July 19, 2024

Recent research published in the journal Cell has revealed a fascinating interaction between gut bacteria and human health, particularly concerning women’s health and postpartum depression. The study found that certain gut bacteria produce gas that stimulates 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 sheds light on 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 tracts, has been increasingly recognized for its significant role in human health. Steroid hormones, which are critical for numerous 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 resultant impact on health were not well understood.

“My lab has a long-standing interest in how gut bacteria metabolize endogenous (host-produced) compounds like hormones and vitamins,” said study author Sloan Devlin, an associate professor, of biological chemistry and molecular pharmacology at Harvard Medical School. “We know that the substrates are biologically active and important for the host, and our general hypothesis is that the bacterially modified products will also be important but will have altered biological activities compared to their substrates because they have altered structures.

“Steroids fit into this category of host-produced, bacterially modified molecules. Megan McCurry (a former grad student in the lab and the first author of this paper) and I dug into the literature and found a huge gap (40 years since the last research publication). Researchers in the 1960s and 1970s found that gut bacteria convert glucocorticoids found in human bile into progestins. However, no bacterial strain was ever deposited in a culture collection, and no genes were ever identified.”

“This was the starting point for Megan’s PhD thesis – to identify the bacteria and genes responsible for 21-dehydroxylation, the name for the chemical process that transforms glucocorticoids into progestins,” Devlin explained.

To investigate the role of gut bacteria in hormone production, researchers conducted a series of experiments involving both human and mouse models. They focused on the conversion of tetrahydrodeoxycorticosterone (THDOC), a glucocorticoid found in bile, into tetrahydroprogesterones (THPs), which include hormones like allopregnanolone used to treat postpartum depression.

The researchers first established that the gut microbiome plays a significant role in the production of THPs. They discovered that feces from germ-free mice contained very low levels of THPs compared to those from specific pathogen-free mice. Germ-free mice are laboratory animals that are completely devoid of all microorganisms, including bacteria, viruses, fungi, and parasites. Pathogen-free mice, in contrast, are free from particular pathogens but not entirely devoid of microorganisms. Unlike germ-free mice, pathogen-free mice mice have a normal microbiome.

The finding indicates that gut bacteria are essential for the conversion of THPs. The researchers also found that the human gut microbiome could perform this conversion, as evidenced by the presence of THPs in stool samples from healthy human subjects.

“Prior to our work, the prevailing understanding was that the host makes steroids – the microbiome was not a part of the conversation. We hope this work reveals that gut bacteria modify steroids that the host produces, and these new molecules could affect host functions.”

“Steroids regulate fundamental processes in mammals: metabolism, response to stress, 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 THP production.”

A key finding was the identification of two bacterial species, Gordonibacter pamelaeae and Eggerthella lenta, which were capable of converting THDOC into THPs. This conversion was found to depend heavily on the presence of hydrogen gas (H2). Hydrogen gas is produced predominantly by gut bacteria during the fermentation of non-digestible carbohydrates.

The study showed that E. coli Nissle 1917 (EcN) produced hydrogen gas, which in turn promoted the 21-dehydroxylation of THDOC into THPs by E. lenta. This indicates a form of cooperative metabolism where the metabolic activities of one bacterial species facilitate hormone production by another.

“We found that bacterial gas production induces metabolite production in the gut. Bacterial gas production (flatulence!) is a highly conserved function of the gut microbiome. Gut bacteria ferment carbohydrates in our diet in order 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 called THPs) by gut bacteria. In other words, THP production is an example of cooperative metabolism by gut bacteria: some bacteria make hydrogen gas, which promotes THP production in other gut bacteria.”

“More broadly, our work implies that gas production affects bacterial metabolism (i.e., affects what small molecules bacteria produce). The effects of gas production on metabolite generation had been largely overlooked, likely because studying gases (e.g., controlling their levels in bacterial cultures) is difficult. Our work suggests that there are likely to be other gut bacterial processes that are significantly affected by, basically, flatulence!”

Importantly, the study uncovered that the levels of THPs were significantly higher in the feces of pregnant women in their third trimester compared to non-pregnant individuals. This suggests that pregnancy induces changes in the gut microbiome that enhance the production of THPs. Metagenomic sequencing revealed that bacteria harboring the gene cluster responsible for this conversion were more abundant in pregnant women, indicating a microbiome shift that could influence hormone levels during pregnancy.

“One hypothesis for why postpartum depression develops is that there is a precipitous drop in some hormones, including some neurosteroids, following delivery, and this drop in neurosteroids causes depression in some women. However, we still don’t understand why some women develop PPD while others don’t (~1 in 7 women develop PPD after birth).”

“One of the most striking results from our paper is that levels of THPs are 100-fold higher in the feces of women in the third trimester of pregnancy compared to non-pregnant people. This change cannot be completely explained by the increase in steroids in bile generally during pregnancy, suggesting that gut bacteria may be contributing to THP production during pregnancy. Indeed, we found that levels of the gene cluster that we identified that makes THPs are significantly higher during late pregnancy compared to non-pregnant people.”

The researchers also performed fecal microbiota transplants from pregnant donors into germ-free mice. The recipient mice exhibited increased levels of THPs in their feces, further supporting the role of the microbiome in hormone production. Additionally, co-colonization of germ-free mice with E. lenta and EcN resulted in significant THP production, demonstrating that these bacteria can work together in vivo to produce hormones from endogenous steroids.

“It’s known from our work and the literature that germ-free mice and rats that lack a microbiome only contain the substrates (the corticoids) in their feces and no THPs. Together, these data suggest that the microbiome strongly contributes to THP production in the gut, and that these THPs may have effects on host health, including behavior.”

Summarizing the findings in simple terms, Devlin explained: “We’ve found that ‘bugs make drugs.’ That is, we’ve found that bacteria in our gut produce allopregnanolone, also known as brexanolone or Zulresso, an FDA-approved drug 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 the abundance of the bacterial genes are substantially increased in the feces of people in their third trimester of pregnancy, suggesting that bacterial production of this compound may have an impact on women’s health, particularly during pregnancy.”

Looking forwards, the researchers said long-term studies tracking hormonal changes throughout pregnancy and postpartum periods are necessary to better understand the microbiome’s role in conditions like postpartum depression.

“We want to do more studies looking longitudinally at feces during the first, second, and third trimesters and after delivery in women who do and do no develop PPD to understand better if the microbiome is contributing to levels of neurosteroids throughout pregnancy and whether the microbiome could contributing to or perhaps preventing PPD. Down the road, as a community, we could think about microbiome-targeted therapies for neurological conditions like depression.”

The study, “Gut bacteria convert glucocorticoids into 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.

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