The Enteric Nervous System: A Link Between Stress and Colitis

肠神经系统 炎症 炎症性肠病 结肠炎 肿瘤坏死因子α 免疫学 医学 地塞米松 溃疡性结肠炎 内分泌学 内科学 疾病
作者
David E. Reed
出处
期刊:Gastroenterology [Elsevier BV]
卷期号:165 (5): 1304-1304
标识
DOI:10.1053/j.gastro.2023.06.016
摘要

Schneider KM, Blank N, Alvarez Y, et al. The enteric nervous system relays psychological stress to intestinal inflammation. Cell 2023;186:2838.e20. Psychological stress has been linked to flares in patients with inflammatory bowel disease (IBD). In pre-clinical models of colitis, stress worsens the degree of inflammation. However, the mechanisms of how stress can exacerbate gastrointestinal (GI) inflammation is not completely understood. A recent study by Schneider et al investigated the link between stress and colitis in mice. First, although psychological stress did not induce colitis, it exacerbated inflammation in both a chemically induced and a genetic deficiency model of colitis, with the strongest effect occurring when stress preceded the induction of colitis. Stress-exacerbated colitis was promoted by a subset of tumor necrosis factor α (TNFα) producing monocytes that accumulated in response to stress-associated enteric glia that secrete colony-stimulating factor 1. When investigating which mediators of the hypothalamic-pituitary-adrenal (HPA) axis were responsible for generation of these stress-associated glia, surprisingly it was glucocorticoids, not catecholamines. Supporting these findings, treating mice with dexamethasone before induction of colitis also resulted in a more severe colitis. In addition to exacerbation of inflammation, stress also delayed GI transit in mice with colitis. There was a decreased proportion of mature enteric neurons, including a decrease in both cholinergic and nitrergic neuronal populations. Again, this could be recapitulated when treating mice with dexamethasone before induction of colitis. However, these findings were not dependent on the enteric glia-monocyte pathway but due to increased transforming growth factor (TGF) β2 within the muscularis. Indeed, neutralizing TGFβ2 prevented loss of nitrergic neurons and restored transit time to that of nonstressed mice. The authors attempted to determine if these findings translated to IBD patients. A correlation between high levels of stress and higher levels of the inflammatory marker C-reactive protein, increases in leukocytes and monocytes in IBD tissue samples, and reported dissatisfaction with bowel habits and obstipation were identified. In a smaller cohort of IBD patients, perceived stress levels moderately correlated disease severity of colonoscopy, monocyte recruitment, TNFα and TGFβ2. This study unlocks mechanisms of how stress can exacerbate gut inflammation. Enteric glia may serve as an intermediary between the HPA axis and immune cells in the gut. Furthermore, stress and inflammation may lead to a loss of mature neurons, leading to GI dysmotility. These effects were mediated by glucocorticoids, a surprising finding given that exogenous steroids are often used to treat IBD flares. These contradictory effects of steroids may be due to the timing of glucocorticoid exposure (eg, before the colitogenic event, steroids prime the gut for an inflammatory response) or the duration of exposure (eg, chronic stress vs acute treatment). Future studies are needed to understand these opposing effects of steroids on inflammation. Regardless, this study highlights that understanding the mental health of IBD patients is an important factor in their treatment.
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