Axonal degeneration is one of the key features of neurodegenerative disorders. In the canonical view, axonal degeneration destructs neural connections and promotes detrimental disease defects. Here, we assessed the enteric nervous system (ENS) of the mouse, non-human primate, and human by advanced 3D imaging. We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis, and similarly, in mouse colons during acute dextran sulfate sodium-induced colitis. However, we unexpectedly revealed that blockage of such axonal degeneration by the Sarm1 deletion in mice exacerbated the colitis condition. In contrast, pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation. We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines. Together, this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon, uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.

轴突变性是神经退行性疾病的主要特征之一。在经典观点中，轴突变性破坏了神经连接并促进了有害的疾病缺陷。在这里，我们通过先进的 3D 成像评估了小鼠、非人类灵长类动物和人类的肠神经系统 (ENS)。我们观察到患有溃疡性结肠炎的人结肠中儿茶酚胺能轴突的严重神经变性，同样，在急性葡聚糖硫酸钠诱导的结肠炎期间，在小鼠结肠中也观察到。然而，我们出人意料地揭示了Sarm1对这种轴突退化的阻断小鼠的缺失加剧了结肠炎的状况。相比之下，儿茶酚胺能轴突的药物消融或化学遗传学抑制抑制了结肠炎症。我们进一步表明，儿茶酚胺能神经递质去甲肾上腺素通过增强 IL-17 细胞因子的表达发挥促炎功能。总之，这项研究表明，ENS 内 Sarm1 介导的神经变性减轻了结肠的局部炎症，揭示了轴突变性在这种疾病背景下的先前未被认识的有益作用。