Microbes and Menopause

Microbes are an important part of the menopause story.

“Why can’t a woman be more like a man?” —Henry Higgins, My Fair Lady

Women produce estrogens, remarkable molecules that can seep through every tissue in the body to find their targets. Those targets include the vagina, uterus, ovaries, and breasts. But somewhat unexpectedly, they also include the gut, the brain, and other bodily systems.

A happy side-effect of estrogens is that they improve cardiovascular and metabolic health. Estrogens can also alter cognition—usually for the better, but not always.

Low levels of estrogen can lead to a lousy mood, as exemplified by postpartum and menopausal depression. These mental maladies can often be alleviated with estrogen treatment. This establishes an important connection between the brain and estrogens.

In typical biological fashion, it quickly gets complicated, because the brain is also affected by the gut. More specifically, the trillions of microbes that call the gut their home. Collectively, they are called the microbiome, and the connection is called the gut-brain axis.

Those microbes are affected by estrogens. In fact there is a distinct cadre of microbes that specialize in estrogens, called the estrobolome. Men, with far lower levels of estrogen, don’t have an estrobolome. This means that premenopausal women have a unique gut microbiome, more diverse than men, from mouth to anus.

It’s a two-way street

As well as estrogen affecting gut microbes, gut microbes in turn help to manage estrogen. Some of the estrogen in the body is protected by guardian proteins that inactivate it and extend its lifespan. Surprisingly, gut bacteria can strip off that protective protein and thus activate the estrogen.

That means the estrobolome is capable of producing estrogen, an unexpected superpower. This makes the microbiome a kind of endocrine gland, an alien gonad.

When this carefully balanced arrangement is breached—for instance by a chronic gut issue—then all hell can break loose, resulting in hormonal imbalance and inflammation. Over time that can lead to cervical and breast cancer, among other diseases.

Microbes have a surprising influence on a woman’s health. We even know the names of some of the players. For example, a recent study found that Bacteroides is associated with breast cancer: every 1% increase in its relative abundance increased the incidence of breast cancer by 5%. On the other hand, Romboutsia and Coprococcus were preventative against breast cancer: each 1% increase in their relative abundance reduced the rate of breast cancer by 91% and 55%, respectively.

After menopause, estrogen levels fall precipitously and women lose their estrobolome. The female microbiome starts to look distinctly male. That has the unfortunate side effect of plunging postmenopausal women into the nasty male world of excess heart and metabolic disease risk.

It’s not just gut microbes that change. Lactobacillus bacteria dominate the vaginal microbiome and produce lactic acid which helps to deter pathogenic bacteria. But after menopause, Lactobacillus levels drop dramatically. With Lactobacillus no longer dominating, the vaginal microbiome becomes less able to fight off invading microbes.

This intertwining of microbes and hormones suggests that we might be able to treat menopausal symptoms in novel ways. Aurea Simon-Soro and colleagues from the University of Sevilla, Spain, are optimistic. They say “Hormonal changes, environmental factors, and microbial dynamics affect menopausal symptoms and women’s health. This insight could drive the development of precise therapies to alleviate symptoms and minimize the risk of related health issues, ultimately enhancing the quality of life for menopausal women.”

Researchers from Albert Einstein College of Medicine agree, saying, “Future studies can examine whether postmenopausal hormone therapy can reverse menopause-related changes in the gut microbiome and restore the estrobolome.”

The genetic contribution

The X chromosome, doubled in women, harbors many immune-related genes. Most of these differences favor women. Women have more immune cells, especially macrophages and dendritic cells, providing them with a more vigorous antibody and immune response to infection. It's not a small difference: women are ten-fold more reactive to viruses than men. So much for being the weaker sex.

As a rule of thumb, men have more and worse infections than women. Men have twice the TB rate and a greater rate of infection by viruses, bacteria, fungi, and parasites – basically a complete buffet of pathogens.

However, as with most things biological, there is a tradeoff. An overly aggressive immune system can target beneficial microbes as well, damaging the gut microbiota. It can also lead to autoimmunity, where your immune system attacks your own tissues. Thus, men may suffer more from infection, but women tend to end up with more autoimmune diseases like lupus, multiple sclerosis, rheumatoid arthritis, and celiac disease.

So figuring out what it means to have a more male microbiome is not clearcut.

Does sex matter?

Women and men are different, but the prevailing attitude for researchers has long been that sex doesn't matter. Worse yet, in most animal studies, scientists have traditionally concentrated on males in order to eliminate the effects of the estrous cycle that females add to the study. That’s why we still know so little about menopause.

Clearly, this is misguided and misses some of the most interesting features of the microbiome and immune system. The NIH has weighed in and now recommends that both sexes be included in research to establish realistic treatments for the entire population, not just males. That’s a good start, although as I reported last week, the NIH is still in limbo, with every grant up for challenge.

Sadly, two of the words that can flag a grant for refusal are “women” and “female”. The people in charge of these machinations are, unsurprisingly, men. As Margaret Atwood said, “Menopause is a pause while you reconsider men.”

We can only hope better minds prevail, because there is a lot of catching up that we need to do in women’s biology.

There’s a movement afoot to valorize women who can bear children. That’s great, but let’s hope we don’t forget that women are still people after menopause, often with renewed purpose. With some good science and a little luck, we can make those later years some of the best.

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References

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