The role of AHR for the gut-skin inflammatory axis

生活在动物和人类体内和体表的微生物及其产生的营养物质或信使物质对健康和疾病至关重要。化学物质可以通过细胞受体感知，并引发适应性反应。其中一种化学传感器，芳烃受体（AHR），是一种转录因子，在与某些小分子化学物质（AHR配体）结合时被激活。AHR配体包括必需氨基酸色氨酸的代谢物，色氨酸由某些肠道细菌产生，但也包括来自食用植物的某些吲哚，例如来自十字花科植物。我们之前已经证明，肠道上皮细胞中AHR的表达会影响肠道微生物群的组成。此外，我们利用基因缺陷小鼠发现，AHR和膳食AHR配体的存在对健康的皮肤屏障很重要，因此可能有助于肠道-皮肤轴。例如，在小鼠模型中，在小鼠饮食中添加AHR配体可以减轻豌豆花生过敏。此外，我们发现，当AHR基因缺失时，皮肤屏障被削弱，甚至可以通过长期喂养AHR配体在野生型小鼠中得到加强。在本项目中，我们将研究AHR在小鼠肠道-皮肤轴中的作用。特别是，我们想要研究AHR必须在哪些细胞中表达才能引起肠道微生物群的变化，即生态失调。我们从初步工作中了解到，肠道上皮细胞ahr缺乏的小鼠与野生型小鼠具有不同的肠道微生物群特征。由于已知某些肠道细菌是AHR配体的特别好的生产者，生态失调可能导致血清中AHR配体的不同水平。我们项目的中心实验是喂养研究，这将使我们能够研究肠道微生物群对皮肤屏障的作用，使用与屏障损伤相关的炎症性皮肤病，特应性皮炎，小鼠。具体来说，我们将通过灌胃将ahr失调小鼠的肠道细菌（“粪便移植”）口服转移到野生型小鼠中，随后使用标准方法诱导ad样炎症，然后对其程度进行彻底表征。类似的实验将使用高亲和力的纯AHR配体进行，这些配体也被该联盟的其他成员使用，并且被怀疑是差异激活AHR途径。这组实验也是关于例如配体和细胞特异性基因表达谱的生成，可用于以后的荟萃分析。最后，我们将在小鼠血清中鉴定AHR配体，并试图将它们与改变的细菌丰度联系起来。从长远来看，我们希望为肠道-皮肤轴的益生菌治疗干预创造一个合理的基础。

Microorganisms that live in and on the body of animals and humans and the nutrients or messenger substances they produce are important for health and disease. Chemicals can be sensed through cellular receptors, and trigger adaptive reactions. One such chemical sensor, the aryl hydrocarbon receptor (AHR), is a transcription factor and becomes activated upon binding to certain small molecule chemicals (“AHR ligands”). AHR ligands include metabolites of the essential amino acid tryptophan, which are generated by certain intestinal bacteria, but are also certain indoles from food plants, e.g. from the family Brassicaceae. We had previously shown that the expression of the AHR in intestinal epithelial cells affects the composition of the intestinal microbiota. In addition, we showed using gene-deficient mice that the presence of AHR and dietary AHR ligands are important for a healthy skin barrier and may thus contribute to the gut-skin axis. For instance, addition of AHR ligands to the mouse diet attenuated pea peanut allergy in a mouse model. Furthermore, we showed that the skin barrier is weakened when the AHR is genetically lost, and could even be strengthened in wild-type mice by long-term feeding of AHR ligands. In the present project, we will investigate the role of the AHR for the gut-skin axis in mice. In particular, we want to investigate in which cells the AHR must be expressed in order to bring about a change in the gut microbiome, i.e. dysbiosis. We know from preliminary work that mice with an AHR-deficiency in intestinal epithelial cells have a different gut microbiota profile than wild-type mice. Since certain gut bacteria are known to be particularly good producers of AHR ligands, dysbiosis could lead to different levels of AHR-ligands in the serum. Central experiments of our project are feeding studies, which will allow us to investigate the role of the gut microbiota for the skin barrier using an inflammatory skin disease associated with barrier damage, atopic dermatitis, in mice. Specifically, we will orally transfer intestinal bacteria (“fecal transplants”) from AHR-deficient mice with dysbiosis into wild-type mice via gavage, and subsequently induce an AD-like inflammation using a standard method, followed by a thorough characterization of its extent. Similar experiments will be performed with high-affinity, pure AHR ligands, which are also used by other members of the consortium, and which are suspected to differentially activate the AHR pathway. This set of experiments is also about the generation of e.g. ligand- and cell-specific gene expression profiles that can be used in later meta-analyses. Finally, we will identify AHR ligands in mouse sera and attempt to associate them with the altered bacterial abundance. In the long term, we want to create a rational basis for therapeutic intervention with probiotic bacteria for the gut-skin axis.