A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Researchers identified a pathway in Clostridium sporogenes that produces twelve compounds, nine of which accumulate in host serum. The pathway uses tryptophan, phenylalanine, and tyrosine as substrates and involves branching and alternative reductases. Genetic manipulation of C. sporogenes modulates serum metabolite levels in gnotobiotic mice, affecting intestinal permeability and systemic immunity. The study reveals that the pathway involves phenyllactate dehydratase as its penultimate step. The findings suggest that the capacity of gut bacteria to produce indolepropionic acid (IPA) is more widespread than previously thought. The research highlights the potential for engineering the gut microbiota to alter circulating metabolites and impact host physiology. The study also shows that IPA production is associated with gut barrier function and immune responses. The work provides insights into the microbial metabolic pathways that contribute to host biology and offers a framework for future research on gut microbiota engineering.A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Researchers identified a pathway in Clostridium sporogenes that produces twelve compounds, nine of which accumulate in host serum. The pathway uses tryptophan, phenylalanine, and tyrosine as substrates and involves branching and alternative reductases. Genetic manipulation of C. sporogenes modulates serum metabolite levels in gnotobiotic mice, affecting intestinal permeability and systemic immunity. The study reveals that the pathway involves phenyllactate dehydratase as its penultimate step. The findings suggest that the capacity of gut bacteria to produce indolepropionic acid (IPA) is more widespread than previously thought. The research highlights the potential for engineering the gut microbiota to alter circulating metabolites and impact host physiology. The study also shows that IPA production is associated with gut barrier function and immune responses. The work provides insights into the microbial metabolic pathways that contribute to host biology and offers a framework for future research on gut microbiota engineering.