Gut metabolite hippuric acid turns up the volume on immunity

Scientists at The Wistar Institute have discovered that the gut metabolite hippuric acid plays a powerful role in regulating the immune system. Produced when gut bacteria break down plant-based compounds like polyphenols from berries and tea, hippuric acid was once thought to be a harmless metabolic byproduct. The new study [1] shows it can act as a potent amplifier of inflammation — helping the body fight infections early, but sometimes pushing immune responses to dangerous extremes in sepsis.

The research, published in Cell Reports, emerged from metabolomic profiling of preclinical infection models. Hippuric acid levels plummeted 24-fold within 48 hours of E. coli infection, signalling that the molecule was actively involved in immune regulation. When researchers restored hippuric acid in these models, pro-inflammatory molecules such as IL-6 and IL-12 surged while anti-inflammatory signals diminished. In other words, the metabolite acts like a ‘volume knob,’ turning up immune activity when needed - but sometimes too far.”

Mechanistically, the team discovered that hippuric acid amplifies signalling through the Toll-like receptor (TLR) pathway via the MyD88 adaptor protein, a key early-warning system for detecting pathogens. This boosts phosphorylation of signalling proteins like IRAK4 and NF-κB, intensifying the inflammatory cascade. Additionally, hippuric acid reshapes macrophage lipid metabolism, driving cholesterol production and lipid remodelling that further sustain inflammation. Blocking cholesterol synthesis with fluvastatin neutralised the immune-boosting effect, linking metabolic state directly to inflammatory responses.

“Hippuric acid isn’t just a metabolic byproduct - it actively controls how the immune system responds,” said Rahul S. Shinde, D.V.M., PhD,,senior author of the study. “This discovery opens up new ways to think about treating sepsis and even reprogramming immune cells in cancer.”

Indeed, human sepsis patients with elevated hippuric acid levels were significantly more likely to die, suggesting the metabolite could serve as both a biomarker and therapeutic target. Beyond sepsis, Shinde’s lab is investigating whether microbial metabolites like hippuric acid could reprogram immunosuppressive macrophages in pancreatic tumours - one of the deadliest cancers - into tumour-fighting cells. The idea is to harness natural metabolic signals, potentially influenced by diet and microbiome composition, to shift immune balance in favour of anti-tumour activity.

The work highlights a growing appreciation for gut-derived metabolites as active modulators of immunity. Molecules once considered minor byproducts may have outsized effects, capable of protecting the body or tipping it into pathological overdrive. Shinde’s team is now exploring long-term effects of diet and microbial metabolism on baseline immune function, asking whether polyphenol-rich foods like berries and tea could subtly shape health outcomes over time.

This study positions hippuric acid as a critical switch in immune regulation, offering insights that span infection biology, metabolic signalling, and immuno-oncology. What was once overlooked in the bloodstream may hold the key to new strategies for disease management and immune modulation.

The research was supported by the National Institutes of Health, the Pancreatic Cancer Action Network, and the Margaret Q. Landenberger Research Foundation.

More information online

1. Aromatic Microbial Metabolite Hippuric Acid Potentiates Pro-Inflammatory Responses in Macrophages Via TLR-MyD88 Signaling and Lipid Remodeling published in Cell Reports