Bifidobacterium longum/infantis can modify the detoxification process of estrogen via glucuronidation and, as a result, may over time reduce free estrogen levels. Reducing free estrogen may, in turn, lower vaginal glycogen availability and, as a result, lactobacilli levels.
Lactobacilli species rely heavily on glycogen as an energy source. This reduction in glycogen could be a potential avenue for resolving cytolytic vaginosis (CV) in those for whom an abundance of estrogen is driving the condition.
This is a hypothetical discussion. No research exists on this specific topic yet.
What is CV?
Cytolytic vaginosis is characterised by excessive proliferation of Lactobacillus species, typically L. crispatus, leading to high levels of lactic acid and a highly acidic vaginal pH. This acidic environment can damage epithelial cells and result in symptoms such as vaginal burning and sticky discharge.
It’s unclear why CV develops in some people and not others, but we do know that abundant estrogen can be a factor.
Understanding lactobacilli and glycogen in the vagina
Estrogen stimulates vaginal epithelial cells to proliferate and differentiate. During this process, the cells synthesise and store glycogen. As the cells are shed, lactobacilli species can utilise the glycogen as an energy source. More food, more bacteria.
Lactobacilli species metabolise glycogen into lactic acid, which supports the vagina’s acidic pH and helps protect against disruptive microbes that could cause infections like bacterial vaginosis (BV) or aerobic vaginitis (AV).
Understanding estrogen and its forms
Estrogens such as estradiol (E2) and estrone (E1) circulate in the bloodstream in two major forms: bound to sex hormone binding globulin (SHBG) or albumin, which act as transporters, or free estrogen.
Unlike bound estrogen, free estrogen can move across cell membranes, and bind to estrogen receptors and exert its power.
The blood transports free estrogen to the liver, where liver cells take up estrogen. Once inside the liver cell, the estrogen undergoes phase II liver detoxification, which includes glucuronidation.
What is glucuronidation?
Glucuronidation is a metabolic pathway responsible for detoxifying many metabolites, including estrogen, in the liver. Glucuronic acid conjugates (binds to) the substance, in our case estrogen, deactivating it.
With estrogen, this process is key to metabolism and clearance by allowing the estrogen to be more water-soluble and able to be excreted in bile through the digestive system or urine.
A conjugated estrogen is less biologically active, as it cannot bind to an estrogen receptor. Estrogen receptors are abundant in vaginal epithelial cells.
The transport and excretion of estrogen
Conjugated estrogens are more water-soluble and can be loaded into bile. Bile is then squirted from the gallbladder into the digestive tract to help digest food, primarily fats.
The estrogen is now in the digestive process, and with a healthy bowel movement each day, it is out of the body and into the toilet. If faeces stay in the bowel for too long, such as in constipation or high numbers of gut bacteria with β-glucuronidase activity, estrogen can be set free and reabsorbed. This process is known as estrogen recycling.
Some conjugated estrogens can be released into the blood and removed via the kidneys, in urine.
How does bifido impact glucuronidation?
Certain Bifidobacterium strains such as B. longum and B. infantis produce enzymes, including β-glucuronidase, which deconjugate glucuronides. That is, in this case, setting estrogen free so it is biologically active again.
But wait, you ask, weren’t we trying to reduce estrogen by binding it up, not setting more of it free? Let’s explore this a little more.
Deconjugating estrogen is likely to increase free estrogen levels temporarily, but over time, it would reduce the amount of estrogen that enters the blood due to recycling from the gut. Remember, the estrogen has come from the blood to the digestive system, where the chances of it being pooped out are high.
If bifidobacterium is deconjugating estrogen in the digestive system, there is much less opportunity for it to re-enter blood circulation, contributing to relative estrogen excess. Meaning, much less opportunity for free estrogen to head to the vagina to set off those estrogen receptors and stimulate the proliferation of vaginal epithelial cells and feed those lactobacilli.
Hormonal feedback systems
If there is less free estrogen in the bloodstream, but the body is not missing out on estrogen, then the signals to produce more won’t be strong. Thus, the outgoing estrogen will increase while the incoming estrogen remains unchanged. Make sense?
What else can Bifido do?
Bifidobacterium might alter other factors like nutrient competition, further reducing glycogen availability to Lactobacillus.
Bifidobacterium strains can compete with lactobacilli species for adhesion sites and resources in the vaginal mucosa. This may reduce L. crispatus dominance via competitive exclusion and support the resolution of CV.
Bifidobacterium species also have immunomodulatory activity that can influence the vaginal environment. A reduction in inflammation or an alteration in cellular immunity may result, which may be less favourable for L. crispatus.
Avenues for further study
To test this theory, we’d need to look into the β-glucuronidase activity of B. longum/infantis in vaginal conditions like CV, but also BV and AV for comparison. Testing estrogen conjugation and free glycogen availability in the presence of these species would also be useful.
We could watch changes in lactobacilli populations and vaginal pH after use of bifido probiotic use, with assessments of vaginal estrogen and glycogen before and after the intervention.
References1–5
- 1.Flores R, Shi J, Fuhrman B, et al. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. J Transl Med. Published online December 2012. doi:10.1186/1479-5876-10-253
- 2.Hu S, Ding Q, Zhang W, Kang M, Ma J, Zhao L. Gut microbial beta-glucuronidase: a vital regulator in female estrogen metabolism. Gut Microbes. Published online August 9, 2023. doi:10.1080/19490976.2023.2236749
- 3.Ervin SM, Li H, Lim L, et al. Gut microbial β-glucuronidases reactivate estrogens as components of the estrobolome that reactivate estrogens. Journal of Biological Chemistry. Published online December 2019:18586-18599. doi:10.1074/jbc.ra119.010950
- 4.Parida S, Sharma D. The Microbiome–Estrogen Connection and Breast Cancer Risk. Cells. Published online December 15, 2019:1642. doi:10.3390/cells8121642
- 5.Sui Y, Wu J, Chen J. The Role of Gut Microbial β-Glucuronidase in Estrogen Reactivation and Breast Cancer. Front Cell Dev Biol. Published online August 12, 2021. doi:10.3389/fcell.2021.631552
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