Cellular and molecular basis of proximal small intestine disorders

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. The proximal small intestine is key for nutrition, metabolism and immune responses, and can be affected by a wide range of disorders. This Review describes the cellular and molecular bases of diseases of the proximal small intestine (including rare monogenic disorders), proposing a mechanism-based taxonomy. Key points The proximal small intestine is a key mucosal surface for nutrition, metabolism, host defence and immune homeostasis. Common disorders that affect duodenal function include infections and immune-mediated disorders (coeliac disease, Crohn’s disease or environmental enteric dysfunction). Monogenic disorders are rare but inform on the large spectrum of molecular mechanisms that enable epithelial absorption, barrier function and immune tolerance. We propose a mechanism-based molecular taxonomy of small intestinal disorders. There is a strong unmet need for further exploration of disease mechanisms and development of targeted treatments.