The gut microbial metabolite 3-indolepropionic acid as a functional neuroprotective agent against intracerebral hemorrhage: integrating epidemiological screening with in vivo validation.

Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Emerging evidence highlights the diet-gut-brain axis in neurological outcomes, yet the specific metabolic mediators remain elusive. This study integrated epidemiological, genetic, and experimental approaches to investigate the potential neuroprotective role of gut-derived metabolites in ICH. Utilizing Global Burden of Disease data and Mendelian randomization analysis, we explored the associations between dietary habits and ICH, and investigated putative causal relationships between specific gut microbiota and disease risk. Subsequent network pharmacology analysis predicted that 3-indolepropionic acid (3-IPA) might exert neuroprotective effects primarily through anti-apoptotic pathways. To evaluate these findings in vivo, we established a mouse model of ICH. Administration of 3-IPA significantly ameliorated neurological deficits and improved cognitive memory in the Morris water maze test. Furthermore, immunofluorescence and Western blot analyses indicated that 3-IPA treatment was associated with the upregulation of the anti-apoptotic protein BCL2 and the reduction of pro-apoptotic markers in the peri-hematomal region. In conclusion, our multidisciplinary study outlines a potential biological pathway linking dietary patterns, gut microbial metabolism, and brain injury recovery. Our findings suggest that the gut microbial metabolite 3-IPA protects against ICH-induced secondary brain injury, potentially by attenuating neuronal apoptosis, highlighting it as a promising metabolic intervention target for ICH therapy.