Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids promote gastrointestinal colonization ofCandida albicans

Abstract

27Candida albicans is the fourth most common cause of systemic nosocomial infections, 28 posing a significant risk in immunocompromised individuals. As the majority of systemic C. 29 albicans infections stem from endogenous gastrointestinal (GI) colonization, understanding the 30 mechanisms associated with GI colonization is essential in the development of novel methods to 31 prevent C. albicans-related mortality. In this study, we investigated the role of microbial-derived 32 short-chain fatty acids (SCFAs) including acetate, butyrate, and propionate on growth, 33 morphogenesis, and GI colonization of C. albicans. Our results indicate that cefoperazone-treated 34 mice susceptible to C. albicans infection had significantly decreased levels of SCFAs in the cecal 35 contents that correlate with a higher fungal load in the feces. Further, using in vivo concentration 36 of SCFAs, we demonstrated that SCFAs inhibit the growth, germ tube, hyphae and biofilm 37 development of C. albicans in vitro. Collectively, results from this study demonstrate that 38 antibiotic-induced decreases in the levels of SCFAs in the cecum enhances the growth and GI 39 colonization of C. albicans. 40 41 42 Keywords: C. albicans, antibiotic treatment, SCFAs, gastrointestinal colonization, hyphae and 43 attachment.44 45 46 47 48 49 50C. albicans, often present in the healthy gastrointestinal (GI) tract, is harmless to the 51 immunocompetent human host with its resident microbiota 1,2 . Though compelling evidence 52 suggests that disturbances in immune regulation contribute to invasive C. albicans infections, 53 antibiotic-induced gut dysbiosis remains a major risk factor for increased C. albicans colonization 54 and dissemination in immunocompromised patients and individuals with antibiotic-associated 55 diarrhea (AAD) [3][4][5][6][7][8][9][10][11][12][13][14][15][16] . Administration of broad-spectrum antibiotics increases the risk of C. albicans 56 colonization in the gut and the source of systemic infections is often found to be the GI tract 13,16-57 20 . In addition, more than 60% of individuals with AAD test positive for C. albicans and patients 58 treated with antibiotics for Clostridium difficile often develop an episode of candidemia 9,10,14,15,21 . 59Taken together, these studies demonstrate that antibiotic-induced gut dysbiosis in 60 immunocompromised individuals and AAD patients leads to increased colonization of C. albicans 61 and this increased intestinal colonization predisposes high-risk patients to systemic candidiasis 62 22,23 . Therefore, understanding the factors involved in antibiotic-induced gut dysbiosis and 63 subsequent GI colonization of C. albicans is critical to treat and prevent C. albicans pathogenesis. 64 65Antibiotic treatment in mice and humans alters the composition of gut microbiota, 66 ultimately leading to changes in the levels of microbial-derived gut metabolites, mainly bile acids 67 and short-chain fatty acids (SCFAs) [24][25][26][27][28] . Alterations in the normal levels of microbial-derive...