Vaginal microbiome once again tied to preterm birth

Preterm birth is major global health challenge.  Today, around 11% of all babies are born prior to 37 weeks, and are considered preterm.  Many of the causes of these preterm births are still unknown, but it is thought that around 25% of them may be related to a bacterial infection that comes from somewhere in the mother’s own body, i.e. her microbiome.  Many studies are now linking specific vaginal bacteria to risk of preterm birth, and other studies have even shown a connection between other microbiome sites, such as the gut and oral microbiome.  Unfortunately, studies on the microbiome and preterm birth are extremely difficult to conduct, so there are just not enough to have any sort of scientific consensus on the topic.  Last week though, a very rigorous study out f Stanford University was published in the Proceedings of the National Academy of Sciences that monitored expectant mothers vagina, gut, and oral microbiome throughout the course of her pregnancy and then for one year after.  Among many interesting findings, which are discussed below, the most important one was yet another connection between bacterial vaginosis and preterm birth.

The researchers monitored the vaginal, distal gut, salivary, and tooth/gum microbiomes of 49 women, 15 of which ended up delivering preterm, over the course of their pregnancy and for one year after.  Interestingly, the non-vaginal sites’ microbiomes remained relatively stable over the duration of the pregnancy, and even for the one year after.  The vaginal microbiome, however, did show some differences during and after pregnancy.

As many of our readers already know, a healthy vaginal flora is dominated by Lactobacilli, but around 20% of American women are dominated by other species, such as Gardnerella vaginalis, and have an overall increased vaginal diversity.  These women have what is known as community state type four, or CST4, and these women could be diagnosed with bacterial vaginosis (BV), though the clinical diagnosis is not so specific.  The other community state types, CST1, 2, 3, and 5, are dominated by different strains of Lactobacilli, and are generally regarded as healthy.  This current research showed that many of the women’s vaginal microbiomes actually shifted between various CST’s during pregnancy, most often shifting to and from CST4.  These transitions had no association with preterm birth, though.  After giving birth the vaginal microbiome became more diverse, and had greater abundances in anaerobic bacteria, such as Peptoniphilus, Prevotella, and Anaerococcus.  In addition, this usually coincided with a decrease in Lactobacilli.  Surprisingly, these changes did not seem to relate to mode of delivery (C-section of vaginal).

CST4 has been linked to preterm birth before, and this was reinforced in this study.  The scientists found that the longer a women’s vaginal microbiome was within CST4, the greater risk she had for preterm birth.  In addition, the abundance of Gardnerella and Ureaplasma, specifically, were linked to preterm birth.

This study reinforces what many microbiome scientists already suspect, and that is the importance of the vaginal flora in preterm birth.  It is unclear at this point if manipulating the vaginal flora prior to, or during pregnancy would help prevent preterm birth, but it is certainly worthy of discussion and clinical testing.  If you are reading this and wondering what your vaginal microbiome is, then we recommend you participate in the citizen science project, YourPrivateBiome, to find out.  You can learn more about it by following this link on our site, or just click the link above.

Episode 8 of The Microbiome Podcast: The vaginal microbiome and the announcement of a new citizen science project with Dr. Jacques Ravel

This week's episode of The Microbiome Podcast featured Dr. Jacques Ravel from the University of Maryland School of Medicine talking about the vaginal microbiome. We all also talked about a new project that Dr. Ravel helped start called Your Private Biome, an open source citizen science project designed to help researchers get a better understanding of how all the bacteria in women’s vaginas – the vaginal microbiome - affects their health. The new project launched today, June 1st, and the AMI is sponsoring free sampling for a number of women and possibly her partner or family members. If you'd like to learn more, click here. Remember to call in to ask any questions about the microbiome that you would like answered on future podcasts. The number is 518-945-8583. 

Listen to the podcast here on our website, here on iTunes, and here on Stitcher. 

For more detailed show notes, read below:

• (1:20) The White House Office of Science and Technology Policy issued a Request for Information (RFI) to solicit ideas from various stakeholders on the future needs of microbiome research. Read the RFI.
• (2:55) A recent paper out of Curtis Huttenhower’s laboratory describing how microbiome samples could be traced back to their hosts and if this could be used to track individuals related to forensics and other applications. Read the paper. Read our blog post on the paper. 
• (5:22) We begin our conversation with Dr. Jacques Ravel. Read more about Dr. Ravel’s research. 
• (5:47) Dr. Jacques Ravel gives an introduction to the vaginal microbiome. Read more about his research laboratory at the University of Maryland School of Medicine.
• (8:23) Dr. Ravel mentions a paper by Dr. Larry Forney about the vaginal microbiome of adolescent girls. Read the paper.  
• (20:10) Other health issues related the microbiome such as bacterial vaginosis and STDs.
• (30:30) A new citizen science project called Your Private Biome that offers women as well as their partners and families that allows women to sample their vaginal microbiome. Read more about Your Private Biome. 
• (34:59) A paper on circumcision and it’s influence on bacterial load on the penis. Read the paper. 
• (40:40) On the after show, David and Bill talk about their own health issues, specifically allergies.
• (46:15) During our conversation of Bill’s cat allergies, we mention the Kitty Microbiome. Learn more here.

New research helps determine what is healthy and unhealthy in the vaginal microbiome

Editor’s note: This blog about the vaginal microbiome is a good primer for this coming Monday’s Microbiome Podcast with Jacques Ravel, where we will discuss the vaginal microbiome and women’s health at length.  There will also be a special announcement during this podcast, so anyone interested should be sure to download it Monday, June 1.

The typical ‘healthy’ vaginal microbiome is dominated by a Lactobacillus.  However many women, especially those of African descent, are not dominated by this genus, and instead have a high diversity of bacteria in their vaginal tract.  This low lactobacilli, high diversity phenotype has been associated with many disease states, such as bacterial vaginosis (BV), preterm birth, and higher rates of sexually transmitted disease (STD) transmission.  (We have written about some of these diseases before, and encourage any interested reader to click the ‘vaginal microbiome’ below this story to learn more.)  Vaginal microbiome research is still in its early days though, and it is not clear why vaginal microbiome not dominated by Lactobacillus should lead to these diseases, and if this phenotype, if asymptomatic, should even be considered unhealthy.  New research though, out of Harvard University, shows that this phenotype does lead to inflammation, and that these inflammatory response can affect reproductive health and STD transmission.  They published their study in the journal Immunity last week.

The scientists studied the vaginal microbiomes of a cohort of 146 HIV negative, asymptomatic, black, South African women.  They discovered that 63% of them were not dominated by Lactobacillus, an extremely high percentage, especially compared to their counterparts in developed countries (38% of black women and 10% of white women).  Nearly half of those women were dominated by Gardneralla vaginalis, which is most commonly associated with BV, and a large percentage of the other half were diagnosed with BV after investigation.  This is especially interesting because, as stated before, all of the women in the cohort claimed to be asymptomatic, but as we are learning, many women are unaware that there is anything wrong.  Overall, the women were able to be grouped into 4 specific phenotypes, those dominated by Lactobacillus iners, those dominated by other Lactobacillus crispatus, those dominated by Gardnerella vaginalis, and those with a high diversity including Gardnerella vaginalis, Fusobacterium gonidiaformans, Prevotella bivia, and Atopobium vaginae (note the lack of Lacotbacillus in this high diversity group). 

The scientists discovered that there were no associations between each vaginal microbiome group and the rate of STDs, contraceptive use, or sexual behavior.  This is important in showing that, at least on first pass, these bacterial communities were not the result of these exogenous factors (nor did they cause them, for that matter).  They also discovered that there was only a loose association between inflammatory cells in the vaginas of these women, and whether or not they had an STD.  The loose association was only observed in women with Chlamydia, and the women with the highest levels of inflammation had no apparent STDs.

The fact that STDs were not strongly associated with inflammation led the researchers to hypothesize that the vaginal microbiome community, rather than STDs, were responsible for vaginal inflammation.  Indeed, when they compared the amount of inflammatory cells in each vagina with the different microbiome groups described earlier, they found a strong association between inflammation and the highly diverse microbiome group.   Moreover, when they tracked individual women over time, those women whose vaginal microbiomes shifted to the high diversity group also increased inflammatory responses.  The researchers then took this work a step further, and identified specific bacteria that were associated with the inflammatory response:  Prevotella amnii, Mobiluncus mulieris, Sneathia amnii, and Sneathia sanguinegens.

Finally, the researchers measured genes for specific receptors in the vagina that are known to trigger an immune response.  They discovered that those women with the high diversity vaginal microbiomes upregulated genes for these receptors, which are known to be activated by bacteria.  Making matters worse, specific immune cells that are triggered by these receptors, which are thought to be critically important to HIV transmission, were found in higher abundances in women in the high diversity vaginal microbiome group.

This paper did a really great job showing that a vaginal microbiome that lacks Lactobacillus is indeed an unhealthy state, because it creates a highly inflammatory vaginal microbiome which likely causes or contributes to many other ailments, beyond just the higher rates of HIV transmission that was demonstrated.  Unfortunately, at the moment, there are no easy ways for women to check which vaginal microbiome they have, but that should be changing soon, and we recommend that all of our readers tune into the Microbiome Podcast this coming Monday to hear a big announcement in this area. 

The vaginal microbiome changes during and after pregnancy

The vaginal microbiome is critically important to a healthy pregnancy, and studies have shown that vaginal dysbiosis during pregnancy can lead to infection and preterm birth.  In order to help understand what the microbiome looks like throughout and just after pregnancy, researchers from England performed longitudinal studies on 42 pregnant women.  They published their results last week in Nature Scientific Reports.

The scientists sequenced the microbiomes of the 42 women throughout their pregnancies, and then for the 6 weeks afterwards for some of the women.  They discovered, in agreement with other literature on the subject, that the vaginal microbiome becomes dominated by Lactobacilli species during pregnancy.  The Lactobacilli are thought to prevent pathogens from colonizing the vagina because they produce lactic acid which decreases the overall pH of the vagina, and they secrete antibacterial toxins.  These Lactobacilli are also important as they are normally the first to colonize the new infants' guts after they pass through the birth canal. 

The researchers also learned that the microbiome shifts away from Lactobacilli and towards a more diverse microbiome in the period immediately following birth.  The new bacteria that colonize are often associated with vaginosis, and these can lead to inflammation and infection of the birth canal in some women.  The scientists suspect this shift occurs because there is a sudden drop in estrogen production upon removal of the placenta.  The increase in circulating estrogen is thought to be important for Lactobacilli colonization, so it makes sense that the rapid decrease in estrogen decreases Lactobacilli abundance.

Finally, this study showed that there were geographic and ethnic variations to the pregnant microbiome.  While each microbiome was associated with a healthy pregnancy, there were important differences, especially on the species level.  For example, Asian and Caucasian women’s pregnant microbiomes were dominated by Lactobacillus gasseri, while this species was absent in black women’s pregnant microbiomes.

This paper helps show the normal progression of the microbiome during and after pregnancy.  With the mounting evidence that the microbiome is often a contributing factor to preterm birth and some post-partum diseases, papers like this one are important to some day discovering the mechanistic basis for our microbiome's association with these issues. 

Could the microbiome help solve crimes?

Much of the residue on the skin that creates a finger print can be attributable to the microbiome.

We know the microbiome varies greatly between individuals, but is it unique enough, and static enough, to be traced back to an individual?  If it is, then it could theoretically be used to tie people back to the scene of a crime.  Unfortunately not everyone defecates during their crimes, and bacteria transferred from skin can degrade rapidly.  What about hair though?  Hair is commonly obtained as evidence in many crimes because it possibly contains human DNA, however the majority does not.  In these cases can the hair be analyzed for bacterial genomes, and then traced back to the perpetrator?  A team of scientists from Australia sought to answer that question in a newly published article from the journal of Investigative Genetics.

 Scalp and pubic hair was sampled from 42 individuals for the study.  The findings showed that while each of the people shared common bacteria, they also contained many unique bacteria.  Even with very little sampling depth, just identifying bacterial phyla, rather than genus or species, was enough to differentiate the people.  This was especially true with pubic hairs, which were much more individualized than the scalp hair.  In addition, the pubic hairs very clearly differentiated males and females based on the abundance of Lactobacillus, which are very abundant in female pubic hairs (as well as the vagina).  Finally, the results showed that the hairs, especially pubic hairs, were stable over a 5 month span.

Overall this study serves as proof of concept for the microbiome being used as forensic evidence.  This could especially be true for sexual assaults where there is no other physical evidence besides pubic hairs.  Interestingly, the study found differentiation between people without characterizing bacterial species or strains.  Higher resolution sequencing would almost certainly allow for higher discrimination in individuals.  So a warning for all the criminals who read this blog, you may want to consider shaving before committing any felonies.

Microbiome possibly a rich source of new drugs

antibiotic inhibiting growth of S. Aureus.

There has been a bit of popular press recently about an article published in Cell by a group of scientists at UCSF.  The research team that published this article had previously developed an algorithm to look at microbial genetic data and identify genes that were coding for natural products (small molecules that have some, usually unknown, purpose).  Natural products are generally produced in low amounts, or only produced under certain conditions, so they are difficult to discover and isolate.  Throughout pharmaceutical industry history, natural products have been a great source for antibiotic and other pharmaceutical development, because several of their functions mediate microbe to microbe interactions.

When the researchers tested the microbiome genes in the Human Microbiome Project's database using this algorithm, they discovered tens of thousands of new, natural products, including over 3000 that are found in the average individual's microbiome.  Of these 3000 they even found a vaginal microbe from a bacteria, Lactobacillus gasseri, that created a molecule that was similar to an antibiotic that is currently in clinical trials.  When the molecule's antibiotic efficacy was tested in the laboratory, the scientists discovered that it was a potent antibiotic towards common gram-positive pathogens.

The microbiome is an extraordinarily complex system which is one of the primary reasons it has taken so long to properly investigate.  This complexity however, could lead to a gold mine of new compounds and molecules to discover, especially in a system where competition, cooperation, and communication between bugs is so high.  Based on this research, I don't think it will be long before a molecule originally discovered in the microbiome is commercialized.