Hippurate metabolite intervention to reduce offspring metabolic dysfunction from maternal obesity

Overview

This research program investigates hippurate, a microbial-host co-metabolite produced through bacterial-mediated phenylalanine metabolism and host-mediated glycine conjugation of benzoic acid, as a novel intervention to reduce metabolic dysfunction in offspring exposed to maternal obesity in utero. Maternal obesity is linked to fetal overgrowth and increased likelihood of childhood and adult obesity. Preliminary findings demonstrate that healthy maternal dietary factors, including omega-3 polyunsaturated fatty acids (PUFAs) and increased fruit and vegetable intake, elevate hippurate concentrations in offspring and breast milk. Exogenous hippurate administration in adult mice reduced diet-induced obesity, improved glucose homeostasis, and decreased visceral adipose tissue (VAT) fibrosis and inflammation. These results suggest hippurate may serve as a signaling metabolite through the GPR109A receptor to improve offspring metabolic health in the context of maternal obesity.

Technical specifications

Key research findings and approach:

• Maternal high-fat diet exposure increased offspring adipocyte diameter, VAT macrophage infiltration, VAT fibrosis, and dysregulated glucose metabolism
• Maternal omega-3 PUFA supplementation (flaxseed oil) attenuated these metabolic abnormalities in offspring
• 16S sequencing identified gut microbes associated with hippurate production that were elevated in offspring exposed to maternal omega-3 supplementation and persisted into adulthood
• Untargeted metabolomics confirmed elevated VAT hippurate concentrations in offspring from omega-3-supplemented dams
• Exogenous hippurate administration reduced high-fat diet weight gain and VAT inflammation in adult mice
• Hippurate is hypothesized to signal through the GPR109A receptor to mediate metabolic benefits

Future validation approach:

• C57BL/6 mice will be placed on control or high-fat diets prior to mating
• Pregnant dams will be randomized to hippurate intervention (15 mM in drinking water) during pregnancy and lactation
• Offspring metabolic assessments including body weight, EchoMRI body composition, and glucose tolerance tests at weaning and postnatal day 91
• Terminal molecular analysis of liver, VAT, and plasma for fibrosis, inflammation, and metabolomics

Technology readiness level

This research is at the preclinical validation stage. Preliminary data from the principal investigator's laboratory have established the foundational hypothesis through mouse model studies demonstrating that maternal dietary interventions and exogenous hippurate administration can reduce metabolic dysfunction. Future validation studies are planned to directly test in utero hippurate exposure on offspring metabolic outcomes using controlled dietary and pharmacological interventions in a well-established mouse model. The work is supported by preliminary evidence linking microbiome-derived metabolites to improved metabolic health, positioning this research toward translational development of hippurate-based interventions for maternal-fetal metabolic health.