The #microbiota and its effect on health has been extensively studied over the past decade. In many studies, the term microbiota has become synonymous with the bacterial component of the microbiota. Other microbes in the microbiota, such as viruses and fungi, have been neglected until recently. This special issue provides some background on the #mycobiota and explores the role of gut fungi in human diseases such as cancer, metabolic diseases, and infection by Clostridiodes difficile, and describes the incidence of fungal infections in transplant patients. The mycobiota, once overlooked, now garners increasing attention.
Introduction
The Human Genome Project spearheaded understanding of the microbiota’s role in human health and disease, catalyzing a deeper exploration of microbial communities inhabiting the body. While initial efforts concentrated on bacteria, a new microbial frontier has emerged: the mycobiota. The mycobiota’s influence extends beyond the human body, as it interacts with environmental factors and other mycobiotas, such as those found in the soil and air. This interconnectivity highlights the need for a holistic approach to studying the mycobiota, considering the complex interplay between fungi, bacteria, bacteriophages, and their respective environments [1].
Initially, the study of the mycobiota experienced many technological limitations [2]. While culture-based techniques failed to capture the full diversity of the mycobiota, molecular methods lacked universally accepted genetic markers and comprehensive databases akin to those for bacteria. The lack of specialized analytical tools, standardized methodologies, and the intrinsic variations in fungal biomass due to diet, oral hygiene, and environmental exposures compounded the challenges researchers faced in studying the mycobiota.
However, a surge in innovative technologies such as next-generation sequencing methods, and metagenomic and amplicon sequencing, have revolutionized our ability to identify and characterize fungal species in the human body. Culture-independent techniques such as quantitative PCR and fluorescence in situ hybridization have enabled the quantification and visualization of fungi in their native environments.
Even though fungal genomes represent a minuscule fraction of the total microbial genome, the secondary metabolites produced during interactions with bacteria and the host cells play a significant role in immune modulation and metabolic homeostasis [3].
Effect of The Mycobiota on Homeostasis
Residents of the mycobiota interact synergistically with each other through various mechanisms. Candida species metabolize complex carbohydrates and make them available to the bacteria Prevotella and Ruminococcus, which in turn release the fermented byproducts to Methanobrevibacter which, in turn, releases methane and carbon dioxide as the end products. This is an example of a syntropic guild [4], which refers to a community of microbes within an ecosystem that collaborate in a mutually beneficial manner.
Immune System Modulation
Fungal commensals can modulate the immune system, its responses and tolerance, and maintain homeostasis. Gut fungal species prompt regulatory T cells (Treg cells) to maintain immune tolerance to commensals. These commensals can activate the macrophages in the innate immune system to release pro-inflammatory cytokines [5], [6], [7], [8]. Fungal antigens influence adaptive immunity by stimulating T-cell responses leading to the formation of memory T cells conferring long-term immunity to fungal infections. Beta-glucans from fungal cell walls interact with dectin-1 (a pattern recognition receptor in the immune system) to modulate and activate inflammatory responses.
A commensal fungal organism, Saccharomyces boulardii, produces a protease that deactivates toxins A and B produced by Clostridium difficile. The organism has been used as a probiotic against several other gastrointestinal pathogens such as Escherichia coli, Helicobacter pylori, Vibrio cholerae, and Shigella flexneri [9]. Probiotic formulas including S. boulardii, Lactobacillus acidophilus, Lacticaseibacillus rhamnosus, and Bifidobacterium breve inhibit biofilms containing E. coli and Candida species.
Dysbiosis of the Mycobiota
Dysbiosis of the mycobiota occurs due to aging, unhealthy diet, poor oral hygiene, use of antibiotics, differences in urban vs rural settings, exposure to soil, and other contaminants in the environment [10]. Consumption of highly processed food and drinks also reduces fungal diversity. Antibiotics like penicillin, clindamycin, and vancomycin cause overgrowth of Candida species, leading to opportunistic infections [11].
The Mycobiome and Metabolic Diseases
Obesity and diabetes mellitus type 2, along with other metabolic diseases, are potentiated by dysbiosis in the gut-liver axis. Research has shown a reduced diversity in fungal organisms, an increase in Candida, Nakaseomyces and Penicillium species, and an inverse correlation with Mucor racemosus with metrics such as body mass index (BMI) and dyslipidemia. Prostaglandins from Candida parapsilosis mediate insulin resistance, hyperglycemia, and lipid deposition, while activation by beta-glycans impairs insulin sensitivity. Other studies revealed a positive association of Rhodotorula with high-density lipoprotein (HDL), and negative associations of Penicillium with BMI and Malassezia with total cholesterol [10], [12].
Effects on the Gastrointestinal System
A dysbiosis of Candida and Malassezia in the gut can promote Inflammatory Bowel Disease (IBD) symptoms, pancreatic adenocarcinoma, and allergic reactions to Aspergillus. Candida also exhibits mutualistic interactions with Streptococcus species in the oral cavity, promoting biofilm formation [13]. Malassezia has been implicated in the progression of colorectal cancer.
The bi-directional communication between the gut and the liver has been studied in immune-modulatory responses in multiple liver diseases [14]. Cirrhosis, alcoholic liver disease (ALD), and non-alcoholic liver disease (NALD), all showed decreased microbial diversity as a common feature, with mycobiota dysbiosis. Specifically, candidalysin, produced by Candida, induces production of pro-inflammatory cytokines and activation of the Nod Like Receptor Protein 3 (NLRP3) inflammasome, which contribute to severe liver damage in NALD [10]. Candida albicans and C. glabrata produce triglycerides, and Saccharomyces and Candida release ethanol to exacerbate NALD.
Studies have shown that the progression of hepatocellular carcinoma could be traced to hepatitis B virus infection and exposure to aflatoxin, produced by Aspergillus species [14]. Interactions between Candida and Enterococcus faecalis have been observed in patients with alcoholic hepatitis.
Effects on the Respiratory System
Early exposure to antibiotics causes microbial dysbiosis that leads to fungal overgrowth, resulting in allergic asthma in children. The presence of Wallemia mellicola in the respiratory tract in animal studies underscores the involvement of the mycobiota in severe asthma.
Altenaria-derived serine protease triggers IL-33 activity, leading to asthma pathogenesis [15]. Increased fungal diversity is observed in allergic rhinitis, with higher levels of Malassezia. Aspergillus fumigatus and Candida albicans aggravate symptoms of cystic fibrosis in the lungs. An abundance of Aspergillus and Cryptococcus is seen in the mycobiota of patients with bronchiectasis. The need to understand the intricacies of the interactions between fungi and bacteria is increased due to new evidence that these biofilms are responsible for antibiotic resistance in the host [16].
Mycobiota and Reproductive Health in Women
The most common fungal species in the vaginal mycobiota is C. albicans, which occupies 70% of the mycobiota. Non-albicans species such as C. krusei, C. parapsilosis, and C. tropicalis are also present. Other commensals include Saccharomycetales, Davidiellaceae, Cladosporium, and Pichia [17].
Several studies have examined the interactions of Candida species with the Lactobacillus bacterial species in the vagina of healthy women [18]. Lactobacilli compete with C. albicans [19], prevent its adherence to the vaginal wall, and inhibit Candida overgrowth by secreting antifungal metabolites. An imbalance in the abundance of beneficial bacteria like Lactobacilli could cause dysbiosis. Furthermore, cross-kingdom interactions of fungi with Streptococcus and E. coli may lead to pre-term birth and sepsis, while Filobasidium and Exophiala have been associated with intra-uterine adhesion.
Between the first and second trimester of pregnancy, the mycobiota composition shifts towards an increase in Saccharomyces enterotype and a decrease in Aspergillus enterotype. The genus Mucor is associated with gestational diabetes and macrosomia, and pre-pregnancy overweight status has a significant role in the mycobial shift [20].
Thus, women’s health is hugely affected by mycobiota dysbiosis, which may suggest targets for probiotic interventions to prevent adverse pregnancy and childbirth outcomes [19].
Mycobiota and Transplant Patients
Solid organ transplant and hemopoietic stem cell transplant patients have a high risk for invasive fungal infections, which increase mortality and morbidity and organ rejection [21]. Heart and lung transplant patients are at high risk for Aspergillus infections, while liver, small intestine, and pancreas are at high risk for Candida infections. Performing careful risk assessments, early detection of fungal infections, customizing therapeutic interventions, and prophylactic antifungal therapy, could increase the chances of a favorable outcome from transplants.
Mycobiota and Cancer
Several fungal species have been implicated in cancer tumorigenesis and progression [22]. Candida species contribute to cancer development, progression, and severity through several mechanisms. For example, they synthesize acetaldehyde which contributes to oral cancer in people with chronic alcoholism by promoting inflammation and carcinogenesis through hypermethylation of tumor suppressor genes; form biofilms to protect against immune responses of the host; and exhibit filamentation as a virulence factor that aids cancer progression [23].
Cross-kingdom interactions of fungal organisms Lichtheimia corymbifera with specific bacterial taxa Campylobacter, Porphyromonas, and Fusobacterium have been implicated in tongue cancer [24]. Fungal dysbiosis increasing Malasezzia interferes with the complement cascade of pancreatic ductal adenocarcinoma, promoting cancer genesis. Thus, modulating this specific interaction of Malasezzia could provide therapeutic interventions for pancreatic cancer [25].
Fungal proteins from Schizosaccharomyces pombi detected in fecal samples could signal the severity of colorectal cancer. Similarly, in bladder cancer patients, an increase in Hypocreales, Tremellales, and Sporidiobiolaies spp was observed, while Saccharomyces was the dominant fungus seen in renal cell carcinoma [26].
Depending on the cancer site, the fungal species, and the metabolic pathway, the host responses and the outcomes were different. Lung cancer had Blastomyces as the dominant species, while Malassezia species were dominant in breast cancer [27]. Gastrointestinal cancers were dominant in either Candida or Saccharomyces. The detection of Candida in gastrointestinal cancer was a predictor of poor survival, while the presence of Candida in head and neck and colon cancers indicated an unfavorable prognosis.
Thus, dysbiosis in fungal species can alter cancer therapy outcomes. Understanding these connections would help to shape targeted therapies for cancer relying on the composition of the mycobiota [28].
Concluding Statements
Our understanding of the mycobiome and its effect on human health is far from complete. Researchers continue to delve into the intricate interactions between the mycobiome and the host through dual RNA-sequencing, metabolomics, and proteomics analyses. Integrating multiple omics data streams provides a comprehensive understanding of these complex relationships. Bioinformatics and computational approaches, including specialized analysis pipelines and machine learning algorithms, are invaluable in deciphering the vast quantities of mycobiome data. Furthermore, databases such as FunOMIC now catalog information on the taxonomy and the functions of the human mycobiota [29].
Unveiling the mycobiota’s colonization, metabolic interactions, and cross-kingdom dynamics with bacteria, protozoa, and viruses, could revolutionize preventive and therapeutic interventions in precision medicine. Mapping these intricate interactions, combined with interdisciplinary collaborations, could pave the way for novel treatment strategies targeting the mycobiota and the many human diseases that are affected by the mycobiota (Fig. 1).
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