Inflammatory bowel diseases (IBDs) are chronic debilitating conditions without cure, the etiologies of which are unknown, that shorten the lifespans of 7 million patients worldwide by nearly 10%. Here, we found that decreased autonomic parasympathetic tone resulted in increased IBD susceptibility and mortality in mouse models of disease. Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10/α7 nicotinic cholinergic vagal pathway. Colonic biopsies from patients with IBDs and mouse models showed an increase in small ubiquitin-like modifier (SUMO)2 and SUMO3 during active disease. In global genetic knockout mouse models, the deletion of Sumo3 protected against development of colitis and delayed onset of disease, whereas deletion of Sumo1 halted the progression of colitis. Bone marrow transplants from Sumo1 -knockout (KO) but not Sumo3 -KO mice into wild-type mice conferred protection against development of colitis. Electric stimulation of the cervical vagus nerve before the induction of colitis inhibited SUMOylation and delayed the onset of colitis in Sumo1 -KO mice and resulted in milder symptoms in Sumo3 -KO mice. Treatment with TAK-981, a first-in-class inhibitor of the SUMO-activating enzyme, ameliorated disease in three murine models of IBD and reduced intestinal permeability and bacterial translocation in a severe model of the disease, suggesting the potential to reduce progression to sepsis. These results reveal a pathway of vagal neuromodulation that reprograms endogenous stress-adaptive responses through inhibition of SUMOylation and suggest SUMOylation as a therapeutic target for IBD.

中文翻译：

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迷走神经刺激通过调节 SUMOylation 改善小鼠结肠炎


炎症性肠病 （IBD） 是一种无法治愈的慢性衰弱性疾病，病因尚不清楚，它使全球 700 万患者的寿命缩短了近 10%。在这里，我们发现自主神经副交感神经张力降低导致小鼠疾病模型中 IBD 易感性和死亡率增加。相反，迷走神经刺激通过独立于经典白细胞介素 10/α7 烟碱胆碱能迷走神经通路的机制抑制翻译后修饰 SUMO化，从而恢复神经调控并改善结肠炎。IBD 患者和小鼠模型的结肠活检显示，在活动性疾病期间，小泛素样修饰物 （SUMO）2 和 SUMO3 增加。在全球基因敲除小鼠模型中，Sumo3 的缺失可防止结肠炎的发展和疾病的延迟发作，而 Sumo1 的缺失阻止了结肠炎的进展。将 Sumo1 -敲除 （KO） 小鼠而不是 Sumo3 -KO 小鼠的骨髓移植到野生型小鼠中，可防止结肠炎的发展。在诱导结肠炎之前对颈迷走神经进行电刺激抑制了 SUMO 化，延缓了 Sumo1 -KO 小鼠结肠炎的发作，导致 Sumo3 -KO 小鼠症状较轻。TAK-981 是 SUMO 激活酶的一流抑制剂，用 TAK-981 治疗改善了三种 IBD 小鼠模型中的疾病，并降低了该疾病严重模型中的肠道通透性和细菌易位，表明有可能减少进展为脓毒症。这些结果揭示了迷走神经神经调控途径，该途径通过抑制 SUMOylation 重新编程内源性应激适应性反应，并表明 SUMOylation 是 IBD 的治疗靶点。