Gut Microbiota from Short-Chain Chlorinated Paraffin-Exposed Mice Promotes Astrocyte Activation by Disrupting the Intestinal Tight Junction via Zonulin Upregulation.

Short-chain chlorinated paraffins (SCCPs) are novel toxicants in food and are reported to possess neurotoxicity. Here, we investigated the mechanism of SCCP-induced astrocyte activation and neuroinflammation. SCCP gavage induced astrocyte activation and neuronal cell death with the changes of gut microbiome and metabolites. Antibiotic cocktail administration to deplete the gut microbiome ameliorated the astrocyte activation and inflammation induced by SCCPs. In fecal microbiota transplantation (FMT) assays, mice that received transplanted gut microbiome from SCCP-treated mice showed increased astrocyte activation and elevated inflammatory response. In addition, SCCP exposure promotes zonulin expression and tight junction injury, and antibiotic cocktail administration inhibited that in the intestinal tract. Increased zonulin and tight junction injury were also observed in SCCPs_FMT mice. The zonulin inhibition protected the tight junction in the intestinal tract from SCCP exposure and suppressed astrocyte activation. In summary, this study proposes a novel possibility for SCCP-induced astrocyte activation and neurotoxicity by the gut microbiome-mediated zonulin expression and tight junction.