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

TLDR

The study investigates hippurate, a microbial benzoate conjugate, as a marker and mediator of metabolic health, building on the role of gut microbial products in host metabolism. Researchers combined urinary H‑1 NMR spectroscopy and gut metagenomics in 271 Danish adults, and performed chronic subcutaneous hippurate infusion in high‑fat‑diet obese mice to test causal effects. Human data showed urine hippurate positively associated with microbial gene richness, metabolic health, and saturated‑fat intake, while mouse experiments demonstrated that chronic hippurate infusion improved glucose tolerance and insulin secretion, confirming its potential as a metabolic health marker and mediator.

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 H-1-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.