The gut, the bad and the harmless: Candida albicans as a commensal and opportunistic pathogen in the intestine

doi:10.1016/j.mib.2020.05.006

Current Opinion in Microbiology

Volume 56, August 2020, Pages 7-15

https://doi.org/10.1016/j.mib.2020.05.006 Get rights and content

Candida albicans is a regular member of the intestinal microbiota in the majority of the human population. This underscores C. albicans’ adaptation to life in the intestine without inducing competitive interactions with other microbes, or immune responses detrimental to its survival. However, specific conditions such as a dysbalanced microbiome, a suppression of the immune system, and an impaired intestinal barrier can predispose for invasive, mostly nosocomial, C. albicans infections. Colonization of the intestine and translocation through the intestinal barrier are fundamental aspects of the processes preceding life-threatening systemic candidiasis. Insights into C. albicans’ commensal lifestyle and translocation can thus help us to understand how patients develop candidiasis, and may provide leads for therapeutic strategies aimed at preventing infection. In this review, we discuss the commensal lifestyle of C. albicans in the intestine, the role of morphology for commensalism, the influence of diet, and the interactions with bacteria of the microbiota.

Introduction

Invasive infections with Candida species are by far the most common cause of nosocomial fungal infections threatening patients of intensive care units (ICUs) and immunocompromised patients or patients with dysfunctional epithelial barriers [1,2]. Most human pathogenic fungi of the genus Candida are not ubiquitously present in the environment like, for example, Aspergillus, or Cryptococcus species, but associated with animals and humans. Systemic candidiasis of humans, therefore, originates from commensal body niches. In Westernized countries, most individuals carry Candida species as commensals in their intestinal microbiota [3,4] and patients show enrichment of Candida species in the majority of cases during prolonged stays in the ICU [5^•] or following transplantation [6]. Abdominal surgery or pathology to organs of the gastrointestinal (GI) tract is a risk factor for the development of intra-abdominal candidiasis [7]. With regard to candidemia, or Candida bloodstream infections, Candida cells can be introduced directly into the bloodstream by contaminated central venous catheters. However, such infections are more commonly associated with Candida parapsilosis, which, in contrast to other Candida species, colonizes the skin [8,9]. The evidence is overwhelming that Candida albicans in the gastrointestinal (GI) tract is a major source of systemic candidiasis [6,8,10] and numerous experimental models have revealed that this fungus can enter the bloodstream by translocating through the intestinal barrier [11,12^••,13]. Therefore, it is essential to comprehend the pathogenesis of systemic candidiasis originating from the intestinal tract. Elucidating C. albicans’ role as a commensal, as well as a pathogen, can help us understand how this otherwise harmless commensal can undergo a shift toward an opportunistic pathogen. Further, it may aid to identify predisposing factors and to provide valuable insights for the development of strategies aimed at preventing candidiasis, an approach that will have a drastic impact on candidiasis-associated mortality [14].

Section snippets

C. albicans as a commensal of the gut

Even though a great deal is known about C. albicans pathogenicity [15], studies dealing with the commensal lifestyle of this fungus have only recently come into focus. [for further recent reviews see: Refs. 16, 17, 18, 19, 20].

As the GI tract of the majority of humans in Westernized societies is colonized by C. albicans [3,4] it can be concluded that this fungus has evolved to interact and compete with numerous bacterial cells and species that colonize this niche. However, as demonstrated in

Influence of diet

The composition and the metabolism of our intestinal microbiota are highly influenced by diet. It is presumed that diet also influences C. albicans colonization of the gut. A Western diet, together with the use of antibiotics, has been posited as one of the reasons that the majority of the Western population is colonized by C. albicans [16]. Non-Western societies, for example, can exhibit much lower colonization rates as compared to many Western countries [18,40]. In murine models, a diet that

Metabolic adaptation to the GI tract

Niche-specific attributes, such as adaptation for effectively utilizing the nutrients that are present, make C. albicans highly efficient in colonizing the GI tract. Glucose levels in the GI tract, particularly the distal GI tract, are low and colonizers are thus obliged to utilize alternative carbon sources [42^•]. C. albicans has noted nutritional flexibility allowing it to adapt readily to the nutritional milieu that it encounters [43^•,44]. The organism is capable of simultaneously using

Phenotypic adaptation to the GI tract

Invasive candidiasis is often associated with filamentous growth, which facilitates the invasion of host tissues [59].

Despite being essential for invasive disease, evidence is mounting that hyphae and expression of hyphal-associated proteins are detrimental for the commensal lifestyle of C. albicans [60^••,61^••,63]. Even though it was revealed that hyphal morphology is abundant during colonization of the intestine and is not associated solely with invasive disease, knockout of the

The benefit of C. albicans as a commensal for human health

From an evolutionary perspective, it is tempting to speculate that C. albicans may have some beneficial effects for human health. Carriage of a potentially dangerous commensal might otherwise be subjected to negative natural selection. It is generally believed that C. albicans colonization may be crucial to educate our immune system. C. albicans colonization of the GI tract of mice, specifically with strains evolved to colonize the intestine, offer immunological protection against systemic

Breaching the boundary: invasion of the epithelial barrier leading to systemic disease

As discussed above, a disturbed microbiota, a suppressed immune system, and/or a defective epithelial barrier can all promote C. albicans translocation through the epithelia barrier into the bloodstream. Uncovering the fungal and host aspects which influence epithelial barrier invasion and translocation may help to answer the question of why C. albicans originating from the gut can cause systemic disease under predisposing factors.

Dissection of C. albicans translocation revealed filamentous

Conclusion

The ability of C. albicans to colonize the human gut as a harmless commensal is also a vital aspect of its role as an opportunistic pathogen. Apart from other Candida species few pathogens exhibit similar strategies of causing infections in predisposed patients. A pressing question is whether or not in a healthy host C. albicans always tries to invade, but the absence of predisposing conditions does not permit invasion. Considering the currently available literature on C. albicans commensalism

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

CRediT authorship contribution statement

Carol A Kumamoto: Conceptualization, Writing - original draft, Writing - review & editing. Mark S Gresnigt: Conceptualization, Writing - original draft, Writing - review & editing. Bernhard Hube: Conceptualization, Writing - original draft, Writing - review & editing.

Acknowledgements

We acknowledge all contributions to the field of C. albicans commensalism and apologize to all colleagues whose work could not be cited due to space limitations. CAK was supported by N.I.H.NIAIDR01 AI118898. MSG was supported by a Humboldt Research Fellowship for Postdoctoral Researchers by the Alexander von Humboldt Foundation, a Research Grant 2019 from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and by the Deutsche Forschungsgemeinschaft (DFG) Emmy Noether

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The gut, the bad and the harmless: Candida albicans as a commensal and opportunistic pathogen in the intestine

Introduction

Section snippets

C. albicans as a commensal of the gut

Influence of diet

Metabolic adaptation to the GI tract

Phenotypic adaptation to the GI tract

The benefit of C. albicans as a commensal for human health

Breaching the boundary: invasion of the epithelial barrier leading to systemic disease

Conclusion

Conflict of interest statement

References and recommended reading

CRediT authorship contribution statement

Acknowledgements

Antimicrob Agents Chemother

Microbiol Immunol

Cell Microbiol

PLoS Pathog

Pathog Dis

Front Microbiol

PLoS One

Invasive candidiasis

Nat Rev Dis Primers

Incidence, risk factors, and long-term outcome of acute leukemia patients with early candidemia after allogeneic stem cell transplantation: a study by the acute leukemia and infectious diseases working parties of European Society for blood and marrow transplantation

Clin Infect Dis

The gut mycobiome of the human microbiome project healthy cohort

Microbiome

Fungi in the healthy human gastrointestinal tract

Virulence

Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness

mBio

High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis

Nat Med

Intra-abdominal candidiasis: the importance of early source control and antifungal treatment

PLoS One

Revisiting the source of candidemia: skin or gut?

Clin Infect Dis

Candida parapsilosis: a review of its epidemiology, pathogenesis, clinical aspects, typing and antimicrobial susceptibility

Crit Rev Microbiol

Candida colonisation as a source for candidaemia

J Hosp Infect

Mucosal damage and neutropenia are required for Candida albicans dissemination

PLoS Pathog

Dectin-1 is not required for controlling Candida albicans colonization of the gastrointestinal tract

Infect Immun

Nosocomial candidemia: an ounce of prevention is better than a pound of cure

Infect Control Hosp Epidemiol

Candida albicans pathogenicity mechanisms

Virulence

Adaptation of Candida albicans during gastrointestinal tract colonization

Curr Clin Microbiol Rep

Adaptation of Candida albicans to commensalism in the gut

Future Microbiol

Candida albicans commensalism in the gastrointestinal tract

FEMS Yeast Res

On commensalism of candida

J Fungi (Basel)

Candida albicans dwelling in the mammalian gut

Curr Opin Microbiol

Activation of HIF-1alpha and LL-37 by commensal bacteria inhibits Candida albicans colonization

Nat Med

Self-regulation of Candida albicans population size during GI colonization

PLoS Pathog

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

PLoS Pathog

The human gut microbial metabolome modulates fungal growth via the TOR signaling pathway

mSphere

Candida albicans induces mucosal bacterial dysbiosis that promotes invasive infection

PLoS Pathog

The human mycobiome in health and disease

Genome Med

Invasive candidiasis: from mycobiome to infection, therapy, and prevention

Eur J Clin Microbiol Infect Dis

The mycobiota: interactions between commensal fungi and the host immune system

Nat Rev Immunol

Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis

Science

Fungal dysbiosis: immunity and interactions at mucosal barriers

Nat Rev Immunol

Immunological consequences of intestinal fungal dysbiosis