Our microbiome is a complex ecosystem, which influences diverse host functions such as metabolism, vitamin synthesis, gut permeability and function, and immunity [
30]. However, understanding the dynamics and how it is controlled are challenging. Foster et al. argued that hosts are under selective pressure to control their microbiota towards the retention of beneficial species [
31]. Therefore, it is possible that mycobiota is also under the selection by the host in favor of its health [
4]. A number of studies revealed that the gut mycobiome plays an important role in maintaining intestinal homeostasis and systemic immunity [
32], while fungal dysbiosis is associated with local and distal inflammatory diseases [
26,
33]. Fungi interact with the immune system via pathogen-associated molecular pattern (PAMPs) that are recognized by innate immune receptors and are often shared between different fungal species. Recent studies show that certain fungal species can provoke cellular adaptive immune responses represented by CD4+ T lymphocytes [
34]. The type of T-cell response required to control different fungal species differs remarkably [
35], which becomes evident in patients with different primary immunodeficiencies [
36]. Especially, Th17 cells, a subset of T-helper cells characterized by producing interleukin (IL)-17A, IL-17F, IL-21, and IL-22, have been described to be of particular importance for protecting against fungi infection. IL-17 functions through activating the IL-17 receptor, which further induces other inflammatory cytokines, chemokines, and antimicrobial peptides to exert anti-fungal activity [
37]. Interestingly, patients with an impairment in Th17 immunity mainly suffer from mucocutaneous candidiasis [
38], while broader fungal susceptibilities are described in patients with innate immune defects [
39]. Consistently, germ-free mice colonized with
C. albicans developed robust Th17 response [
40], and
C. albicans is a major target of human Th17 cells that can be identified in virtually all individuals [
27,
41]. Induction of
C. albicans-specific Th17 responses in healthy humans seems to occur during homeostatic interaction with the host in the absence of obvious inflammation. This is in line with intestinal commensal
C. albicans colonization in mice, where Th17 cells are induced in the gut and mesenteric lymph nodes in the absence of any fungal infection or excessive inflammation [
40,
42].
C. albicans-specific T-cell responses also broadly modulate human anti-fungal Th17 immunity via propagating Th17 cells cross-reactivity to other fungal species, such as
Aspergillus fumigatus (
A. fumigatus) [
27], that rather generates a tolerogenic regulatory T-cell (Treg) response in healthy humans [
35,
43]. These cross-reactive Th17 cells expand in patients with asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis, contributing to fungus-induced pathological inflammation in the lung [
27]. Whether
C. albicans-driven cross-reactive Th17 cells also contribute to other gut-distal diseases merits further investigation. Besides
C. albicans, human Th17 responses have also been described to target other fungi, especially
Malassezia spp.[
27,
28].
Saccharomyces cerevisiae (
S. cerevisiae) spores have been described to favor a Th17 inducing environment under in vitro conditions [
44]. However, overall, only few microbial species and in particular
C. albicans have been identified as potent inducers of Th17 responses in humans [
27], suggesting a specialized interaction pattern with the human host.
In contrast to the homeostatic interaction,
Candida overgrowth is linked to several diseases, including IBD [
45‐
47], alcohol-associated liver disease (ALD) [
48,
49], obesity [
50], and liver cirrhosis [
51], and also exacerbates experimental colitis in mice [
47,
52,
53].
Malassezia restricta has also been linked to IBD. In a mouse model of colitis, it exacerbates disease severity by stimulating inflammatory responses via CARD9, a signaling adaptor for anti-fungal defense as well as a genetic risk factor linked to Crohn’s disease and ulcerative colitis [
47,
54]. Intestinal inflammation and epithelial damage in IBD may enhance interaction of fungi and immune cells, since
C. albicans-specific Th17 responses are increased in the blood of Crohn’s disease patients [
27]. Anti-
S. cerevisiae antibodies (ASCA), that are cross-reactive to
C. albicans, can be detected in a subset of Crohn´s patients [
55] and are also elevated in patients with ALD and associated with increased mortality in patients with alcoholic hepatitis [
48].
Whether fungus-specific T-cell responses are altered in ALD is currently unknown. However, increased levels of Th17 cells and their cytokines are found in blood and livers of patients with chronic liver diseases [
56‐
58], and recombinant IL-17A administration induces non-alcoholic steatohepatitis (NASH) in mice [
57]. In ALD, elevated serum Th17 cytokines correlated with the progression of liver damage [
58], while Th17 inhibition ameliorated experimental ethanol-induced steatohepatitis [
59]. Future studies are needed to investigate a potential direct interaction between
C. albicans and Th17-mediated pathology in chronic liver diseases.
Similar to bacteria, fungi can also affect host metabolism and health. For example,
S. cerevisiae exacerbate colitis in a mouse model by enhancing host purine metabolism and increasing the systemic level of uric acid [
60]. Specific
Malassezia spp. can produce metabolites acting as virulence factors that promote inflammation and further contribute to diseases, while other metabolic products may downregulate inflammatory mediator production [
61].
Malassezia furfur converts tryptophan into several indole compounds, including malassezin, indirubin, and indolo [3,2-b] carbazole (ICZ), as potent ligands for the aryl hydrocarbon receptor (AhR). AhR is a nuclear receptor expressed in all skin cell types, activation of which has been linked to skin homeostasis and certain skin diseases [
61]. In healthy skin, AhR signaling contributes to keratinocyte differentiation, skin pigmentation, and skin barrier function. Several studies have shown that blocking AhR signaling prevents or treats skin cancer, whereas activating AhR could be beneficial in inflammatory skin diseases [
62]. Therefore, AhR signaling could be a promising target for skin diseases. Taken together, these studies show the importance of fungi and their metabolites for host health and disease. Understanding their interactions will facilitate a better understanding of disease pathogenesis and identification of targets for new therapy.