Frontiers in Human Mycobiome in Health and Disease

Introduction

The humans are colonized by abundant and diverse fungi, collectively referred to as mycobiome which has garnered much less attention to date than the colonizing bacterial microbiome. The advancement of next-generation high throughput sequencing technologies have expanded our knowledge substantially in human microbiome and gradually in human mycobiome in association with health and disease [1, 2]. Different fungal taxa were identified in the intestines, oral cavity, skin, vagina and lungs, varying across body sites [3], and also over time and with diet, environment and diseases [4, 5]. In human gut, Aspergillus, Candida, Debaryomyces, Malassezia, Penicillium, Pichia, Saccharomyces, Cladosporium, Clavispora, Cyberlindnera, and Galactomyces are the most prevalent fungal genera [6, 7, 8]. Particularly, the species Candida albicans colonizes the oropharynx, genital, and gastrointestinal mucosa of 30-70% of healthy individuals [9]. Moreover, fungi of the genus Malassezia predominated the skin mycobiome [10], while Aspergillus species and Scedosporium species are regularly inhaled by lungs in humans [3]. In addition, fungal genera including Candida and Saccharomyces were identified in breastmilk [11, 12]. Edible mushrooms, plant pathogen and xerophiles (all fungi) were found in vegetarian gastrointestinal tract [13, 14].

Fungi have been existing at low levels in human, as commensals without causing disease in steady state, which however, under conditions of host immunosuppression, bloom to cause a life-threatening illness. For instance, in diease settings, Cryptococcus neoformans leads to lung pathologies [15], Mallassezia leads to skin disorders [16], Candida leads to airway inflammation [17] and Porphyromonas gingivalis leads to periodontitis [18]. Apart from the pathogenic role of fungi, certain fungi (Candia albicans or Saccharomyces cerevisiae) were revealed to be able to safeguard local and systemic immunity against injury to mucosal tissues, positively calibrating the responsiveness of circulating immune cells [19]. The dual role of human commensal fungi remains to be further defined in humans, given the large variability in human health and disease state.

A number of studies have shown mycobiome dysbiosis in diseases, including inflammatory bowel disease [20, 21], obesity [22], antibiotic-associated diarrhea [23], hepatitis [24] and graft versus host disease [25] It is often assumed that fungal diversity should be greater in more severe cases of a disease [15]. Prior studies indicate that patients with diseases such as ulcerative colitis, Crohn’s disease, and gastric ulcers were more heavily colonized with the species Candida albicans [26, 27]. In obese gut mycobiomes, the phylum Ascomycota, classes Sacharomycetes, Tremellomycetes and Cystobasidiomycetes, families Erythrobasidiaceae and Dipodascaceae and genera Aspergillus, Eurotium and Rhodotorula were found increased, compared to non-obese gut mycobiomes [22]. In addition, Cladosporium herbarum and Candida albicans were detected as the most abundant species in 80% of patients with diabetic foot ulcers, a common result of diabetes-induced chronic skin infections [28]. These two highly abundant fungi may form polymicrobial biofilms when co-cultured in vitro with bacteria, although their relatedness with wound healing versus exacerbation has yet to be dissected. Albeit, most of the current mycobiome studies in human diseases were associative without definitive causal or consequential role established, which necessitates more efforts to be devoted to unveiling the function of fungi, as well as the underlying mechanisms of actions, in humans.

Of note, causal relationships are always complex in several specific diseases and conditions, synergistic or competitive interactions between the mycobiome and the bacterial microbiome also play critical roles in health and disease. Antibiotic treatment is often associated with the results of fungal expansion in the gastrointestinal tract [29, 30]. Similarly, gut environment may favor fungi at the cost of bacteria at the condition of Crohn’s diseases [21], uncovering a balance between bacterial and fungal communities in healthy and steady state. However, the alterations in the mycobiome is primary or secondary to the disruption of bacterial microbiome in diseases remains unknown.

As our knowledge of human-associated fungi is largely lacking compared to a wealthy knowledge of human commensal bacteria, both in terms of the mycobiome composition and function, it is imperative to develop complete and accurately curated database for mycobiome analysis, and to functionally elucidate the symbiotic versus pathogenic roles of human fungi under various conditions for host physiology. Due to the multi-dimensional inter- and intra- kingdom interactions, the intricate fungal-fungal, fungal-bacterial and fungal-viral relationships also warrant in-depth investigation for improving our perception of the inner-working of the complex human microbiome in health and disease.

References

• Huseyin CE, Rubio RC, O Sullivan O, Cotter PD, Scanlan PD (2017) The fungal frontier: a comparative analysis of methods used in the study of the human gut mycobiome. Frontiers in microbiology 8: 1432-1446.
• Kabeer FA, Jabir T, Krishnan KP, Mohamed Hatha Abdulla (2019) Metagenomic data of fungal community in Kongsfjorden, Arctic using Illumina next generation sequencing. Data in brief 22: 195-198.
• Underhill DM, Iliev ID (2014) The mycobiota: interactions between commensal fungi and the host immune system. Nature Reviews Immunology 14(6): 405-416.
• David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, et al. (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505(7484): 559-563.
• Ward TL, Dominguez Bello MG, Heisel T, Al Ghalith G, Knights D, et al. (2018) Development of the human mycobiome over the first month of life and across body sites. MSystems 3(3): e00140-17.
• Auchtung TA, Fofanova TY, Stewart CJ, Nash AK, Wong MC, et al. (2018) Investigating colonization of the healthy adult gastrointestinal tract by fungi. MSphere 3(2): e00092-18.
• Borges FM, de Paula TO, Sarmiento MRA, de Oliveira MG, Pereira MLM, et al. (2018) Fungal diversity of human gut microbiota among eutrophic, overweight, and obese individuals based on aerobic culture-dependent approach. Current microbiology 75(6): 726-735.
• Nash AK, Auchtung TA, Wong MC, Smith DP, Gesell JR, et al. (2017) The gut mycobiome of the Human Microbiome Project healthy cohort. Microbiome 5(1): 153-165.
• Raimondi S, Amaretti A, Gozzoli C, Simone M, Righini L, et al. (2019) Longitudinal survey of fungi in the human gut: ITS profiling, phenotyping and colonization. Frontiers in microbiology 10: 1575-1586.
• Byrd AL, Belkaid Y, Segre JA (2018) The human skin microbiome. Nature Reviews Microbiology 16(3): 143-155.
• Brooks B, Matthew RO, Brian AF, Robyn Baker, Brian CT, et al. (2017) Strain-resolved analysis of hospital rooms and infants reveals overlap between the human and room microbiome. Nature communications 8(1): 1-7.
• Heisel T, Nyaribo L, Sadowsky MJ, Gale CA (2019) Breastmilk and NICU surfaces are potential sources of fungi for infant mycobiomes. Fungal Genetics and Biology 128: 29-35.
• Suhr MJ, Banjara N, Hallen Adams HE (2016) Sequence‐based methods for detecting and evaluating the human gut mycobiome. Letters in applied microbiology 62(3): 209-215.
• Hallen Adams HE, Stephen D Kachman, Jaehyoung Kim, Ryan M Legge, Inés Martínez (2015) Fungi inhabiting the healthy human gastrointestinal tract: a diverse and dynamic community. Fungal ecology 15: 9-17.
• Huffnagle GB, Noverr MC(2013) The emerging world of the fungal microbiome. Trends in microbiology 21(7): 334-341.
• Prohic A, Jovovic Sadikovic T, Krupalija Fazlic M, Kuskunovic Vlahovljak S (2016) Malassezia species in healthy skin and in dermatological conditions. International journal of dermatology 55(5): 494-504.
• Kim YG, Udayanga KG, Totsuka N, Weinberg JB, Núñez G, et al. (2014) Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2. Cell host & microbe 15(1): 95-102.
• Hajishengallis G, Liang S, Payne MA, Hashim A, Jotwani R, et al. (2011) Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell host & microbe 10(5): 497-506.
• Jiang TT, Shao TY, Ang WXG, Kinder JM, Turner LH, et al. (2017) Commensal fungi recapitulate the protective benefits of intestinal bacteria. Cell host & microbe 22(6): 809-816.
• Ott SJ, Kühbacher T, Musfeldt M, Rosenstiel P, Hellmig S, et al. (2008) Fungi and inflammatory bowel diseases: alterations of composition and diversity. Scandinavian journal of gastroenterology 43(7): 831-841.
• Sokol H, Leducq V, Aschard H, Pham HP, Jegou S, et al. (2017) Fungal microbiota dysbiosis in IBD. Gut 66(6): 1039-1048.
• Rodríguez MM, Daniel Pérez, Felipe Javier Chaves, Eduardo Esteve, Pablo Marin Garcia, et al. (2015) Obesity changes the human gut mycobiome. Scientific reports 5: 14600-14614.
• Krause R, Reisinger EC (2005) Candida and antibiotic-associated diarrhoea. Clin Microbiol Infect 11(1): 1-2.
• Chen Y, Chen Z, Guo R, Chen N, Lu H, et al. (2011) Correlation between gastrointestinal fungi and varying degrees of chronic hepatitis B virus infection. Diagnostic microbiology and infectious disease 70(4): 492-498.
• Marty FM, Lee SJ, Fahey MM, Alyea EP, Soiffer RJ, et al. (2003) Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood 102(8): 2768-2776.
• Kumamoto CA (2011) Inflammation and gastrointestinal Candida colonization. Current opinion in microbiology 14(4): 386-391.
• Quinton JF, Sendid B, Reumaux D, Duthilleul P, Cortot A, et al. (1998) Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut 42(6): 788-791.
• Kalan L, Loesche M, Hodkinson BP, Heilmann K, Ruthel G, et al. (2016) Redefining the chronic-wound microbiome: fungal communities are prevalent, dynamic, and associated with delayed healing. MBio 7(5): e01058-16.
• Dollive S, Chen YY, Grunberg S, Bittinger K, Hoffmann C, et al. (2013) Fungi of the murine gut: episodic variation and proliferation during antibiotic treatment. PloS one 8(8): e71806.
• Downward JRE, Falkowski NR, Mason KL, Muraglia R, Huffnagle GB (2013) Modulation of post-antibiotic bacterial community reassembly and host response by Candida albicans. Scientific reports 3: 2191.