Mahmoudi et al. Gut Pathog (2021) 13:31 https://doi.org/10.1186/s13099-021-00426-4 Gut Pathogens REVIEW Open Access The role of mycobiota-genotype association in infammatory bowel diseases: a narrative review Elaheh Mahmoudi1, Sayed‑Hamidreza Mozhgani2 and Niusha Sharifnejad3,4* Abstract Infammatory bowel disease (IBD) is a chronic infammatory disease afecting various parts of the gastrointestinal tract. A majority of the current evidence points out the involvement of intestinal dysbiosis in the IBD pathogenesis. Recently, the association of intestinal fungal composition With IBD susceptibility and severity has been reported. These studies suggested gene polymorphisms in the front line of host defense against intestinal microorganisms are considered to play a role in IBD pathogenesis. The studies have also detected increased susceptibility to fungal infec‑ tions in patients carrying IBD‑related mutations. Therefore, a literature search was conducted in related databases to review articles addressing the mycobiota‑genotype association in IBD. Keywords: Infammatory bowel disease, IBD, Fungal microbiota, Intestinal mycobiota, Single nucleotide polymorphisms, SNPs Infammatory bowel disease pathogenesis microorganisms. Te functional alteration of these cells Infammatory bowel disease (IBD) is a chronic relaps- is hypothesized to be associated with IBD [4]. Bacteria as ing disease afecting various parts of the gastrointestinal the predominant organisms of the gastrointestinal tract tract and encompasses two common disorders: Crohn’s gained the greatest attention in IBD microbial studies disease (CD) and Ulcerative Colitis (UC). IBD is a world- [5–7]. Nonetheless, the association of intestinal fungal wide issue, especially in urban and westernized countries composition with mucosal infammation in both CD and among young individuals [1], assumed to result from UC has recently become into consideration [8–11]. Of an improper and continuous infammatory response to note, increased IBD fares were associated with increased commensal microbes in a genetically susceptible host global fungal load accompanied by alteration of certain [2]. So far, the pathogenesis of the disease is considered fungal species in the microbiota [12–14]. to be a combination of genetic predisposition and envi- To date, numerous gene polymorphisms are found ronmental factors. Te majority of current evidence to be connected to IBD susceptibility [15] and sever- emphasizes the involvement of intestinal dysbiosis in IBD ity; for instance, an increased colitis severity was driven pathogenesis [3]. While intestinal epithelial cells (IECs) by activation of Leucine-rich repeat kinase 2 (LRRK2), are constantly exposed to microbial components; they an important enzyme that regulates innate immunity are regarded not only as a structural but also a functional through nuclear factor kappa B (NF-κB) signaling path- barrier in the front line of host defense against intestinal way [16]. Some articles studied the association of specifc intestinal bacterial microbiota with gene polymorphisms *Correspondence: [email protected] [17, 18]. However, few have focused on the role of fun- 3 Student Research Committee, Alborz University of Medical Sciences, gal subsets in the intestine. Te purpose of this study was Karaj, Iran Full list of author information is available at the end of the article to discuss the association of fungal fora with IBD and © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mahmoudi et al. Gut Pathog (2021) 13:31 Page 2 of 9 review the articles connecting the gene polymorphisms fungal diversity in the host gut microbiota. Specifc Can- with intestinal mycobiota in IBD cases. dida taxa were also found to have increased abundance in the IBD samples [30]. An additional study with de-novo Anti‑Saccharomyces cerevisiae antibody pediatric IBD cases revealed a shift from the Ascomy- Te frst sparks of fungi role in IBD pathogenesis fared cota-predominant mycobiota in HS to a diferent fun- by detecting elevated levels of anti-Saccharomyces cer- gal spectrum with a predominance of Basidomycetes in evisiae mannan antibodies (ASCA) in the sera of IBD- patients with de-novo IBD without the conficting impact afected patients since the early 90 s [19, 20]. A twin study of antibiotics or immunosuppression [32]. Later, another in 2005 has detected ASCA in CD cases more frequently study investigated the possible fungal dysbiosis index in compared with healthy controls [21]. ASCA was also IBD; the fecal fungal composition of 235 patients with found commonly in CD patients with a positive family IBD and 38 HS showed an increased Basidiomycota-to- history of IBD [22] and even in unafected relatives of CD Ascomycota ratio that was dramatically higher in patients patients [23]. ASCA was not only detected in answer to with IBD fares compared to patients in remission and Saccharomyces antigens but also in response to Candida HS [8]. Tere was also a negative correlation between the albicans or the presence of anti-β2 glycoprotein I anti- abundance of S. cerevisiae and C. albicans in fecal sam- bodies in CD patients [24, 25]. Marrakchi et al. revealed ples of IBD subjects, suggesting a competitive environ- a positive correlation of caspase recruitment domain- ment between these two species in the gut [8, 33]. Te containing protein 15 (CARD15)/nucleotide-binding oli- study also described a complex fungal-bacterial interac- gomerization domain-containing protein 2 (NOD2) gene tion in the fecal composition of subjects [8]. mutation, an important intracellular pattern recognition As opposed to Sokol and Mukhopadhya et al., Qiu and receptor (PRR) that is expressed by dendritic cells (DCs), colleagues did not detect any signifcant diference in the macrophages, and IECs [26], with ASCA expression in abundance of Ascomycota, Basidiomycota, and the ratio IBD-afected patients [27]. of Ascomycota-to-Basidiomycota between the HS and UC patients. However, there was a prominent variation IBD afecting intestinal mycobiota in the abundance of Aspergilli between the groups [11]. In addition to animal studies, some articles are conveying A recent report studied the cultivable intestinal myco- the alteration of intestinal mycobiome in human subjects biota presented in feces obtained from 34 pediatric CD with IBD. Ott et al. frst described signifcantly higher patients, 27 pediatric UC patients, and 32 healthy chil- fungal diversity in patients with CD in comparison with dren. Te authors observed increased load of S. cerevisiae healthy controls, albeit no disease-specifc fungal spe- and Candida sp. in IBD patients, which was in line with cies were present in the CD and UC group [28]. Ever previous studies. Likewise, Di Paola et al. concluded that since, many studies have consistently shown an elevated the presence of S. cerevisiae was associated with a favora- abundance of Candida sp. in IBD fecal samples [29–31]. ble intestinal environment for benefcial bacterial genera, Lewis et al. have reported an increased amount of S. cer- such as Faecalibacterium; whereas the absence of normal evisiae [29], whereas Hoarau et al. reported a reduction fungal fora or presence of unusual fungal species were in intestinal S. cerevisiae abundance in IBD patients [31]. conjugated with the presence of potential pathogenic Another study in 2009 reported a signifcantly elevated C. bacteria that might lead to IBD [34]. Te latest article by albicans population obtained from fecal samples of CD Nelson et al. reported an increased abundance of Can- patients (44%) and their healthy relatives (38%) compared dida sp. and a decreased Basidiomycota-to-Ascomycota to healthy controls [22]. Li et al. assessed 19 patients ratio, in contrast to the previous literature, in CD cases with active CD and 7 healthy individuals and discovered [35]. Of note, the discrepancies between these studies increased fecal fungal richness and diversity in C. albi- might stem from diferent fungal extraction methods. In cans, Aspergillus clavatus, Cryptococcus neoformans, and this regard, we provided additional information for these a decrease in S. cerevisiae in CD patients. Te diversity of studies, including the fungal extraction method and the the fecal fungal community was also positively correlated sample source, in Table 1. with serum C-reactive protein level and the CD activity index [13]. Another study in 2016, revealed a signifcant Innate immunity against fungi increase in global fungal load in both infamed and non- Several