Human Gut Mycobiome in IBD

The human microbiota is a diverse microbial ecosystem associated with many beneficial physiological functions, as well as numerous disease etiologies. Dominated by bacteria, the microbiota also includes commensal populations of fungi, viruses, archaea, and protists. Unlike bacterial microbiota, which was extensively studied in the past two decades, these non-bacterial microorganisms, their functional roles, and their interaction with one another or with host immune system have not been as widely explored. This review covers the recent findings on the fungal communities of the human gastrointestinal microbiota, termed the “mycobiome”, and their involvement in health and disease, with particular focus on the pathophysiology of inflammatory bowel disease.


Introduction
[2] [2] [3][4] [5] [6] [7][8] [9] Human mycobiome research 5 6 11 [10] [11] [12] [13] [14] [15] [16] [17] [18] [14] [19] [20] [21] [22] [23] Human gut mycobiome [24] [25] Encyclopedia 2020 doi: 10.32545/encyclopedia202004.0011.v1 1 suggest that the human gut is populated by three fungal phyla, Ascomycota, Basidiomycota, and Zygomycota, with the "core" 10 genera identified in the majority of gastrointestinal tract samples consisting of Candida (particularly C. albicans), Saccharomyces (particularly S. cerevisiae), Penicillium, Aspergillus, Cryptococcus, Malassezia (particularly M. restricta), Cladosporium, Galactomyces, Debaryomyces, and Trichosporon. The composition of gut mycobiome seems to be dynamic over time and far more variable than the composition of bacteria, both in humans and in mice. Most studies consider fungi as commensal organisms in the gut, acquired early in life. This has recently been challenged claiming that fungi do not routinely colonize the gastrointestinal tract of healthy adults, instead postulating that all fungi identified in the human stool samples could be explained by their presence in the mouth or the diet. Indeed, diet is perceived as a crucial factor affecting the composition and variability of gut mycobiome. For instance, gut mycobiome content was found to considerably differ between individuals having different dietary patterns, i.e., vegetarians and people on a conventional Western diet. Additionally, reports suggest that the abundance of Candida in the gut positively correlated with high carbohydrate diets, and inversely correlated to consumption of total saturated fatty acids, while recent intake of short-chain fatty acids reduced the abundance of Aspergillus. Another notable finding of this study was the co-occurrence of Candida with particular bacterial (Prevotella and Rumminococcus) and archaeal genera (Methanobrevibacter), providing support for the interkingdom syntrophic relationships in host metabolism.
One of the first indications that fungi play a role in modulating gut homeostasis is the use of Saccharomyces boulardii as a constituent of herbal medicine traditionally utilized in Southeast Asia to reduce the severe diarrhea in patients with cholera. S. boulardii is still prescribed as a probiotic to prevent diarrhea and intestinal colonization with Clostridioides difficile following antibiotic therapy and is efficient in preventing recurrent C. difficile infections.
The positive effects of S. boulardii come from inactivating pathogen toxins and directly inhibiting the growth and invasion of intestinal pathogens, as well as boosting the host immunity and exerting anti-inflammatory functions in ulcerative colitis, Crohn's disease, and C. difficile colitis. A recent report suggests beneficial effects of another probiotic yeast, Candida kefyr, in reducing the severity of colitis in animal models by decreasing the abundance of Bacteroides and lowering IL-6 production, thus attenuating inflammation in the intestine.
Although fungi can exert beneficial effects to host health, the disturbance of gut mycobiota was also implicated in various gastrointestinal diseases. A recent study demonstrated no significant changes in mycobiome richness between obese and non-obese subjects; however, some specific compositional differences were noted. The most prevalent genus in non-obese individuals was Mucor, with its abundance significantly higher in non-obese individuals, and inversely correlated with metabolic markers of obesity. In colorectal cancer (CRC), an alteration of fungal composition and ecology was observed, characterized by an increased Basidiomycota/Ascomycota ratio, depletion of S. cerevisiae, as well as enrichment of Rhodotorula, Malassezia, and Acremonium genera along with several Aspergillus species (including A. flavus, a major producer of highly toxic carcinogen aflatoxin), suggesting their possible contribution towards CRC pathogenesis. Insights into gut mycobiota playing a role in irritable bowel syndrome (IBS) were also reported. Decreased fungal diversity and dysbiosis were found in IBS patients, correlating mycobiota signature with visceral hypersensitivity, which is considered as one of the major pathophysiological features of IBS. Interestingly, treatment with fungicides could recover the visceral hypersensitivity to normal levels. This finding is in accordance with a previous study that reported yeast-free diets and antifungal treatments as helpful for IBS subjects. In addition, S. boulardii was found to be effective in improving symptoms and the quality of life in IBS patients.
The majority of research on the effects of gut mycobiota in gastrointestinal diseases was however concentrated on intestinal inflammation and IBD (Table 1). Even before the advent of molecular methods and next-generation sequencing (NGS), increased levels of anti-S. cerevisiae antibodies (ASCA) were commonly found in the serum of CD patients, suggesting the host's immune responses toward intestinal fungi. These antibodies, raised against mannan, a component in the fungal cell wall, were soon identified as a reliable diagnostic biomarker for CD and predictors of the disease course. ASCA also recognize many other fungi, including Candida. Indeed, reduced fungal diversity and significantly increased abundance of specific Candida species were found in pediatric IBD patients.
tropicalis in familial CD, as well as C. glabrata in colonic biopsy samples from patients with CD. Besides elevated Basidiomycota/Ascomycota ratio in IBD patients in comparison to healthy controls and in IBD flares vs. IBD remission, fungal dysbiosis in IBD patients is also characterized by increased levels of Gibberella moniliformis, Alternaria brassicola, Aspergillus clavatus, and Cystofilobasidiaceae, while Saccharomyces cerevisiae and Malassezia sympodialis are markedly decreased. Additionally, studies confirm fungal burden is increased in both CD and UC, with the fungal cells translocating trough the intestinal barrier during the chronic stage of colitis.   in patients with CD, identifying the higher rate of fungal infections in treated subjects. Both IL-17 and IL-22 might act as inducers of antimicrobial peptides (AMPs) in epithelial cells and were reported as protective against mucosal fungal infections.
The significant role of mycobiome in maintaining human homeostasis, as well as in disease etiology, is slowly unveiling. The impact of the diverse fungal communities on human health needs to be determined in more detail in order to expand the current "bacteriocentric" view of human microbiota and provide more holistic understanding of the human superorganism. To achieve this task, two important prerequisites are essential: (1) expanding fungal reference genomes in the currently available databases for reliable identification of those microorganisms; (2) establishing uniform methods of detection for fungal commensal populations to ensure consistent and comparable evaluation of fungal abundance in different human body sites. The improved tools and the newly generated data would provide deeper insight into human mycobiome and the possibilities of its exploitation in promoting human health and ameliorating disease. Although microbiome-directed therapy is still in its infancy, studies conducted thus far suggest that direct or indirect alterations in human mycobiome may improve health outcomes in inflammatory diseases such as IBD. [61] [62] [63] Conclusion