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