Introduction

Infection by Leishmania spp. in patients diagnosed with inflammatory bowel disease (IBD) is an uncommon infectious complication. The use of anti-TNF-α is well known risk factor for Leishmania infection (LI), particularly in some endemic areas, but only a few case series have been reported in the literature, mainly in the Mediterranean basin.

Aims & Methods

Aim: To evaluate the main demographic, IBD-disease features and risk factors as well as LI disease characteristic and required treatment among IBD patients who develop LI.
Methods: This is a retrospective, observational, multicenter study conducted in twenty-five Spanish hospitals, promoted by the Young Group of GETECCU, including patients diagnosed with IBD and subsequent diagnosis of LI.

Results

We collected a total of 73 patients, 48 of them were men (65.8%) with a mean age of 48 ± 15.06 years. 92% of patients resided in the Mediterranean basin, an endemic area of Leishmania. Only 1 patient was born outside of Spain. Nineteen percent of patients were smokers and 16.4% had some comorbidities.
Fifty patients had Crohn's disease (CD) (68.5%) with ileocolonic involvement (30.1%) and inflammatory behaviour (45.2%) and 42.9% had perianal disease. 94% of CD patients were on clinical remission at the time of LI diagnosis. In addition, 23 patients had ulcerative colitis (UC) (31.5%), being extensive colitis the most frequent extent (78.3%), and all of them were on clinical remission or had mild disease activity. 69 patients (94.5%) were under immunosuppressive and/or biologic treatment during the 6 months prior to the LI. 6.8% were on immunosuppressants monotherapy, 42.5% in combotherapy and 38.4% under biologic monotherapy. Regarding biological treatment, 97% of patients were under AntiTNF and only 2 patients were under treatment with Ustekinumab.
Regarding the characteristics of LI, 62 patients presented cutaneous involvement (85%), 9 visceral (12%) and the rest presented mucocutaneous involvement.
Symptoms associated to LI were fever (9.6%), abdominal pain (4.1%) and constitutional syndrome (8.2%), moreover 24.7% required hospital admission. Regarding the location of the skin lesions, the most frequent were the upper limbs (35.6%) followed by lower limbs (30.1%).
The treatment used for LI was systemic amphotericin in 60.3% of patients and pentavalent antimonials in 35.4%; the remaining patients were treated with other treatments, including miltefosine. LI solved at one month in 33 patients (45.2%) and at one year in 95.3% of patients, and only 11% of patients had recurrent LI.
Treatment was stopped temporarily in 38.4% of patients and definitively in 27.4%, starting Ustekinumab (36.8%), Vedolizumab (15.8%) and antiTNF (10.6%) and the rest of the patients remained without biological treatment after the LI.

Conclusion

The usage of antiTNF is associated to LI in IBD patients, but LI could also happen under inmunossupresants or ustekinumab therapy. Although cutaneous involvement is the most frequent manifestation, 12% of patients have visceral involvement or LI recurrences. This infectious complication should be considered in IBD patients in endemic areas.

Disclosure

No Conflict of Interest.

Introduction

No single pharmacological approach is currently available for the treatment of inflammatory bowel disease (IBD) in active and maintenance stages. As evidence is growing on the immuno-modulatory activities of the G-protein coupled receptor GPR120 and on its role in modulating the pathophysiology of IBD, its potential as a therapeutic target for this disease is worthy of exploration.

Aims & Methods

Herein, we have developed DFL23806, a new GPR120 selective small molecule agonist, and propose it as a potential therapeutic approach for IBD. We employed our in-house proprietary Exscalate platform for molecular docking simulations to define the site and mode of binding of the compound with the receptor and used in vitro studies and in vivo models (murine dextran sodium sulfate (DSS)-induced acute and chronic colitis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis models) to characterize the mechanism of action of our molecule and evaluate its therapeutic effects.

Results

DFL23806 is a selective agonist of human and mouse GPR120 that can activate both the G-protein dependent and independent signaling (β-arrestin pathway) of the receptor. DFL23806 has been designed to have high metabolic stability and reach the ileum and colon at optimal concentrations that allow for the activation of GPR120 while, notably, delaying its internalization. This can lead to prolonged periods of signal transduction compared to other commercially available GPR120 agonists and amplification of signaling effects. In vivo, intrarectal treatment with DFL23806 exerted consistent immunomodulatory action in DSS-induced acute colitis in mice. Moreover, oral treatment with DFL23806 significantly inhibited both DSS- and TNBS-induced chronic colonic inflammation and fibrosis by improving the disease activity index, endoscopic score, and reducing body weight loss and colonic tissue damage. Interestingly, DFL23806 treatment also modulated the composition of microbiota, inhibiting the concentration of pathogenic bacteria, and rescued intestinal dysbiosis induced by TNBS.

Conclusion

These results suggest that the stimulation of GPR120 could be an effective strategy for managing colitis, and that DFL23806 has great potential as a therapeutic for the treatment of IBD.

Disclosure

The authors are employees of Dompé farmaceutici s.p.a., Italy. The company has interests in the development of GPR120 selective agonist for the treatment of IBD and metabolic diseases.

Introduction

Inflammatory bowel disease (IBD), a chronic inflammatory disease of the gastrointestinal tract, is caused by various factors, including genetic factors and environmental factors, as well as dysregulated immune responses. LMT503, a novel organic small-molecule compound, has the potential to suppress pro-inflammatory cells and induce anti-inflammatory cells by modulating their cell metabolisms. We evaluated the anti-inflammatory effects of LMT503 in a murine adoptive T cell transfer-induced colitis model.

Aims & Methods

This study was conducted to evaluate the anti-inflammatory effect of LMT503 in the murine chronic colitis model. Naïve CD4⁺CD25^-CD45RB^high CD62L^high T cells that were isolated from wild-type mice by flow cytometry based-method and transferred to Rag1 knock-out mice by intraperitoneal injection to induce murine adoptive T cell transfer-induced colitis. LMT503 was orally administrated (50mg/kg, 100mg/kg) for 2 weeks starting at 5 weeks after naïve T cell transfer. The disease activity index (DAI) was checked daily, and histopathological score, macroscopic injury score, and colon length were evaluated upon sacrifice. Macrophages and T cells from the spleen were analyzed by flow cytometry. Gene expression in colon tissue was measured by qRT-PCR and cytokine profiles in plasma was measured by cytometric bead array. Myeloperoxidase (MPO) activity was measured using the MPO activity kit.

Results

Oral administration of LMT503 ameliorated adoptive T cell transfer-induced colitis in mice. The DAI, histopathological score, and macroscopic injury score were significantly decreased after the administration of LMT503 in a dose-dependent manner. The LMT503-treated group showed significantly increased mucin production in the colon. Th1, Th17 cells, and M1 macrophages in the spleen were suppressed, and M2 macrophages were induced by the administration of LMT503. MPO activity and gene expressions of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in colon tissue were suppressed by the administration of LMT503. And the level of inflammatory cytokines, such as IL-2, TNF-α, and IFN-γ, in plasma were significantly suppressed by the administration of LMT503. Especially, LMT503 treatment significantly increased the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a), a master regulator of mitochondrial biogenesis, suggesting that LMT503 modulates cellular metabolism towards an anti-inflammatory metabolism.

Conclusion

Our data suggest that the anti-inflammatory effect of LMT503 ameliorates murine adoptive T cell transfer-induced colitis by modulating cellular metabolism and immune cell modulation. Therefore, LMT503 may be a novel therapeutic drug that opens new avenues for the treatment of IBD.

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