Although the number of therapeutic options for the treatment of inflammatory bowel disease (IBD) has increased in recent years, patients suffer from decreased quality of life due to non-response or loss of response to the currently available treatments. An increased understanding of the disease’s etiology could provide novel insights for treatment strategies in IBD. Lymphatic system components are generally linked to immune responses and presumably related to inflammatory diseases pathophysiology. This review aims to summarize findings on immune-mediated mechanisms in lymphoid tissues linked with IBD pathogenesis and (potential) novel treatments. Enhanced innate and adaptive immune responses were observed in mesenteric lymph nodes (MLNs) and other lymphoid structures, such as Peyer’s patches, in patients with IBD and in animal models. Furthermore, the phenomenon of lymphatic obstruction in the form of granulomas in MLNs and lymphatic vessels correlates with disease activity. There is also evidence that abnormalities in the lymphatic stromal components and lymph node microbiome are common in IBD and could be exploited therapeutically. Finally, novel agents targeting lymphocyte trafficking have been added to the treatment armamentarium in the field of IBD. Overall, gut-associated lymphoid tissue plays a key role in IBD immunopathogenesis, which could offer novel therapeutic targets.

Background and Aims: Intestinal fibrosis in Crohn’s disease (CD) frequently leads to stricture formation, with current treatment options limited to endoscopic balloon dilation and surgery. This underscores the urgent need for anti-fibrotic therapies. Our objective was to identify therapeutic targets and compounds capable of reversing the fibrotic gene expression profile of mucosal fibroblasts in CD. Methods: We derived a fibrotic gene signature via fibroblasts isolated from stricturing CD tissue and conducted a meta-regression analysis across three publicly available transcriptomic datasets, to identify key differentially expressed genes (DEGs) in fibrostenotic CD. Drug repurposing platforms (iLINCS, L1000, CLUE-io) were implemented to screen compounds with high druggability, for their potential to reverse this pro-fibrotic profile. Transcription factors, microRNAs, and drugs targeting the fibrostenotic signature were identified using the TRRUST, miRWalk, and DGIdb databases, ultimately forming a drug–gene interaction network. The STITCH platform was used to predict compound-protein binding affinities. Promising compounds were subsequently evaluated in vitro, using mucosal fibroblasts derived from fibrostenotic CD patients, and the effect on the expression of selected protein targets was measured via ELISA and immunofluorescence staining. Results: The top upregulated DEGs included fibroblast activation protein (FAP), IL-7 receptor, and transcription factor AP-2 gamma. The drug–gene interaction network analysis identified IL-6 among the most druggable targets. Of 6783 pharmaceutical agents, PI3K inhibitors and histone deacetylase blockers were the most effective in reversing the fibrotic signature via a FAP- and IL-6-dependent mechanism. Conclusion: This integrative approach identified potential anti-fibrotic compounds and molecular targets in CD-associated fibrostenosis, supporting future development of effective therapies.

Etrasimod is an oral selective sphingosine-1 phosphate receptor modulator, and its anti-inflammatory mechanism of action in inflammatory bowel diseases is not completely understood. It targets pro-inflammatory immune cells expressing sphingosine-1-phosphate receptors during their migration from the lymphatic system to the circulation and intestinal mucosa. Reductions in certain lymphocyte subsets in the peripheral blood have been reported, but its effects in lymph nodes remain unknown. This study investigated changes in leukocyte subpopulations in peripheral lymph nodes and blood in Crohn’s disease patients treated with etrasimod. Moderate-to-severe Crohn’s disease patients participated in this randomized, double-blind study, within the phase 2 CULTIVATE clinical trial. At baseline and after 14 weeks of etrasimod treatment, peripheral blood and inguinal lymph node biopsies were obtained. Isolated peripheral blood mononuclear cells and lymph node leukocyte populations were analyzed at single cell level using mass cytometry at both timepoints. The immunophenotyping revealed 15 innate and adaptive major immune cell populations, as well as 14 subpopulations of CD4+ and CD8+ T-cells. In peripheral lymph nodes, etrasimod resulted in significant accumulation of naïve, central memory, and effector memory CD4+ T-cells (+10.7%, +4.2%, and +2.3%, respectively; all p = 0.03), as well as naïve CD8+ T-cells (+4.2%; p = 0.03). Conversely, these subsets were reduced in peripheral blood (−6.2%, −6.0%, −2.0%, and −2.2%, respectively; all p = 0.03). Naïve and memory B-cells decreased in the circulation (−1.7%, p = 0.057; −0.6%, p = 0.03, respectively) but were unchanged in the lymph nodes. Innate immune cell populations remained mostly unaffected in both compartments. Our data indicate that etrasimod’s pharmacodynamic effect is related primarily with the attenuation of the T-cell mediated inflammation with minor changes in B-cells. However, additional follow-up studies are needed for the validation of these observations in the context of Crohn’s disease.