Citation: Day AW, Kumamoto CA (2023) Interplay between host and Candida albicans during commensal gut colonization. PLoS Pathog 19(9): e1011607. https://doi.org/10.1371/journal.ppat.1011607

Editor: Mary Ann Jabra-Rizk, University of Maryland, Baltimore, UNITED STATES

Published: September 14, 2023

Copyright: © 2023 Day, Kumamoto. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Research in the Kumamoto lab was supported by grant R01 AI118898 from the National Institutes of Health (to C.A.K.). A.D. was supported by training grant T32AI007422 from the National Institutes of Health. The funders had no role in study design, data collection or the decision to publish the manuscript.

Competing interests: The authors declare that there are no competing interests.

Mammals are naturally colonized with a diverse consortium of microbes composed of bacteria, fungi and other organisms. Although fungi make up a small percentage of the total microbial community, they have significant effects on the gastrointestinal ecosystem. For example, the presence of fungal species in the gut community affects the host immune system [1]. The bacterial community is affected by the presence of fungi and the response of the bacterial community to antibiotic stress is altered when a fungus is introduced. Additionally, fungi affect gut metabolite levels with impacts on the physiology of the host. In this communication, we will discuss some of the ways that the fungus Candida albicans interacts with its host, including the beneficial effects of C. albicans against disease due to Clostridioides difficile infection. We also consider the effects of C. albicans colonization on the gut–brain axis.

On the contrary, C. albicans does not have a major environmental reservoir and can be acquired by human infants early in life [2], probably from caregivers. C. albicans is thought to colonize its host as a normal member of the human gut microbiome for long periods of time without causing disease. If the host becomes immunocompromised, colonizing C. albicans can disseminate from the gut and cause potentially life-threatening candidiasis [3]. Invasive candidiasis is usually caused by endogenous organisms [4].

During experimental murine colonization, gene expression in C. albicans cells was found to differ depending on the immune status of the host [5]. Expression of EFG1, encoding a key transcription factor that regulates many important activities of C. albicans, was higher during colonization of healthy mice (BALB/c) and lower during colonization of immunodeficient mice (nu/nu BALB/c). Under experimental conditions, immunodeficient mice showed no evidence of disease but the colonizing fungi responded to their immunodeficiency by expressing lower levels of EFG1.

The mechanism for coupling gene expression in colonizing fungi to the status of the host’s immune response rests on natural variability in EFG1 expression from cell to cell and the properties of low Efg1 activity cells [5,6]. These cells can be considered “testers” of the host’s immune status. Changes in EFG1 expression probably occur early during the transition of a host from an immunocompetent to immunosuppressed state and may herald the change in the fungal population from benign commensals to invasive pathogens.

Variation in expression of another C. albicans transcription factor, Ume6, during commensal colonization promotes the protective Th17 response of the host [7] providing additional evidence that variability in C. albicans gene expression impacts the interaction between C. albicans and the host. These examples illustrate the nuanced interactions between host and C. albicans that allow each to respond to changes in the other.

Several studies show that C. albicans and bacteria affect each other’s virulence. For example, we analyzed the effect of pre-colonization with C. albicans on the susceptibility of mice to Clostridioides (formerly Clostridium) difficile infection and demonstrated a protective effect of pre-colonization against this important infection. C. difficile infection (CDI) is the most common nosocomial infection in the United States and is responsible for considerable morbidity and mortality. We asked whether the presence of C. albicans in the gut community would alter the course of CDI. Results showed that the presence of C. albicans was protective against lethal CDI in mice [8].

C. albicans pre-colonization was associated with changes in the host GI tract. Stronger expression of the protective cytokine IL-17A was detected in C. albicans pre-colonized mice [8]. Additionally, changes in the gut metabolome associated with C. albicans colonization affected disease severity [9]. Specifically, elevated levels of unsaturated fatty acids were observed in C. albicans colonized mice and feeding mice without C. albicans a source of unsaturated fatty acids (olive oil) was protective against lethal CDI. Further, C. difficile cultured in laboratory media containing oleic acid (the major fatty acid constituent of olive oil) grew but with reduced expression of toxin genes. Also, C. difficile cells recovered from the cecal epithelium of olive oil-fed mice exhibited reduced toxin gene expression. The results thus show that C. albicans colonization changed the gut metabolite environment in a way that reduced C. difficile virulence.

C. albicans is not the only organism that is protective against C. difficile infection. Commensal bacteria such as Clostridium scindens [10], Lachnospiraceae [11], and Paraclostridium bifermentans [12] are also protective against murine CDI. The mechanisms involved in protection differ, but these results show that multiple commensal organisms can protect against this bacterial infection.

C. albicans shows interaction with other bacterial species. Pre-colonization with C. albicans reduced the virulence of Pseudomonas aeruginosa following oral inoculation of neutropenic mice [13]. In contrast, some combinations of C. albicans and bacteria have the opposite effect and increase virulence [14–16]. Additionally, some bacteria such as Enterococcus and Pseudomonas express antifungal activities [17,18]. These findings demonstrate that C. albicans–bacterial interactions affect virulence in multiple ways and are consequential for the host.

Gastrointestinal colonization by C. albicans resulted in altered behavior in mice [19]. Mice colonized with C. albicans had elevated afternoon corticosterone and an anxiety-like phenotype due to dysregulation of lipid metabolism and perturbation of the endocannabinoid system [19]. Endocannabinoids are signaling lipids that regulate synaptic transmission and modulate inflammation, neurological development, memory formation, anxiety, and depression [20]. Based on the functions of the endocannabinoid system, it is likely that C. albicans or other microbes that alter the endocannabinoid system would have other behavioral impacts. In fact, in a chronic unpredictable stress model, microbiota dysbiosis and endocannabinoid perturbations contributed to the development of depressive-like behavior [21].

Furthermore, C. albicans affects other pathways such as immune responses that could modulate neuroinflammation. Additionally, C. albicans impacts plasma levels of ketones such as β-hydroxybutyrate [22], a lipid molecule that has neuroprotective effects. β-hydroxybutyrate was reduced in mice colonized with microbiomes from humans with alcohol use disorder [23] and this reduction correlated with depression-like behavior and altered social behavior in these mice.