Lesson 14: Mycobiome Copy

The mycobiome and microbiome may be perceived as being in a state of homeostasis. One of the ways the bacteria in the microbiome to keep the mycobiome in check is the production of extracellular substances that inhibit the growth or yeast-to-hyphae transition of pathobionts, such as Candida albicans. Clinically, the use of these substances to prevent pathogenicity may potentially offer an alternative to antifungal drugs, as these skew the mycobiota and select for drug-resistant strains.

The commensal microbiota is known to produce a wide range of metabolites, which have inhibitory effects to pathogens, such as short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), secondary bile acids, bacteriocins, and antimicrobial peptides. The human gut is inhabited by diverse microorganisms that play crucial roles in health and disease. Gut microbiota dysbiosis is increasingly considered as a vital factor in the etiopathogenesis of irritable bowel syndrome (IBS), which is a common functional gastrointestinal disorder with a high incidence all over the world. However, investigations to date are primarily directed to the bacterial community, and the gut mycobiome, another fundamental part of gut ecosystem, has been underestimated. Intestinal fungi have important effects on maintaining gut homeostasis just as bacterial species.

Gut Mycobiome

Gut mycobiome is a general designation of intestinal fungi and their collective genome. Actually, the mycobiome inhabits not only gastrointestinal tract but also skin, respiratory tract, genitourinary tract, and other mucosal surfaces in the human host. The microorganisms in human body contain bacteria, archaea, fungi, and virus, and the number of microbial cells is estimated up to 10¹⁴, which is 10 times over the number of human cells (Cani, 2018). The gastrointestinal tract is the most heavily colonized organ; moreover, the colon alone covers more than 70% of the whole microorganisms in humans (Ley et al., 2006; Sekirov et al., 2010). Compared to the great number of bacterial microbes, fungi were reported to make up fewer than 0.1% of microorganisms in gastrointestinal tracts (Qin et al., 2010). With the development of microbial detection methods, our understanding of fungal microbes is progressing forward step by step. Initially, fungi were detected based on the traditional culture-dependent methods such as growth on media, microscopic observation, and biochemical analysis. Whereas, only a few of fungal species can be detected due to the fact that most of them are non-culturable. Applications of molecular techniques detecting microbes without the need of cultivation immensely boost the exploration of novel species in fungal communities. In recent years, next generation sequencing, which is also called high-throughput sequence, has been widely employed in microbiome detection. Similar to 16 s rRNA sequencing for bacteria, fungal spectrum as well can be reestablished through RNA sequencing. The most applied techniques for detecting fungi are 18S rRNA and internal transcribed spacer (ITS) sequencing. 18S rRNA sequencing can identify fungi at species level, and the highly conserved regions reflect phylogenetic relationships among species. ITS regions include ITS1 located between 18S and 5.8S genes and ITS2 between 5.8S and 28S rRNA. As ITS regions are not part of highly conserved areas of the ribosomal DNA, the variability of ITS is greater than 18S rRNA. Therefore, ITS regions are divergent enough among fungi to characterize fungal strains at species and even subspecies level. Actually, of the two methods mentioned above, which one is more suitable for detecting gut mycobiome still remains controversial.

Fungi are ubiquitous microbes existing in diverse environments and are indispensable members of human intestinal ecosystem. Commensal fungi are much less studied than bacteria, as fungi constitute a tiny fraction of the symbiotic microbes in humans and most of them are unculturable. Despite this, steady work has been carried out to explore this mysterious organism in recent years. The composition of fungi on the skin, oral, airway, genitourinary tract, and gastrointestinal tract has been sequenced through culture-dependent or -independent methods (Huffnagle and Noverr, 2013). Some possible factors influencing the colonization of fungal microbiota such as genetic factors, diet, and immune response, are reported (Cui et al., 2013). Gut mycobiome is receiving increasing research interests due to its potential associations with various digestive diseases, including inflammatory bowel disease (IBD), IBS, colorectal cancer (CRC), and so on (Bożena et al., 2016). Among the studies of fungi- and gut-associated diseases, most frequently explored is IBD (Richard et al., 2015; Sartor and Wu, 2017; Sokol et al., 2017). Instead, only a few articles reported that this eukaryotic microbe or its metabolites have associated with irritable bowel syndrome (IBS) and how they interact with one another is still largely unknown.

IBS is one of the most common functional gastrointestinal diseases with high prevalence worldwide. According to Rome IV, IBS is defined as a symptom-based disorder with the presence of recurrent abdominal pain associated with defecation or changes in bowel habits. (Ford et al., 2017) In recent decades, IBS has gained extensive attention owing to its increasing incidence and various detrimental effects on human health. This chronic functional disease was reported to influence 7–21% of the global population (Lovell and Ford, 2012), and the prevalence in Asia is approximately 10% (Sperber et al., 2017). IBS is classified into four subtypes, named as IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed IBS (IBS-M), and unsubtyped IBS (IBS-U; Longstreth et al., 2006; Mearin et al., 2016). The subtyping of IBS provides guidance for therapeutic strategies. However, the clinical classification is based on the various symptoms self-reported by patients, which may result in the discrepant or weak therapeutic efficacy. Emerging evidence proposes that managements targeted at pathophysiologic mechanisms could be more effective and economical (Chang and Talley, 2010; Mayer et al., 2015; Holtmann et al., 2017).

As a multifactorial disease with no single-disease model could entirely explain it, the precise mechanisms of IBS are still far from being completely understood (Oświęcimska et al., 2017). Several possible pathways referring to the initiation and progression of IBS symptoms have been identified, including psychological stress (Chang, 2011; Qin et al., 2014), infection/inflammation, antibiotics exposure (Ianiro et al., 2016; Klem et al., 2017), immune dysfunctions (Spiller and Garsed, 2009), abnormal brain-gut axis (Fichna and Storr, 2012; Jin et al., 2016; Moloney et al., 2016), and altered gut microbiota (Ringel-Kulka et al., 2015; Raskov et al., 2016). Genetic predisposition (Gazouli et al., 2016) and some environmental factors (e.g., diet and pollution; Lackner et al., 2014; Gibson et al., 2015; Marynowski et al., 2015) have also been revealed to be associated with IBS onset. One of the important causes for IBS is intestinal dysbiosis, which has drawn extensive attention and become a focal realm in the researches of gastroenterology. The composition of gut microbiota is proved to be evidently different in IBS patients relative to healthy individuals. Although a great number of studies on the contribution of intestinal microbiota to IBS emerge rapidly, nearly exclusive focus of intestinal microbiota is given on the bacterial species. Conversely, the role of gut mycobiome is underestimated. In this article, possible roles of mycobiome acting in the pathogenesis of IBS were provided (Figure 1), and potential mycobiome-directed therapeutic strategies for IBS were also described.