Mycobiome Research Articles

Exercise-changed gut mycobiome as a potential contributor to metabolic benefits in diabetes prevention: an integrative multi-omics study

ABSTRACT Background The importance of gut microbes in mediating the benefits of lifestyle intervention is increasingly recognized. However, compared to the bacterial microbiome, the role of intestinal fungi in exercise remains elusive. With our established randomized controlled trial of exercise intervention in Chinese males with prediabetes (n = 39, ClinicalTrials.gov:NCT03240978), we investigated the dynamics of human gut mycobiome and further interrogated their associations with exercise-elicited outcomes using multi-omics approaches. Methods Clinical variations and biological samples were collected before and after training. Fecal fungal composition was analyzed using the internal transcribed spacer 2 (ITS2) sequencing and integrated with paired shotgun metagenomics, untargeted metabolomics, and Olink proteomics. Results Twelve weeks of exercise training profoundly promoted fungal ecological diversity and intrakingdom connection. We further identified exercise-responsive genera with potential metabolic benefits, including Verticillium, Sarocladium, and Ceratocystis. Using multi-omics approaches, we elucidated comprehensive associations between changes in gut mycobiome and exercise-shaped metabolic phenotypes, bacterial microbiome, and circulating metabolomics and proteomics profiles. Furthermore, a machine-learning algorithm built using baseline microbial signatures and clinical characteristics predicted exercise responsiveness in improvements of insulin sensitivity, with an area under the receiver operating characteristic (AUROC) of 0.91 (95% CI: 0.85–0.97) in the discovery cohort and of 0.79 (95% CI: 0.74–0.86) in the independent validation cohort (n = 30). Conclusions Our findings suggest that intense exercise training significantly remodels the human fungal microbiome composition. Changes in gut fungal composition are associated with the metabolic benefits of exercise, indicating gut mycobiome is a possible molecular transducer of exercise. Moreover, baseline gut fungal signatures predict exercise responsiveness for diabetes prevention, highlighting that targeting the gut mycobiome emerges as a prospective strategy in tailoring personalized training for diabetes prevention.

From Skin and Gut to the Brain: The Infectious Journey of the Human Commensal Fungus Malassezia and Its Neurological Consequences.

The human mycobiome encompasses diverse communities of fungal organisms residing within the body and has emerged as a critical player in shaping health and disease. While extensive research has focused on the skin and gut mycobiome, recent investigations have pointed toward the potential role of fungal organisms in neurological disorders. Among those fungal organisms, the presence of the commensal fungus Malassezia in the brain has created curiosity because of its commensal nature and primary association with the human skin and gut. This budding yeast is responsible for several diseases, such as Seborrheic dermatitis, Atopic dermatitis, Pityriasis versicolor, Malassezia folliculitis, dandruff, and others. However recent findings surprisingly show the presence of Malassezia DNA in the brain and have been linked to diseases like Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. The exact role of Malassezia in these disorders is unknown, but its ability to infect human cells, travel through the bloodstream, cross the blood-brain barrier, and reside along with the lipid-rich neuronal cells are potential mechanisms responsible for pathogenesis. This also includes the induction of pro-inflammatory cytokines, disruption of the blood-brain barrier, gut-microbe interaction, and accumulation of metabolic changes in the brain environment. In this review, we discuss these key findings from studies linking Malassezia to neurological disorders, emphasizing the complex and multifaceted nature of these cases. Furthermore, we discuss potential mechanisms through which Malassezia might contribute to the development of neurological conditions. Future investigations will open up new avenues for our understanding of the fungal gut-brain axis and how it influences human behavior. Collaborative research efforts among microbiologists, neuroscientists, immunologists, and clinicians hold promise for unraveling the enigmatic connections between human commensal Malassezia and neurological disorders.

A genomic compendium of cultivated human gut fungi characterizes the gut mycobiome and its relevance to common diseases

The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.

Changes in the type 2 diabetes gut mycobiome associate with metformin treatment across populations.

This is the largest to-date multi-country cohort characterizing the human gut mycobiome, and the first to investigate potential perturbations in gut fungi from oral pharmaceutical treatment. We demonstrate the reproducible effects of metformin treatment on the human and murine gut mycobiome and highlight a need to consider metformin as a confounding factor in investigations between type 2 diabetes mellitus and the gut microbial ecosystem.

Oxidative stress induced by the human microbiota yeast component as a micromycetes pathogenicity factor

The introduction of MALDI-ToF mass spectrometry into routine microbiological diagnostics has led to a widely extended list of identified microorganisms. This phenomenon also affected mycological studies. Rare basidiomycetes and ascomycetes began to be detected in various types of pathological material. It is often difficult to assess a role of isolated micromycetes in the pathogenesis of a certain disease. In addition to generally admitted pathogenicity factors, such as aggression enzymes, adhesive activity, and toxin formation, induction or inhibition of reactive oxygen species can play a prominent role in pathogenesis of infectious diseases. In our study, we evaluated the total prooxidant and total antioxidant activity of cultivated ascomycete and basidiomycete yeasts from the human intestinal mycobiome. The strains of micromycetes assessed here were obtained from a fecal culture study from patients with gastrointestinal tract pathology and healthy people undergoing a routine medical examination. Identification was carried out analyzing morphological, cultural, biochemical properties and confirmed by mass spectrometry. The total prooxidant and antioxidant activity was assessed by the induced or inhibited malondialdehyde formation during Tween-80 oxidation. It was found that the level of total prooxidant activity in Rhodotorula mucilaginosa, Geotrichum candidum, Candida albicans, Pichia kudriavzevii significantly exceeds the level of total antioxidant activity, and the Pichia kudriavzevii prooxidase activity was more than twice as high as in other studied micromycetes. The revealed ability of some fungi to induce oxidase stress can be considered as one of significant pathogenicity factors of microorganisms that cause pathomorphological changes in human intestinal tissues.

Phylogenetic analyses reveal insights into interdomain horizontal gene transfer of microbial lipases

Microbial lipases play a pivotal role in a wide range of biotechnological processes and in the human skin microbiome. However, their evolution remains poorly understood. Accessing the evolutionary process of lipases could contribute to future applications in health and biotechnology. We investigated genetic events associated with the evolutionary trajectory of the microbial family LIP lipases. Using phylogenetic analysis, we identified two distinct horizontal gene transfer (HGT) events from Bacteria to Fungi. Further analysis of human cutaneous mycobiome members such as the lipophilic Malassezia yeasts and CUG-Ser-1 clade (including Candida sp. and other microorganisms associated with cutaneous mycobiota) revealed recent evolutionary processes, with multiple gene duplication events. The Lid region of fungal lipases, crucial for substrate interaction, exhibits varying degrees of conservation among different groups. Our findings suggest the adaptability of the fungal LIP family in various genetic and metabolic contexts and its potential role in niche exploration.

Le rôle du mycobiome en santé

AbstractThe human mycobiome, which varies according to its location, remains a small entity compared with the other components of the microbiome. It appears to play an important role in health, notably as an activator of inflammation and immunity. The mycobiome is formed at birth and can vary according to delivery mode and the infant's diet. Throughout life, the mycobiome varies depending on a number of factors, including diet, age, sex and treatments. In the lung, as in the digestive tract, the mycobiome shows great intra-individual variability and changes according to the dietary or airborne exposome. The pulmonary or digestive "core mycobiome" is mainly composed of Candida-type yeasts (Saccharomycotina) and Malassezia spp. Fungal dysbiosis has been described in several pathologies, in particular chronic inflammatory diseases, but also cancers and non-fungal infectious diseases. Candida spp., which are involved in mycobiome, appear to play a pro-inflammatory role or even promote tumorigenesis. This review summarizes current knowledge of the mycobiome at different anatomical sites and its role in human health. Knowledge of the mycobiome in healthy subjects will eventually enable us to investigate fungal dysbiosis and its diagnostic or prognostic factors.

Assessment of DNA extraction methods for human gut mycobiome analysis.

The gut mycobiome plays an important role in the health and disease of the human gut, but its exact function is still under investigation. While there is a wealth of information available on the bacterial community of the human gut microbiome, research on the fungal community is still relatively limited. In particular, technical methodologies for mycobiome analysis, especially the DNA extraction method for human faecal samples, varied in different studies. In the current study, two commercial kits commonly used in DNA extraction, the QIAamp® Fast DNA Stool Mini Kit and DNeasy PowerSoil Pro Kit, and one manual method, the International Human Microbiome Standards Protocol Q, were compared. Furthermore, the effectiveness of two different bead-beating machines, the Mini-Beadbeater-16 and FastPrep-24TM 5G, was compared in parallel. A mock fungal community with a known composition of fungal strains was also generated and included to compare different DNA extraction methods. Our results suggested that the method using the DNeasy PowerSoil Pro Kit and Mini-Beadbeater-16 provides the best results to extract DNA from human faecal samples. Based on our data, we propose a standard operating procedure for DNA extraction from human faecal samples for mycobiome analysis.

Exploring the Link Between the Gut Mycobiome and Neurological Disorders

Long‐standing theories link genetics, environmental factors, and microbial dysbiosis as causes of neurological diseases. Even though the role of the human gut mycobiome in these disorders has drawn a lot of attention, recent research has begun to shed light on another microbial component, the gut mycobiome, and its potential involvement in neurological diseases. In an effort to comprehend the connection between the gut mycobiome and neurological illnesses, this exploratory investigation concentrates on the complex interactions between fungal populations and the central nervous system. This study investigates the mechanisms through which fungus species and their metabolites impact brain health and disease progression by evaluating the body of literature and recent discoveries. It also investigates how the gut mycobiome affects the blood–brain barrier’s integrity, the control of neurotransmitters, and immune system modulation. The outcomes provide new information on therapeutic approaches that target the fungal component of the gut microbiota and imply that changes in the composition and function of the gut mycobiome contribute to the onset and progression of neurological diseases. It is necessary to conduct more studies to clarify the precise mechanisms underpinning the gut mycobiome’s impact on neurological illnesses and to investigate the possibility of new diagnostic and therapeutic approaches based on fungus modulation.

Shotgun metagenomics reveals interkingdom association between intestinal bacteria and fungi involving competition for nutrients

BackgroundThe accuracy of internal-transcribed-spacer (ITS) and shotgun metagenomics has not been robustly evaluated, and the effect of diet on the composition and function of the bacterial and fungal gut microbiome in a longitudinal setting has been poorly investigated. Here we compared two approaches to study the fungal community (ITS and shotgun metagenomics), proposed an enrichment protocol to perform a reliable mycobiome analysis using a comprehensive in-house fungal database, and correlated dietary data with both bacterial and fungal communities.ResultsWe found that shotgun DNA sequencing after a new enrichment protocol combined with the most comprehensive and novel fungal databases provided a cost-effective approach to perform gut mycobiome profiling at the species level and to integrate bacterial and fungal community analyses in fecal samples. The mycobiome was significantly more variable than the bacterial community at the compositional and functional levels. Notably, we showed that microbial diversity, composition, and functions were associated with habitual diet composition instead of driven by global dietary changes. Our study indicates a potential competitive inter-kingdom interaction between bacteria and fungi for food foraging.ConclusionTogether, our present work proposes an efficient workflow to study the human gut microbiome integrating robustly fungal, bacterial, and dietary data. These findings will further advance our knowledge of the interaction between gut bacteria and fungi and pave the way for future investigations in human mycobiome.1fa3y2hSmo38JAQk6TMPiwVideo

70P The human intratumor mycobiome is significantly influenced by an individual's race

70P The human intratumor mycobiome is significantly influenced by an individual's race

Enterotypes of the human gut mycobiome

BackgroundThe fungal component of the human gut microbiome, also known as the mycobiome, plays a vital role in intestinal ecology and human health. However, the overall structure of the gut mycobiome as well as the inter-individual variations in fungal composition remains largely unknown. In this study, we collected a total of 3363 fungal sequencing samples from 16 cohorts across three continents, including 572 newly profiled samples from China.ResultsWe identify and characterize four mycobiome enterotypes using ITS profiling of 3363 samples from 16 cohorts. These enterotypes exhibit stability across populations and geographical locations and significant correlation with bacterial enterotypes. Particularly, we notice that fungal enterotypes have a strong age preference, where the enterotype dominated by Candida (i.e., Can_type enterotype) is enriched in the elderly population and confers an increased risk of multiple diseases associated with a compromised intestinal barrier. In addition, bidirectional mediation analysis reveals that the fungi-contributed aerobic respiration pathway associated with the Can_type enterotype might mediate the association between the compromised intestinal barrier and aging.ConclusionsWe show that the human gut mycobiome has stable compositional patterns across individuals and significantly correlates with multiple host factors, such as diseases and host age.CJ96cDD7W-mAM3Q8ovNQ4eVideo

Position statement: Recommendations on the diagnosis and treatment of Malassezia folliculitis.

Malassezia is a lipophilic yeast that is a part of the human mycobiome. Malassezia folliculitis appears when the benign colonization of the hair follicles, by the Malassezia yeasts, becomes symptomatic with pruritic papules and pustules. Although Malassezia folliculitis is common in hospital departments, diagnosing and treating it varies among dermatologists and countries. The European Academy of Dermatology and Venereology Mycology Task Force Malassezia folliculitis working group has, therefore, sought to develop these recommendations for the diagnosis and management of Malassezia folliculitis. Recommendations comprise methods for diagnosing Malassezia folliculitis, required positive findings before starting therapies and specific treatment algorithms for individuals who are immunocompetent, immunocompromised or who have compromised liver function. In conclusion, this study provides a clinical strategy for diagnosing and managing Malassezia folliculitis.

The Role of the Mycobiome in Women’s Health

Although the human bacteriome and virome have gained a great deal of attention over the years, the human mycobiome has been far more neglected despite having significant value and implications in human health. In women, mycobiome profiles in breastmilk, vaginal regions, the gut, skin, and the oral cavity can provide insight into women's health, diseases, and microbiome dysbiosis. Analyses of mycobiome composition under factors, such as health, age, diet, weight, and drug exposure (including antibiotic therapies), help to elucidate the various roles of women's mycobiome in homeostasis, microbiome interactions (synergistic and antagonistic), and health. This review summarizes the most recent updates to mycobiome knowledge in these critical areas.

Aneuploidy and gene dosage regulate filamentation and host colonization by Candida albicans

Aneuploidy is a frequent occurrence in fungal species where it can alter gene expression and promote adaptation to a variety of environmental cues. Multiple forms of aneuploidy have been observed in the opportunistic fungal pathogen Candida albicans, which is a common component of the human gut mycobiome but can escape this niche and cause life-threatening systemic disease. Using a barcode sequencing (Bar-seq) approach, we evaluated a set of diploid C. albicans strains and found that a strain carrying a third copy of chromosome (Chr) 7 was associated with increased fitness during both gastrointestinal (GI) colonization and systemic infection. Our analysis revealed that the presence of a Chr 7 trisomy resulted in decreased filamentation, both invitro and during GI colonization, relative to isogenic euploid controls. A target gene approach demonstrated that NRG1, encoding a negative regulator of filamentation located on Chr 7, contributes to increased fitness of the aneuploid strain due to inhibition of filamentation in a gene dosage-dependent fashion. Together, these experiments establish how aneuploidy enables the reversible adaptation of C. albicans to its host via gene dosage-dependent regulation of morphology.

Host Factors Associated with Gut Mycobiome Structure.

Recent studies revealed a significant role of the gut fungal community in human health. Here, we investigated the content and variation of gut mycobiota among subjects from the European population. We explored the interplay between gut fungi and various host-related sociodemographic, lifestyle, health, and dietary factors. The study included 923 participants. Fecal DNA samples were analyzed by whole-metagenome high-throughput sequencing. Subsequently, fungi taxonomic profiles were determined and accompanied by computational and statistical analyses of the association with 53 host-related factors. Fungal communities were characterized by a high prevalence of Saccharomyces, Candida, and Sporisorium. Ten factors were found to correlate significantly with the overall mycobiota variation. Most were diet related, including the consumption of chips, meat, sodas, sweetening, processed food, and alcohol, followed by age and marital status. Differences in α- and/or β-diversity were also reported for other factors such as body mass index (BMI), job type, autoimmunological diseases, and probiotics. Differential abundance analysis revealed fungal species that exhibited different patterns of changes under specific conditions. The human gut mycobiota is dominated by yeast, including Saccharomyces, Malassezia, and Candida. Although intervolunteer variability was high, several fungal species persisted across most samples, which may be evidence that a core gut mycobiota exists. Moreover, we showed that host-related factors such as diet, age, and marital status influence the variability of gut mycobiota. To our knowledge, this is the first large and comprehensive study of the European cohort in terms of gut mycobiota associations with such an extensive and differentiated host-related set of factors. IMPORTANCE The human gut is inhabited by many organisms, including bacteria and fungi, that may affect human health. However, research on human gut mycobiome is still rare. Moreover, the large European-based cohort study is missing. Here, we analyzed the first large European cohort in terms of gut mycobiota associations with a differentiated host-related set of factors. Our results showed that chips, meat, sodas, sweetening, processed food, beer, alcohol consumption, age, and marital status were associated with the variability of gut mycobiota. Moreover, our analysis revealed changes in abundances at the fungal species level for many investigated factors. Our results can suggest potentially valuable paths for further, narrowly focused research on gut mycobiome and its impact on human health. In the coming era of gut microbiome-based precision medicine, further research into the relationship between different mycobial structures and host-related factors may result in new preventive approaches or therapeutic procedures.

Mycobiome and Mycobiome-Associated Diseases.

The human body is host to a large number of commensal microbial species such as bacteria, fungi, and viruses. Among these, the human mycobiome is often neglected as a potential cause of disease, as it is thought to be comparatively much less abundant and less diverse than the human bacteriome. Additionally, most fungi are not easily cultured, even in specific media. Hence, their study has been limited to date, mainly because of the unavailability of methods used for their detection. However, the utilization of a novel metagenomic methodology will enable the identification of well-characterized mycobiomes in several parts of the human body and broaden our knowledge of their contribution to human health and disease. In this article, we review the role of the human mycobiome in the gut, respiratory organs, skin, genital tract, and carcinogenesis, highlighting the correlations between the human mycobiome and mycobiome-associated diseases.

Gut mycobiome dysbiosis contributes to the development of hypertension and its response to immunoglobulin light chains.

Human gut microbiome has gained great attention for its proposed roles in the development of hypertension. The fungal microbiome in the human gut (i.e. the mycobiome) is beginning to gain recognition as a fundamental part of our microbiome. However, the existing knowledge of human mycobiome has never revealed the association between gut mycobiome and hypertension. It is known that inflammation and immunity contribute to human hypertension. Here, we sought to investigate whether gut mycobiome could predict the development of hypertension and its association with immunoglobulin light chains. Participants were classified into three cohorts: prehypertension (pre-HTN), hypertension (HTN), and normal-tension (NT) based on their blood pressure. Fresh samples were collected, and the ITS transcribed spacer ribosomal RNA gene sequence was performed. An immunoturbidimetric test was used to examine the serum levels of immunological light chains. Subjects in both of the states of pre-HTN and HTN had different fungal microbiome community compared to the NT group (FDR<0.05). Slightly higher levels of fungal richness and diversity were observed in the groups of pre-HTN and HTN. The relative abundance of Malassezia increased in the HTN group compared to that in the NT group, and the relative abundance of Mortierella enriched in the NT group. For the pre-HTN group, the relative abundance of Malassezia was positively associated with serum the concentration of light chain (LC) κ (r=0.510, P=0.044); for the HTN group, the relative abundance of Mortierella was positively associated with the serum concentration of LC κ (P<0.05), the relative abundance of Malassezia was positively associated with both the serum concentrations of LC κ and LC λ (r>0.30, P<0.05). Our present study demonstrated that gut fungal dysbiosis occurred in the state of prehypertension, and fungal dysbiosis can predict the dysregulation of serum light chains in hypertension patients. Further study on modulating gut fungal community should be focused on balancing the immunological features in hypertension.

Neglected mycobiome in HIV infection: Alterations, common fungal diseases and antifungal immunity.

Human immunodeficiency virus (HIV) infection might have effects on both the human bacteriome and mycobiome. Although many studies have focused on alteration of the bacteriome in HIV infection, only a handful of studies have also characterized the composition of the mycobiome in HIV-infected individuals. Studies have shown that compromised immunity in HIV infection might contribute to the development of opportunistic fungal infections. Despite effective antiretroviral therapy (ART), opportunistic fungal infections continue to be a major cause of HIV-related mortality. Human immune responses are known to play a critical role in controlling fungal infections. However, the effect of HIV infection on innate and adaptive antifungal immunity remains unclear. Here, we review recent advances in understanding of the fungal microbiota composition and common fungal diseases in the setting of HIV. Moreover, we discuss innate and adaptive antifungal immunity in HIV infection.

The Human Mycobiome: Colonization, Composition and the Role in Health and Disease.

The mycobiome is the fungal component of the human microbial ecosystem that represents only a small part of this environment but plays an essential role in maintaining homeostasis. Colonization by fungi begins immediately after birth. The initial mycobiome is influenced by the gestational age of a newborn, birth weight, delivery method and feeding method. During a human’s life, the composition of the mycobiome is further influenced by a large number of endogenous and exogenous factors. The most important factors are diet, body weight, age, sex and antibiotic and antifungal therapy. The human mycobiome inhabits the oral cavity, gastrointestinal tract, respiratory tract, urogenital tract and skin. Its composition can influence the gut–brain axis through immune and non-immune mediated crosstalk systems. It also interacts with other commensals of the ecosystem through synergistic and antagonistic relationships. Moreover, colonization of the gut by opportunistic fungal pathogens in immunocompromised individuals can lead to clinically relevant disease states. Thus, the mycobiome represents an essential part of the microbiome associated with a variety of physiological and pathological processes. This review summarizes the current knowledge on the composition of the mycobiome in specific sites of the human body and its role in health and disease.