Testosterone and KPC-Kp gut colonization: is there a link?

Maria Teresa Pagano1, Alessandra Oliva2, Elena Ortona3, Claudio Maria Mastroianni2, Maria Cristina Gagliardi1

1Department of Infectious Diseases, National Institute of Health, Rome, Italy; 2Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy; 3Center for Gender-Specific Medicine, National Institute of Health, Rome, Italy

Received 5 June 2025; accepted 15 July 2025

Dear Editors,

KPC-producing Klebsiella pneumoniae (KPC-Kp) accounts for a significant proportion of hospital-acquired infections and is a major concern particularly in healthcare settings like intensive care units (ICU), due to the multitude of invasive procedures and medical devices used, the prolonged antibiotic therapy, and the critical conditions of these patients.

Intestinal colonization by KPC-Kp is a risk factor for developing subsequent nosocomial infection1 and for this reason it is crucial to screen for KPC-Kp colonization as well as potential related factors.

Sex hormones play an important role in various physiological processes including the immune response and through their modulation they can affect host-microbe interactions and the microbiota. The immune response differs between women and men. Women show enhanced innate and adaptive responses to infections compared to men, with the flip side of excessive inflammatory reactions and autoimmune diseases. Men are generally more prone to bacterial, viral and fungal infections and to severe disease courses.2

In particular, testosterone is generally anti-inflammatory. It modulates immune function by reducing the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 suppressing NF-κB, a key transcription factor in inflammation. Moreover, testosterone enhances regulatory T cells and reduces neutrophil and macrophage activity.3 Consequently, men typically have lower baseline inflammation than postmenopausal women, partly due to testosterone’s effects. On the other hand, chronic inflammation lowers testosterone. In particular, inflammatory cytokines inhibit testosterone production by suppressing Leydig cell function in the testes and by interfering with the hypothalamic pituitary gonadal (HPG) axis.4 Accordingly, low testosterone levels are often associated with chronic inflammatory conditions, and as inflammation increases with age (‘inflammaging’), testosterone naturally declines.5

An inverse relationship between serum concentrations of testosterone and persistent Escherichia coli nasal carriage has been demonstrated in men aged 55 years.6 Moreover, testosterone has been shown to suppress the invasion and colonization of human prostate epithelial cells by uropathogenic Escherichia coli.7

These data raise the question of whether testosterone may have a protective role against microbial colonization.

To investigate this issue, we recruited 16 male patients (5 under 50 years of age and 11 over 51 years of age), hospitalized in the ICU and non-ICU wards of Policlinico Umberto I hospital of Rome with a KPC-Kp positive rectal swab (ethical approval Prot. Number 394/17; 0966/2023).

At the moment of KPC-Kp colonization, we measured plasma concentrations of testosterone by Enzyme-Linked Immunosorbent Assay (ELISA - R&D Systems, Minneapolis, MN, USA; intra-assay: CV 3.1%, inter-assay: CV 6.3%).

We observed extremely low hormone levels (Figure 1) irrespective of patients’ age (under 50 years: 0.39-1.64 ng/ml; over 51 years: 0.46-1.14 ng/ml) when compared to the plasma concentration range of age-matched non-colonized healthy donors (under 50 years: 2.49-8.36 ng/ml; over 51 years: 1.96-7.40 ng/ml).




Overall, this observation provides support for a relationship between testosterone and host colonization and opens the path for further studies with a larger patient population for a better understanding of the role of hormonal factors in host colonization. Indeed, to the best of our knowledge, no data exploring the relationship between sex hormones and KPC-Kp colonization or subsequent systemic infections in KPC-Kp colonized patients have been published so far. In light of this, a role of plasma testosterone levels as a potential biomarker of colonization status potentially influencing the risk of development of infection cannot be excluded. In this eventuality, a routine screening for hypotestosteronemia could be considered by healthcare providers for an appropriate management of bacterial colonization.

References

1. Giannella M, Trecarichi EM, De Rosa FG, Del Bono V, Bassetti M, Lewis RE, et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infection among rectal carriers: a prospective observational multicentre study. Clin Microbiol Infect. 2014;20(12):1357-62.

2. Gay L, Melenotte C, Lakbar I, Mezouar S, Devaux C, Raoult D, et al. Sexual dimorphism and gender in infectious diseases. Front Immunol. 2021;12:698121.

3. Vancolen S, Sébire G, Robaire B. Influence of androgens on the innate immune system. Andrology. 2023;11(7):1237-44.

4. Monageng E, Offor U, Takalani NB, Mohlala K, Opuwari CS. A review on the impact of oxidative stress and medicinal plants on leydig cells. Antioxidants (Basel). 2023;12(8).

5. Grandys M, Majerczak J, Zapart-Bukowska J, Duda K, Kulpa JK, Zoladz JA. Lowered serum testosterone concentration is associated with enhanced inflammation and worsened lipid profile in men. Front Endocrinol (Lausanne). 2021;12:735638.

6. Stensen DB, Småbrekke L, Olsen K, Grimnes G, Nielsen CS, Ericson JU, et al. Circulating sex steroids and Staphylococcus aureus nasal carriage in a general male population. Epidemiol Infect. 2022;150:e93.

7. Ho CH, Fan CK, Yu HJ, Wu CC, Chen KC, Liu SP, et al. Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK/STAT-1 signaling pathway. PLoS One. 2017;12(12):e0190317.

Authors’ contribution statement. All authors contributed equally to this work and approved the final version of the manuscript.

Conflicts of interest statement. All authors declare no conflicts of interest.

Ethical approval and informed consent. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the local Institutional Review Board (approval Prot. Number 394/17; 0966/2023). All participants were informed about the aims of the survey and provided their consent to the use and publication of the aggregated data for research purposes.

Funding sources statement. This research was supported by EU funding within the MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT).

Correspondence to:

Maria Cristina Gagliardi

Department of Infectious Diseases

National Institute of Health

Viale Regina Elena 299

00161 Rome, Italy