Sex and the Microbiome

"Instead of ignoring our differences, we need to accept and transcend them." —Sheryl Sandberg

A lot is going on in your gut.

Source: Maksym Azovtsev/iStock

Mental disorders are not gender-neutral. Far more women than men suffer from depression, for instance, while men are more likely to be autistic. These sex differences are intriguing, and the most obvious explanation is hormones.

The latest research also shows that mental issues have a connection to inflammation, which typically originates in the gut. So it may not be surprising to find out that gut microbes are also not gender-neutral. Some gut diseases, like IBS, occur twice as often in women than men—and IBS is strongly associated with depression and anxiety. Men and women with depression have changes in their microbiome that are different from healthy people and different from each other.

Gut microbes, in general, are different between men and women, likely due to those same hormonal influences. This is supported by the fact that male and female microbial differences don't show up until puberty when hormones start in earnest.

Men motor on with stable levels of testosterone, while women have fluctuating levels of estrogen. These oscillations might explain why women have a more diverse and variable microbiome than men. These different microbiomes, in turn, can give rise to sex differences in the immune response. And these different immune responses can lead to different psychiatric conditions. If it all sounds deliriously complicated, you're paying attention.

The genetic component

The gut microbiome is partly moderated by genetics. Genetic variations in immunity, in particular, have an impact on your gut microbes. 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 10-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 the complete buffet of pathogens.

However, as with most things biological, there is a tradeoff. An excessively eager immune system can make it hard on beneficial microbes and can lead to autoimmunity, where your immune system attacks your own tissue. Thus, men may suffer more from infection, but women tend to end up with more autoimmune diseases, like lupus, multiple sclerosis, Sjogren's syndrome, Graves disease, rheumatoid arthritis, and celiac disease.

We are surrounded and outnumbered

There are 20,000 human genes, each specifying a protein. It's mind-boggling that these are all the ingredients you need to make a human.

Shockingly, there are hundreds of thousands of bacterial genes in our guts! They seriously outnumber our own genes. Some of them are bacteria-specific, but a surprising number of them have human analogs. It turns out, we have a lot in common with our gut microbes.

Amazingly, some gut microbes can both create and respond to steroids—including sex hormones like estrogen. Microbes use these chemicals to talk to each other, which is the same role these chemicals play in our own bodies. But they may also be using these chemicals to talk to us.

Maybe men really do have an inner woman—in their gut. But it goes both ways: Women have an inner man when they harbor testosterone-producing bacteria. In this sense, your microbiome acts like a gonad, producing different sex hormones depending on which microbes your gut happens to favor. Crazy as it seems, your gut microbes may have their own gender identification.

The idea that mere bacteria—with no sex of their own—contribute to animal sexuality is a bit humbling. Sex hormones affect your metabolism and behavior, and this is particularly important during puberty. Altering sex hormones during the teen years may have long-term effects that can't be reversed by later hormone treatments. More research is needed to see what impact, if any, the gut microbiome may have on gender identity.

Does sex matter?

Women and men are different, but the prevailing attitude for researchers has long been that sex doesn't matter. In mouse studies, scientists have traditionally concentrated on males in order to eliminate the effects of the estrous cycle on their data.

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. It's about time.

Given the sexual differences in these syndromes, it may be time to look at sex-dependent therapies. Do women and men need different probiotics? If you get a fecal transplant, should you take donations from hormonal teenagers? Should you worry about the sex of the donor?

We need to care for patients with a more holistic approach that includes the gut along with mental issues. And we need to take sex and gender into account when we do. It's time to call a truce in the battle of the sexes. This is a war we can all win.