Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10⁺ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.

在 24 小时内，小肠 (SI) 暴露于每日变化的食物和微生物组衍生的抗原负荷，但保持严格的免疫稳态，当遗传易感个体受到干扰时，可能导致克罗恩病。在这里，我们证明饮食内容和节律性通过调节 SI 微生物组来调节昼夜变化的 SI 上皮细胞 (SIEC) 转录景观。我们用 SIEC 主要组织相容性复合物 (MHC) II 类来举例说明这一概念，它由不同的黏膜粘附 SI 共生体进行昼夜调节，同时支持上皮内 IL-10 ^{+的下游昼夜活动}调节 SI 屏障功能的淋巴细胞。这种昼夜调节的饮食-微生物组-MHC II 类-IL-10-上皮屏障轴被生物钟紊乱、摄食时间或含量的改变或上皮特异性 MHC II 类消耗破坏，导致大量微生物产品流入，驱动克罗恩- 样肠炎。总的来说，我们强调了调节 SI 微生物组、免疫和屏障功能的营养特征，并确定了沿着这个轴的饮食、上皮和免疫检查点，这些检查点可能在未来的克罗恩病干预中得到利用。