The role of the gut mycobiota in influencing the immune system and inflammation-related diseases

The educational content in this post, elaborated in collaboration with Lesaffre, was independently developed and approved by the GMFH publishing team and editorial board.

What evidence supports the importance of the gut mycobiota in immunity?

Initially, the resident mycobiota (fungal community) in the gastrointestinal tract was considered a passive component of the microbiome that could become pathogenic secondary to a disrupted intestinal milieu or a decreased immune response. However, recent research has shown that the gut mycobiota is actively involved in shaping host digestive and immune homeostasis.

The gut mycobiota may directly or indirectly interact with the host immune system through fungal-fungal, fungal-bacterial and fungal-host interactions. In a video interview with GMFH editors, Mathias L. Richard from the French National Institute for Agriculture, Food and Environment (INRAE) explained that the main pathway involved in gut fungi and immune system crosstalk is the C-type lectin pathway through Dectin-1, 2 and 3 receptors, among others. To a lesser extent, toll-like receptors, which are a type of pattern-recognition receptor expressed in innate immune cells such as dendritic cells and macrophages, are also involved in fungal detection by the immune system.

It may also be possible that metabolites or virulence factors produced by gut fungi themselves drive immune responses. For instance, that is the case of the toxin candidalysin produced by the gut commensal Candida albicans. While low levels of candidalysin are linked to a commensalism relationship between the host and C. albicans, increased candidalysin levels can lead to damage in host cells and tissues driving disease.

In the other direction, the influence of host immunity on the gut mycobiota is also feasible. For instance, a suppression of immune defense as a result of an immunosuppressive drug regimen or an immunocompromised status can favor the overgrowth of fungi such as Candida, which otherwise remain peaceful members of the commensal gut microbiome.

The gut mycobiota emerges as a potential therapeutic target in inflammation-related diseases

Human gut mycobiota alterations and impaired immunity to intestinal fungi have been observed in patients with inflammatory diseases, which suggests that the gut mycobiota is an active player in immune-associated pathologies.

Preclinical findings in mice and observational data in humans have revealed a role for the mycobiota in gastrointestinal diseases. Indeed, what we know so far about the role of the gut mycobiota in host immune systems and intestinal inflammation comes mainly from patients with inflammatory bowel diseases and irritable bowel syndrome.

Active inflammation in patients with IBD promotes changes in the gut mycobiota composition, independent of the therapeutic regimen. Among the gut fungi involved, Candida species appear to be consistently associated with the progression and development of intestinal inflammation. In addition, strain-level variability rather than gut mycobiota composition alone may be an important driver of sensitivity in IBS.

The role of the gut mycobiota in inflammation-mediated diseases is also supported by the proven efficacy of yeast probiotics such as S. cerevisiae in intestinal inflammation. Despite the variability observed in mycobiota studies due to technical issues, mycobiota alterations in terms of diversity and composition have also been identified in type 2 diabetes, asthma and alcoholic liver diseases. According to Mathias L. Richard: “The main genera identified in these modifications of the gut mycobiota are Candida and Saccharomyces with, in many studies, an increase of Candida and a decrease of Saccharomyces.”

Yeast probiotics for immune-related diseases

The abovementioned changes in the gut mycobiota, in the context of intestinal and extraintestinal diseases with a strengthened inflammatory response, suggest the possibility of restoring gut mycobiota as a potential target.

Yeast probiotics belonging to Saccharomyces genera have been widely studied as an efficacy and safety tool for managing gastrointestinal diseases, such as antibiotic-associated diarrhea and IBS, and preventing Clostridioides difficile infection. The two fungal species currently used as a probiotic in humans include very specific strains of S. boulardii and S. cerevisiae.

Immune-mediated mechanisms may also be involved in the efficacy of yeast probiotics for managing gastrointestinal diseases. A resolution of inflammatory processes and gut microbiota modulation towards an increase in short-chain fatty acids such as butyrate, which have anti-inflammatory properties, have also been reported as putative mechanisms of action for yeast probiotics such as S. cerevisiae CNCM I-3856. “Data also show the reduction of inflammatory molecules like interleukin-8 using yeast probiotics or an improved epithelial healing, while immunological mechanisms have not yet been fully described,” acknowledges Mathias L. Richard.

Take-home messages

• The gut mycobiota might directly or indirectly communicate with the host immune system, shaping the development of gastrointestinal diseases such as IBD.
• Fungal dysbiosis is associated with immune-mediated diseases related to the gut (e.g., Crohn’s disease and ulcerative colitis) and beyond (e.g., type 2 diabetes).
• The benefits of yeast probiotics in gastrointestinal diseases are partly mediated through immune mechanisms.

References:

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Naglik JR, Gaffen SL, Hube B. Candidalysin: discovery and function in Candida albicans infections. Curr Opin Microbiol. 2019; 52:100-109. doi: 10.1016/j.mib.2019.06.002.

Jawhara S. How gut bacterial dysbiosis can promote Candida albicans overgrowth during colonic inflammation. Microorganisms. 2022; 10(5):1014. doi: 10.3390/microorganisms10051014.

Richard ML, Sokol H. The gut mycobiota: insights into analysis, environmental interactions and role in gastrointestinal diseases. Nat Rev Gastroenterol Hepatol. 2019; 16(6):331-345. doi: 10.1038/s41575-019-0121-2.

Van Thiel IAM, Stavrou AA, de Jong A, et al. Genetic and phenotypic diversity of fecal Candida albicans in irritable bowel syndrome. Sci Rep. 2022; 12(1):5391. doi: 10.1038/s41598-022-09436-x.

Sokol H, Leducq V, Aschard H, et al. Fungal microbiota dysbiosis in IBD. Gut. 2017; 66(6):1039-1048. doi: 10.1136/gutjnl-2015-310746.

Roselletti E, Sabbatini S, Ballet N, et al. Saccharomyces cerevisiae CNCM I-3856 as a new therapeutic agent against oropharyngeal candidiasis. Front Microbiol. 2019; 10:1469. doi: 10.3389/fmicb.2019.01469.

Mourey F, Decherf A, Jeanne JF, et al. Saccharomyces cerevisiae I-3856 in irritable bowel syndrome with predominant constipation. World J Gastroenterol. 2022; 28(22):2509-2522. doi: 10.3748/wjg.v28.i22.2509.