Background and Aims: The pathobiology of the non-destructive inflammatory bowel disease (IBD) lymphocytic colitis (LC) is poorly understood. Our aim was to define a LC-specific transcriptome to gain insight into LC pathology, identify genetic signatures uniquely linked to LC, and uncover potentially druggable disease pathways. Methods: We performed whole mucosa bulk RNA-sequencing of LC and CC samples from patients with active disease, and healthy controls (n=4-10 per cohort). Differential gene expression was analyzed by gene-set enrichment and deconvolution analyses to identify pathologically relevant pathways and cells, respectively, altered in LC. Key findings were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared our sequencing data to a previous cohort of ulcerative colitis and Crohn's disease patients (n=4 per group) to distinguish non-destructive from classic IBD. Results: The LC-specific transcriptome was defined by a limited mucosal immune response against microbiota compared to CC and classic IBD samples. In contrast, we noted a distinct induction of regulatory non-coding RNA species in LC samples. Moreover, compared to CC, we observed decreased water channel and cell adhesion molecule gene expression, which was associated with reduced intestinal epithelial cell proliferation. Conclusions: We conclude that LC is a pathomechanistically distinct disease that is characterized by a dampened immune response despite massive mucosal immune cell infiltration. Our results point to regulatory micro-RNAs as a potential disease-specific feature that may be amenable to therapeutic intervention.

C.E.H., S.K. and A.M. received financial support from Ferring Pharmaceuticals (Switzerland). A.M. has received salary for consultancies from Tillotts Pharma AG, Ferring, Vifor and Dr Falk Pharma; speaker's honoraria from Tillotts Pharma AG and Vifor. The remaining authors declare no conflicts of interest.

This work was supported by grants from Ferring Pharmaceuticals (Switzerland); ALF (Region Östergötland, Sweden); the Knut and Alice Wallenberg Foundation (KAW, Sweden) to A.M.; and DFG research unit miTarget 5042 to P.R. These institutions had no role in study design, data collection and analysis, or manuscript preparation.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Informed written consent was obtained from all subjects, and their data were handled according to current regulations (EU2016/679, corrigendum 23 May 2018). Ethical approval was issued by Linköping's regional ethical committee to conduct studies in microscopic colitis, including CC and LC (Dnr 2015/31-31).

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All data produced in the present study are available upon reasonable request to the authors.