Using Bayesian modelling to investigate factors governing antibiotic-induced Candida albicans colonization of the GI tract.

Jyoti Shankar,Hong Liu,Stephanie Mounaud,Liliana Losada,Scott G Filler,Norma V Solis,Sebastian Szpakowski,William C Nierman

doi:10.1038/srep08131

Abstract

Receipt of broad-spectrum antibiotics enhances Candida albicans colonization of the GI tract, a risk factor for haematogenously-disseminated candidiasis. To understand how antibiotics influence C. albicans colonization, we treated mice orally with vancomycin or a combination of penicillin, streptomycin, and gentamicin (PSG) and then inoculated them with C. albicans by gavage. Only PSG treatment resulted in sustained, high-level GI colonization with C. albicans. Furthermore, PSG reduced bacterial diversity in the colon much more than vancomycin. Both antibiotic regimens significantly reduced IL-17A, IL-21, IL-22 and IFN-γ mRNA levels in the terminal ileum but had limited effect on the GI fungal microbiome. Through a series of models that employed Bayesian model averaging, we investigated the associations between antibiotic treatment, GI microbiota, and host immune response and their collective impact on C. albicans colonization. Our analysis revealed that bacterial genera were typically associated with either C. albicans colonization or altered cytokine expression but not with both. The only exception was Veillonella, which was associated with both increased C. albicans colonization and reduced IL-21 expression. Overall, antibiotic-induced changes in the bacterial microbiome were much more consistent determinants of C. albicans colonization than either the GI fungal microbiota or the GI immune response.

Highlights

Receipt of broad-spectrum antibiotics enhances Candida albicans colonization of the GI tract, a risk factor for haematogenously-disseminated candidiasis
To examine the factors that influence the level of C. albicans GI colonization, we contrasted the effects of a combination of penicillin, streptomycin and gentamicin (PSG) with those of vancomycin in a mouse model
Our results indicate that members of the antibiotic-influenced bacterial microbiome had the most consistent and substantial influence on C. albicans colonization than either the fungal microbiome or the local immune response

Summary

Introduction

Receipt of broad-spectrum antibiotics enhances Candida albicans colonization of the GI tract, a risk factor for haematogenously-disseminated candidiasis. PSG reduced bacterial diversity in the colon much more than vancomycin Both antibiotic regimens significantly reduced IL-17A, IL-21, IL-22 and IFN-c mRNA levels in the terminal ileum but had limited effect on the GI fungal microbiome. Risk factors for developing disseminated and invasive candidiasis include the receipt of broad-spectrum antibiotics, immunosuppression, and colonization with Candida species. In immunodeficient and malnourished mice, introduction of Lactobacillus species into the GI tract decreased GI C. albicans burden and resulted in lower mortality[10,11] These results suggest that the composition of the GI tract microbiota influences the level of C. albicans colonization. A mechanistic understanding of the tri-faceted interface of antibiotic action on the local immune response, GI bacterial and fungal microbiota, and C. albicans colonization is essential for developing strategies to reduce the incidence of candidiasis. The mouse model provided us a controlled platform to perform our experiments

Methods

Results

Conclusion