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

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Brial, F, Chilloux, J, Nielsen, T, Vieira-Silva, S, Falony, G, Andrikopoulos, P, Olanipekun, M, Hoyles, L ORCID: https://orcid.org/0000-0002-6418-342X, 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 and Dumas, M-E, 2021. Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health. Gut. ISSN 0017-5749

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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.

Item Type:	Journal article
Publication Title:	Gut
Creators:	Brial, F., Chilloux, J., Nielsen, T., Vieira-Silva, S., Falony, G., Andrikopoulos, P., Olanipekun, M., Hoyles, L., Djouadi, F., Neves, A.L., Rodriguez-Martinez, A., Mouawad, G.I., Pons, N., Forslund, S., Le-chatelier, E., Le Lay, A., Nicholson, J., Hansen, T., Hyötyläinen, T., Clément, K., Oresic, M., Bork, P., Ehrlich, S.D., Raes, J., Pedersen, O.B., Gauguier, D. and Dumas, M.-E.
Publisher:	BMJ Publishing Group
Date:	11 May 2021
ISSN:	0017-5749
Identifiers:	Number Type 10.1136/gutjnl-2020-323314 DOI 1432487 Other
Rights:	© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. 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/.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	28 Apr 2021 13:47
Last Modified:	31 May 2021 15:03
URI:	https://irep.ntu.ac.uk/id/eprint/42769