September 2013

Gut bacteria may be a source of male steroid hormones

Fig. 8: cortisol metabolism
Cortisol metabolism by the human gut microbiome. Members of the human gut microbiome are capable of reducing, and epimerizing the 3-oxogroup, reducing the Δ4-bond, oxidation/reduction of the 20-oxo-group, removing the side-chain by steroid-17,20-desmolase, 21α-dehydroxylation, and epimerizing the 17-oxo-group of 11β-OHAD. Click on the image to see a larger version of it.

Looks like there is more than one fount for male steroid hormones in the body. In a paper recently out in the Journal of Lipid Research, researchers show that a bacterial species converts glucocorticoids into androgens, a group of male steroid hormones. The implication is that the host endocrine system may not be the only source of androgens and other regulatory molecules: The gut microbiome may be another.
 
Phillip Hylemon at the Virginia Commonwealth University explains that there has been evidence since the 1960s that secondary bile acids, which are microbial products made from the primary bile acids secreted by the gallbladder, are associated with gastrointestinal diseases, such as colon cancer and cholesterol gallstones. “A small number of microbes inhabiting the (gastrointestinal) tract are the sole source of these molecules,” he explains.
 
His group and others have worked out how the bacterium Clostridium scindens carries out the primary-to-secondary bile acid transformation. But it turns out C. scindens also can make androgens from glucocorticoids. Why is this important?
 
Hylemon explains that, in the gut, androgens can be further modified by other members of the gut microbiota to make testosterone-type derivatives. “It is possible that these steroid metabolites interact with host nuclear receptors or other gut organisms. In males, for instance, the prostate gland is against the rectum wall. Therefore, androgens produced by gut bacteria are capable of passively diffusing into this organ, perhaps altering the physiology of cells in the prostate,” he says.
 
C. scindens is the only bacterium in the human GI tract known to convert glucocorticoids into androgens, but how does it do it?
 
Hylemon and colleagues decided to use high-throughput nucleic acid sequencing to identify the genes encoding the enzymes involved in this biotransformation. They knew the genes were turned on by cortisol, a stress-induced steroid hormone. By comparing levels of mRNA from C. scindens cultivated in broth with and without cortisol, the investigators reasoned that they would be able to identify candidate genes.
 
They identified a cluster of genes that encode a transketolase whose sequence is different from those involved in carbohydrate metabolism. A question now is if the C. scindens transketolase evolved to carry out the biotransformation of glucocorticoids into androgens specifically.
 
The implication of the work is that a bacterium like C. scindens could play an important role in the endocrine system. “It is generally agreed in the field that the gut microbiota constitute a virtual organ. We believe that, like other organs in the body, this organ has specialized cells that produce hormones that may be derived from host-synthesized bile acids and steroid hormones,” says Hylemon. Because the gut microbiome can produce hormones, Jason Ridlon, the first author on the paper, says, “we consider the gut microbiome to be an endocrine organ.”
 
The investigators now would like to see if androgen-like molecules produced by the gut microbiome have the same effects on physiology as do the ones generated by the host endocrine system. Hylemon says, “Our next step is to screen bacterial-generated bile acids and steroid hormone metabolites for their ability to bind to and activate host G-protein-coupled receptors and nuclear receptors.”

Rajendrani MukhopadhyayRajendrani Mukhopadhyay (rmukhopadhyay@asbmb.org) is the senior science writer and blogger for ASBMB. Follow her on Twitter (www.twitter.com/rajmukhop), and read her ASBMB Today blog, Wild Types.


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