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在最大限度减少营养物质吸收的同时执行其作用。 与微生物群的炎性或不良免疫相互作用。管理吸收不仅需要 通过肠道上皮细胞对营养物质进行分类，并将这些营养物质输送到专门的血液和 淋巴管存在于小肠的每个绒毛中。反过来，这些血管和淋巴管 集体管理肠道流出可能需要依靠专门的机制来限制 将微生物信号传播到肺或肝脏等远端部位，以避免下游器官损伤。它是 现在认识到，例如，酒精性和非酒精性肝损伤基本上是由微生物驱动的 通过门静脉从肠道转移到肝脏。同样，肺损伤也可能随之而来 淋巴中的有害物质，通过胸腔导管获得血液，然后迅速流入肺部。还没有 防止肠道粘膜微生物信号传播的机制仍然存在 不完全理解的，可能对粘膜屏障进行有计划的操纵，如在接种疫苗或 疾病治疗，比需要的风险更大，或导致意外。例如，我们的初步数据表明 有文献记载的和似乎违反直觉的肝损伤可能是由抗肿瘤坏死因子中和引起的 治疗肠炎性疾病的抗体疗法可能至少部分是由于干扰了 白细胞介导的对引流静脉血管系统的监测，该血管系统可清除逃逸的微生物 到达肝脏之前的肠道粘膜。为了填补这些基本知识空白，我们在此建议 描述肠道的不同区域如何编程白细胞依赖和非白细胞 保护下游细胞和组织免受微生物信号传播的战略。在目标1中，我们 重点介绍从肠道引流静脉血中去除吞噬细胞的整个微生物的作用机制 逃脱肠道粘膜屏障，以其他方式将微生物运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不同地运输和中和可溶性物质。 微生物信号，如脂多糖，可以无意中逃脱上皮屏障，促进炎症。这 工作将包括对淋巴和血液引流的全面蛋白质组和脂组学评估不同 肠道黏膜区域，与专家合作者合作，并利用我们实验室的专业知识 在淋巴生物学和最近关于将肠道货物运输到肠道排出静脉血液的研究中。

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.