Fungi and mammals share a co-evolutionary history and are involved in a complex web of interactions. Studies focused on commensal bacteria suggest that pathological changes in the microbiota, ...historically known as dysbiosis, are at the root of many inflammatory diseases of non-infectious origin. However, the importance of dysbiosis in the fungal community - the mycobiota - was only recently acknowledged to have a pathological role, as novel findings have suggested that mycobiota disruption can have detrimental effects on host immunity. Fungal dysbiosis and homeostasis are dynamic processes that are probably more common than actual fungal infections, and therefore constantly shape the immune response. In this Review, we summarize specific mycobiota patterns that are associated with fungal dysbiosis, and discuss how mucosal immunity has evolved to distinguish fungal infections from dysbiosis and how it responds to these different conditions. We propose that gut microbiota dysbiosis is a collective feature of complex interactions between prokaryotic and eukaryotic microbial communities that can affect immunity and that can influence health and disease.
The body is host to a wide variety of microbial communities from which the immune system protects us and that are important for the normal development of the immune system and for the maintenance of ...healthy tissues and physiological processes. Investigators have mostly focused on the bacterial members of these communities, but fungi are increasingly being recognized to have a role in defining these communities and to interact with immune cells. In this Review, we discuss what is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites.
The intestinal microbiota comprises diverse fungal and viral components, in addition to bacteria. These microbes interact with the immune system and affect human physiology. Advances in metagenomics ...have associated inflammatory and autoimmune diseases with alterations in fungal and viral species in the gut. Studies of animal models have found that commensal fungi and viruses can activate host-protective immune pathways related to epithelial barrier integrity, but can also induce reactions that contribute to events associated with inflammatory bowel disease. Changes in our environment associated with modernization and the COVID-19 pandemic have exposed humans to new fungi and viruses, with unknown consequences. We review the lessons learned from studies of animal viruses and fungi commonly detected in the human gut and how these might affect health and intestinal disease.
The mammalian intestine is colonized by a wealth of microorganisms—including bacteria, viruses, protozoa, and fungi—that are all integrated into a functional trans-kingdom community. Characterization ...of the composition of the fungal community—the mycobiota—has advanced further than the much-needed mechanistic studies. Recent findings have revealed roles for the gut mycobiota in the regulation of host immunity and in the development and progression of human diseases of inflammatory origin. We review these findings here while placing them in the context of the current understanding of the pathways and cellular networks that induce local and systemic immune responses to fungi in the gastrointestinal tract. We discuss gaps in knowledge and argue for the importance of considering bacteria-fungal interactions as we aim to define the roles of mycobiota in immune homeostasis and immune-associated pathologies.
Iliev and colleagues review the impact of the gut mycobiota on the regulation of host immunity in homeostasis and in human disease and discuss the current understanding of the mechanisms that underlie these effects.
Fungal microorganisms (mycobiota) comprise a small but immunoreactive component of the human microbiome, yet little is known about their role in human cancers. Pan-cancer analysis of multiple body ...sites revealed tumor-associated mycobiomes at up to 1 fungal cell per 10
tumor cells. In lung cancer, Blastomyces was associated with tumor tissues. In stomach cancers, high rates of Candida were linked to the expression of pro-inflammatory immune pathways, while in colon cancers Candida was predictive of metastatic disease and attenuated cellular adhesions. Across multiple GI sites, several Candida species were enriched in tumor samples and tumor-associated Candida DNA was predictive of decreased survival. The presence of Candida in human GI tumors was confirmed by external ITS sequencing of tumor samples and by culture-dependent analysis in an independent cohort. These data implicate the mycobiota in the pathogenesis of GI cancers and suggest that tumor-associated fungal DNA may serve as diagnostic or prognostic biomarkers.
The study of the intestinal microbiota has begun to shift from cataloging individual members of the commensal community to understanding their contributions to the physiology of the host organism in ...health and disease. Here, we review the effects of the microbiome on innate and adaptive immunological players from epithelial cells and antigen-presenting cells to innate lymphoid cells and regulatory T cells. We discuss recent studies that have identified diverse microbiota-derived bioactive molecules and their effects on inflammation within the intestine and distally at sites as anatomically remote as the brain. Finally, we highlight new insights into how the microbiome influences the host response to infection, vaccination and cancer, as well as susceptibility to autoimmune and neurodegenerative disorders.
Studying the microbial composition of internal organs and their associations with disease remains challenging due to the difficulty of acquiring clinical biopsies. We designed a statistical model to ...analyze the prevalence of species across sample types from The Cancer Genome Atlas (TCGA), revealing that species equiprevalent across sample types are predominantly contaminants, bearing unique signatures from each TCGA-designated sequencing center. Removing such species mitigated batch effects and isolated the tissue-resident microbiome, which was validated by original matched TCGA samples. Gene copies and nucleotide variants can further distinguish mixed-evidence species. We, thus, present The Cancer Microbiome Atlas (TCMA), a collection of curated, decontaminated microbial compositions of oropharyngeal, esophageal, gastrointestinal, and colorectal tissues. This led to the discovery of prognostic species and blood signatures of mucosal barrier injuries and enabled systematic matched microbe-host multi-omic analyses, which will help guide future studies of the microbiome’s role in human health and disease.
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•Decontaminated microbial compositions for 3,689 gastrointestinal cancer samples•Resolved “mixed-evidence” species with gene and nucleotide resolution•Identified prognostic species and blood signatures of mucosal barrier injury•Enabled matched multi-omic, pan-cancer analyses of host-microbe interactions
Dohlman et al. present The Cancer Microbiome Atlas, a public database of decontaminated, tissue-resident microbial profiles of TCGA gastrointestinal cancer tissues. As these profiles are matched to specific TCGA tissue samples, this work allows identification of prognostic species and provides a resource for performing multi-omic, pan-cancer analyses of host-microbe interactions.
Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating host immune homeostasis and inflammatory disease. Nonetheless, the ...mechanisms governing immunity to gut fungal communities (mycobiota) remain unknown. We identified CX3CR1
mononuclear phagocytes (MNPs) as being essential for the initiation of innate and adaptive immune responses to intestinal fungi. CX3CR1
MNPs express antifungal receptors and activate antifungal responses in a Syk-dependent manner. Genetic ablation of CX3CR1
MNPs in mice led to changes in gut fungal communities and to severe colitis that was rescued by antifungal treatment. In Crohn's disease patients, a missense mutation in the gene encoding CX3CR1 was identified and found to be associated with impaired antifungal responses. These results unravel a role of CX3CR1
MNPs in mediating interactions between intestinal mycobiota and host immunity at steady state and during inflammatory disease.
While the use of probiotics to treat or prevent inflammatory bowel disease (IBD) has been proposed, to this point the clinical benefits have been limited. In this report we analyzed the immunological ...activity of three strains of Lactobacillus to predict their in vivo efficacy in protecting against experimental colitis.
We compared the immunological properties of Lactobacillus plantarum NCIMB8826, L. rhamnosus GG (LGG), L. paracasei B21060 and pathogenic Salmonella typhimurium (SL1344). We studied the stimulatory effects of these different strains upon dendritic cells (DCs) either directly by co-culture or indirectly via conditioning of an epithelial intermediary. Furthermore, we characterized the effects of these strains in vivo using a Dextran sulphate sodium (DSS) model of colitis. We found that the three strains exhibited different abilities to induce inflammatory cytokine production by DCs with L. plantarum being the most effective followed by LGG and L. paracasei. L. paracasei minimally induced the release of cytokines, while it also inhibited the potential of DCs to both produce inflammatory cytokines (IL-12 and TNF-alpha) and to drive Th1 T cells in response to Salmonella. This effect on DCs was found under both direct and indirect stimulatory conditions - i.e. mediated by epithelial cells - and was dependent upon an as yet unidentified soluble mediator. When tested in vivo, L. plantarum and LGG exacerbated the development of DSS-induced colitis and caused the death of treated mice, while, conversely L. paracasei was protective.
We describe a new property of probiotics to either directly or indirectly inhibit DC activation by inflammatory bacteria. Moreover, some immunostimulatory probiotics not only failed to protect against colitis, they actually amplified the disease progression. In conclusion, caution must be exercised when choosing a probiotic strain to treat IBD.
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