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

Psychological 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 α2-/β-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 α2-adrenergic receptors (idazoxan), β-adrenergic receptor (β-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 β-AR inhibitors 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 β-AR blockade but not α2-adrenergic, CRH, or glucocorticoid inhibition. SDR also induced microbial dysbiosis, characterized by reduced α -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 expression of key oxidative enzymes, especially DUOX2, and alleviated both chemically and infectious colitis severity. These findings provide strong evidence that social stress sensitizes the gut to inflammation through β-adrenergic and NADPH oxidase-driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD.