Effects of arylhydrocarbon receptor ligands 2,3,7,8-TCDD and dietary indole-3-carbinol on the gut microbiome, immune-mediated barrier function and metabolism

对免疫系统和新陈代谢的不利影响是二恶英和其他所谓的持久性有机污染物（POPs）的典型有害影响。这些污染物仍然存在于环境中。发展中国家尤其关注持久性有机污染物污染，因为往往缺乏适当的排放控制。二恶英与内源性转录因子芳烃受体（AHR）结合，从而控制细胞基因程序。二恶英的主要接触途径是食物。因此，令人惊讶的是，很少有研究关注二恶英对肠道和肠道免疫系统的影响。最近对AHR缺陷小鼠的研究表明，AHR对于肠道免疫系统的功能和肠道共生菌与致病菌的平衡是必要的。事实上，人们对微生物群在（肠道）免疫和健康中的重要作用的兴趣急剧增加。激活AHR（例如通过某些植物化学物质或肠道细菌的产物）可以防止炎症过程。缺乏AHR或饮食中缺乏AHR配体可导致对某些感染的易感性增加。食物成分对刺激AHR信号和调节肠道微生物群很重要。相比之下，人们几乎完全不知道二恶英和其他持久性有机污染物是否以及如何损害肠道微生物群，从而可能对肠道免疫或代谢健康产生不利影响。我们想用鼠标模型来解决这个问题。我们将首次研究暴露在二恶英中导致的微生物变化，以及在西方饮食的背景下，这对免疫屏障功能有什么影响。我们将进一步建立和使用一种新的筛选方法，通过流式细胞术测量微生物组模式。我们的结果(i)对于更好地评估二恶英本身和其他与环境相关的AHR配体的风险很重要，（ii）对于使用膳食AHR配体对肠道微生物群、肠道免疫系统和代谢产生积极影响的方法很重要。

Adverse effects on the immune system and metabolism are characteristic harmful effects of dioxins and other so-called persistent organic pollutants (POPs). These pollutants are still present in the environment. POP pollution is of particular concern in developing countries, as appropriate emission control is often lacking. Dioxins bind to the endogenous transcription factor aryl hydrocarbon receptor (AHR), and thereby control cellular gene programs. The main route of exposure for dioxins is food. It is therefore surprising that very few studies exist which look at the effects of dioxin on the intestine and the intestinal immune system. Recent research using AHR-deficient mice has shown that the AHR is necessary for a functioning intestinal immune system and the balance of commensal versus pathogenic intestinal bacteria. Indeed, interest has increased dramatically in the microbiome as an important player in (gut) immunity and health. Activation of the AHR (e.g. by certain phytochemicals or products of by gut bacteria) prevent inflammatory processes. Lack of AHR or a lack of AHR ligands in the diet can lead to increased susceptibility to certain infections. Food ingredients are important to stimulate the AHR signaling and regulate the gut microbiome. In contrast, it is almost completely unknown whether and how dioxins and other persistent organic pollutants damage the gut microbiome, and thus might adversely affect gut immunity or metabolic health. We want to address this gap using the mouse model. We will examine for the first time which microbial changes are caused by dioxin exposure, and what consequences this has for immune barrier function and in the context of a Western-diet. We will furthermore establish and use a novel screening method by flow-cytometric measurements of microbiome patterns. Our results are (i) important for better risk assessment for dioxins themselves and other environmentally relevant AHR ligands, and (ii) for the approaches, using dietary AHR ligands to influence the gut microbiome, intestinal immune system, and metabolism positively.