Characterization of immunomodulatory dialkylresorcinols from the human-associated HACEK bacteria

Endogenous metabolites from the human microbiome play a crucial role in human health and disease. Their involvement in immune and inflammatory regulatory processes both under physiological conditions and diseases renders them essential for pathological research and therapeutic development. However, the microbial metabolites that mediate interactions between the host and microbiome remain largely undefined. Here, we explored a group of ketoacyl synthases from Eikenella spp. that constitute the HACEK group of human opportunistic pathogens through global genome mining. In vivo and in vitro verification of these enzymes resulted in the production of three dialkylresorcinols, which were found to act as agonists of the aryl hydrocarbon receptor and reduce the inflammatory factors of multiple immune cells. These results demonstrate that human-associated Eikenella spp. are capable of producing bioactive aromatic polyketides, which may suggest a molecular mechanism of immunomodulation by the human microbiota. Endogenous metabolites from the human microbiome are pivotal in immune regulation, yet their specific roles remain largely undefined. Here, the authors identify ketoacyl synthases from Eikenella spp. that produce dialkylresorcinols, which act as aryl hydrocarbon receptor agonists, potentially revealing a mechanism for microbiota-driven immunomodulation and advancing therapeutic development.