Gut region-specific mechanisms that limit dissemination of microbial signals from the intestine

摘要 肠粘膜的一个主要问题是执行其在营养吸收中的作用，同时最大限度地减少 与微生物组的炎症或不良免疫相互作用。管理吸收不仅需要 通过肠上皮细胞分选营养物，而且还将这些营养物输送到专门的血液， 存在于小肠的每个绒毛中的淋巴管。反过来，血液和淋巴管， 集体管理肠道流出可能需要依赖于专门的机制， 将微生物信号传播到远端部位，如肺或肝，以避免下游器官损伤。是 例如，现在认识到，酒精性和非酒精性肝损伤主要是由微生物引起的， 通过门静脉从肠道输送到肝脏。同样，肺损伤可能会随之而来， 淋巴中的有害物质通过胸导管进入血液，然后迅速流入肺部。然而 防止来自肠粘膜的微生物信号传播的机制仍然存在 不完全理解，可能对粘膜屏障进行有计划的操作，如接种疫苗或 疾病治疗，风险大于需要或导致意外。例如，我们的初步数据表明， 抗TNF中和可能导致的有记录的和看似违反直觉的肝损伤 治疗肠炎性疾病的抗体疗法可能至少部分是由于 白细胞介导的对引流静脉血管系统的监视，其去除了逃逸的微生物。 在到达肝脏之前先破坏肠粘膜。为了填补这些基本知识空白，我们在此建议： 描述肠的不同区域如何编程白细胞依赖性和白细胞非依赖性 保护下游细胞和组织免受微生物信号传播的策略。在目标1中，我们 集中于从肠道引流静脉血中吞噬去除全微生物的机制， 逃逸肠粘膜屏障并以其它方式将微生物递送到更深的组织或远端位置。 在目标2中，我们将比较小肠和结肠如何差异地转运和中和可溶性 微生物信号，如LPS，可以无意中逃脱上皮屏障，促进炎症。这 努力将包括全面的蛋白质组学和脂质组学评估淋巴和血液引流不同 与专家合作，利用我们实验室的专业知识， 在淋巴生物学和最近的研究在运输肠道货物到肠道引流静脉血。

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.