Effects of sexual dimorphism and estrous cycle on murine Clostridioides difficile infection

Clostridioides difficile infection (CDI) is responsible for the majority of identifiable antibiotic-associated diarrhea. Women are more susceptible to CDI than men. In this study, we show that female mice developed more severe CDI than males. Furthermore, females in estrus developed only mild CDI 1-2 days later, while females in proestrus developed deadly disease. Mirroring the delayed effect of the estrous cycle, pre-infection prolactin levels formed a complex network with immunoglobulins and cytokines that affected early CDI severity one day after challenge. Similarly, pre-infection progesterone and luteinizing hormone formed a network that affected CDI two days after challenge. As expected, immune effectors early in the infection formed a hormone-independent network that concurrently correlated with CDI severity. Interestingly, early infection follicular stimulating hormone levels created a network that affected the CDI recovery phase. In summary, murine sexual hormones affect CDI progression by affecting the immune system both before and during disease progression.