Morgan Ethan W, Dong Fangcong, Annalora Andrew, Murray Iain A, Wolfe Trenton, Erickson Reece, Gowda Krishne, Amin Shantu G, Petersen Kristina S, Kris-Etherton Penny M, Marcus Craig, Walk Seth T, Patterson Andrew D, Perdew Gary H
bioRxiv. 2023 Jan 27:2023.01.26.525691. doi: 10.1101/2023.01.26.525691.
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of cell-based models for cancer and rheumatoid arthritis. We present data here that reframe AHR biology to include the presence of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.
芳烃受体（AHR）是一种配体激活的转录因子，通过调节细胞分化、代谢、屏障功能和免疫反应等细胞功能，在稳态维持中发挥不可或缺的作用。一类重要但了解甚少的AHR激活剂是源自色氨酸宿主和细菌代谢的化合物。肠道微生物群的共生细菌是已知能激活AHR的色氨酸代谢物的主要生产者，而宿主也通过色氨酸代谢产生AHR激活剂。我们使用基于靶向质谱的代谢物谱分析来确定这些代谢物在常规小鼠、无菌小鼠和人类血清中的存在及代谢来源。令人惊讶的是，无菌小鼠和常规小鼠血清中许多色氨酸代谢物的浓度相当。因此，尽管小鼠血清中许多主要的AHR激活色氨酸代谢物存在于粪便和盲肠内容物中，但它们是由宿主产生的。正如我们在此所展示的，AHR激活很少在相关浓度的混合物背景下进行研究。使用基于细胞的试验探索了单个和混合代谢物的AHR激活潜力，同时使用配体结合竞争试验和配体对接模拟来评估检测到的代谢物作为AHR激动剂。在癌症和类风湿性关节炎的基于细胞的模型背景下，研究了已鉴定代谢物的生理和生物医学相关性。我们在此展示的数据重新构建了AHR生物学，以纳入普遍存在的色氨酸代谢物，增进了我们对AHR稳态活性和AHR相关疾病模型的理解。
