Gut bacterial metabolism produces neuroactive steroids in pregnant women

A multitude of bioactive compounds are produced by the gut microbiota, including metabolites with notable antimicrobial or immunomodulatory effects.Perhaps the most compelling of these compounds, however, are the ones with the potential to affect human mood and behavior.In an article published recently in Cell, McCurry et al. demonstrated that human gut bacteria are capable of producing neuroactive steroids, including a drug clinically approved by the United States Food and Drug Administration (FDA) for the treatment of postpartum depression.Steroids are a diverse class of compounds characterized by four fused rings of carbon and include biologically important compounds such as cholesterol and sex hormones.Steroids are also critical in the gut: bile, secreted into the gastrointestinal tract to aid digestion, is mainly composed of cholesterol-derived bile acids and a smattering of other bioactive steroids.Once in the gut, bilederived compounds are "ripe for the picking" in terms of microbial metabolism, and are subjected to a dizzying array of modifications by gut bacteria.McCurry et al. demonstrated that bile-derived glucocorticoids-a class of steroids implicated in glucose metabolism and immune function-can be modified by gut bacteria to produce progestins, a class of sex hormones and neurosteroids (Fig. 1) [1].These bacterially produced progestins include allopregnanolone, the above-mentioned treatment for postpartum depression.The specific type of chemical transformation required to convert glucocorticoids to progestins was already suspected to exist in the gut microbiome; however, microbiological and molecular details have been lacking.McCurry et al. showed that members of the Eggerthellaceae family, in particular Gordonibacter pamelaeae and Eggerthella lenta, were capable of modifying glucocorticoids into progestins via 21-dehydroxylation in vitro.Moreover, the authors were able to identify a four-gene cluster responsible for the enzymatic activity.Although a clean knock-out of the system was not possible (and it is, therefore, unclear whether all four genes were strictly necessary), the authors used homologous expression to demonstrate that the cluster was sufficient to confer 21-dehydroxylation activity in related strains.The abundance of G. pamelaeae and E. lenta, and of the identified genes correlated with progestin abundance in human feces.It therefore seems highly likely that these players are responsible for in vivo production of progestins in the gut.Microbial activity in communities is rife with co-dependencies, a property that can complicate single-strain in vitro studies.This