Gut Bacteria Shape Intestinal Microhabitats Occupied by the Fungus Candida albicans.

The human gut microbiota is composed of diverse microbes that not only compete but also rely on one another for resources and access to microhabitats in the intestine [1, 2]. Indeed, recent efforts to map the microbial biogeography of the gastrointestinal tract have revealed positive and negative co-associations between bacterial taxa [3, 4]. Here, we examine the spatial organization that the most prominent fungus of the human flora, Candida albicans, adopts in the gut of gnotobiotic mice either as the sole colonizer or in the presence of single bacterial species. We observe that, as a lone colonizer, C. albicans cells are distributed either adjacent to the inner mucus layer in the colon or throughout the intestinal lumen. In contrast to this pattern, in the presence of the saccharolytic Bacteroides thetaiotaomicron, the fungal cells localize to the interior of a Bacteroides-promoted outer mucus layer in which fungal and bacterial cells are in close association. We show that, in vitro, although mucin provides minimal support to the proliferation of the fungus, barely altering its transcriptional landscape, Bacteroides- and glucanase-processed mucin can better fuel the growth of C. albicans. Our observations illustrate how a commensal fungus can settle in an intestinal microhabitat generated by the presence of a single gut bacterial taxon.

Identification of Candida albicans regulatory genes governing mucosal infection.

The fungus Candida albicans thrives on a variety of human mucosae, yet the fungal determinants that contribute to fitness on these surfaces remain underexplored. Here, by screening a collection of C. albicans deletion strains in a mouse model of oral infection (oropharyngeal candidiasis), we identify several novel regulatory genes that modulate the fitness of the fungus in this locale. We investigate in detail the interplay between the host mucosa and one of the identified mutants and establish that the C. albicans transcription regulator CUP9 is a key determinant of mucosal colonisation. Deletion of cup9 resulted in the formation of more foci of colonisation and heightened persistence in infected tongues. Furthermore, the cup9 mutant produced longer and denser filaments in the oral mucosa without eliciting an enhanced local immune response. Consistent with its role in oral colonisation, we show that CUP9's top target of regulation is a major effector of Candida's adherence to buccal cells. Finally, we establish that CUP9 also governs the interplay of the fungus with vaginal epithelial cells and has a role in vaginal infections, another common mucosal disease associated with Candida. Thus, our findings reveal a mechanism whereby C. albicans can regulate proliferation on mucosal surfaces.

The yeast form of the fungus Candida albicans promotes persistence in the gut of gnotobiotic mice.

Many microorganisms that cause systemic, life-threatening infections in humans reside as harmless commensals in our digestive tract. Yet little is known about the biology of these microbes in the gut. Here, we visualize the interface between the human commensal and pathogenic fungus Candida albicans and the intestine of mice, a surrogate host. Because the indigenous mouse microbiota restricts C. albicans settlement, we compared the patterns of colonization in the gut of germ free and antibiotic-treated conventionally raised mice. In contrast to the heterogeneous morphologies found in the latter, we establish that in germ free animals the fungus almost uniformly adopts the yeast cell form, a proxy of its commensal state. By screening a collection of C. albicans transcription regulator deletion mutants in gnotobiotic mice, we identify several genes previously unknown to contribute to in vivo fitness. We investigate three of these regulators-ZCF8, ZFU2 and TRY4-and show that indeed they favor the yeast form over other morphologies. Consistent with this finding, we demonstrate that genetically inducing non-yeast cell morphologies is detrimental to the fitness of C. albicans in the gut. Furthermore, the identified regulators promote adherence of the fungus to a surface covered with mucin and to mucus-producing intestinal epithelial cells. In agreement with this result, histology sections indicate that C. albicans dwells in the murine gut in close proximity to the mucus layer. Thus, our findings reveal a set of regulators that endows C. albicans with the ability to endure in the intestine through multiple mechanisms.