Social stress worsens colitis through beta-adrenergic-driven oxidative stress in intestinal mucosal compartments

Abstract

AbstractPsychological stress is a known risk factor for inflammatory bowel disease (IBD), but the mechanisms linking stress to worsened disease remain unclear. Because distinct stress paradigms activate different neuroimmune circuits, it is critical to investigate model-specific effects. We examined how social stress primes the gut for heightened inflammation and whether this is mediated by specific neuroendocrine pathways, including 2-/{beta}-adrenergic (sympathetic) or glucocorticoid/ corticotropin-releasing hormone receptor (CRHR1) (HPA axis) signaling. Mice were exposed to social disruption (SDR) stress and pre- treated with pharmacological antagonists targeting 2-adrenergic receptors (idazoxan), {beta}-adrenergic receptor ({beta}-AR) (propranolol), glucocorticoid receptor (mifepristone), or CRHR1 (antalarmin). Intestinal epithelial cell (IEC) gene expression and microbiota composition were assessed following SDR. To determine disease impact, SDR was combined with either Citrobacter rodentium infection or dextran sulfate sodium (DSS)-induced colitis, with interventions including the {beta}-AR inhibitor propranolol and the NADPH oxidase inhibitor apocynin. SDR significantly upregulated expression of Dual oxidase 2 (Duox2), Dual oxidase maturation factor 2 (Duoxa2), and inducible nitric oxide synthase 2 (Nos2) in IECs (2- to 8- fold, p < 0.0001), effects reversed by {beta}-AR blockade but not 2-adrenergic, CRH, or glucocorticoid inhibition. SDR also induced microbial dysbiosis, characterized by reduced alpha-diversity and compositional shifts, which was rescued by propranolol. Stress exacerbated disease severity in both infectious (C. rodentium) and chemically induced (DSS) colitis, amplifying colonic expression of Duox2, Nos2, and Ccl2, especially. Apocynin mitigated stress-induced ROS/RNS production and body weight loss even prior to colitis onset, reduced colonic gene expression of key oxidative enzymes, and alleviated both chemically and infectious colitis severity. These findings provide strong evidence that social stress sensitizes the gut to inflammation through {beta}-adrenergic and NADPH oxidase-driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD. HighlightsSocial disruption (SDR) and restraint stress (RST) activate distinct neuroendocrine pathways, with SDR driving epithelial ROS/RNS pathways via {beta}-adrenergic signaling. {beta}-adrenergic blockade prevents SDR-induced epithelial priming, microbial dysbiosis, and colitis exacerbation. NADPH oxidase inhibition with apocynin mitigates stress-induced oxidative stress and disease severity across different colitis models. Findings identify {beta}-adrenergic and redox pathways as therapeutic targets for stress-exacerbated IBD.