DOP08 A novel multiomic approach to unravel the mechanisms of action of biologics and tofacitinib in Inflammatory Bowel Disease

Abstract

Abstract Background Inflammatory bowel diseases (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), are complex and heterogeneous diseases characterized by a multifactorial etiology. IBD prevalence is increasing worldwide. The availability of diverse treatments with different mechanisms of action have revolutionized the ability to achieve clinical remission and endoscopic healing. The aim of this study was to achieve a deeper understanding of the mechanism of action and response to different IBD treatments using a multiomic approach. Methods We analysed the metabolome of serum and urine, metagenome of stool samples and transcriptome and proteome of mucosal biopsies from 53 patients with moderate-to-severe CD and 50 UC patients initiating biologic therapy (anti-TNF, ustekinumab or vedolizumab) or tofacitinib. Patients were assessed at 14 weeks for endoscopic remission and were categorized into responders or non-responders. The methodologies employed in this study were RNA-seq analysis, liquid chromatography-mass spectrometry, nuclear magnetic resonance, and 16S rRNA gene sequencing. Results The multiomic analyses revealed substantial alterations in the transcriptome, proteome, metabolome and metagenome of both responders and non-responders IBD patients before and after treatment (14 weeks) to different biologics and tofacitinib (Table 1). Gene enrichment analysis showed notewhorthy differences in all study comparisons, except for patients with CD and UC who did respond to anti-TNF and tofacitinib. Functional enrichment analysis of differentially expressed proteins indicated several processes that could be potentially involved in the mechanisms of action of different treatments. More differences were observed in lipoproteins than in serum and urine metabolites in the different study comparisons. Finally, metagenomic findings indicated changes in the composition of gut bacteria communities among CD patients treated with ustekinumab and UC patients treated with tofacitinib (responders vs non-responders at 14 weeks) (Figure 1). Conclusion The present study provides novel insights into the mechanisms of action of different IBD treatments from a multiomic approach. Nonetheless, multiomic data integration and validation studies are needed to confirm these findings within a more extensive and independent cohort of patients.