Multiomics analysis dissects the molecular foundation of perianal fistulas associated with Crohn’s disease and of cryptoglandular origin

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BACKGROUND AND OBJECTIVE: Perianal fistulas, either of cryptoglandular origin (CgF) or associated with Crohn's disease (CDF), have limited treatment options and pose a tremendous burden for affected patients. We recently showed that the epithelial-mesenchymal transition (EMT) contributes to CDF pathogenesis, but detailed mechanisms need further evaluation. Here, we performed multiomics analysis to gain further molecular insights into fistula pathogenesis. DESIGN: Rectal biopsies, swabs, fistula curettage, and serum samples were derived from patients with either CDF (n = 23) or CgF (n = 17) and analyzed by bulk RNA sequencing, metagenomics, untargeted metabolomics, or multiplex-ELISA, where appropriate. RESULTS: Transcriptomics revealed striking differences in gene expression between rectal mucosa and fistula tract samples. However, the transcriptomes of CDF and CgF were comparable, and genes involved in EMT, inflammation and tumor necrosis factor signaling were prominent in both fistula types. A set of 18 genes was found to be differentially expressed in CDF and CgF and might allow discrimination. The overall microbiome composition within fistula tracts did not differ between CDF and CgF patients, but there was a significant difference in rectal microbiome compositions. On a species level, we detected an enrichment of disease-specific, pathogenic species in the fistula tracts. Of note, Bacteroides ssp., Fusobacterium animalis, and Staphylococcus aureus prevailed within CDF. CONCLUSION: Our data demonstrate only minor differences in the transcriptome and the microbiome between CDF and CgF, but clear differences when compared to rectal mucosa biopsies. Thus, our data suggest that the molecular makeup underlying the pathophysiology of fistulas might be comparable between CDF and CgF.

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