The enteric nervous system (ENS) controls several intestinal functions including motility and nutrient handling, which can be disrupted by infection-induced neuropathies or neuronal cell death. We investigated possible tolerance mechanisms preventing neuronal loss and disruption in gut motility after pathogen exposure. We found that following enteric infections, muscularis macrophages (MMs) acquire a tissue-protective phenotype that prevents neuronal loss, dysmotility, and maintains energy balance during subsequent challenge with unrelated pathogens. Bacteria-induced neuroprotection relied on activation of gut-projecting sympathetic neurons and signaling via β₂-adrenergic receptors (β2AR) on MMs. In contrast, helminth-mediated neuroprotection was dependent on T cells and systemic production of interleukin (IL)-4 and IL-13 by eosinophils, which induced arginase-expressing MMs that prevented neuronal loss from an unrelated infection located in a different intestinal region. Collectively, these data suggest that distinct enteric pathogens trigger a state of disease or tissue tolerance that preserves ENS number and functionality.

肠神经系统 (ENS) 控制多种肠道功能，包括运动和营养处理，这些功能可能会因感染引起的神经病或神经元细胞死亡而中断。我们研究了在病原体暴露后防止神经元丢失和肠道运动中断的可能耐受机制。我们发现，在肠道感染后，肌层巨噬细胞 (MMs) 获得了一种组织保护表型，可防止神经元丢失、运动障碍，并在随后受到不相关病原体的攻击时保持能量平衡。细菌诱导的神经保护作用依赖于肠道投射交感神经元的激活和通过 β _{2发出的信号}-MM 上的肾上腺素能受体 (β2AR)。相比之下，寄生虫介导的神经保护作用依赖于 T 细胞和嗜酸性粒细胞对白细胞介素 (IL)-4 和 IL-13 的全身产生，这会诱导表达精氨酸酶的 MM，从而防止位于不同肠道区域的无关感染引起的神经元丢失。总的来说，这些数据表明，不同的肠道病原体会引发疾病状态或组织耐受性，从而保持 ENS 的数量和功能。