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. 2021 Sep 30;13(1):56.
doi: 10.1186/s13099-021-00453-1.

Association of LRRK2 rs11564258 single nucleotide polymorphisms with type and extent of gastrointestinal mycobiome in ulcerative colitis: a case-control study

Niusha Sharifinejad  1   2 , Seyed Hamidreza Mozhgani  3   4 , Mahmood Bakhtiyari  4   5 , Elaheh Mahmoudi  6
Affiliations

Association of LRRK2 rs11564258 single nucleotide polymorphisms with type and extent of gastrointestinal mycobiome in ulcerative colitis: a case-control study

Niusha Sharifinejad et al. Gut Pathog. .

Abstract

Background: Recently, the role of endogenous microbiota and the genotype-microbiota correlation in inflammatory bowel disease (IBD) pathogenesis have been highlighted. However, fungi, as the second most prevalent residents of the intestine, and their primary receptor, Dectin-1, are underrated. Thus, we conducted the first human study investigating the association of Leucine-rich repeat kinase 2 (LRRK2) polymorphism (rs11564258) with type and the extent of intestinal fungi in IBD patients.

Material and methods: A case-control study was performed on 79 ulcerative colitis (UC)-patients (case group) and 58 healthy subjects (HS group). DNA was extracted from blood samples of both groups and amplified with the primers designed for the specific locus containing the LRRK2 polymorphism (rs11564258) and then sequenced. Dectin-1 and LRRK2 mRNA expression levels were also determined. Furthermore, the type and prevalence of fecal yeast species were surveyed in case and control groups.

Results: A positive correlation was observed between rs11564258 polymorphism and UC susceptibility (p = 0.008 vs. HS). Patients with active UC had the highest rate of isolated fungal colonies (50.41%), followed by patients with non-active UC (24.6%) and HS (25%). These results showed a relationship between UC severity with the increased fungal load. Candida albicans had the highest prevalence in both UC (78.7%) and HS groups (55.8%). Whereas Saccharomyces cerevisiae was the second most common species detected in HS (15.23%), it was significantly reduced in the UC patient group (1.68%) (P = 0.0001). On the other hand, single nucleotide polymorphism (SNP, rs11564258) was not correlated with the increased fungal flora in the UC patients. The expression of LRRK2 and Dectin-1 mRNA detected in blood samples was notably higher in the UC patients (P < 0.01) than in the HS group, without being affected by rs11564258 polymorphism.

Conclusions: Here, we disclosed that LRRK2 mediates Dectin-1 signaling pathway activation and subsequent inflammation in the UC patients without being affected by the presence of SNP rs11564258. Our data showed an increased global fungal load in the UC patients along with elevated UC susceptibility in cases carrying rs11564258 polymorphism. However, more clinical investigations, particularly in larger populations with different ethnic groups, are required to support this conclusion.

Keywords: Dectin-1; Fungal microbiota; Inflammatory bowel diseases (IBD); Leucine-rich repeat kinase 2 (LRRK2); rs11564258 polymorphism.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a H&E stained colon sections of HS, non-active UC, and active UC samples. The picture was taken using an Olympus D330 digital camera (Olympus, Tokyo, Japan) (×40 magnifications). b Damage scores ranged from 0 to 4, as described in the text. Scales were judged based on the number and extent of PMN infiltration, mucosal disruption, crypt abscess, crypt atrophy, goblet cell depletion, fibrosis, and granuloma. c There was no significant difference between the average UC severity scores of the SNP-positive and SNP-negative patients in the UC group. Data are presented as mean ± SD
Fig. 2
Fig. 2
a Relative change of Dectin-1 and LRRK2 mRNA level in HS, non-active UC, and active UC. (*P = 0.01), (** P = 0.001) (***P = 0.0001). b SNP (rs11564258) did not affect gene expression level of Dectin-1 and LRRK2 mRNA in all groups (p > 0.05)
Fig. 3
Fig. 3
Frequency of fungal species isolated from UC patients (active and non active) and HS. Fungal composition was determined using ITS2 sequencing. Our results showed the a CFU abundance (per gram) and b relative abundances (%) of fecal mycobiota in patients with UC and HS. Data are presented as mean ± SD. (*P = 0.01), (**P = 0.001) (***P = 0.0001)
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