The intestinal immune system has the challenging role of tolerating foreign nutrients and the luminal microbiome, while excluding or eliminating pathogens; failure in these processes leads to a range of intestinal diseases such as food allergies, Celiac Disease, Inflammatory Bowel Diseases and gastrointestinal infections. However, how the immune system decides to mount a tolerogenic or inflammatory response remains incompletely understood. We observed that a wide range of immune responses could be achieved by topological segregation of immune reactions into different gut draining lymph nodes, according to compartmentalized lymphatic drainage from functionally distinct gut segments. This represents a novel axis of diet and gut-microbiome to host communication, and explains how tolerogenic and immunogenic decisions in mLNs can occur simultaneously, thus shedding light on how adaptive immune homeostasis is achieved in the gut- and how it may fail if compartments are mixed or perturbed.