The gut microbiota metabolite IAA modulates gut-brain axis to alleviate reproductive endocrine dysfunction in PCOS.

BACKGROUND

Circadian rhythm disruption (CD) and gut microbiota dysbiosis are emerging drivers of the polycystic ovary syndrome (PCOS). However, the specific microbial metabolites mediating the gut-brain-ovary axis remain poorly defined, limiting the development of targeted microecological therapies.

OBJECTIVES

We aimed to identify the functional role of the gut microbiota-derived metabolite indole-3-acetic acid (IAA) in PCOS, dissecting its peripheral and central mechanisms in ameliorating reproductive-endocrine phenotypes.

METHODS

Multi-omics analyses of clinical PCOS cohorts (feces, serum, follicular fluid) were integrated with CD and DHEA-induced rodent models. Mechanistic pathways were dissected using microbiota-depleted (ABX) models, pharmacokinetic profiling, in vivo chemogenetics via Fos-CreERT2 transgenic mice, and gene silencing (Clock siRNA) in vitro, combined with histological and immunological evaluations.

RESULTS

We established the essential role of the gut microbiota in development of CD-induced PCOS phenotypes in rats. Integrating this finding with multi-omics profiling, we identified a profound impairment in indole biosynthesis, characterized by significantly diminished serum IAA levels in both PCOS rat models and clinical patients. Exogenous IAA supplementation across multiple PCOS rodent models ameliorated hyperandrogenism, restored estrous cyclicity, and improved ovarian pathology. Mechanistically, IAA exerted an integrated protective effect across the gut-brain axis. Locally, IAA reinforced intestinal barrier integrity via a CLOCK-dependent pathway, restricting lipopolysaccharide (LPS) translocation and systemic inflammation. Concurrently, IAA treatment suppressed the pathological hyperactivity of ventromedial hypothalamus (VMH) neurons. Crucially, the therapeutic efficacy of IAA was neutralized in microbiota-depleted models, indicating that its restorative function is fundamentally contingent upon a pre-existing dysbiotic context.

CONCLUSIONS

Our study suggests that the gut microbiota plays a pivotal role in mediating CD-induced PCOS-like phenotypes. IAA functions as a crucial microbial mediator that alleviates PCOS by concurrently restoring peripheral intestinal barriers, dampening systemic inflammation, and rectifying central VMH neuroendocrine hyperactivity. These findings highlight IAA as a microbiota-dependent precision modulator for resetting the gut-brain-ovary axis in PCOS.