Dissecting the small RNA code of inflammatory bowel disease

Emerging evidence demonstrates that noncanonical small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs), rRNA-derived small RNAs (rsRNAs), and Y RNA-derived small RNAs (ysRNAs), are highly abundant in various tissues and cell types and play critical roles in numerous biological processes. These noncanonical sncRNAs are also present in bodily fluids with great potential as disease biomarkers. We leveraged an existing sncRNA dataset to characterize the profiles of tsRNAs, rsRNAs, and ysRNAs in the peripheral blood of patients with inflammatory bowel disease (IBD)—comprising both ulcerative colitis (UC) and Crohn’s disease (CD)—alongside healthy controls (HCs) and symptomatic controls (SCs) within a Swedish cohort (n = 205). Our analysis revealed an overall similar dysregulation pattern of noncanonical sncRNAs among the UC, CD, and SC samples compared to HCs. Our co-expression analysis between sncRNAs and genes suggests elevated oxidative stress as a potential universal regulator of tsRNA/rsRNA/ysRNA biogenesis in IBD. Further, we developed a molecular signature composed of 21 tsRNA/rsRNA/ysRNA families, which clearly distinguished IBD patients from HCs in the Swedish cohort. However, this signature showed a diminished signal in a German cohort (n = 242), in which the IBD patients were treatment-exposed. As a comparison, a 25-miRNA based signature was also developed, which also showed a fairly good classification power between HCs and patients in the Swedish cohort, but was less robust reflected by a stronger baseline divergence between the Swedish and German cohorts. Our findings suggest the potential of tsRNA/rsRNA/ysRNA profiles as biomarkers for IBD and provide clues for further functional and mechanistic investigations.