Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.

尽管肠道微生物群可以影响中枢神经系统（CNS）自身免疫性疾病，但肠上皮对中枢神经系统自身免疫性疾病的贡献尚不清楚。在这里，我们发现肠上皮多巴胺 D2 受体 (IEC DRD2) 在多发性硬化症动物模型中促进性别特异性疾病进展。肠上皮细胞中选择性缺乏Drd2的雌性小鼠表现出中枢神经系统炎症反应减弱并减缓疾病进展。相反，通过苯乙胺给药过度表达或激活 IEC DRD2 会加剧疾病的严重程度。这伴随着溶菌酶表达和肠道微生物群组成的改变，包括乳酸菌物种丰度的减少。此外，用 N2-乙酰基-L-赖氨酸（一种源自乳杆菌的代谢物）治疗可抑制小胶质细胞活化和神经变性。综上所述，我们的研究表明，IEC DRD2 过度活跃会影响肠道微生物丰度，并以女性偏向的方式增加对 CNS 自身免疫性疾病的易感性，为 CNS 自身免疫性疾病的性别特异性干预开辟了未来途径。