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

肠道的正常发育和动态平衡需要肠道微生物和宿主的肠道免疫系统之间形成一种复杂的、最终有益的关系。这种关系受到肠道粘膜屏障的限制和控制，这些屏障将管腔肠道微生物与潜在的免疫细胞隔开。它还受到环境因素的调节，如通过胃肠道的饮食营养物质，然而，人们对环境因素在远端部位(如皮肤)也调节肠道功能的可能性知之甚少。其中一个因素是阳光，特别是紫外线(UV)B光谱，它会在皮肤内诱导包括维生素D(VD3)在内的几种代谢物的产生，这可能会对全身产生影响。我们发现，将小鼠剃毛背部的皮肤暴露在非破坏性的窄带UVB光下，会导致它们的粪便微生物群迅速变化，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IL-22和抗菌素凝集素REG3在小肠粘膜和Peyer‘s斑块中的表达显著增加，同时Paneth细胞的数量和大小也增加，Paneth细胞是表达抗菌剂的上皮细胞的一个亚群。值得注意的是，这些变化与VD3无关，因为它们也发生在暴露于UVB光下的VD3受体缺陷小鼠中。 为了确定参与的介质，我们对UVB暴露后的小鼠的血清进行了代谢组学筛查。在上调的因素中，有几种色氨酸代谢物，包括吲哚-3-甲醛。已知这些代谢物可以激活芳烃受体(AhR)，这是一种转录因子和环境化学物质的传感器，可以诱导IL-22的产生。其他研究发现，UVB照射不能显著上调AhR缺陷小鼠的IL-22表达。也不会引起肠道微生物群的明显变化。因此，我提出了一种新的模式，通过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诱导肠道上皮细胞、免疫和微生物动态平衡的显著变化，通过AhR激活。 为了更好地确定这些变化的影响以及涉及的机制，我将(I)确定紫外线照射后肠道微生物组的组成和功能如何变化，(Ii)确定紫外线照射小鼠肠道内上调的IL-22的细胞来源，并阐明其对紫外线照射小鼠肠道和微生物区系反应的影响；(Iii)进一步探讨AhR信号在紫外线照射引起的肠道反应中的作用。综上所述，这些研究将提供原理证据，证明作用于皮肤的环境因素，如UVB光，可以触发显著调节肠道内稳态的反应。

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.