PM2.5 exacerbates brain injury in diarrhea-predominant irritable bowel syndrome mice via the disruption of the microbiota-gut-brain axis and the restoring effect of resveratrol.

Fine particulate matter (PM2.5) poses escalating neurological risks, but its impact on susceptible populations, such as those with diarrhea-predominant irritable bowel syndrome (IBS-D), via the gut-brain axis remains unclear. This study investigated whether PM2.5 exacerbates gut-brain axis dysfunction in IBS-D mice and whether resveratrol (RES) offers protection. Six mouse models were established: CON, IBS-D, IBS-D + RES, PM2.5, PM2.5+IBS-D, and PM2.5+IBS-D + RES. Using 16S rRNA sequencing and non-targeted metabolomics, we assessed gut microbiota, metabolic profiles, intestinal sensitivity, brain histology, and anxiety-like behaviors. Protein levels of IL-6, MCP-1, 5-HT, Iba-1, iNOS, MDA, and GSH in brains, along with tryptophan, Tryptophan Hydroxylase 1, 5-HT, cholesterol, ZO-1, and Occludin in intestines, were quantified. PM2.5 exposure significantly exacerbated neuroinflammation, hippocampal damage, and anxiety-like behaviors in IBS-D mice. These changes were accompanied by gut barrier injury (downregulation of ZO-1/Occludin), dysbiosis (altered proportions of probiotics/pathogens), metabolic disruption (elevated tryptophan and cholesterol), increased intestinal and brain 5-HT, and elevated brain IL-6/MCP-1. Notably, PM2.5 exposure further enhanced microglial activation (increased Iba-1) and pro-inflammatory enzyme expression (elevated iNOS), induced oxidative stress in the brain, and suppressed intestinal IDO1. Crucially, RES effectively reversed these abnormalities by restoring probiotic abundance, normalizing tryptophan/cholesterol metabolism, and reinforcing gut-brain barriers, thereby suppressing neuroinflammation and anxiety-like behaviors. Our findings reveal that PM2.5 promotes brain injury via the microbiota-gut-brain axis in susceptible IBS-D mice, highlighting the tryptophan-tryptophan hydroxylase-5-HT pathway as a key mechanism. This study not only elucidates a novel neurotoxic mechanism of PM2.5 but also identifies RES as a promising intervention against its hazardous effects.