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

正常的肠道发育和体内平衡需要肠道微生物与宿主肠道免疫系统之间复杂而最终有益的关系。这种关系受到肠道黏膜屏障的限制和控制，这些屏障将肠道微生物与潜在的免疫细胞隔离开来。它也受到环境因素的调节，如通过胃肠道的膳食营养素，然而，对于远端部位（如皮肤）的环境因素调节肠道功能的可能性知之甚少。其中一个因素是阳光，尤其是紫外线（UV）B光谱，它会诱导皮肤内几种代谢物的产生，包括维生素D (VD3)，这可能会对全身产生影响。我们发现，将小鼠剃光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。它还引起小肠黏膜和Peyer's斑块中细胞因子白细胞介素(IL)-22和抗菌凝集素REG3的表达显著增加，同时Paneth细胞（一种表达抗菌的上皮细胞）的数量和大小增加。值得注意的是，这些变化与VD3无关，因为在暴露于UVB光下的VD3受体缺陷小鼠中也发生了这些变化。

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.