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.

References

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2. Ostanin DV, Bao J, Koboziev I, et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am J Physiol Gastrointest Liver Physiol. 2009;296(2):G135-G146.
3. Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186(7):4234-4243.
4. Burke JR, Cheng L, Gillooly KM, et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci Transl Med. 2019;11(502):eaaw1736.
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Introduction

Liver transplant is the only definitive treatment for chronic liver disease (CLD). Referral to a hepatologist for consideration for liver transplant should be made when a patient with CLD experiences a hepatic decompensation or has a MELD score ≥ 15. Failure to refer in a timely manner can result needing a liver transplant evaluation (LTE) in the inpatient setting while a patient is experiencing acute decompensation.

Aims & Methods

We aimed to compare the clinical presentation of patients undergoing LTE in the inpatient setting versus the outpatient setting to identify potential risk factors for requiring urgent evaluation. A list of all LTEs performed at our institution between 10/2017-8/2021 was obtained. Medical records were preliminarily reviewed for evaluation setting (Inpatient vs. Outpatients); evaluations for re-transplantation and acute liver failure were excluded. After all Inpatients (n=159) were identified, Outpatients (n=159) were selected at random to create a sample matched for age, gender, race, and ethnicity (n=318). Data were collected using our institutions electronic medical record and outside health records as obtained during LTE process. “Prior decompensations” refers to the number of the following clinical decompensations experienced prior to the time of LTE: ascites, hepatic encephalopathy (HE), variceal/acute UGIB, SBP and HRS. Categorical variables and continuous were compared between using Fisher’s Exact test, and student’s T test, respectively.

Results

Alcohol was the most common CLD etiology (42.1% Inpatient, 48.4% Outpatient). Inpatients tended to live further from our center than Outpatients (p=0.079). Inpatients had significantly higher MELD-Na scores (27.1 ± 8 vs. 13.3 ± 6; p<0.0001). Malnutrition was more common in 5.6 times more common in inpatients than outpatients (OR 5.6, 95% CI 2.9-10.8, p<0.001).. A similar proportion of patients had 1 hospitalization. But inpatients were 3 times as likely to have had ≥ 1 liver-related hospital admission prior to LTE (p<0.0001). Inpatients had significantly more prior decompensations than Outpatients prior to inpatient LTE (3.2 ± 1.4 vs. 1.8 ± 1.1, p<0.001), with the greatest differences in SBP and HRS.

Conclusion

Multiple liver-related hospitalizations and malnutrition may be considered a risk factor for ultimately needing inpatient LTE and should be taken seriously by health care providers caring for patients with CLD. Episodes of SBP and HRS should prompt providers to consider immediate or urgent LTE referral regardless of other factors.

References

Multiple liver-related hospitalizations may be considered a risk factor for ultimately needing inpatient LTE and should be taken seriously by health care providers caring for patients with CLD. Episodes of SBP and HRS should prompt providers to consider immediate or urgent LTE referral regardless of other factors.

Disclosure

D Devuni has received grant funding from Sequana Medical and receives grant support from the NIAAA (AA017986-11), both for research unrelated to this work.