Candida albicans: From Commensal to Opportunistic Pathogen

Dietary Influences

Diet and antibiotics are factors that impact the composition and metabolic activity of the gut microbiota. A suggested reason for the intestinal colonization of most people from Westernized countries with Candida albicans and low colonization rates in non-Westernized populations is the use of a Western diet and antibiotics. In mouse models of colonization resistance, the resident bacterial community is essential in preventing colonization by C. albicans: while healthy mice with an intact microbiota are resistant to colonization, mice treated with antibiotics against anaerobes or germ-free mice are susceptible to colonization. This "colonization resistance" works in part by altering the metabolic environment to inhibit fungal growth, and commensal bacteria also activate the immune system to increase production of the antimicrobial peptide LL-37, further blocking Candida colonization. In contrast, certain diets can promote its establishment. In mice, feeding a diet that undermines the growth and function of protective bacteria—such as Lactobacillus—allows C. albicans to colonize and, under immunosuppression, to translocate. Pro-colonization diets have been shown to consist largely of corn starch, sucrose, and soybean oil. But if coconut oil, high in medium-chain fatty acids, is added to this same diet, intestinal C. albicans colonization is greatly diminished, despite other nutrients present that promote its growth.

Candida albicans in the Intestine

From an evolutionary perspective, Candida albicans likely benefits human health as a commensal organism—otherwise carrying this potential pathogen would have been disfavored by natural selection. It is widely believed that intestinal colonization by C. albicans helps "train" our immune system. Gut colonization also influences T cell responses. The critical colonization-driven Th17 response necessary for mucosal immunity can protect against systemic candidiasis. The benefit for the host in maintaining this relationship may be not only the protection from Candida infections, but also cross-protective responses against other pathogens. However, the intestinal C. albicans–induced Th17 response can be detrimental as well, for example, by promoting inflammatory airway diseases. In addition to this protection, the fungus can also benefit by outcompeting other microbes or by tipping the balance of the gut microbiota. For instance, the clearance of intestinal Candida by antifungal drugs can cause fungal dysbiosis, which results in the activation of gut CX3CR1+ mononuclear phagocytes that favor the development of allergic airway disease. Although C. albicans overgrows in the gut during antibiotic treatment—when antagonistic bacteria are cleared—it actually supports bacterial diversity during the recovery phase. Colonization with C. albicans after antibiotic treatment leads to recovery of Bacteroidetes and growth of Enterococcus faecalis, but long-term C. albicans have a negative impact on Lactobacillus reduction. High Candida albicans loads in ulcerative colitis patients before fecal microbiota transplantation (FMT) is positively associated with bacterial diversity after FMT. However, colonization with a stable and high amount of Candida after FMT is a negative prognostic factor for ulcerative colitis patients. In general, C. albicans is a part of complex "fungus–host–microbiota" communication, having an impact on the host's immune response and community composition. Whether it is going to be helpful for the host or harm him, depends on the host and the host's context.

Figure 3. Mechanisms which contribute to a commensal versus pathogenic life style of C. albicans
(Source: Kumamoto CA, et al. 2020)

Imbalance of the microbiota, immune suppression, or defects in the epithelial barrier all favor the translocation of Candida albicans through the epithelium into the blood stream, where dissemination and systemic infection can occur if the host is susceptible. Understanding the mechanisms of fungal invasion of and transit across host epithelial barriers provides insight into the circumstances in which gut-derived C. albicans can cause disease. Studies of C. albicans translocation show that hyphal growth, tissue-damaging ability, and impaired barrier integrity are key for its passage via transcellular routes, accompanied by necrotic death of infected cells. Mutants unable to adhere, form hyphae, or induce damage are severely deficient in translocation. Like with certain members of the gut microbiota, some intestinal epithelial cells are more consequential than others: in epithelial models containing M cells, C. albicans selectively adheres to and translocates through M cells. In contrast, other epithelial properties are involved in resisting translocation: mucins are suppressive of C. albicans virulence and infection models containing goblet cells that secrete mucus are far less prone to translocation. Intestinal epithelial cells also upregulate NF-κB signaling as a protective response to fungal invasion during infection; and epithelial cells lacking NF-κB are dramatically more susceptible to C. albicans–induced injury. The gut's resident immune cells comprise a second line of defense – for instance, CX3CR1+ mononuclear phagocytes are adept at fungal recognition and prompt an antifungal response.