Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids correlate with increased gastrointestinal colonization of Candida albicans

Jack Guinan,Shaohua Wang,Tony R Hazbun,Hariom Yadav,Shankar Thangamani

doi:10.1038/s41598-019-45467-7

Abstract

Candida albicans is the fourth most common cause of systemic nosocomial infections, posing a significant risk in immunocompromised individuals. As the majority of systemic C. albicans infections stem from endogenous gastrointestinal (GI) colonization, understanding the mechanisms associated with GI colonization is essential in the development of novel methods to prevent C. albicans-related mortality. In this study, we investigated the role of microbial-derived short-chain fatty acids (SCFAs) including acetate, butyrate, and propionate on growth, morphogenesis, and GI colonization of C. albicans. Our results indicate that cefoperazone-treated mice susceptible to C. albicans infection had significantly decreased levels of SCFAs in the cecal contents that correlate with a higher fungal load in the feces. Further, using in vivo concentration of SCFAs, we demonstrated that SCFAs inhibit the growth, germ tube, hyphae and biofilm development of C. albicans in vitro. Collectively, results from this study suggest that antibiotic-induced decreases in the levels of SCFAs in the cecum enhances the growth and GI colonization of C. albicans.

Highlights

C. albicans, often present in the healthy gastrointestinal (GI) tract, is harmless to the immunocompetent human host with its resident microbiota[1,2]
While mechanisms of colonization resistance to enteric pathogens by commensal bacteria are speculated to include immune responses, competition for nutrients, pH modulation, and synthesis of antimicrobial and antifungal compounds[17,24,25,26,27], the mechanisms associated with colonization resistance to C. albicans remain poorly understood
Commensal bacteria produce a variety of bioactive molecules; short-chain fatty acids (SCFAs) have emerged as key regulators of gut homeostasis for colonization resistance against enteric pathogens[14,16,24]

Summary

Introduction

C. albicans, often present in the healthy gastrointestinal (GI) tract, is harmless to the immunocompetent human host with its resident microbiota[1,2]. More than 60% of individuals with AAD test positive for C. albicans and patients treated with antibiotics for Clostridium difficile often develop an episode of candidemia[5,6] Taken together, these studies demonstrate that antibiotic-induced gut dysbiosis in immunocompromised individuals and AAD patients leads to increased colonization of C. albicans and this increased intestinal colonization predisposes high-risk patients to systemic candidiasis[11,12]. Alterations in the normal levels of microbial-derived bile acids and SCFAs have been implicated in the growth, colonization, and pathogenesis of enteric pathogens including C. difficile[13,14,16]. To investigate if antibiotic treatment alters the levels of microbial-derived SCFAs and GI colonization of C. albicans, we treated mice with cefoperazone and determined the levels of SCFAs and the C. albicans load in the cecal and fecal contents, respectively. Our results indicate that SCFAs inhibit the growth and morphogenesis of C. albicans and may potentially regulate the GI colonization of this fungal pathogen

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Conclusion