Forgotten fungi—the gut mycobiome in human health and disease

FEMS Microbiology Reviews, fuw047, 41, 2017, 479–511 doi: 10.1093/femsre/fuw047 Advance Access Publication Date: 18 April 2017 Review Article REVIEW ARTICLE Chloe E. Huseyin1,2,3 , Paul W. O’Toole2,3 , Paul D. Cotter1,2 and Pauline D. Scanlan2,∗ 1 Teagasc Food Research Centre, Moorepark, Fermoy, Cork P61 C996, Ireland, 2 APC Microbiome Institute, Biosciences Institute, University College Cork, Cork T12 YT20 Ireland and 3 School of Microbiology, University College Cork, Cork T12 YT20, Ireland ∗ Corresponding author: APC Microbiome Institute, Biosciences Institute, University College Cork, Office 5.10, Fifth Floor, Biosciences Building, Ireland. Tel: +353 (21) 4901335; E-mail: One sentence summary: Review of mycobiome in human health and disease. Editor: Gerhard Braus ABSTRACT The human body is home to a complex and diverse microbial ecosystem that plays a central role in host health. This includes a diversity of fungal species that is collectively referred to as our ‘mycobiome’. Although research into the mycobiome is still in its infancy, its potential role in human disease is increasingly recognised. Here we review the existing literature available on the human mycobiota with an emphasis on the gut mycobiome, including how fungi interact with the human host and other microbes. In doing so, we provide a comprehensive critique of the methodologies available to research the human mycobiota as well as highlighting the latest research findings from mycological surveys of different groups of interest including infants, obese and inflammatory bowel disease cohorts. This in turn provides new insights and directions for future studies in this burgeoning research area. Keywords: gut microbiome; mycobiome; fungi; intestinal disease INTRODUCTION Complex microbial ecosystems such as the human gastrointestinal (GI) tract harbour a diversity of microorganisms including bacteria, archaea, viruses and microbial eukarya (Rajilić-Stojanović, Smidt and de Vos 2007; Qin et al. 2010; Parfrey, Walters and Knight 2011; Clemente et al. 2012; Parfrey et al. 2014; Hamad, Raoult and Bittar 2016). However, the myriad of species that are potentially present are found at varying abundance levels and, thus, the presence of predominant species’ may result in microorganisms that are less common being overlooked (Huber et al. 2007). This ‘rare biosphere’ (Sogin et al. 2006) that inhabits the human GI tract includes the fungal component or gut ‘mycobiome’ (Ghannoum et al. 2010). The human gut mycobiome is receiving increased research attention (Andersen, Nielsen and Stensvold 2013; Cui, Morris and Ghedin 2013; Kumamoto 2016) due to its potential involvement in the aetiology of numerous gut-associated diseases (Ott et al. 2008; Iliev and Underhill 2013; Sokol et al. 2016). This increasing interest is largely driven by recent findings that specific fungi can modulate the host immune response and consequently may be a risk factor in immunological disorders in genetically susceptible individuals (Iliev et al. 2012). There is also an ever greater appreciation that the mycobiome may act as a reservoir for potentially opportunistic pathogens in immunocompromised hosts (Chen et al. 2011; Miceli, Dı́az and Lee 2011; Polvi et al. 2015) and may play a role in many diseases that are not obviously related to, or influenced by, the gut (Chen et al. 2011; Received: 20 June 2016; Accepted: 4 January 2017  C FEMS 2017. All rights reserved. For permissions, please e-mail: 479 Forgotten fungi—the gut mycobiome in human health and disease 480 FEMS Microbiology Reviews, 2017, Vol. 41, No. 4 Strati et al. 2016a). Conversely, the potential health benefits or probiotic effects of some fungal species are known but have yet to be fully explored (Hatoum, Labrie and Fliss 2012). Historically, researchers have relied on in vitro culturing as the primary means of investigating fungi from the gut environment (Finegold, Attebery and Sutter 1974). However, the vast majority of microbes in the gut, including fungi, are considered refractory to cultivation which has led to large discrepancies between data obtained from culture-dependent and independent methods (Chen et al. 2011; Gouba, Raoult and Drancourt 2013; Browne et al. 2016). Although recent advances in molecular techniques that circumvent the necessity to culture microbes have been made, this research has largely focused on the non-fungal component of this ecosystem. Nonetheless, a number of important studies into the human mycobiome that use such methods are emerging. These include studies into the aetiology of various GI diseases (Ott et al. 2008; Iliev et al. 2012; Lewis et al. 2015; Hoarau et al. 2016; Mar et al. 2016) as well as the effect of fungal prevalence in immunocompromised hosts (Chen et al. 2011; Mukherjee et al. 2014). Mycobiome studies have also investigated the significance of subject age (Gewolb et al. 1999; Strati et al. 2016b) including children (Heisel et al. 2015) and adults (Scanlan and Marchesi 2008), gender (Strati et al. 2016b), geographical locations (Nam et al. 2008; Hamad et al. 2012), underlying conditions such as diabetes and obesity (Gouba, Raoult and Drancourt 2013; Mar Rodrı́guez et al. 2015; Kowalewska et al. 2016) and eating disorders (EDs) such as anorexia nervosa (Gouba, Raoult and Drancourt 2014a), together with fungal diversity associated with different body sites (Zhang et al. 2011; Nguyen, Viscogliosi and Delhaes 2015) (Fig. 1). Here we review the existing literature on the human gut mycobiome in order to provide a comprehensive insight into both the methodologies available to research the gut mycobiota and also to highlight the latest research findings. We also draw on research into what is known about the human mycobiota at other body sites, in addition to detailing how fungi interact with the human host and data from other gut microbiota studies to provide both comparative insight and productive direction for future studies in this burgeoning research area. METHODOLOGIES TO STUDY THE HUMAN INTESTINAL MYCOBIOME Culture-dependent methods As outlined, scientists have traditionally relied on culturedependent techniques when attempting fungal surveys of complex microbial ecosystems (Horton and Bruns 2001), including the human GI tract (Finegold, Attebery and Sutter 1974; Hoog et al. 2005). These fungal investigations generally utilised traditional microbiological techniques such as microscopy (De Repentigny, Phaneuf and Mathieu 1992), biochemical assays (Khatib et al. 2001) and/or growth on selective media (Ouanes et al. 2013) as until relatively recently, alternatives to these methods were not developed or were too expensive for use in many laboratories. Researchers using selective media for mycobiome research typically perform a serial dilution of faecal samples, followed by plating onto various media that have been supplemented with antibiotics (Scanlan and Marchesi 2008). These plates are Figure 1. Timeline of (...truncated)