Microbial metabolite indole‐3‐propionic acid preserves astrocytic mitochondrial mitofusin 2 to limit neuroinflammation after traumatic brain injury
Ziwen Zhang, Kai Wang, Liangbo Wang, Wencong Li, Hao Guo, Meng Xu, Tinghao Wang, Jiahui Ren, Ting Zhu, Jiahui Wang, Wenxing Cui, Jinpeng Zhou, Yang Tian, Liying Han, Chengxuan Guo, Shuoyao Ma, Qiang Wang, Zhihong Li, Yaning Cai, Jingyu Dong, Xun Wu, Haixiao Liu, Yan QuAbstract
The gut–brain axis connects the gastrointestinal tract and the central nervous system (CNS), helping maintain CNS homeostasis. Gut microbiome dysbiosis has been linked to the pathogenesis and progression of traumatic brain injury (TBI). Using sequencing‐based profiling of gut microbes and metabolites, we found that lower serum indole‐3‐propionic acid (IPA) levels were significantly associated with increased cerebral edema and poorer neurological outcomes in patients. In a mouse TBI model, oral IPA supplementation markedly reduced lesion volume, preserved blood–brain barrier integrity, decreased neuronal apoptosis and cerebral edema, and improved neurological function. Mechanistically, IPA directly activated the aryl hydrocarbon receptor in astrocytes and suppressed interferon regulatory factor 1‐driven induction of the ring finger and FYVE‐like domain containing E3 ubiquitin protein ligase (RFFL). This suppression prevented RFFL‐dependent ubiquitination of mitofusin 2 (MFN2), thereby preserving mitochondrial dynamics and curtailing the release of astrocyte‐derived neurotoxic factors and chemokines that drive peripheral immune cell infiltration. Astrocyte‐specific deletion of RFFL reproduced the neuroprotective effects of IPA, limiting immune cell infiltration, reducing lesion size and edema, and enhancing recovery. Together, these findings identify gut‐derived IPA as a neuroprotective regulator in TBI and reveal an IPA → AhR → IRF1 → RFFL → MFN2 pathway that maintains astrocytic mitochondrial homeostasis, thereby restraining reactive astrogliosis and neuroinflammation. Thus, IPA and components of this pathway represent promising therapeutic targets for mitigating secondary injury after TBI.