Defining a novel skin-gut axis that controls immune and microbial homeostasis in the mammalian GI tract.

适当的肠道发育和体内平衡需要在常驻肠道微生物和宿主的肠道免疫系统之间形成复杂且最终有益的关系。这种关系受到肠粘膜屏障的限制和控制，肠粘膜屏障将肠道微生物与潜在的免疫细胞隔离开来。它还受到环境因素的调节，例如通过胃肠道的膳食营养素，然而，对作用于远端部位（例如皮肤）的环境因素也调节肠道功能的潜力知之甚少。一个这样的因素是阳光，特别是紫外线（UV）B光谱，其诱导皮肤内包括维生素D（VD 3）的几种代谢物的产生，这可能具有全身效应。我们发现，将小鼠剃光背部的皮肤暴露于非损伤性窄带UVB光下，导致其粪便微生物组发生快速变化，包括微生物总数显著减少，微生物多样性增加。它还导致细胞因子白细胞介素（IL）-22和抗微生物凝集素REG 3在小肠粘膜和派伊尔集合淋巴结中的表达显著增加，与潘氏细胞（表达抗微生物剂的上皮细胞的子集）的数量和大小增加一致。值得注意的是，这些变化是独立的VD 3，因为它们也发生在VD 3受体缺陷小鼠暴露于UVB light.To确定参与的介质，我们进行了代谢组学筛选小鼠的血清UVB曝光后。在上调的因子中有几种色氨酸代谢物，包括吲哚-3-甲醛。已知这些代谢物激活芳香烃受体（AhR），其是一种转录因子和可诱导IL-22产生的环境化学物质的传感器。另外的研究发现，UVB暴露不能显著上调AhR缺陷小鼠中的IL-22表达。或引起肠道微生物组的明显变化。因此，我提出了一种新的范式，即UVB暴露可以诱导皮肤内的代谢物，这些代谢物通过血液流动，通过AhR激活引起肠上皮、免疫和微生物稳态的显著变化。为了更好地定义这些变化的影响以及所涉及的机制，我将（i）定义UVB暴露后肠道微生物组的组成和功能如何变化，（ii）鉴定UVB暴露小鼠肠道内上调的IL-22的细胞来源，并阐明其对肠道和微生物群对UVB的反应的影响;（iii）进一步探索AhR信号传导在肠道对UVB皮肤暴露的反应中的作用。总之，这些研究将提供原理证明，即作用于皮肤的环境因素，如UVB光，可以触发显著调节肠道稳态的反应。

Proper intestinal development and homeostasis requires a complex and ultimately beneficial relationship to develop between resident gut microbes and the host's intestinal immune system. This relationship is limited and controlled by the intestinal mucosal barriers that segregate luminal gut microbes from the underlying immune cells. It is also modulated by environmental factors such as the dietary nutrients that pass through the gastrointestinal tract, however little is known about the potential for environmental factors acting at distal sites (such as the skin) to also modulate gut function. One such factor is sunlight, and particularly the ultraviolet (UV)B spectrum which induces the production of several metabolites including vitamin D (VD3) within the skin, that potentially have systemic effects. We found that exposing the skin on the shaved backs of mice to non-damaging narrow band UVB light led to a rapid change in their stool microbiome, including a significant decrease in total microbe numbers, and an increase in microbial diversity. It also caused significant increases in expression of the cytokine interleukin (IL)-22 and the antimicrobial lectin REG3 in the small intestinal mucosa and Peyer's patches, in concert with an increase in the number and size of Paneth cells, a subset of antimicrobial expressing epithelial cells. Notably these changes were independent of VD3, as they also occurred in VD3 receptor deficient mice exposed to UVB light.To identify the mediators that were involved, we performed a metabolomics screen on the serum of mice following UVB exposure. Among the upregulated factors were several tryptophan metabolites including indole-3-carboxaldehyde. These metabolites are known to activate the arylhydrocarbon receptor (AhR), a transcription factor and sensor for environmental chemicals that can induce IL-22 production. Additional studies found UVB exposure was unable to significantly upregulate IL-22 expression in AhR deficient mice. or induce overt changes in their gut microbiome. I therefore propose a novel paradigm whereby UVB exposure can induce metabolites within the skin that travel via the bloodstream to induce dramatic changes in intestinal epithelial, immune and microbial homeostasis via AhR activation.To better define the impact of these changes, as well as the mechanisms involved, I will (i) define how the gut microbiome composition and function changes following UVB exposure, (ii) identify the cellular source of the upregulated IL-22 within the intestines of UVB exposed mice, and clarify its effects on the gut and microbiota responses to UVB; (iii) further explore the role of AhR signaling in the intestinal response to UVB skin exposure. Taken together, these studies will provide proof of principle that environmental factors acting on the skin, such as UVB light can trigger responses that significantly modulate intestinal homeostasis.