Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation
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Cellular and Molecular Life Sciences
REVIEW
Gut microbiota‑derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation Jing‑Ru Liu1 · Hua Miao1 · De‑Qiang Deng2 · Nosratola D. Vaziri3 · Ping Li4 · Ying‑Yong Zhao1 Received: 23 May 2020 / Revised: 31 August 2020 / Accepted: 12 September 2020 © Springer Nature Switzerland AG 2020
Abstract The gut microbiota has a crucial effect on regulating the intestinal mucosal immunity and maintaining intestinal homeostasis both in health and in disease state. Many effects are mediated by gut microbiota-derived metabolites and tryptophan, an essential aromatic amino acid, is considered important among many metabolites in the crosstalk between gut microbiota and the host. Kynurenine, serotonin, and indole derivatives are derived from the three major tryptophan metabolism pathways modulated by gut microbiota directly or indirectly. Aryl hydrocarbon receptor (AHR) is a cytoplasmic ligand-activated transcription factor involved in multiple cellular processes. Tryptophan metabolites as ligands can activate AHR signaling in various diseases such as inflammation, oxidative stress injury, cancer, aging-related diseases, cardiovascular diseases (CVD), and chronic kidney diseases (CKD). Accumulated uremic toxins in the body fluids of CKD patients activate AHR and affect disease progression. In this review, we will elucidate the relationship between gut microbiota-derived uremic toxins by tryptophan metabolism and AHR activation in CKD and its complications. This review will provide therapeutic avenues for targeting CKD and concurrently present challenges and opportunities for designing new therapeutic strategies against renal fibrosis. Keywords Intestinal flora · Tryptophan metabolites · Chronic kidney disease · Natural products Abbreviations AHR Aryl hydrocarbon receptor AHRR AHR repressor protein ARNT AHR nuclear translocator CKD Chronic kidney disease Jing-Ru Liu and Hua Miao are co-first authors. * Ping Li [email protected] * Ying‑Yong Zhao [email protected] 1
Faculty of Life Science, & Medicine, Northwest University, No. 229 Taibai North Road, Xi’an 710069, Shaanxi, China
2
Department of Nephrology, Urumqi Chinese Medicine Hospital, No. 590 Fridenly South Road, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
3
Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, CA 92897, USA
4
Beijing Key Lab for Immune‑Mediated Inflammatory Diseases, Department of Nephrology, Institute of Clinical Medical Science, China-Japan Friendship Hospital, Beijing 100029, China
COX-2 Cyclooxygenase-2 CVD Cardiovascular diseases CYP Cytochrome P450 family DKD Diabetic kidney disease ESRD End-stage renal disease I3A Indole-3-aldehyde IAA Indole-3-acetic acid IDO Indoleamine 2,3-dioxygenase ILA Indole-3-lactic acid IS Indoxyl sulfate HIF Hypoxia-inducible transcription factor NF-κB Nuclear factor kappa B PAHs Polycyclic aromatic hydrocarbons TCDD 2,3,7,8-tetrachlorodibenzo-p-dio
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