Hall Brantley, Levy Sophia, Dufault-Thompson Keith, Ndjite Glory Minabou, Weiss Ashley, Braccia Domenick, Jenkins Conor, Yang Yiyan, Arp Gabi, Abeysinghe Stephenie, Jermain Madison, Wu Chih Hao, Jiang Xiaofang
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, College Park, MD 20742, United States.
Center for Bioinformatics and Computational Biology, University of Maryland, College Park, College Park, MD 20742, United States.
bioRxiv. 2023 Feb 8:2023.02.07.527579. doi: 10.1101/2023.02.07.527579.
The degradation of heme and the interplay of its catabolic derivative, bilirubin, between humans and their gut microbiota is an essential facet of human health. However, the hypothesized bacterial enzyme that reduces bilirubin to urobilinogen, a key step that produces the excretable waste products of this pathway, has remained unidentified. In this study, we used a combination of biochemical analyses and comparative genomics to identify a novel enzyme, BilR, that can reduce bilirubin to urobilinogen. We delineated the BilR sequences from other members of the Old Yellow Enzyme family through the identification of key residues in the active site that are critical for bilirubin reduction and found that BilR is predominantly encoded by Firmicutes in the gut microbiome. Our analysis of human gut metagenomes showed that BilR is a common feature of a healthy adult human microbiome but has a decreased prevalence in neonates and IBD patients. This discovery sheds new light on the role of the gut microbiome in bilirubin metabolism and highlights the significance of the gut-liver axis in maintaining bilirubin homeostasis.
血红素的降解及其分解代谢衍生物胆红素在人类与其肠道微生物群之间的相互作用是人类健康的一个重要方面。然而，将胆红素还原为尿胆原这一产生该途径可排泄废物的关键步骤中所假设的细菌酶仍未被鉴定出来。在本研究中，我们结合生化分析和比较基因组学来鉴定一种新型酶BilR，它可以将胆红素还原为尿胆原。我们通过鉴定活性位点中对胆红素还原至关重要的关键残基，将BilR序列与老黄色酶家族的其他成员区分开来，并发现BilR主要由肠道微生物群中的厚壁菌门编码。我们对人类肠道宏基因组的分析表明，BilR是健康成年人类微生物群的一个常见特征，但在新生儿和炎症性肠病患者中的患病率降低。这一发现为肠道微生物群在胆红素代谢中的作用提供了新的线索，并突出了肠-肝轴在维持胆红素稳态中的重要性。
