Bildstein Tania, Charbit-Henrion Fabienne, Azabdaftari Aline, Cerf-Bensussan Nadine, Uhlig Holm H
Great Ormond Street Hospital for Children, Department of Paediatric Gastroenterology, London, UK.
Department of Genomic Medicine for Rare Diseases, Necker-Enfants Malades Hospital, APHP, University of Paris-Cité, Paris, France.
Nat Rev Gastroenterol Hepatol. 2024 Oct;21(10):687-709. doi: 10.1038/s41575-024-00962-9. Epub 2024 Aug 8.
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.
小肠近端，包括十二指肠和空肠，不仅致力于营养物质的消化和吸收，也是一个高度受调控的免疫部位，暴露于环境因素之下。宿主对病原体的保护性反应以及对食物抗原的耐受性是小肠的基本功能。维持这些功能的细胞生态和分子途径很复杂。乳糜泻、环境性肠道功能障碍或十二指肠克罗恩病等常见免疫介导疾病突出了适应不良的问题。超过100种罕见单基因疾病的范围不断扩大，为营养吸收、上皮内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提供了信息。在此，在总结近端肠道功能基础的结构和细胞特征后，我们讨论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。我们提出一种基于机制的综合分类法，并讨论最新的实验方法，以深入了解这些在全球范围内造成重大疾病负担的疾病的新机制以及对治疗干预的影响。
