptide Y (NPY) expression in both the colon and medial prefrontal cortex (mPFC). CUMS also altered neuronal activation and disrupted key neurotransmitter (GABA, Glu, 5-HT) balance in the mPFC. Rifaximin treatment ameliorated these behavioral deficits, restored colonic endocrine function, and increased NPY levels in both the colon and mPFC. Furthermore, it normalized CUMS-induced alterations in neuronal activation and neurotransmitter balance. Crucially, functional knockdown of NPY in the mPFC not only reduced colonic NPY expression in control rats but also abolished the anxiolytic effects of rifaximin in CUMS-treated rats. In summary, this study suggests that in the CUMS model, rifaximin can play an anxiolytic and antidepressant effect, and its mechanism may be related to the rifaximin's regulation on NPY mediated gut-brain axis between colon and mPFC.