Gut microbial 3α‐hydroxysteroid dehydrogenase promotes depression in males via degrading testosterone

Abstract Abnormal gut microbiota is associated with the occurrence of depression, but the specific pathophysiological role of gut microbiota in the pathogenesis of depression is still unknown. We found that the levels of serum steroid hormone testosterone in male patients with depression were lower than in healthy controls. Using testosterone as the only carbon source, the testosterone‐degrading bacteria Arthrobacter koreensis was isolated from fecal of low testosterone male patients with depression. We found that A. koreensis administration in mice led to reduced serum testosterone levels and depression‐like behaviors, which were improved by antibiotic treatment. Using whole genome sequencing, the gene mediating testosterone degradation in A. koreensis was identified and annotated as 3α‐hydroxysteroid dehydrogenase (3α‐HSD). Escherichia coli heterologously expressing 3α‐HSD obtained the capacity to degrade testosterone, causing depression‐like behaviors after gavage to mice. Testosterone supplementation improves depression‐like behavior in mice induced by gavage of Escherichia coli heterologously expressing 3α‐HSD. Finally, the universality of 3α‐HSD in gut of male patients with depression was higher than that of healthy controls. Overall, our results revealed a new pathway that potentially links testosterone degradation by gut microbes harboring 3α‐HSD enzymes to the pathogenesis of depression. Gut microbial 3α‐HSD can induce depression in mice via testosterone degradation. This means that 3α‐HSD expressed by gut bacteria may be a potential target for depression in men.