ABSTRACT A major concern of the intestinal mucosa is to execute its role in absorption of nutrients while minimizing inflammatory or adverse immune interactions with the microbiome. Managing absorption entails not only sorting of nutrients by intestinal epithelial cells but also delivery of those nutrients to specialized blood and lymphatic vessels present in each villus of the small intestine. In turn, the blood and lymphatic vessels that collectively manage outflow from the gut may need to rely on specialized mechanisms that operate to limit dissemination of microbial signals to distal sites like the lung or the liver to avoid downstream organ injury. It is now appreciated, for instance, that alcoholic and nonalcoholic liver damage is driven substantially by microbial transit from the gut to the liver via the portal vein. Likewise, pulmonary damage can ensue in response to injurious cargo in lymph that gains access to blood via the thoracic duct and quickly next flows to the lungs. Yet mechanisms protecting against dissemination of microbial signals from the intestinal mucosa remain incompletely understood, possibly making planned manipulations of the mucosal barrier, as in vaccination or disease therapy, riskier than needed or resulting in surprises. For instance, our preliminary data suggest that the documented and seemingly counterintuitive liver damage that can result from anti-TNF neutralizing antibody therapy to treat inflammatory disease of the bowel may be due, at least in part, to disruption of leukocyte-mediated surveillance of the draining venous vasculature that removes microbes that escape the intestinal mucosal before they arrive to the liver. To fill in these basic knowledge gaps, we propose herein to delineate how different regions of the intestine program leukocyte-dependent and leukocyte-independent strategies to protect downstream cells and tissues against dissemination of microbial signals. In aim 1, we focus on mechanisms operative in phagocytic removal from gut-draining venous blood of whole microbes that escape the intestinal mucosal barrier and otherwise deliver the microbes to deeper tissues or distal locations. In aim 2, we will compare how the small bowel and colon may differentially transport and neutralize soluble microbial signals, like LPS, that can inadvertently escape the epithelial barrier to promote inflammation. This effort will include comprehensive proteomic and lipidomic evaluation of lymph and blood draining different regions of the gut mucosa, working with expert collaborators and taking advantage of our laboratory’s expertise in lymphatic biology and recent studies in the transport of intestinal cargo into gut-draining venous blood.