Gut metabolite IPA alleviates white matter post-ICH injury by enhancing myelin debris phagocytosis via Stap1 inhibition

Intracerebral hemorrhage (ICH) causes neurological dysfunction and white matter injury (WMI) characterized by myelin loss, axonal injury and myelin debris accumulation. Microglia-mediated debris clearance is critical for WMI repair. The microbiota-gut-brain axis plays an essential role in the central nervous system diseases, one of the ways in which gut microbiota affects brain is via producing metabolites. Indole-3-proprionic acid (IPA), a tryptophan-derived metabolite that mainly produced by Clostridium sporogenes , exhibits anti-inflammatory and neuroprotective properties. However, its effect on ICH remains unclear. This study aims to investigate the IPA level after ICH and the therapeutic effects of IPA on neurological deficits and WMI, as well as the potential mechanisms underlying IPA-mediated neuroprotection.

Methods

An ICH model was established using C57BL/6 mice, which then received intragastric IPA (20 mg/kg/day). Fecal abundance of IPA-related genes and IPA levels in feces and plasma were measured by qPCR and UPLC-MS/MS. Behavioral tests, qPCR, and immunofluorescence staining were used to assess neurological function, myelin integrity, and axonal injury. In vitro , BV2 microglia, with or without Stap1 knockdown, were co-cultured with myelin debris to assess IPA’s effects on phagocytosis. Additionally, targeted plasma IPA profiling was performed in 30 ICH patients and 30 matched healthy controls.

Results

The relative abundance of IPA production-related genes and IPA levels in feces and plasma were significantly decreased after ICH and remained low into the chronical phase. After IPA administration, the neurological deficits, myelin loss and axonal injury of mice with ICH were significantly improved. In vitro , IPA increased BV2 microglia myelin debris phagocytosis by inhibiting Stap1 expression. IPA levels were significantly reduced in ICH patients, consistent with ICH mouse model.

Conclusions

Our findings demonstrated that the gut microbiota-derived metabolite IPA could facilitate neurological deficits recovery and alleviate WMI, which could be a promising therapeutic strategy to improve ICH prognosis.