Human enzymes defy science by producing key metabolites without gut microbes

A new study published in Nature Metabolism has upended long-held beliefs about the origins of indole and phenol compounds in the human body. Researchers found that human enzymes can produce these metabolites independently of gut microbes. This challenges the assumption that such compounds come mainly from microbial activity. The team used a multi-omic approach, combining metabolomics, genomics, and enzymology to investigate the source of these metabolites. Experiments in germ-free animal models and microbial-free cell cultures confirmed that host enzymes alone could synthesise indoles and phenols. They identified specific enzymes capable of converting tryptophan and tyrosine into diverse forms of these compounds through non-microbial pathways.

The study also revealed differences in metabolic capacity across tissues. This suggests that local production of indoles and phenols may have direct physiological effects within the body. Such findings imply that host metabolism plays a more autonomous role than previously thought.

The discovery has wider implications for medicine. It suggests a need to reassess microbiome-targeted therapies and diagnostics, as host-derived metabolism may influence their effectiveness. Additionally, the findings could reshape pharmacokinetics and toxicology, since host pathways may alter drug metabolism, efficacy, and toxicity. This work expands the understanding of host-microbiome interactions, showing that humans possess inherent metabolic capabilities once attributed solely to microbes. It also opens new avenues for drug development, offering potential treatments for diseases tied to irregular metabolism of indoles and phenols.