In a striking fusion of microbiology and neuropsychiatry, a recent study has unveiled a surprising mechanism by which nasal colonization by Staphylococcus aureus can influence brain chemistry and behavior. This groundbreaking research elucidates the biochemical interplay between a common bacterial inhabitant of the human nose and sex hormone metabolism, revealing a novel path through which microbes may modulate mental health. What emerges is a complex portrait of how bacterial enzymes interfere with host steroid hormones, ultimately driving depressive-like behaviors in mice, spotlighting the microbiome’s understudied role as a neuroendocrine modulator.
At the heart of this discovery lies the identification of a specific gene, named hsd12, within the genome of a S. aureus nasal isolate. Researchers focused on this gene after a thorough genomic search aimed at uncovering short-chain dehydrogenase/reductase (SDR) family enzymes, known for their central roles in steroid metabolism in hosts. Unlike classical virulence factors, hsd12 codes for an oxidoreductase enzyme with the ability to degrade sex hormones like estradiol and testosterone. This enzymatic function had been previously undescribed in S. aureus, thrusting the bacterium’s metabolic capabilities into a new light.
To pinpoint the impact of hsd12, scientists cloned and expressed multiple candidate hsd genes in Escherichia coli, providing a controlled system to evaluate enzymatic activity against key sex hormones. Remarkably, only the strain expressing hsd12 demonstrated potent conversion of testosterone to androstenedione and estradiol to estrone. This finding established hsd12 as a bona fide bacterial 17β-hydroxysteroid dehydrogenase (17β-HSD), an enzyme class critically involved in hormone homeostasis in mammals. The enzymatic conversion performed by hsd12 essentially inactivates active sex hormones, disrupting systemic hormone balance.
Further in vitro assays using culture filtrates from wild-type S. aureus and an isogenic hsd12 deletion mutant confirmed the functional role of this gene in hormone degradation. While wild-type bacteria efficiently converted testosterone and estradiol, the hsd12-deficient strain showed markedly diminished enzymatic activity, corroborating the gene’s pivotal role in steroid metabolism. Importantly, these modifications occurred without impairing the bacterial growth or baseline virulence factor gene expression, underscoring the targeted effect mediated by hsd12.
Moving beyond the petri dish, the study leveraged sophisticated mouse models to explore behavioral consequences arising from S. aureus nasal colonization. Female mice colonized with wild-type S. aureus expressing hsd12 displayed clear anxiety-like and depression-like behaviors in well-validated assays such as the open field test (OFT), forced swim test (FST), and tail suspension test (TST). Intriguingly, mice colonized with the hsd12 knockout strain showed no significant deviation from control groups, directly linking bacterial hormone metabolism to neuropsychiatric phenotypes.
Hormonal measurements in colonized mice provided mechanistic insights, as estradiol levels in the nasal cavity and midbrain of female mice were significantly reduced upon colonization by wild-type S. aureus. Correspondingly, male mice subjected to chronic unpredictable mild stress (CUMS) and nasal colonization also exhibited decreased testosterone levels when exposed to the wild-type strain but not the hsd12 mutant. These findings indicate that bacterial hormone degradation disrupts the local and central steroid environment, potentially impairing neuroendocrine regulation linked to mood control.
At the molecular level, analysis of midbrain gene expression revealed altered transcription of tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2), key enzymes in the biosynthesis pathways of dopamine and serotonin respectively. Both neurotransmitters are heavily implicated in the etiology of depression and anxiety. Correspondingly, biochemical assays highlighted diminished concentrations of these neurotransmitters in the midbrain of mice colonized with hsd12-expressing S. aureus, reinforcing the connection between bacterial enzymatic activity, hormone depletion, and altered neurochemical signaling.
Importantly, the study showed that bacterial colonization itself did not provoke overt inflammation or systemic illness in mice, as indicated by consistent weight, temperature, cytokine profiles, and histological assessments across groups. This suggests that the depressive phenotype arises specifically through hormone degradation rather than a generalized immune response, emphasizing a nuanced biological dialogue rather than conventional pathogen-induced sickness behavior.
The findings invite a re-examination of S. aureus, commonly considered a benign or opportunistic pathogen, as an influencer of mental health via endocrine disruption. The identification of a conserved hsd12 gene across multiple S. aureus strains indicates that sex hormone metabolism by nasal bacteria may be a widespread phenomenon with clinical ramifications. Given that S. aureus is a frequent colonizer of the human nasal vestibule, the translational implications are profound, hinting at microbial contributions to mood disorders in humans.
This study challenges the existing paradigm that treats depression as an isolated central nervous system disorder, reinforcing the concept of a microbiota-gut-brain or, more broadly, microbiota-nose-brain axis. Such axes provide a framework for how microorganisms can subtly modulate neuroendocrine circuits through biochemical means rather than overt pathogenicity. The integration of microbiology, endocrinology, and behavioral neuroscience marks a frontier in understanding the multifactorial origins of psychiatric conditions.
Moreover, therapeutic strategies derived from these insights could pivot towards targeted microbiome modulation to preserve hormonal integrity and mental health. Approaches could include the development of inhibitors to bacterial 17β-HSD enzymes, probiotics that compete with S. aureus strains harboring hsd12, or personalized nasal microbiome interventions in patients with depression. These strategies represent a novel class of psychobiotic therapies grounded in microbial endocrinology.
Notably, the model used in this work, employing nasal colonization rather than systemic infection, offers a compelling analogue for asymptomatic human carriage that still exerts functional consequences. It also underscores the importance of anatomical niche-specific interactions between microbes and host physiology. The nasal cavity, traditionally overlooked as a site of neuroendocrine influence, may play a pivotal role in shaping brain function via microbial metabolites.
The genetic precision tools employed, including the generation of an isogenic hsd12-deletion mutant, allowed the authors to attribute causality with remarkable confidence. The minimal off-target genomic effects and unaltered bacterial growth reinforce that hsd12’s hormone-degrading activity is the critical determinant of behavioral changes, rather than secondary factors linked to overall bacterial fitness or virulence.
Future research directions naturally include investigation of the prevalence and activity of hsd12-expressing S. aureus strains within human populations, particularly among individuals with mood disorders. Correlative studies and eventually interventional trials will be essential to establish the translational relevance of these findings in humans. Additionally, the interplay between microbial hormone degradation and host immune signaling merits exploration, given the complex crosstalk regulating mental states.
This pioneering work exemplifies the depth of biological complexity that arises from host-microbe interactions beyond classical infection paradigms. By revealing that nasal bacteria can enzymatically modify critical sex hormones and thereby induce behavioral alterations, it opens new vistas in our understanding of depression etiology. The hope is that such mechanistic insight will inspire innovative diagnostic and therapeutic avenues that integrate microbiology into psychiatric care.
In summary, the evidence presented revolutionizes our appreciation of S. aureus from a simple colonizer to an active participant in neuroendocrine regulation and mood modulation. The hsd12 gene serves as a molecular fulcrum for this interaction, providing a direct biochemical link between bacterial metabolism and depressive phenotypes. As we continue to unravel the microbial dimensions of mental health, these findings remind us that the boundaries between microbiology and brain science are increasingly blurred, with profound implications for human wellbeing.
Subject of Research:
Mechanism by which Staphylococcus aureus nasal colonization influences host sex hormone metabolism and induces depressive-like behavior in mice.
Article Title:
Nasal Staphylococcus aureus carriage promotes depressive behaviour in mice via sex hormone degradation.
Article References:
Xiang, G., Wang, Y., Ni, K. et al. Nasal Staphylococcus aureus carriage promotes depressive behaviour in mice via sex hormone degradation. Nat Microbiol (2025). https://doi.org/10.1038/s41564-025-02120-6
Tags: Biochemical interactions in neuropsychiatryDepressive behaviors in miceEnzymatic roles in steroid metabolismGene hsd12 in Staphylococcus aureusHormone metabolism and behaviorImpact of bacteria on moodMicrobial influence on brain chemistrymicrobiome and mental healthNasal Staphylococcus aureus colonizationNeuroendocrine modulation by bacteriaShort-chain dehydrogenase/reductase enzymesSteroid hormone degradation by microbes
