Mycobiota in gastrointestinal diseases

Abstract

New insights gained through the use of state-of-the-art technologies, including next-generation sequencing, are starting to reveal that the association between the gastrointestinal tract and the resident mycobiota (fungal community) is complex and multifaceted, in which fungi are active participants influencing health and disease. Characterizing the human mycobiome (the fungi and their genome) in healthy individuals showed that the gastrointestinal tract contains 66 fungal genera and 184 fungal species, with Candida as the dominant fungal genera. Although fungi have been associated with a number of gastrointestinal diseases, characterization of the mycobiome has mainly been focused on patients with IBD and graft-versus-host disease. In this Review, we summarize the findings from studies investigating the relationship between the gut mycobiota and gastrointestinal diseases, which indicate that fungi contribute to the aggravation of the inflammatory response, leading to increased disease severity. A model explaining the mechanisms underlying the role of the mycobiota in gastrointestinal diseases is also presented. Our understanding of the contribution of the mycobiota to health and disease is still in its infancy and leaves a number of questions to be addressed. Answering these questions might lead to novel approaches to prevent and/or manage acute as well as chronic gastrointestinal disease.

Key points

• The mycobiome (the resident fungal community and their genome), is a key component of the human microbiome
• Within a microbiome, there are interactions between and within species or genera among fungi and bacteria
• Alterations within the mycobiota are associated with different diseases
• The mycobiota might directly or indirectly interact with the host immune system
• Interactions between the mycobiota and host immune system can lead to exacerbation of gastrointestinal diseases such as IBD

Introduction

The association between fungi and gastrointestinal disease has been documented since the 18^th century, with a special focus on candidiasis. One of the first observations of this association was the study by Rosen von Rosenstein,¹ who described oral candidiasis that extended to the stomach and intestines. In addition, the first reported case of gastrointestinal candidiasis in an infant was described in this period.¹ Subsequent case reports published in the 19^th century documented Candida infection of the stomach, colon^{2, 3} and ileum.⁴ Candida gastrointestinal infections occur less frequently than oesophageal infection, with the stomach being the most common site of infection in the gastrointestinal tract.¹

 

Historically, fungi such as Candida were considered passive colonizers of the microbial community that could become pathogenic as the result of a change in the environment, for example the loss or reduction of bacterial neighbours (due to use of antibiotics) or suppression of immune defence (as a result of an immunosuppressive drug regimen). However, studies performed in the past decade have demonstrated that fungi have a complex, multifaceted role in the gastrointestinal tract and are active participants in directly influencing health and disease through fungal–bacterial, fungal–fungal and fungal–host interactions.

 

Advances in sequencing technology have provided the ability to profile the microbiome, with emphasis on the bacterial component. However, studies are now beginning to define the fungal component of the human microbiome (the mycobiome). A historical perspective of the interactions between fungi and the gastrointestinal tract and a description of the current state of research on the mycobiota as it pertains to the gastrointestinal tract in health and disease is provided in this Review.

 

Of note, a search of the mycobiome literature shows clear variability between different studies, which can be attributed to the lack of standardized methods to characterize the mycobiome. A multitude of differences occur across studies: sample types; collection times and protocols; DNA extraction methods; varying amplification targets; sequencing methods; differences in algorithms and online database composition; and variation in data cleaning steps and bioinformatics approaches. Therefore, development of standardized methods in microbiome (both bacterial and fungal) analyses is critical. Efforts to address standardization have been initiated and variables that influence microbiome research are being optimized.^{5, 6, 7}

 

Figure 1: Normal and abnormal interactions between fungi and the host immune system in gastrointestinal tissue.

APCs present fungal antigens as MHC class II conjugates to T-cell receptors on naive T cells. T cells then differentiate into T helper cells (T_H1 or T_H17), which secrete different proinflammatory and anti-inflammatory cytokines leading to recruitment of humoral and cellular factors of innate immunity. a | In healthy tissues, immune homeostasis is maintained by interdependent control exerted by T_H1 cytokines and T_REG cells. b | In patients with IBD, dysfunctional regulation of T_H1 or T_H17 pathways triggers an unregulated inflammatory response and recruitment of innate immune cells. Increases in cytokine levels can trigger oxidative tissue damage and recruitment of proteolytic peptides and enzymes, eventually manifesting as gastrointestinal disease. Furthermore, activation of the T_H2 pathway can lead to plasma cells detecting fungal cell wall antigens and producing antiglycan antibodies (ASCA, ALCA and ACCA). Abbreviations: ACCA, anti-chitobioside carbohydrate IgA antibodies; ALCA, anti-laminaribioside carbohydrate IgG antibodies; APC, antigen presenting cell; ASCA, anti-S. cerevisiae antibodies; mac, macrophage; NK, natural killer cell; NO, nitrogen oxide; PAMP, pathogen-associated molecular pattern; PRR, pattern-recognition receptor; ROS, reactive oxygen species; T₀, naive T cell; T_H1, type 1 T helper cell; T_H17, type 17 T helper; T_REG, regulatory T cell.

Conclusions

Studies performed to date on the role of the mycobiota in gastrointestinal diseases have just started to scratch the surface and demonstrate that the fungal community is a critical player in the pathogenesis of these diseases. Although studies performed so far have started to characterize the mycobiome in health and disease, and show potential links, it is important to note that such links reflect association rather than causation. Moreover, most studies have focused on the role of Candida and its effect on the host immune system. Focusing on one microbial kingdom (bacteria or fungi) whilst analysing the microbiome in a sample (for example, oral wash, gut biopsies or faecal pellets) provides limited insight.⁹⁶ To expand our knowledge and obtain deeper insight into the role of the microbiome in health and disease, future studies should also characterize the different microorganisms (bacteria, fungi and viruses) in the same sample types.

 

There is still a long way to go and several questions remain to be answered regarding the contribution of the gut mycobiota to the pathogenesis of gastrointestinal diseases (Box 1). Research funding to address these questions will be instrumental and will lead the way to develop novel approaches to prevent, manage and treat gastrointestinal disease.

Nature Reviews Gastroenterology & Hepatology | Review

Published online 11 November 2014

Pranab K. Mukherjee,^1, Boualem Sendid,^2, Gautier Hoarau,^2, Jean-Frédéric Colombel,^3, Daniel Poulain^2, & Mahmoud A. Ghannoum^1,