A gut microbial metabolite of dietary polyphenols reverses obesity-driven hepatic steatosis
Year: 2022
Type: article
Abstract: The molecular mechanisms by which dietary fruits and vegetables confer cardiometabolic benefits remain poorly understood. Historically, these beneficial properties have been attributed to the antioxidant activity of flavonoids. Here, we reveal that the host metabolic benefits associated with flavonoid consumption hinge, in part, on gut microbial metabolism. Specifically, we show that a single gut microbial flavonoid catabolite, 4-hydroxyphenylacetic acid (4-HPAA), is sufficient to reduce diet-induced cardiometabolic disease (CMD) burden in mice. The addition of flavonoids to a high fat diet heightened the levels of 4-HPAA within the portal plasma and attenuated obesity, and continuous delivery of 4-HPAA was sufficient to reverse hepatic steatosis. The antisteatotic effect was shown to be associated with the activation of AMP-activated protein kinase α (AMPKα). In a large survey of healthy human gut metagenomes, just over one percent contained homologs of all four characterized bacterial genes required to catabolize flavonols into 4-HPAA. Our results demonstrate the gut microbial contribution to the metabolic benefits associated with flavonoid consumption and underscore the rarity of this process in human gut microbial communities.
Authors: Lucas J. Osborn, Karlee Schultz, William Massey, Beckey DeLucia, Ibrahim Choucair, Venkateshwari Varadharajan, Rakhee Banerjee, Kevin Fung, Anthony J. Horak, Danny Orabi, Ina Nemet, Laura E. Nagy, Zeneng Wang, Daniela S. Allende, Belinda B. Willard, Naseer Sangwan, Adeline M. Hajjar, Christine McDonald, Philip P. Ahern, Stanley L. Hazen, J. Mark Brown, Jan Claesen
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: American Cancer Society, Prevent Cancer Foundation, Cleveland Clinic, Case Comprehensive Cancer Center, Case Western Reserve University, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Heart, Lung, and Blood Institute, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Molecular Medicine Training Program, G2962895936, G3029803738, G3120016720, G3142428437, G375919370, Gut Microbiota and Cardiometabolic Diseases, G5822270753, G5831745892, High-End Instrumentation (HEI) Grant Program (S10), G611941197, G6125894215, The Role of Bacterial Choline Metabolism in Host Stress Responses, G6597168886, G6631868199, G7370530595, G75750593, Microbial metabolites and Innate Immunity in AH: Biomarkers of injury and repair, Metaorganismal Endocrinology in Cardiometabolic Disease, G9000202443, Alcohol and tissue injury, from mechanisms to treatments, Case Comprehensive Cancer Center Support Grant, Uncovering aryl polyene biology to identify new drug targets in Gram-negative bacterial pathogens
OpenAlex ID: W4309825526