Recent research published in the journal Cell revealed a fascinating interplay between gut bacteria and human health, particularly as it relates to women’s health and postpartum depression. The study found that some gut bacteria produce gases that stimulate other bacteria to convert glucocorticoids, a type of steroid, into progestins. Progestins are hormones involved in pregnancy and are used in treatments for postpartum depression. This discovery highlights the potential role of the gut microbiome in regulating hormones and influencing women’s health.
The gut microbiome, a complex community of microorganisms living in our digestive tract, is increasingly recognized for its important role in human health. Steroid hormones, essential for many physiological processes including metabolism, stress response, sexual development, reproduction and behavior, can be chemically modified by gut bacteria.
Researchers have found correlations between gut bacterial composition and levels of these steroid hormones, particularly during pregnancy. However, the exact mechanisms by which gut bacteria modify these hormones and the resulting impact on health were not well understood.
“My lab has long been interested in how gut bacteria metabolize endogenous (host-produced) compounds like hormones and vitamins,” said study author Sloan Devlin, associate professor of in biological chemistry and molecular pharmacology at Harvard Medical School. “We know that substrates are biologically active and important to the host, and our general hypothesis is that bacterially modified products will also be important but will have altered biological activities relative to their substrates because they have altered structures.
“Steroids fall into this category of molecules produced by the host and modified by bacteria. Megan McCurry (former graduate student in the lab and first author of this paper) and I dug into the literature and discovered a huge gap (40 years since the last research publication). Researchers in the 1960s and 1970s discovered that gut bacteria converted glucocorticoids in human bile into progestins. However, no bacterial strain has ever been deposited in a culture collection and no gene has ever been identified.
“This was the starting point for Megan’s doctoral thesis: identifying the bacteria and genes responsible for 21-dehydroxylation, the name for the chemical process that converts glucocorticoids into progestins,” Devlin explained.
To study the role of gut bacteria in hormone production, the researchers conducted a series of experiments involving human and mouse models. They focused on converting tetrahydrodeoxycorticosterone (THDOC), a glucocorticoid found in bile, into tetrahydroprogesterones (THP), which include hormones like allopregnanolone used to treat postpartum depression.
Researchers first established that the gut microbiome plays an important role in THP production. They found that feces from germ-free mice contained very low levels of THP compared to those from specific pathogen-free mice. Germ-free mice are laboratory animals completely free of all microorganisms, including bacteria, viruses, fungi and parasites. In contrast, pathogen-free mice are free of particular pathogens but not entirely free of microorganisms. Unlike germ-free mice, pathogen-free mice have a normal microbiome.
This finding indicates that gut bacteria are essential for THP conversion. Researchers also found that the human gut microbiome could perform this conversion, as evidenced by the presence of THP in stool samples from healthy human subjects.
“Before our work, the prevailing view was that the host was making steroids – the microbiome was not part of the conversation. We hope this work reveals that gut bacteria modify steroids produced by the host, and that these new molecules could affect host functions.
“Steroids regulate fundamental processes in mammals: metabolism, stress response, sexual development, reproduction, salt and water balance, and behavior. The fact that gut bacteria produce new steroids suggests that gut bacteria act as an additional endocrine organ that controls hormone levels in the body. In our study, we particularly looked at the production of THP.
A key discovery was the identification of two bacterial species, Gordonibacter pamelaeae And Eggerthella down, which were able to convert THDOCs to THP. It was found that this conversion strongly depends on the presence of hydrogen gas (H2). Hydrogen gas is produced primarily by gut bacteria during the fermentation of indigestible carbohydrates.
The study showed that E.coli Nissle 1917 (EcN) produced hydrogen gas, which promoted the 21-dehydroxylation of THDOC to THP in E. slow. This indicates a form of cooperative metabolism in which the metabolic activities of one bacterial species facilitate the production of hormones by another.
“We discovered that the production of bacterial gases induces the production of metabolites in the intestine. The production of bacterial gas (flatulence!) is a highly conserved function of the gut microbiome. Gut bacteria ferment carbohydrates in our food to produce energy, and some of the byproducts are gases like H2, CO2, and methane. Hydrogen is the predominant gas produced by gut bacteria.
“We found that hydrogen gas is necessary and sufficient for robust production of allopregnanolones (also known as THP) by gut bacteria. In other words, THP production is an example of cooperative metabolism by gut bacteria: some bacteria produce hydrogen gas, which promotes THP production in other gut bacteria.
“More broadly, our work implies that gas production affects bacterial metabolism (i.e. affects the small molecules produced by bacteria). The effects of gas production on metabolite generation have been largely neglected, probably because the study of gases (e.g., monitoring their levels in bacterial cultures) is difficult. Our work suggests that there are probably other intestinal bacterial processes that are primarily affected by flatulence! »
Importantly, the study found that THP levels were significantly higher in the stools of pregnant women during their third trimester than in non-pregnant people. This suggests that pregnancy induces changes in the gut microbiome that enhance THP production. Metagenomic sequencing revealed that bacteria harboring the gene cluster responsible for this conversion were more abundant in pregnant women, indicating a shift in the microbiome that could influence hormone levels during pregnancy.
“One hypothesis explaining why postpartum depression develops is that there is a sudden drop in certain hormones, including certain neurosteroids, after childbirth, and that this drop in neurosteroids causes depression in some women. However, we still don’t understand why some women develop PPD while others do not (about 1 in 7 women develop PPD after birth).
“One of the most striking findings from our paper is that THP levels are 100 times higher in the stools of women in the third trimester of pregnancy than in non-pregnant people. This change cannot be fully explained by the increase in steroids in bile overall during pregnancy, suggesting that gut bacteria may contribute to THP production during pregnancy. Indeed, we found that the levels of the group of genes we identified that produce THPs are significantly higher in late pregnancy than in non-pregnant people.
The researchers also carried out transplants of fecal microbiota from pregnant donors into germ-free mice. The recipient mice showed increased levels of THP in their stool, further supporting the role of the microbiome in hormone production. Additionally, cocolonization of germ-free mice with E. slow And ThisN resulted in significant production of THP, demonstrating that these bacteria can work together alive to produce hormones from endogenous steroids.
“It appears from our work and the literature that germ-free mice and rats lacking a microbiome only contain the substrates (corticosteroids) in their stools and no THP. Together, these data suggest that the microbiome strongly contributes to the production of THPs in the gut and that these THPs may have effects on host health, including behavior.
Summarizing the results in simple terms, Devlin explained: “We found that ‘insects make drugs.’ That is, we discovered that the bacteria in our gut produce allopregnanolone, also known as brexanolone or Zulresso, a drug approved by the FDA to treat postpartum depression. Allopregnanolone was a known natural product and neurosteroid, but we discovered that gut bacteria make it and also how they make it (the genes responsible). We also found that levels of this molecule as well as bacterial gene abundance are significantly increased in the stools of people during their third trimester of pregnancy, suggesting that bacterial production of this compound could impact women’s health, especially during pregnancy. .”
Looking ahead, researchers said long-term studies of hormonal changes throughout pregnancy and postpartum periods are needed to better understand the role of the microbiome in conditions such as postpartum depression. .
“We are interested in doing more studies looking longitudinally at stools during the first, second and third trimesters and after delivery in women who do or do not develop PPD to better understand whether the microbiome contributes to neurosteroid levels throughout the throughout pregnancy and whether the microbiome contributes to neurosteroid levels throughout pregnancy could contribute to or perhaps prevent PPD. In the future, as a community we might consider therapies targeted at the. microbiome for neurological diseases like depression.
The study, “Gut bacteria convert glucocorticoids to progestins in the presence of hydrogen gas,” was authored by Megan D. McCurry, Gabriel D. D’Agostino, Jasmine T. Walsh, Jordan E. Bisanz, Ines Zalosnik, Xueyang Dong, David. J. Morris, Joshua R. Korzenik, Andrea G. Edlow, Emily P. Balskus, Peter J. Turnbaugh, Jun R. Huh, and A. Sloan Devlin.