Antibiotic-resistant bacteria, specifically methicillin-resistant Staphylococcus aureus (MRSA), are increasingly recognized as one of the foremost contributors to illness and mortality globally. These pathogens present significant challenges for healthcare systems, as evidenced by research from Murray et al. (2022). Interestingly, about one-third of the population carries S. aureus, including MRSA, in their noses or on their skin without exhibiting any symptoms. However, if these bacteria manage to enter the body, they can initiate severe and often life-threatening infections, as detailed in studies by Sakr et al. (2018) and Castleman et al. (2018).

Recent investigations have revealed that the gut can also act as a reservoir for MRSA. According to a study by Piewngam and Otto in 2024, approximately 20% of healthy individuals carry MRSA within their intestines. This asymptomatic colonization poses heightened risks for bloodstream infections and has been linked to increased transmission in both community and hospital environments through contact with inanimate objects, as highlighted by Squier et al. (2002). Despite the known risks, little research has been dedicated to understanding how MRSA colonizes the gut and why certain individuals are more susceptible to this colonization than others. In a groundbreaking paper published in eLife, Ken Cadwell and his team, including first author Alannah Lejeune, shed light on the factors influencing MRSA colonization in the gut (Lejeune et al., 2024).

The research team, comprising experts from prestigious institutions such as New York University, the University of Pennsylvania, and St. Jude Childrens Research Hospital, conducted experiments using two distinct populations of laboratory mice: NYU mice, bred at New York University, and JAX mice, sourced from Jackson Laboratories. Notably, female NYU mice demonstrated the ability to clear MRSA from their gastrointestinal tracts, while both male and female JAX mice, as well as male NYU mice, remained persistently colonized. This disparity suggests a significant role of the microbiotathe diverse community of microorganisms residing in the gutin influencing MRSA colonization rates, corroborating previous studies that highlighted similar patterns with other pathogens (Caballero-Flores et al., 2023).

Upon analyzing the microbiota of the different mouse populations, the researchers found that female NYU mice possessed a unique composition of gut microbes compared to both male and female JAX mice. When female JAX mice were housed alongside female NYU mice, allowing for microbiota transfer, they were able to successfully clear MRSA from their systems. Surprisingly, both male and female NYU mice exhibited similar microbiota, indicating that additional factors, beyond microbial composition, influence MRSA colonization. This finding mirrors epidemiological data in humans where men are more commonly colonized with MRSA, affirming that mouse models can serve as reliable representations of human colonization patterns (Humphreys et al., 2015).

Figure 1: MRSA colonization in the gut of mice is microbiota- and sex-dependent. The illustration depicts the differences in gut microbiota between female and male mice bred at New York University (NYU) and Jackson Laboratories (JAX), which affects MRSA colonization.

Building on their findings, Lejeune et al. aimed to uncover the sex-dependent factors that contributed to the observed differences between male and female mice. They analyzed gene expression patterns in response to MRSA colonization in the gut of NYU mice, focusing on genes related to the activity and migration of immune cells. The results revealed distinct gene expression profiles for male and female mice. Notably, females showed increased expression of genes that are crucial for T cell and neutrophil activitiesimmune cells responsible for long-term immunity and rapid immune responses, respectively (Sun et al., 2023).

Interestingly, while the T cell response appeared unusual given the brief exposure to MRSA, the researchers confirmed the vital role of T cells in eliminating MRSA from the guts of female mice through genetically modified models and cell depletion experiments. The specific subset of T-helper cells known as Th17 cells, which play a pivotal role in activating neutrophils, was identified as essential for the clearance of MRSA. These findings align with prior research that emphasizes the importance of neutrophils in controlling MRSA colonization and infection throughout the body (Rigby and DeLeo, 2012).

To explore the mechanisms behind the observed sex-dependent immune responses in the gut, the team investigated two unique characteristics of female mice: the presence of an extra X chromosome and the influence of female sex hormones. When immune cells from female XX mice were transplanted into male counterparts, the MRSA was not cleared from the male mices guts. However, the removal of ovariesa key source of female sex hormonesnegatively impacted MRSA clearance in female mice. Similarly, female mice lacking estrogen receptors showed elevated levels of MRSA in their guts. Further experiments involving transgenic mice facilitated a separation of hormonal and chromosomal distinctions between the sexes, reinforcing the conclusion that female hormones enhance the clearance of MRSA.

The implications of this research are significant, paving the way for future studies to determine whether specific microbes within the gut microbiota can stimulate Th17 cells in an estrogen-dependent manner, thereby activating neutrophils to eliminate MRSA. Additionally, researchers are eager to explore whether other pathogens can be eradicated from the gut using similar mechanisms. The knowledge gained from this study could potentially lead to the development of new decolonization strategies, significantly reducing the risk of invasive infections. Most importantly, this research underscores the necessity of considering sex as a critical biological variable when investigating host-pathogen interactions, a factor that can lead to pivotal discoveries in the field.