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. 

Americans swap foods with Africans and their microbiomes follow – fiber, fat and cancer risk

Phuto pap and porridge, a traditional South African, high fiber, meal.

Despite having similar genetic backgrounds, African Americans are thirteen times more likely to develop colon cancer than rural South Africans.  Indeed, environmental factors, rather than genetics, are thought to be the major factor in developing colon cancer, because recent immigrants’ children’s risk is more similar to where they are living than to their parents’ homeland.  This environmental risk could be primarily caused by a number of factors, such as antibiotic use or drug use, but many scientists believe that diet, and its influence on the microbiome, is primarily responsible.  As it turns out, rural Africans eat much more fiber (almost 5x more) and much less fat (almost 3x less) than African Americans, and these differences have drastic effects on the microbiomes of their hosts.  Not only are the most abundant bacterial species different, but the major metabolites vary greatly as well.  Scientists from the University of Pittsburgh came up with the clever idea of swapping the foods of rural South Africans and African Americans, to investigate how this dietary intervention would affect each group’s microbiomes and risk for colon cancer.  They published the results of their study in Nature Communications last week.

The researchers studied 20 middle aged African American men and 20 middle aged rural South African men.  They each had their microbiomes and colons studied for two weeks while eating their normal diets, and then again for two weeks after swapping diets.  Initially, the Americans had microbiomes dominated by Bacteroides and the Africans by Prevotella.  After the diet though, they noticed a rapid shift in these populations, and it corresponded to an increase in colonic inflammation for the Africans and decrease in the Americans.  In addition, an increase in butyrate, the short chained fatty acid (SCFA) that is thought to be beneficial to health, followed the fiber diet as well, and a decrease was associated with eating the high fat diet; this makes sense, as butyrate is produced as a metabolite of fiber fermentation by the microbiome.  Interestingly, prior to the diet change a top-level analysis of all the metabolic end products of the microbiome showed that Africans produced more of every single one studied except for choline, which is related to heart disease.  Many of the metabolites studied, including choline, followed their diet switch, and were produced according to the food eaten, rather than the person eating it.  Perhaps most importantly, secondary bile acids, which are produced by the microbiome and may be carcinogenic and an important cause of colon cancer, followed the diet as well.  Africans, who produced much fewer secondary bile acids than Americans while consuming their regular diet, had a 400% increase in production after the diet switch, and vice versa for the Americans, who had a 70% decrease.

This study really illustrates the importance of diet on the output of the microbiome.  These metabolites can directly influence our health, and may be more important to our well-being than the bacteria that produce them.  According to this study, it appears that eating more veggies and less fat, something that parents have been saying for a long time, fits in with our understanding of the microbiome.  As Erica Sonnenburg said in our podcast 3 weeks ago, “Feed your microbiome at every meal!”

Gut bacteria protect against malaria transmission

Malaria is a deadly disease transmitted through mosquitoes and most widespread in tropical and subtropical regions around the world, especially in Africa. According to the Center for Disease Control and Prevention (CDC), 627,000 people died in 2012 and there were a total of 207 million cases worldwide. Through studying the microbiome, scientists last week published a major discovery in Cell that may lead to better vaccinations for malaria that could help prevent the disease from being transmitted.

Scientists in Portugal, collaborating with colleagues in the United States, Australia, and Mali, found that the parasite the causes malaria, Plasmodium, expresses the same sugar molecule that is seen in a type of Escherichia coli (E. coli).  This sugar molecule from the E. coli called alpha-gal (a-gal) results in the body’s immune system producing antibodies against this molecule and therefore also protecting against the malaria parasite. It is known that adults who are exposed to malaria are at lower risk of contracting the disease than children under the age of 5 and the researchers hypothesized that this was due to the children lacking this specific E. coli in their body and therefore unable to fight back against Plasmodium exposure.   

The scientists studied the gut bacteria of a group of individuals in Mali who had very high rates of malaria transmission. They found that those who had higher levels of anti-a-gal antibodies had lower risk of transmitting malaria and those with low levels of these antibodies had greater risk of transmitting the disease.  This showed that children are at greater risk for the disease because they do not produce enough anti-a-gal antibodies to prevent the parasite from infecting the body.

The scientists also found that the transmission of the parasite is blocked almost immediately following its introduction into the body through the skin. The antibodies against a-gal attach to the Plasmodium as soon as it is exposed to the body, and a part of the immune system called the component cascade is activated, killing the parasite before it can leave the skin and reach the blood stream.   

They found that by vaccinating mice against a kind of a-gal, the mice produced enough anti-a-gal antibodies that were highly efficient in protecting the mice from malaria transmission.  The scientists believe that it may now be possible to translate this work to humans and develop vaccines that would increase anti-a-gal antibodies and prevent malaria transmission. If successful, vaccinations could be given to children who are at high risk for the disease and could prevent hundreds of thousands of deaths every year.  These findings also illustrate the protective aspects of the microbiome in regulating immunity, and the potential treasure-trove of molecules produced by the microbiome that could be used in therapeutics.

Humans lack gut bacterial diversity compared to their ape ancestors

The diversity of microbes in the human body has important consequences on disease and nutrition, with less diversity often linked to autoimmune diseases, obesity, and gastrointestinal disorders. In a study published this week in the journal Proceedings of the National Academy of Sciences, researchers studied the evolution of the human microbiome by comparing the microbial communities in the gut of human’s closest relatives, the African apes, to human’s. They found that the human microbiome had much less diversity than that of African apes, and even less diversity was observed in American’s guts compared to humans in non-industrialized nations.

The scientists collected hundreds of fecal samples from wild chimpanzees from Tanzania, wild bonobos from the Democratic Republic of the Congo, and wild gorillas from Cameroon, as well as from humans living urban lifestyles in the U.S. and Europe, rural lifestyles in Malawi, preindustrial lifestyles in southern Amazon rainforests of Venezuela, and hunter-gatherer lifestyles in Tanzania.

Results of the identification of microbes found in each fecal sample showed that the human gut microbiome is significantly less diverse than that of apes, even though there are also substantial differences among the multiple ape species. These findings confirm that microbial diversity has decreased significantly during human evolution and has changed even more rapidly in humans than among ape populations.

People living in urban cities in the United States had the least microbiome diversity, which could be a result of cultural differences, differences in diet, increase in c-section prevalence, increased use of antibacterial cleaning products, and antibiotics. As we have seen in previous studies, lower levels of microbiome diversity in humans has been linked to both immune system and gastrointestinal diseases. At this point we don’t fully understand the implications that these changes in human gut diversity over time are having but it is important to better understand this as we develop new therapeutics by manipulating the microbial communities in our gut.