UC Davis

The development of extra-intestinal co-morbidities, such as anxiety, depression, and cognitive deficits, due to an impaired microbiota-gut-brain (MGB) axis in children with inflammatory bowel diseases (IBD) remains an important area of investigation. Exposure to inflammation during early adolescence, a critical period for gut and brain development, alters MGB axis signaling, potentially leading to long-term behavioral deficits and intestinal dysbiosis. Therefore, finding potential treatments that resolve the dysregulation of the MGB axis are crucial to mitigate behavioral and cognitive deficits in children with IBD. In this study, we utilized a mouse model of pediatric IBD to determine if supplementation with tributyrin, a prodrug of butyrate, a short-chain fatty acid (SCFA) and key microbial metabolite, can restore long-term impairments to the MGB axis caused by dextran sodium sulfate (DSS)-induced colitis at weaning. We found that butyrate supplementation, via tributyrin administration, mitigates behavioral and cognitive deficits and persistent inflammation in the distal colon in adulthood. As peroxisome proliferator-activated receptor gamma (PPARγ) is a known butyrate sensor that has been identified as a potential therapeutic target for IBD, we hypothesized that the beneficial effects of butyrate supplementation are mediated by PPARγ. We showed that tributyrin treatment restored colitis-induced alteration of PPARγ signaling in the distal colon and hippocampus. To assess whether PPARγ was mediating butyrate-induced MGB axis benefits in IBD, we next employed mice with a conditional knockout (cKO) of Pparg on intestinal epithelial cells (IECs), compared to wildtype littermate controls. Preliminary studies show that PPARγ IEC cKO increases the severity of DSS-induced colitis at P29, as well as increases the persistent inflammation in the adult distal colon caused by pediatric colitis. Behavioral testing indicates that Pparg IEC cKO may increase anxiety-like behavior and decrease recognition memory in adulthood, however no alteration to gene expression in the adult hippocampus was detected. Taken together, these studies demonstrated the effectiveness of supplementation with a beneficial microbial metabolite as a potential novel treatment to restore impairments to the MGB axis in pediatric IBD.