Microbiome determinants and physiological effects of the benzoate-hippurate microbial-host co-metabolic pathway

Title: Microbiome determinants and physiological effects of the benzoate-hippurate microbial-host co-metabolic pathway
Authors: Brial, F
Chilloux, J
Nielsen, T
Vieira-Silva, S
Falony, G
Hoyles, L
Neves, A
Rodriguez-Martinez, A
Mouawad, GI
Pons, N
Forslund, S
Chatelier, EL
Le Lay, A
Nicholson, J
Hansen, T
Clément, K
Bork, P
Ehrlich, D
Raes, J
Pedersen, O
Gauguier, D
Dumas, M-E
MetaHIT consortium
Item Type: Working Paper
Abstract: Objective Gut microbial products are involved in type 2 diabetes, obesity and insulin resistance. In particular, hippurate, a hepatic phase 2 conjugation product of microbial benzoate metabolism, has been associated with a healthy phenotype. This study aims to identify metagenomic determinants and test protective effects of hippurate. Design We profiled the urine metabolome by 1H Nuclear Magnetic Resonance (NMR) spectroscopy to derive associations with metagenomic sequences in 271 middle-aged Danish individuals to identify dietary patterns in which urine hippurate levels were associated with health benefits. We follow up with benzoate and hippurate infusion in mice to demonstrate causality on clinical phenotypes. Results In-depth analysis identifies that the urine hippurate concentration is associated with microbial gene richness, microbial functional redundancy as well as functional modules for microbial benzoate biosynthetic pathways across several enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate, independently of gene richness, accounts for links with metabolic health that we previously associated with gene richness. We then demonstrate causality in vivo through chronic subcutaneous infusions of hippurate or benzoate (20 nmol/day) resulting in improved glycemic control in mice fed a high-fat diet. Hippurate improved insulin secretion through increased β-cell mass and reduced liver inflammation and fibrosis, whereas benzoate treatment resulted in liver inflammation. Conclusion Our translational study shows that the benzoate-hippurate pathway brings a range of metabolic improvements in the context of high-fat diets, highlighting the potential of hippurate as a mediator of metabolic health.
Issue Date: 16-Dec-2019
URI: http://hdl.handle.net/10044/1/87331
DOI: 10.1101/2019.12.15.876672
Publisher: Cold Spring Harbor Laboratory
Copyright Statement: © 2019 The Author(s). It is made available under a CC-BY-NC-ND 4.0 International license.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: MR/L01632X/1
MR/L01632X/1
Keywords: MetaHIT consortium
MetaHIT consortium
Publication Status: Published
Open Access location: https://doi.org/10.1101/2019.12.15.876672
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer



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