PT  - JOURNAL ARTICLE
AU  - François Brial
AU  - Julien Chilloux
AU  - Trine Nielsen
AU  - Sara Vieira-Silva
AU  - Gwen Falony
AU  - Petros Andrikopoulos
AU  - Michael Olanipekun
AU  - Lesley Hoyles
AU  - Fatima Djouadi
AU  - Ana L Neves
AU  - Andrea Rodriguez-Martinez
AU  - Ghiwa Ishac Mouawad
AU  - Nicolas Pons
AU  - Sofia Forslund
AU  - Emmanuelle Le-chatelier
AU  - Aurélie Le Lay
AU  - Jeremy Nicholson
AU  - Torben Hansen
AU  - Tuulia Hyötyläinen
AU  - Karine Clément
AU  - Matej Oresic
AU  - Peer Bork
AU  - Stanislav Dusko Ehrlich
AU  - Jeroen Raes
AU  - Oluf Borbye Pedersen
AU  - Dominique Gauguier
AU  - Marc-Emmanuel Dumas
TI  - Human and preclinical studies of the host–gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health
AID  - 10.1136/gutjnl-2020-323314
DP  - 2021 May 05
TA  - Gut
PG  - gutjnl-2020-323314
4099  - http://gut.bmj.com/content/early/2021/05/11/gutjnl-2020-323314.short
4100  - http://gut.bmj.com/content/early/2021/05/11/gutjnl-2020-323314.full
AB  - 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.Data are available upon reasonable request to the corresponding authors