The proximal part of the small intestine, including duodenum and jejunum, is not only dedicated to nutrient digestion and absorption but is also a highly regulated immune site exposed to environmental factors. Host-protective responses against pathogens and tolerance to food antigens are essential functions in the small intestine. The cellular ecology and molecular pathways to maintain those functions are complex. Maladaptation is highlighted by common immune-mediated diseases such as coeliac disease, environmental enteric dysfunction or duodenal Crohn’s disease. An expanding spectrum of more than 100 rare monogenic disorders inform on causative molecular mechanisms of nutrient absorption, epithelial homeostasis and barrier function, as well as inflammatory immune responses and immune regulation. Here, after summarizing the architectural and cellular traits that underlie the functions of the proximal intestine, we discuss how the integration of tissue immunopathology and molecular mechanisms can contribute towards our understanding of disease and guide diagnosis. We propose an integrated mechanism-based taxonomy and discuss the latest experimental approaches to gain new mechanistic insight into these disorders with large disease burden worldwide as well as implications for therapeutic interventions.

小肠的近端部分，包括十二指肠和空肠，不仅负责营养物质的消化和吸收，而且也是暴露于环境因素的高度调节的免疫部位。针对病原体的宿主保护性反应和对食物抗原的耐受性是小肠的重要功能。维持这些功能的细胞生态和分子途径很复杂。常见的免疫介导疾病，如乳糜泻、环境性肠道功能障碍或十二指肠克罗恩病，凸显了适应不良。 100 多种罕见单基因疾病的范围不断扩大，揭示了营养吸收、上皮稳态和屏障功能以及炎症免疫反应和免疫调节的致病分子机制。在这里，在总结了近端肠道功能的结构和细胞特征之后，我们讨论了组织免疫病理学和分子机制的整合如何有助于我们对疾病的理解并指导诊断。我们提出了一种基于综合机制的分类法，并讨论了最新的实验方法，以获得对这些在全球范围内具有巨大疾病负担的疾病的新机制见解以及对治疗干预的影响。