TY - JOUR T1 - Psychological stress disrupts intestinal epithelial cell function and mucosal integrity through microbe and host-directed processes JF - bioRxiv DO - 10.1101/2021.10.25.465765 SP - 2021.10.25.465765 AU - Jacob M. Allen AU - Amy R. Mackos AU - Robert M. Jaggers AU - Patricia C. Brewster AU - Mikaela Webb AU - Chia-Hao Lin AU - Chris Ladaika AU - Ronald Davies AU - Peter White AU - Brett R. Loman AU - Michael T. Bailey Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/26/2021.10.25.465765.abstract N2 - Psychological stress alters the gut microbiota and predisposes individuals to increased risk for enteric infections and chronic bowel conditions. Intestinal epithelial cells (IECs) are responsible for maintaining homeostatic interactions between the gut microbiota and its host. In this study, we hypothesized that disruption to colonic IECs is a key factor underlying stress-induced disturbances to intestinal homeostasis. Conventionally raised (CONV-R) and germ-free (GF) mice were exposed to a social disruption stressor (Str) to ascertain how stress modifies colonic IECs, the mucosal layer, and the gut microbiota. RNA sequencing of IECs isolated from CONV-R mice revealed a robust pro-inflammatory (Saa1, Il18), pro-oxidative (Duox2, Nos2), and antimicrobial (Reg3b/g) transcriptional profile as a result of Str. This response occurred concomitant to mucus layer thinning and signs of microbial translocation. In contrast to their CONV-R counterparts, IECs from GF mice or mice treated with broad spectrum antibiotics exhibited no detectable transcriptional changes in response to Str. Nevertheless, IECs from Str-exposed GF mice exhibited an altered response to ex vivo bacterial challenge (increased dual Oxidase-2 [Duox2] and nitric oxide synthase-2 (Nos2)), indicating that STR primes host IEC pro-oxidative responses. In CONV-R mice stress-induced increases in colonic Duox2 and Nos2 (ROS generating enzymes) strongly paralleled changes to microbiome composition and function, evidencing Str-mediated ROS production as a primary factor mediating gut-microbiota dysbiosis. In conclusion, a mouse model of social stress disrupts colonic epithelial and mucosal integrity, a response dependent on an intact microbiota and host stress signals. Together these preclinical findings may provide new insight into mechanisms of stress-associated bowel pathologies in humans.Competing Interest StatementThe authors have declared no competing interest.IECIntestinal epithelial cellROSReactive oxygen speciesCONV-RConventionally-raisedGFGerm-freeIlInterleukinSaaSerum amyloid aDuoxDual oxidaseReg3Regenerating islet-derived protein 3Nos2nitric oxide synthase-2 ER -