Bidirectional host–microbe signaling through cortisol metabolism by the gut bacterium Agathobaculum desmolans

Microbial endocrinology has developed principally around bacterial metabolism of catecholamines, yet the intestinal lumen receives far larger quantities of host steroids. Here we characterize cortisol metabolism by Agathobaculum desmolans ATCC 43058 as a model for the HPA axis arm of this interaction. Cortisol elicited extensive transcriptional remodeling, dominated by induction of the steroid-17,20-desmolase pathway but extending to motility, sporulation, and mobile genetic elements. Recombinant DesAB preferentially cleaved cortisol and displayed substrate-specificity distinct from Clostridium scindens DesAB. Its product, 11β-hydroxyandrostenedione, is a precursor of 11-oxygenated androgens that agonize the nuclear androgen receptor; in primary mouse intestinal cells it induced MAPK, cytokine, and cell-adhesion programs and altered VCAM1, CSF1, CSF1R and IGFBP6 abundance. Bacterial cortisol metabolism therefore transforms a host glucocorticoid signal into an androgenic one, establishing the sterolbiome as a mechanistically tractable arm of microbial endocrinology.