The immune anatomy of the small intestine facilitates regulatory responses

The intestinal immune system monitors the body's largest interface with the environment. It must prevent adverse responses to ingested material, while protecting itself from harm, constraining the inflammatory potential of gut microbiota, and detecting pathogens. Gut immune anatomy and distribution of its microbiota may help explain how it manages these roles. The lymphatics of the jejunum and proximal ileum are anatomically independent of the rest of the gut. Mesenteric lymph nodes in these lymphatics specialize in regulatory functions. This proximal region of the small intestine, with the greatest exposure to ingested materials, is functionally sterile. The combination of lymphatic segmentation and asymmetric distribution of the microbiota allows specific functionality within regions of the small intestine which are exposed to different immune challenges. Villus lacteals draining into local lymph nodes are a route of absorption of a range of macromolecules from the small intestine enabling first-pass immunological screening of gut contents, analogous to first-pass metabolism in the liver via the portal circulation. These observations suggest an anatomical segregation enabling regulatory responses to ingested matter without compromising systemic immunity, and the potential for novel therapeutic approaches to inflammatory diseases.