Introduction

Endogenous hydrogen sulfide (H₂S) and H₂S-prodrugs contribute in the maintenance of gastrointestinal (GI) integrity and redox balance. Biological effects of any H₂S-donor was predominantly mitochondrial. However, even non-targeted H₂S-releasing compounds were shown to decrease the non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrotoxicity but when applied in relatively high doses. Importantly, new derivatives of NSAIDs, such as H₂S-naproxen (ATB-346, Antibe Therapeutics Inc., Canada) or H₂S-ketoprofen (ATB-352) exerted GI safety compared to mother compounds in preclinical or clinical studies. However, mitochondria were not considered as a direct molecular targets for H₂S-prodrugs in terms of attenuation of NSAIDs gastrotoxicity. Targeted delivery of H₂S to gastric mitochondria to improve NSAIDs-pharmacology remains overlooked.

Aims & Methods

Thus, we aimed here to evaluate for the first time if i.g. treatment with mitochondria-targeted and H₂S-releasing AP39 counteracts development of NSAIDs-induced gastric mucosal injuries. Wistar rats were treated i.g. with vehicle, AP39 (0.004-0.5 mg/kg), AP-219 (0.02 mg/kg) as structural control without H₂S-releasing ability, or AP39 + SnPP (10 mg/kg) as a heme oxygenase (HMOX) inhibitor. Next, animals were administered i.g. with acetylsalicylic acid (ASA, 125 mg/kg) as NSAIDs representative to induce translational hemorrhagic gastric lesions. NSAIDs-gastrotoxicity was assessed micro- and macroscopically. Gastric mucosal activity of mitochondrial complexes IV and V, as well as DNA oxidation were assessed biochemically. Gastric mucosal and/or serum content of IL-1b, IL-10, TNF-a, TGF-b1/2/3, ARG1, GST-a, or phosphorylation of NF-κB, ERK, Akt, JNK, STAT3/5 were evaluated by microbeads-fluorescent xMAP®-assay. Gastric mucosal mRNA level of HMOX-1/2, COX-1/2, SOD-1/2 were determined by real-time PCR.

Results

AP39 (but not AP219) dose-dependently (0.02 and 0.1 mg/kg) diminished the development of NSAID-induced gastric lesions and DNA oxidation, restoring mitochondrial complexes activity, ARG1, GST-a protein levels and increasing anti-oxidative HMOX-1 and SOD-2 expression. AP-39 decreased proteins levels or phosphorylation of state-of-the-art gastric mucosal inflammation/oxidation-sensitive markers. Pharmacological inhibition of HMOX-1 attenuated AP39-gastroprotection.

Conclusion

We showed that mitochondria-targeted H₂S, released from very low i.g. doses of AP-39 improved gastric mucosal capacity to cope with NSAIDs-induced mitochondrial dysfunction and redox imbalance, mechanistically requiring the activity of anti-oxidative HMOX-1 and mitochondrial SOD-2. We assume that mitochondria-targeted H₂S moieties could significantly increase the GI-safety of NSAIDs-pharmacology.

Introduction

Weight regain and dumping syndrome (DS) are two relevant long term adverse events after Roux-en-Y Gastric Bypass (RYGB). Both these conditions are related to the dilation of the gastro-jejunal anastomosis. Transoral outlet reduction (TORe) is minimally invasive endoscopic procedure that was introduced to treat these conditions when medical treatment fails. As every endoscopic procedure, TORe is repeatable per definition. In this case series, we evaluate the technical feasibility and short and medium-term outcomes of the redo TORe in patients with weight regain and/or DS recurrence after primary TORe.

Aims & Methods

A retrospective analysis was done on a prospective database including patients that underwent TORe between January 2015 and October 2021; patients who received a re-TORe because of progressive loss of satiety and weight regain (≥50% of weight loss after primary TORe), or recurrence of DS were included in the analysis. DS recurrence was defined as Sigstad’s dumping score ≥7. Sigstad’s score, early and late Arts Dumping Score (ADS) questionnaires, and percentage of total body weight loss (%TBWL) were assessed at baseline, at 6 and 12 months after re-TORe.

Results

Of 92 patients that underwent TORe, 10 required a re-TORe. Indication to re-TORe was weight regain alone in 3 patients, while the remaining 7 repeated the procedure due to both DS recurrence and weight regain. The median time between the primary TORe and the re-TORe was 28 months (range 14-64 years). The median weight regain was 217% (IQR 400) compared to weight at primary TORe and 31.3 % (IQR 16) compared to weight at RYGB. The median Sigstad’s score for patients with recurrent DS was 14 (IQR 4.5), while median early ADS was 5 (IQR 9.5) and late ADS was 8 (IQR 3.5). The redo TORe was technically feasible in all patients. No periprocedural adverse events occurred. Mean percentage of total body weight loss (%TBWL) was 7.7% (IQR 2) at 1 month, 10.1% (IQR 14.2) at 6 months and 10.1% (IQR 18) at 12 months. 6/7 patients undergoing re-TORe because of recurrent DS reached 6- and 12-months follow-up. 3/6 patients had a complete remission of DS maintained at 1 year. Trends of symptoms-based questionnaire for DS are reported in table 1.

Conclusion

According to our experience, redo TORe is technically feasible and has good short and medium-term outcomes in terms of weight loss and DS control. As such, repeating the procedure should be considered before referring patients for revision surgery.

Introduction

Chronic constipation (CC) is one of the most frequent non-motor features of Parkinson’s Disease (PD). Previous studies highlighted the association of CC with PD duration and severity [1]. Furthermore, gut microbiota changes and brain-gut-axis (BGA) dysregulation are common in PD and these alterations are related with clinical manifestations [2,3]. For this reason, probiotics, balancing the gut microbiota, are emerging as a potential therapeutic approach in PD patients.

Aims & Methods

Objective: To evaluate the patients’ satisfaction rates as well as gastroenterological and neurological effects of the administration of a synbiotic in PD patients with CC.
Methods: This study enrolled patients with stable PD who fulfilled Rome IV Criteria for CC or irritable bowel syndrome with constipation (IBS-C). Patients received a synbiotic treatment (Enterolactis ® duo, 4 sachets/day, containing probiotic Lactobacillus casei and prebiotic inulin) for 12 weeks. Two primary endpoints were chosen to monitor the satisfaction with therapy (SWT). SWT was defined when patients were satisfied (satisfaction score >4 on a 7-point Likert scale) or improved after therapy (increase in the global rating of change scale of at least two points on a -7 to +7 visual analogue scale). In addition, a gastrointestinal (GI) evaluation with the Patient Assessment of Constipation-symptoms questionnaire (PAC-SYM), number of complete bowel movements per week, Bristol stool Scale (BSS) were calculated before and after the treatment. The neuropsychological evaluation was performed by the Montreal Cognitive Assessment (MoCA), Movement Disorder Society-Sponsored Revision of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), SCales for Outcomes in Parkinson’s disease - Autonomic Dysfunction (SCOPA-AUT), Toronto Alexithymia Scale (TAS-20), Reading the Mind in the Eyes Test (RMET), Parkinson Anxiety Scale (PAS), State-Trait Anxiety Inventory (STAI-Y), Beck Depression Inventory (BDI II), Hamilton depression rating scale (HAM-D) pre- and post-intervention.

Results

30 patients (10 F) were consecutively enrolled. Satisfaction >4 (endpoint 1) significantly changed from 17% to 60% patients after treatment, p = 0.002. The calculated satisfaction score significantly increased from 4(1) to 5(2) (median (IQR), p = 0.003. Improvement after treatment (endpoint 2) was achieved by 83% of patients. The Global Rating of Change Score changed significantly from 0(3) to 4(2)(median (IQR), p < 0.001. Moreover, a beneficial effect of treatment was shown on GI symptoms. Specifically, PAC-SYM Questionnaire score changed from 1.42(0.94) to 0.91(0.77), p < 0.001, number of complete bowel movements per week from 3(3.5) to 5.5(4.1) p < 0.001 and Bristol stool Scale (BSS) from 2(2) to 3(2) p < 0.001. After treatment PD patients performed better in motor and non-motor features. Specifically, the scores (median (IQR) of TAS-20 significantly changed from 55.0 (22) to 49.5 (21), p=0.03, SCOPA-AUT from 17.0 (7) to 13.5 (10), p = 0.002, MDS-UPDRS part 1 from 13.5 (13) to 9.0 (6), p = 0.001, HAM-D score from 12.5(10) to 9.0 (12), p = 0.045. PAS-A showed a trend towards significance from 7.0(6) to 5.0(7), p = 0.06.

Conclusion

Our results showed that a considerable number of PD patients with CC or IBS-C were satisfied with their defecation after treatment. GI symptoms as well as motor and non-motor features in PD patients improved. Our data suggest that the addition of a synbiotic Enterolactis ® duo may be a useful therapeutic approach in PD possibly acting on the gut-brain-gut axis.

References

References
[1] Krogh K, Ostergaard K, Sabroe S, Laurberg S. Clinical aspects of bowel symptoms in Parkinson’s disease. Acta Neurol Scand. 2008;117(1):60-64.
[2] Shen T, Yue Y, He T, Huang C, Qu B, Lv W, Lai HY. The Association Between the Gut Microbiota and Parkinson’s Disease, a Meta-Analysis. Front Aging Neurosci. 2021 Feb 12;13:636545.
[3] Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015;30(3):350-358.

Introduction

The pathogenesis of irritable bowel syndrome with constipation (IBS-C) remains unclear. Several studies reported that gut dysbiosis had been observed in IBS patients. The treatment of IBS mostly focuses on symptomatic therapy. Acupuncture is one of the alternative therapies for IBS symptoms. However, the effects of acupuncture on symptoms and gut microbiota profiles of IBS-C patients are still unclear. The present study aimed to determine the alterations of the gut microbiota profiles between IBS-C patients and healthy subjects as well as to investigate the effect of electroacupuncture (EA) on the alterations of the profiles of gut microbiota and IBS symptoms in IBS-C patients.

Aims & Methods

We aim to determine the alterations of the gut-brain-microbiota axis between IBS-C patients and healthy subjects and to investigate the effect of electroacupuncture on the alterations of the gut-brain-microbiota axis in IBS-C patients. Thirty-two participants were enrolled in the study, including 16 healthy participants, as the control group and 16 IBS-C patients. Clinical data, blood, and fecal samples were collected from all participants. Then, 16 IBS-C patients were treated with EA nine times for 1 month. Clinical data, blood, and feces were collected in those IBS-C patients at 2-time points: after the end of EA and 1-month follow-up.

Results

Irritable bowel syndrome symptoms severity scale scores (IBS-SSS) and Irritable bowel syndrome quality of life (IBS-QoL) of IBS patients were significantly greater than the control group. There was no significant difference in cognition and depression scores in Hospital Anxiety and Depression Scale (HADs) between the control and the IBS-C groups. A significant increase in serum cortisol level in the IBS-C group was observed when compared to controls. Clinical outcomes of IBS symptoms were significantly improved after EA. These significances were also found in the 1-month follow-up. There was no significant change in serum cortisol levels following EA therapy. Regarding gut microbiota profiles, alpha diversity was not different between the four groups: control, IBS-C, after EA treatment, and 1-month follow-up. However, the beta diversity was significantly different among groups. The beta diversity used of PERMANOVA analysis showed a significant difference between the controls and IBS-C patients (PERMANOVA q-value < 0.05 in Bray-Curtis, Jaccard, and unweighted UniFrac distances). Immediately after EA therapy in IBS-C patients, the beta diversity showed no difference between pre- and post-treatment. Interestingly, the cluster of gut microbiota profiles shifted away from the IBS group and was similar to the control group after a 1-month follow-up.​

Conclusion

Our findings demonstrated the differences in profiles of gut microbiota profiles between IBS-C patients and healthy, and EA treatment showed the benefit of improving clinical outcomes and profiles of gut microbiota.

References

Chang L, Sundaresh S, Elliott J, Anton P, Baldi P, Licudine A, et al. Dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis in irritable bowel syndrome. Neurogastroenterology & Motility. 2009.
Chen Y, Zhao Y, Luo D-n, et al. Electroacupuncture regulates disorders of gut-brain interaction by decreasing corticotropin-releasing factor in a rat model of IBS. Gastroenterology research and practice. 2019.
Tan L-h, Li K-g, Wu Y-y, et al. Effect of electroacupuncture at different acupoints on the expression of NMDA receptors in ACC and colon in IBS rats. Evidence-Based Complementary and Alternative Medicine. 2019.
Tap J, Derrien M, Törnblom H, Brazeilles R, Cools-Portier S, Doré J, et al. Identification of an intestinal microbiota signature associated with severity of irritable bowel syndrome. Gastroenterology. 2017.
Labus JS, Osadchiy V, Hsiao EY, et al. Evidence for an association of gut microbial Clostridia with brain functional connectivity and gastrointestinal sensorimotor function in patients with irritable bowel syndrome, based on tripartite network analysis. Microbiome. 2019.
Song Y-F, Pei L-X, Chen L, et al. Electroacupuncture relieves irritable bowel syndrome by regulating IL-18 and gut microbial dysbiosis in a trinitrobenzene sulfonic acid-induced post-inflammatory animal model. The American journal of Chinese medicine. 2020.
etc.

Disclosure

The authors declared that they have no conflicts of interest.

Introduction

There are no established treatments for esophageal anastomotic stricture refractory to endoscopic balloon dilation (EBD). Patients experience a reduced quality of life and suffer a financial burden after surgery until the strictures are relieved. New treatments for refractory anastomotic stricture are clearly needed. Local steroid injection is reported to improve the effects of EBD. In addition, EBD with local steroid injection is a current community standard treatment for patients with refractory anastomotic stricture after esophagectomy, although the effect is limited. A new endoscopic treatment for such strictures is radial incision and cutting (RIC), which improves strictures by cutting through scar tissue at the stricture site with an electrocautery knife and removing any fibrous tissue that may cause re-stricture. However, the evidence for its effectiveness is limited to retrospective studies and small case series.

Aims & Methods

The aim of this multicenter, randomized, open-label, phaseⅡ/Ⅲ trial was to investigate the safety and the superiority of RIC with steroid injection compared with EBD with steroid injection for patients with refractory anastomotic stricture after esophagectomy for thoracic esophageal cancer. This is the first randomized controlled trial in the world for patients with refractory esophageal anastomotic strictures. Patients with Dysphagia Score ≥2 (able to swallow only semisolid foods or liquids) who had strictures through which a conventional endoscope (diameter, 9.6–10.4 mm) did not pass despite three or more EBDs or bougienage dilations were eligible for this trial. The primary endpoint in the phase II part was proportion of hemorrhages, post-operative esophageal perforations, esophageal hemorrhages, pneumothorax, lung or mediastinum infections or other unexpected adverse events. Co-primary endpoints in the phase III part were re-stricture-free survival and number of dilations for 24 weeks after treatment. This study was registered with the Japan Registry of Clinical Trials jRCTs031180177.

Results

From May 2014 to March 2022, 130 patients were enrolled from 32 institutions participating Gastrointestinal Endoscopy Study Group of the Japan Clinical Oncology Group and 65 patients each were randomized to EBD arm and RIC arm. The median number of dilations before registration was five in each arm. Dysphagia Score represented grade 2 (able to swallow semisolid foods) in 104 (80.0%) patients, grade 3 (able to swallow liquids only) in 25 (19.2%) patients, and grade 4 (unable to swallow liquids) in 1 (0.8%) patient in whole of study. Grade 3/4 pre-defined adverse events occurred in 1 (1.5%) patient in each arm. Median re-stricture-free survival in EBD arm was 10.6 weeks (95% CI: 6.9-20.1 weeks) and 8.7 weeks (95% CI: 7.1-10.9 weeks) in RIC arm (hazard ratio 1.22, 90% CI 0.85-1.74, one-sided p=0.82). The median number of dilations for 24 weeks after initial treatment was once (IQR: 0-2) in EBD arm and twice (IQR: 0-4) in RIC arm (one-sided p=0.99). The proportion of patients with anastomotic diameter >10 mm at 8 weeks after treatment was 27.7% (95% CI: 17.3-40.2%) in EBD arm and 24.6% (95% CI: 14.8-36.9%) in RIC arm.

Conclusion

RIC with steroid injection was not superior to repeated EBD with steroid injection for refractory anastomotic stricture after esophagectomy. EBD combined with steroid injection remains the standard of care for refractory anastomotic stricture after esophagectomy.