Addendum: BV is not just a sexually transmitted infection

 Although I think that the last blog (https://gmodestmedblogs.blogspot.com/2025/03/bacterial-vaginosis-sexually.html ) made a strong argument that bacterial vaginosis (BV) can be a sexually transmitted infection, with fewer recurrences in women by the use of antibiotics in their male partners, I do think that BV is considerably more complex than that. This was brought up to me by Rebecca Perkins, a gynecologist with a well-recognized expertise in HPV infection and a strong promoter for HPV vaccination. She wrote to me in response to this prior blog, “I don’t think we can quite characterize BV as an STI— I have many patients aged 80-100 who have not had sex in decades and have BV. I think it’s really interesting that treating partners helps but it’s definitely not in the same category as chlamydia”.

 -- I also have seen women of various ages who do develop BV without any sexual activity. And the association of BV with alkalinization of the vagina (by soaps, vaginal deodorants, etc) is a quite plausible explanation for many women. Hence this current addendum/broadening of the complexity of BV infections:

 

An article a few years ago reviewed the evidence to date regarding the role of the vaginal microbiota in developing BV (see vaginal microbiota NatMicro2022 in dropbox, or  doi.org/10.1038/s41564-022-01083-2), noting the following:

-- Lactobacillus species

    -- Lactobacilli are often dominant in the vaginal microbiota, though about 25% of North American women have vaginal microbiota consisting of obligate and facultative anaerobes, many of them not associated with BV (Prevotella, Atopobium, Sneathia, Megasphaera, and Peptoniphilus), but also Gardnerella. 

        -- of note, there are several different strains of lactobacilli, including L. crispatus, L. gasseri, L. jensenii, and L. iners, with some very different functionality amongst them: of the 2 most common, L. crispatus is thought to offer the most BV protective benefits and L. iners offers the least protection (see the article for more on the physiology here, but it turns out that for L. crispatus and L. ines, the relative proportion of these species can change relatively quickly depending on various factors including differences in expression of immune factors by host issues. Also, importantly, there are profound functional differences: both produce lactic acid, which decreases BV prevalence,  but unlike L. crispatus, L. iners only produces the L-isomer of lactic acid that is much less effective than the D-isomer; also. only L. crispatus produces the BV-protective H₂O₂). And, L. crispatus is more effective in decreasing the ability of harmful bacteria from proliferating, and it is more stable than L. iners:  https://pmc.ncbi.nlm.nih.gov/articles/PMC3722878/, and https://pmc.ncbi.nlm.nih.gov/articles/PMC8645935/

            -- global studies (in North America, South America, Europe, Africa and Asia) have found that the most prevalent species in the vaginal microbiota are L. iner, L. crispatus and Gardnerella vaginalis

            -- in women whose vaginal microbiota is not dominated by Lactobacillus species, they have higher vaginal pH (>4.5) and increases in odorific biogenic amines (though many of these women with BV do not have symptoms)

        -- and there are many different subspecies of Gardnerella as well, with different ones often colonized in the same person simultaneously, and the different subspecies have different BV pathogenic potential (as is true with lactobacillus).

      

-- vaginal microbiota are quite different in younger and older women, though less is known about these groups:

    -- younger women: the vaginal microbiota is less likely to be dominated by Lactobacillus species; and in premenarchal girls, their vaginal microbiota seem to play a role in the development of urinary tract infections

    -- menopausal women: there is a general increase in the vaginal pH to  >4.7, with an associated change in the microenvironment for the microbiota, and these changes may be responsible for the genitourinary syndrome of menopause, which seems to be reversed by hormone replacement therapy (though I am not recommending hormone replacement therapy, this finding confirms a presumptive association with low estrogen states)

         -- the cervix normally produces mucus that coats the vagina; this mucus protects the vaginal epithelium and may serve as a source of nutrition for the vaginal microbiota. The layer of mucus is typically depleted in menopausal women, presumably due to decreased estrogen levels

 

-- factors known to change the vaginal microbiota:

        -- contraceptive practices:

            -- male and female condoms: though condoms do have their place in birth control, they may play a direct role in increasing a vaginal inflammatory state and changing the vaginal microbiota:

            -- condoms often have spermicidal gels as is also the case with diaphragm use, cervical cap, or creams, films, foams, gels, or suppositories

            -- and condoms (male and female) are often made with latex that itself can create an inflammatory state in the vaginal microbiome

            -- some but not all studies have found an association between copper IUDs and microbiota changes

            -- however, oral contraceptives and depot medroxyprogesterone injections do not seem to have much effect on the microbiome

        -- stress/cortisol: psychosocial stress and high cortisol levels (eg, by stimulation of the hypothalamic-pituitary-adrenal axis) are associated with increased BV risk, with research finding that cortisol is itself a risk factor for developing BV likely because it modulates the estrogen-induced deposition and accumulation of glycogen in the vaginal epithelium

            -- stress is associated with increased incidence and prevalence of BV in both pregnant and non-pregnant women (see https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00568/full , which goes through lots of the data on this)

         -- there are profound microbiota changes at the onset of the time of menstruation, and also following unprotected vaginal intercourse: https://www.frontiersin.org/journals/microbiomes/articles/10.3389/frmbi.2022.1055472/full

              -- the biophysical and hormonal fluctuations during menstruation are important to susceptibility to infections (eg BV and candida are more common around the time of menses)

              -- the vaginal mucus thickens by progesterone exposure seen in the peri-ovulatory phase

              -- and another change over the menstrual cycle: the vaginal mucosa has T cells and antigen-presenting cells normally

                -- these cells also increase in response to inflammatory triggers

                -- and the vaginal mucosal immune levels have been found to increase immediately before ovulation, with lower levels of the time of menses

                -- and ?? perhaps with condom use and stress?? which may be inflammatory triggers. Other inflammatory conditions??

            -- during unprotected vaginal intercourse, semen is alkaline and raises the vaginal pH, potentially changing the vaginal microbiota composition and perhaps introducing the microbes from the penile microbiota, for example

 

-- it is important to remember that the relationship between specific vaginal micro-organisms and clinical disease is not a consistent phenomenon: 

    -- many women with BV are asymptomatic, with the BV detected on routine vaginal examinations (this is also true for candida, where about 10-20% of women are colonized)

    -- but the lack of a consistent relationship between the plethora of specific organisms (gardnerella species, but also species of prevotella, porphyromonas, bacteroides, peptostreptococcus, mobiluncus, megasphaera, sneathia, clostridiales and mycoplama hominis, ureaplasma urealyticum), does lead to more questions requiring more studies. are there other microbes or perhaps complex specific combinations of different microbes that lead to the microbiota changes that lead to clinical BV infections? other non-tested comorbidites? for example, a chronic inflammatory state may be associated with increased risk of BV infection (eg perhaps by changes in the local immune system, changes in pH,... as noted above). Other inflammatory conditions (HIV, diabetes, other STIs, cigarette smoking, higher BMI) do seem to be associated with increased risk of BV. and perhaps BV is associated with other diseases that have chronic inflammation?? not so many studies have been done, but there are some studies suggesting that rheumatoid arthritis is associated with increased gut Gardnerella vaginalis. ??leading to BV??. What about the many other conditions that are documented that have an inflammatory effect on the gut microbiome and perhaps then infect the vaginal one??

 

So, as with the gut microbiome, there are impressive changes in the vaginal microbiota that may well have profound physiological effects

    -- for the gut microbiome, we do know that diet, exercise, stress, depression, medications, diabetes, metabolic syndrome, etc, etc  are associated with clinically significant microbiota changes

        -- for example studies have suggested that red meat (https://gmodestmedblogs.blogspot.com/2023/10/red-meat-increases-risk-for-diabetes.html ) triggers increases in TMAO, a profound atherogen; and metformin improves glucose tolerance in part through changes in the microbiome (https://gmodestmedblogs.blogspot.com/2022/08/metformin-its-many-faces-and-potential.html ); there are profound relationships between the gut microbiome and, for example, the brain (gut-brain axis) and the liver (gut-liver axis); and the gut microbiome is very sensitive to the external environment (diet, exercise, meds, etc). ie, these gut and vaginal microbiomes are really important for general body health (as well as the microbiomes on the skin and in the upper and lower respiratory tracts). And  microbiome changes are an extremely important  link between our external environments and our internal health outcomes (ie, the gut microbiome does better when the external environments it is exposed to are healthier)

        -- we do have reasonable linkages between the vaginal microbiome (which also changes quite rapidly) and stress, meds, condoms, different stages of the menstrual cycle, oral and topical estrogens, etc. And it would be great to have more data on foods, exercise, etc, as we have with the gut microbiome

        -- and, per the prior BV blog, there are important vaginal changes from BV that have reasonable documentation of adverse events, such as acquiring and transmitting HIV, increased risk for other sexually transmitted diseases (GC, chlamydia, trichomonas, HSV-2, syphilis, as well as an association with both the incidence and prevalence of HPV, risk of cervical cancers, and non-sexually-transmitted diseases such as urinary tract infections, vulvovaginal candidiasis, PID, spontaneous preterm birth, and premature rupture of the fetal membranes, though some of these associations are not found in all studies). So, BV can apparently be a really bad actor.

 -- but, as mentioned in the prior BV blog and above, it is hard to pinpoint a single organism as the causative agent in BV:

    -- the accepted 4 Koch's criteria (though there are some limitations, both practical and ethical) for establishing a microorganism as the causative agent of a disease that are not well-met: "the organism must be present in all cases of the disease" , "the pure culture of the microorganism must cause the same disease when inoculated into a healthy, susceptible host"  and "the microorganism must be re-isolated from the experimentally infected host and identified as identical to the original isolate": these are difficult to accomplish with BV given that there are so many putative organisms and even differences within their subtypes. This does raise the question of whether the many putative organisms associated with BV are actually the bad actors here. Or is it other more perverse microbes that cause the PID and other problems, but the gardnerella etc are just innocent bystanders that are found on culture because they are so plentiful??

-- ie, we do need more studies to answer the many remaining BV questions. one important one for clinicians and patients, for example, is whether asymptomatic BV found on pelvic exam is associated with the many adverse conditions associated with it, as noted above? if so, would routine testing and treating decreased these bad outcomes? we certainly have the H Pylori model, where testing and treating asymptomatic H Pylori infection can decrease the incidence of gastric carcinoma and some other bad outcomes (lots of prior blogs on this, eg see https://gmodestmedblogs.blogspot.com/2023/06/h-pylori-common-in-us-veterans.html).

    -- as with many clinical issues, we really need more information/studies that are so important for problems like BV, which have potentially very bad consequences yet are remarkably prevalent… And, of course, there is the concern that the current US government and their lack of interest in public health/defunding research, is really front and center here.

 

geoff

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