T-Cell miRNA Profile Distinguishes IBD and Predicts Treatment Escalation

Previous research suggests that a class of biomolecules known as microRNAs (miRNAs), which are involved in the regulation of gene expression following transcription, are important to the pathogenesis of inflammatory bowel diseases (IBD) by influencing innate and adaptive immunity. However, until recently, the expression and relevance of miRNAs in key immune cell populations of patients with IBD was not fully understood.

By performing genetic sequencing on white blood cells isolated from patients with Crohn’s Disease and Ulcerative Colitis, a team of scientists from the University of Edinburgh and University of Oxford in the United Kingdom have found that the miRNA expression profiles of immune cells from patients with IBD differ from those of healthy controls and could potentially predict the need for more aggressive immunosuppression, discoveries that could influence the diagnosis and treatment of IBD in the clinic.

“Over the last 2 decades, genetic studies have identified over 200 disease risk loci that associate with Inflammatory Bowel Disease. Yet, despite this progress, genetics only explain upto 20% of the disease variance, implying other mechanisms are at play, including epigenetic mechanisms,” the study’s first-author, Dr. Rahul Kalla, explained to ImmunoFrontiers.

“Since the discovery of microRNAs (miRNAs) in nematodes, they have been described in numerous species including humans and are known to regulate a large number of important biological processes. miRNAs are being increasingly explored as potential biomarkers and as new drug targets; ‘miravirsen’ being the most developed therapy, targeting an antisense to miR-122 and limiting hepatitis C viral replication.”

“The aim of our study was to understand the expression of cell-specific miRNAs within the circulating blood of people with Inflammatory Bowel Disease. Given accessing blood in the clinic is easier and less invasive than the current tests, such as endoscopy, we aimed to develop a blood-based biomarker to help diagnose IBD and predict which patients may go on to require potent medical treatments or surgery.”

In a two-stage prospective multi-centre case control study, next generation small RNA sequencing was performed on a discovery cohort of immunomagnetically separated leucocytes from 32 IBD patients and healthy controls. Differentially expressed signals were validated in whole blood in 294 patients using quantitative PCR. Correlations were analysed with IBD disease subtype, including need for potent medical treatments or surgery as a marker of progressive disease using Cox proportional hazards.”

“In stage 1, each leucocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and healthy controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. These signals were validated in an independent cohort in stage 2. miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20–3.27; logrank p = 1.80 × 10–3), in particular Crohn’s disease;  subtype of IBD [HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4]. Similarly, miR-3615 and miR-4792 remained relevant prognostic markers in IBD.”

“Integrative analysis with paired gene expression data showed significant correlations with 63 of the 240 predicted gene targets. Pathway analysis (KEGG) showed enrichment of 1 pathway that regulated cell-cell adherens junctions (gene targets: MAPK1, ACTB, ACTG1 and WASF2) critical to intestinal homeostasis and relevant in the pathogenesis of IBD.”

Their research findings could influence both the diagnosis and treatment of Crohn’s Disease and Ulcerative Colitis. “Our study has identified unique miRNA profiles in circulating leucocytes in IBD compared to controls. These miRNAs show promise as blood-based biomarkers in diagnosing and predicting disease course in IBD,” Dr. Kalla stated. “Furthermore, integrative miRNA-mRNA analysis has identified key pathways that are regulated by miR-1307-3p, relevant in the pathogenesis of this disease.”

The team, whose research was published in the Journal of Crohn’s and Colitis, included scientists from Norway, Sweden, and Spain in addition to the United Kingdom. Dr. Amy Buck and Dr. Jack Satsangi were co-senior authors.

Moving forwards, the scientists plan to better characterize the molecular signature of immune cells in patients with IBD, with the long-term goal of discovering molecular mechanisms that could lead to the development of more effective therapies.

“Precision medicine and tailoring therapies based on the underlying disease biology is now a key unmet need in the management of this debilitating condition. Our group is now exploring the complete multi-omic profiles of patients with an aggressive disease course over time to better understand their unique molecular biology and identify key pathways that may be targeted with novel therapeutics in the future.”

Dr. Kalla’s take-home message for readers: “miRNA profiles are highly cell-specific and are differentially regulated in CD4+ T-cells in IBD compared to controls. These miRNAs represent biomarkers in diagnosis and show promise as prognostic biomarkers in disease.”

“Further work is now needed to explore the function of these miRNAs in T-cells and the effect of perturbing their regulatory circuits on intestinal inflammation, test their performance as prognostic markers in independent cohorts and explore the utility of miRNA-based therapies in the field of IBD.”

Kalla R, Adams AT, Ventham NT, et al. (2020) Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease. Journal of Crohn’s and Colitis, 14(12): 1724–1733.