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Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health.

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Title: Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health.
Authors: Brial, F
Chilloux, J
Nielsen, T
Vieira-Silva, S
Falony, G
Andrikopoulos, P
Olanipekun, M
Hoyles, L
Djouadi, F
Neves, AL
Rodriguez-Martinez, A
Mouawad, GI
Pons, N
Forslund, S
Le-Chatelier, E
Le Lay, A
Nicholson, J
Hansen, T
Hyötyläinen, T
Clément, K
Oresic, M
Bork, P
Ehrlich, SD
Raes, J
Pedersen, OB
Gauguier, D
Dumas, M-E
Item Type: Journal Article
Abstract: OBJECTIVE: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health. DESIGN: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes. RESULTS: In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion. CONCLUSION: Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.
Issue Date: 11-May-2021
Date of Acceptance: 18-Apr-2021
URI: http://hdl.handle.net/10044/1/89365
DOI: 10.1136/gutjnl-2020-323314
ISSN: 0017-5749
Publisher: BMJ Publishing Group
Start Page: 2105
End Page: 2114
Journal / Book Title: Gut
Volume: 70
Issue: 11
Copyright Statement: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Commission of the European Communities
Funder's Grant Number: MR/L01632X/1
MR/L01632X/1
305312
Keywords: colonic microflora
glucose metabolism
intestinal microbiology
obesity
colonic microflora
glucose metabolism
intestinal microbiology
obesity
Gastroenterology & Hepatology
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
Publication Status: Published
Conference Place: England
Open Access location: https://gut.bmj.com/content/early/2021/05/11/gutjnl-2020-323314.long
Online Publication Date: 2021-05-11
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Faculty of Medicine
School of Public Health



This item is licensed under a Creative Commons License Creative Commons