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 toxicantsinfood and are reported to possess neurotoxicity. Here, we investigatedthe mechanism of SCCP-induced astrocyte activation and neuroinflammation.SCCP gavage induced astrocyte activation and neuronal cell death withthe changes of gut microbiome and metabolites. Antibiotic cocktailadministration to deplete the gut microbiome ameliorated the astrocyteactivation and inflammation induced by SCCPs. In fecal microbiotatransplantation (FMT) assays, mice that received transplanted gutmicrobiome from SCCP-treated mice showed increased astrocyte activationand elevated inflammatory response. In addition, SCCP exposure promoteszonulin expression and tight junction injury, and antibiotic cocktailadministration inhibited that in the intestinal tract. Increased zonulinand tight junction injury were also observed in SCCPs_FMT mice. Thezonulin inhibition protected the tight junction in the intestinaltract from SCCP exposure and suppressed astrocyte activation. In summary,this study proposes a novel possibility for SCCP-induced astrocyteactivation and neurotoxicity by the gut microbiome-mediated zonulinexpression and tight junction.

Automated summary

Short-chain chlorinated paraffins (SCCPs) are toxic substances found in food that have been shown to have neurotoxic effects. This study investigated the mechanism by which SCCP exposure activates astrocytes and leads to neuroinflammation. The results showed that SCCP intake caused astrocyte activation and neuronal cell death, accompanied by changes in the gut microbiome and its metabolites. Depleting the gut microbiome through antibiotic treatment reduced astrocyte activation and inflammation induced by SCCPs. Furthermore, fecal microbiota transplantation from SCCP-treated mice to healthy mice resulted in increased astrocyte activation and inflammation. SCCP exposure also led to increased expression of zonulin and damage to tight junctions in the intestinal tract, which were inhibited by antibiotic treatment. These findings suggest that SCCP-induced astrocyte activation and neurotoxicity may be mediated by the gut microbiome-mediated zonulin expression and tight junction impairment.