Introduction

Antibiotic resistance is a growing challenge in the eradication of Helicobacter pylori (Hp). However, the benefits of sensitivity-guided approach compared to empirical regimens is to be established. In this study, we evaluated the effectiveness of the recommended therapeutic protocols, as well as the factors linked to therapeutic failure.

Aims & Methods

A single centre, prospective cohort study, including all consecutive patients undergoing Hp eradication therapy between 2013 and 2022. The evaluated therapeutic protocols were the triple therapy (TRI), concomitant quadruple therapy (QUADC), sequential quadruple therapy (QUADS), and bismuth-based quadruple therapy (QUADB). We analysed the demographic and clinical characteristics of the population, and compared the regimens’ effectiveness, adherence and adverse events.

Results

Included 523 patients, 57% female, with a median age of 56 years (IQR 46-65). The main indication for eradication was dyspepsia (59.8%). The prescribed therapeutic protocols were QUADC in 34.4% of patients, QUADB in 28.7%, TRI in 25.6%, and QUADS in 11.3%. The compliance rate was 97.1%, with no significant differences between the regimens (p=0.49). According to intention-to-treat analysis, the eradication rates in naive patients were TRI 76.1%, QUADS 82%, QUADB 91.1% and QUADC 92.5%. There were statistically significant differences between QUADB/QUADC vs. QUADS/TRI eradication rates (91.9% vs. 78.3%, p<0.001) and adverse event rates (16.2% vs. 4.4%, p<0.001). Multivariate analysis demonstrated an association between therapeutic failure and the following: previous eradication therapy (OR-2.6; 95%CI: 1.5-4.6), noncompliance (OR-80.1; 95%CI: 9.8-664.6) and lack of statin use (OR-2.7; 95%CI: 1.2-6.1).

Conclusion

Bismuth-based quadruple therapy and concomitant quadruple therapy are the most effective therapeutic regimens. To achieve the best eradication rates, attention should be direct to significantly modifiable factors such as non-compliance or absence of concomitant statin use.

Introduction

Endoscopic submucosal dissection (ESD) is the first-line treatment for superficial gastric lesions with a negligible or very low risk of lymph node metastasis. However, a permanent risk of developing metachronous lesions persists. We intend to analyze the risk factors associated with the development of metachronous lesions in a population of patients undergoing ESD.

Aims & Methods

Prospective cohort study conducted at a single centre, involving patients who underwent gastric ESD for lesions between 2017 and 2023, with a follow-up period of ≥ 6 months. Lesion characteristics were analyzed, including the rate of metachronous lesions, and logistic regression was performed to identify risk factors associated with the development of metachronous lesions.

Results

Included 78 ESDs performed on gastric epithelial lesions (59% female), with a mean age of 70.3±7.9 years. Regarding family history of gastric adenocarcinoma, 17.9% of patients had a first-degree relative. Among the analyzed lesions: 42.3% measured between 0-20mm, 57.7% ≥ 20mm; 12.8% were sessile, 71.8% flat and 15.4% depressed; 19.2% were located in the cardia, fundus or body, 21.8% in the incisura angularis and 59% in the antrum. Regarding histological findings: 42.3% low-grade dysplasia, 30.8% high-grade dysplasia, 23.1% intramucosal adenocarcinoma and 3.8% adenocarcinoma with submucosal invasion. Nine metachronous lesions (11.5%) were detected, with a median time of occurrence of 24 [13-32] months. In the analysis of risk factors, statistical significance was found for location outside the antrum (21.6% vs. 1.9%; p=0.002) and the presence of adenocarcinoma (23.8% vs. 7%; p=0.039), but not for size ≥20mm (13.7% vs. 5.1%; p=0.178) or ulceration of the lesion (9.1% vs. 10.1%; p=0.915). Logistic regression analysis revealed that only location outside the antrum had a significant risk for the development of metachronous lesions (OR 13.4; 95% CI: 1.4-127.1).

Conclusion

Given the permanent risk of developing metachronous lesions, the identification of associated risk factors is important as it may eventually allow for the adaptation of surveillance programs.

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

1. Erben U, Loddenkemper C, Doerfel K, et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7(8):4557-4576.
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.
5. Kiesler P, Fuss IJ, Strober W. Experimental Models of Inflammatory Bowel Diseases. Cell Mol Gastroenterol Hepatol. 2015;1(2):154-170.

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

Retrograde cricopharyngeus dysfunction (R-CPD) is a newly recognized disorder characterized by self-reported inability to belch, accompanied by gastrointestinal symptoms such as chest pain, gurgling noises, bloating and flatulence. It has been linked to ineffective relaxation of the upper esophageal sphincter (UES) in response to gastroesophageal gas reflux, and botulinum toxin (Botox) injection into the UES has demonstrated success in case series (1). However, in the absence of adequate testing, the diagnosis is often missed. Recently, high resolution impedance manometry (HRiM) with belch provocation was suggested as a diagnostic tool (2)

Aims & Methods

Our aim was to confirm manometric findings in patients with R-CPD before and after Botox injection, and to compare with HRiM in control patients and healthy volunteers.
We performed a retrospective analysis of HRiM in patients with suggestive symptoms and control patients from May 2021 to April 2023. Ten swallows and a rapid drinking challenge with sparkling water (until symptom provocation) were added to the Chicago IV protocol, followed by an observation period. Control patients were referred for HRiM for different symptoms/conditions. In 8 patients, HRiM was repeated after Botox injection. The same HRiM protocol was used in 15 healthy volunteers. Gastroesophageal gas reflux was defined as a rapid increase in impedance (>3000Ω) from distal to proximal channels, air entrapment as a period of high impedance levels (>3000Ω) in ≥ 2 proximal channels and oscillations as a continuous up and down movement of air.

Results

HRiM with belch provocation test was available for 35 patients before, and 8 patients after Botox injection. Normal UES relaxation occurred after deglutition in all. Contrary to that, there was a significant increase in UES pressure during a gas reflux event as compared with before (p=0.0042). Mean observation period after belch provocation was 9.5min. We observed a mean of 8.3 gastroesophageal gas reflux events, which resulted in UES relaxation in 6% of events. Median air entrapment time was 35 seconds (range 0-640), oscillations lasted 70 seconds (0-690). After Botox injection, 6/8 patients improved, and were able to belch during HRiM, with significant decrease in UES pressures. Air entrapment time was significantly reduced to a median of 0 seconds (0-30).
In control patients (n=18), median air entrapment time after belch provocation test was 38 seconds (0-250). In healthy volunteers (n=15) median air entrapment time was 29 seconds (range 0-60). Both control patients and healthy volunteers had gastroesophageal gas reflux events. In contrast with R-CPD patients, they had significantly lower UES pressures during a reflux event as compared with before, allowing adequate belching in all.

Conclusion

We can confirm a pattern of suggestive symptoms, and typical anomalies on HRiM with belch provocation test, which is not present in control patients or healthy volunteers. Especially UES pressures during gas reflux are able to discriminate R-CPD patients from controls. These findings can provide a basis for a diagnostic algorithm and a standardized HRiM protocol for patients presenting with ‘inability to belch’.

References

1. Bastian RW, Smithson ML. Inability to Belch and Associated Symptoms Due to Retrograde Cricopharyngeus Dysfunction: Diagnosis and Treatment. OTO Open. 2019;3(1):2473974X19834553. Published 2019 Mar 15. doi:10.1177/2473974X19834553
2. Oude Nijhuis RAB, Snelleman JA, Oors JM, et al. The inability to belch syndrome: A study using concurrent high-resolution manometry and impedance monitoring. Neurogastroenterol Motil. 2022;34(5):e14250. doi:10.1111/nmo.14250