Depressive symptoms in some people may be linked to activity of particular enzyme, according to study

We’ve known for a long time that there is an intricate relationship between our hormones, our gut, and our mental health, but unraveling the intertwining of the most closely related connections within our bodies has proven difficult.

A new study has found one enzyme that links all three, and its presence may be responsible for depression in some women of childbearing age.

Wuhan University medical researcher Di Lei and colleagues compared the blood serum of 91 women aged 18 to 45 with depression and 98 women without depression. Incredibly, women with depression had nearly half the serum levels of estradiol, the main form of estrogen our bodies use during our fertile years.

The idea that estradiol is associated with depression in people with low levels of female reproductive hormones has been around for over 100 years. It is known that the natural decrease in estradiol during menopause and after pregnancy is associated with negative mood changes.

Other conditions, including polycystic ovary syndrome (in which the ovaries produce higher than normal levels of the sex hormones known as androgens, resulting in an imbalance in reproductive hormones) and congenital adrenal hyperplasia (a group of genetic disorders in which the body lacks essential enzyme). to produce certain hormones) can also cause low estradiol levels and depression.

The association of depression with estradiol probably explains why it is more common in women than in men.

It is produced in the ovaries, and after housework, including regulating the menstrual cycle, estradiol is metabolized in the liver and then passed into the intestines. Here, the hormone is partially reabsorbed back into the bloodstream to maintain circulating estrogen levels.

With this knowledge, the researchers investigated the activity of estradiol in the gut.

Within two hours of adding estradiol to the faecal microbiome samples of women with depression, hormone levels dropped by 78%. Meanwhile, in a test tube of microbiome samples from non-depressed women, hormone levels dropped by only 20%.

The scientists also transplanted gut microbiomes from 5 depressed women into mice that had a 25% decrease in serum estradiol levels compared to control mice.

It seems clear that the gut microbiome is responsible for the increased breakdown of this hormone in our digestive system.

To isolate the microbe responsible, Li and his team placed microbiome samples of depressed women on an agar plate and gave them estradiol as their sole source of nutrition. After two hours, more than 60% of estradiol is hydrolyzed to estrone.

White droplets with smooth fuzzy edges bloomed, and using mass spectrometry, the researchers identified the microbe, a strain of bacteria they named Klebsiella aerogenes TS2020.

“These results indicate that K. aerogenes TS2020 can reduce blood levels of estradiol in mice and induce depressive behavior,” the researchers explain in their paper.

Genetic analysis has shown that K. aerogenes converts estradiol to estrone with an enzyme called 3β-HSD (3β-hydroxysteroid dehydrogenase). Placing the gene for this enzyme in Escherichia coli and then infecting mice with this bacterium resulted in the same decrease in estradiol levels and symptoms of depression.

Administration of estrone to mice did not increase depressive behavior, and excess estrone was ruled out as a problem. Li and his colleagues also ruled out the presence of other molecules.

E. coli-producing 3β-HSD mice also had lower levels of estradiol in the brain, including the hippocampus, a brain region known to be heavily involved in depression. All of this together indicates that an enzyme produced by microbes is causing problems in the brain.

In a previous study, researchers found elevated levels of the same enzyme in male patients with depression. The enzyme can also break down testosterone.

The researchers explain: “By combining these two studies, we suggest that the 3β-HSD enzyme is involved in the development of depression and that this relationship is independent of gender. We believe that K. aerogenes in faeces is not the only intestinal bacteria that can produce 3β- HSD Our metagenomic sequencing data showed that “Bacteroides thetaiotaomicron and Clostridia possess 3β-HSD. However, there may be other gut bacteria that produce 3β-HSD that are below the detection limit of metagenomic sequencing. Bacteria that can produce 3β-HSD need further study.” study.”

Some attention has been given to estrogen replacement therapy as a potential treatment for depression in women, but if the pathway found here is accurate, 3β-HSD-producing bacteria could lead to relapses.

They noted that “estradiol-specific bacteria in the gut, especially the enzymes expressed by these bacteria, may be a better target for intervention.”

This study was published in the journal Cell Metabolism.

Source: Science Alert