Caetano-Silva Elisa, Hilt Miranda, Valishev Ivan, Lim Casey, Kasperek Mikaela, Shrestha Akriti, McCusker Robert, Armstrong Heather, Loman Brett, Bailey Michael, Allen Jacob M
Department of Health and Kinesiology, University of Illinois at Urbana-Champaign, 906 S Goodwin Ave, Urbana, IL 61801, USA.
Division of Nutritional Sciences, University of Illinois at Urbana Champaign, 905 S Goodwin Ave, Urbana, IL 61801, USA.
bioRxiv. 2025 Jul 18:2025.07.15.664961. doi: 10.1101/2025.07.15.664961.
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 pretreated 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 infection or dextran sulfate sodium (DSS)-induced colitis, with interventions including the β-AR inhibitor propranolol and the NADPH oxidase inhibitor apocynin. SDR significantly upregulated expression of Dual oxidase 2 , Dual oxidase maturation factor 2 , and inducible nitric oxide synthase 2 in IECs (2- to 8-fold, < 0.0001), effects reversed by β-AR blockade but not α2-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 () and chemically induced (DSS) colitis, amplifying colonic expression of , , and 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 β-adrenergic and NADPH oxidase-driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD.
心理压力是炎症性肠病（IBD）的一个已知风险因素，但压力与疾病恶化之间的联系机制仍不清楚。由于不同的应激模式会激活不同的神经免疫回路，因此研究特定模型的影响至关重要。我们研究了社会压力如何使肠道易于发生炎症加剧，以及这是否由特定的神经内分泌途径介导，包括α2-/β-肾上腺素能（交感神经）或糖皮质激素/促肾上腺皮质激素释放激素受体（CRHR1）（下丘脑-垂体-肾上腺轴）信号传导。将小鼠暴露于社会破坏（SDR）应激，并使用靶向α2-肾上腺素能受体（咪唑克生）、β-肾上腺素能受体（β-AR）（普萘洛尔）、糖皮质激素受体（米非司酮）或CRHR1（安他乐）的药理拮抗剂进行预处理。在SDR后评估肠道上皮细胞（IEC）基因表达和微生物群组成。为了确定疾病影响，将SDR与感染或葡聚糖硫酸钠（DSS）诱导的结肠炎相结合，干预措施包括β-AR抑制剂普萘洛尔和NADPH氧化酶抑制剂夹竹桃麻素。SDR显著上调了IEC中双氧化酶2、双氧化酶成熟因子2和诱导型一氧化氮合酶2的表达（2至8倍，<0.0001），β-AR阻断可逆转这些影响，但α2-肾上腺素能、促肾上腺皮质激素释放激素或糖皮质激素抑制则不能。SDR还诱导了微生物失调，其特征是α多样性降低和组成变化，普萘洛尔可使其恢复。压力加剧了感染性（）和化学诱导（DSS）结肠炎的疾病严重程度，尤其放大了结肠中、和的表达。夹竹桃麻素甚至在结肠炎发作前就减轻了应激诱导的活性氧/氮氧化物产生和体重减轻，降低了关键氧化酶的结肠基因表达，并减轻了化学性和感染性结肠炎的严重程度。这些发现提供了强有力的证据，表明社会压力通过β-肾上腺素能和NADPH氧化酶驱动的氧化应激使肠道对炎症敏感，突出了减轻应激加剧的IBD的潜在治疗靶点。
