Researchers at Wuhan University have identified a molecule produced by gut bacteria that may contribute to depressive symptoms in a subset of individuals. The finding, described in Cell Metabolism, adds a new dimension to understanding how gut biology can influence mood and mental health, highlighting a potential gut-brain connection that is relevant to both clinical research and future therapies in North America and beyond.
In a comparative analysis, the team examined blood samples from 91 women aged 18 to 45 who were diagnosed with depression and 98 women who did not have depressive symptoms. They observed that serum levels of estradiol, a key estrogen hormone, were markedly lower in the depressed group—nearly half the level seen in controls. This pattern suggests a link between hormonal status and mood disorders, inviting further exploration into how hormonal fluctuations intersect with gut microbiota dynamics.
Estradiol originates in the ovaries and, after fulfilling its biological roles, is processed in the liver and released into the intestinal tract. There, portions of the hormone are reabsorbed into the bloodstream, forming a recycling loop known as enterohepatic circulation. The researchers proposed that gut bacteria might disrupt this loop, thereby reducing circulating estradiol levels. To test this, they exposed estradiol to stool microbiome samples from depressed women in a laboratory dish. Within two hours, estradiol concentrations plummeted by 78 percent in the presence of microbiota from depressed cases, whereas samples derived from non-depressed individuals showed only a 20 percent reduction. The result points to bacterial activity as a potential driver of hormonal depletion linked to depressive states.
Further experiments implicated a bacterium named Klebsiella aerogens TS2020 in the erosion of estradiol. This finding was supported by mouse studies in which transplantation of the depressed women’s gut microbiota into healthy animals led to the emergence of depressive-like behaviors. Interestingly, introducing the antibiotic cefotaxime alleviated these mood-related changes in the mice, underscoring a possible microbiome-driven mechanism for symptom modulation and suggesting that microbial balance can influence affective states in vivo.
The team identified the microbial 3β-HSD enzyme as a critical factor enabling estradiol destruction. When the gene encoding this enzyme was inserted into the genome of a common strain of E. coli, the bacterium gained the capacity to degrade estradiol and, in the mouse model, reproducibly induced depressive-like phenotypes. In these animals, estradiol levels declined not only in the bloodstream but also within brain regions implicated in mood regulation, including the hippocampus, highlighting a direct link between microbial metabolism, hormonal signaling, and neural circuits linked to depression.
These observations support a model in which certain gut microbes contribute to mood disorders by producing enzymes that break down hormones essential for brain function. The authors emphasize that microbial composition and enzyme activity could determine an individual’s susceptibility to depression, pointing to a complex interplay between host physiology and the gut ecosystem that warrants further investigation in diverse populations across North America and elsewhere.
In a prior line of research, similar enzymatic activity was detected at higher levels in men with depression, where the same enzyme also targeted testosterone, suggesting a broader hormonal impact driven by microbial enzymes. The researchers caution that additional bacterial species may possess related capabilities, potentially broadening the range of hormones affected by gut microbes and influencing mood and overall health in multiple ways.
While estrogen-based therapies have been explored in the past as potential treatments for depressive symptoms, the new findings raise questions about their efficacy in individuals with a gut microbiome profile that actively degrades estrogens. If gut bacteria rapidly metabolize administered hormones, therapeutic strategies may need to consider microbiome state and enzyme activity to achieve meaningful clinical benefits.