Introduction

Around 23% of adults in Europe are obese, with levels reaching one third in certain countries [1]. Due to its minimal invasiveness, intragastric botulinum toxin (BTX-A) injection, has become an alternative option for patients who don’t want to undergo bariatric surgery. Nevertheless, there is ongoing debate regarding its clinical effectiveness [2-4]. In 2015, the European Medicines Agency granted permission for the use of daily subcutaneous (sc) liraglutide 3mg as an aid for weight loss in overweight and obese adults. Based on literature, there have been no studies combining gastric ΒΤΧ-Α and liraglutide administration for weight management. Therefore, we decided to conduct a retrospective study using data from our clinic record files to present the results of our experience with this approach so far.

Aims & Methods

Aim of this retrospective, cohort study is to investigate the safety and efficacy of combining intragastric BTX-A with sc liraglutide 3mg for weight management in obese and overweight individuals. A total of 300 units (U) of BTX-A were diluted in 20ml of normal saline 0.9%. Injections containing 0.5ml of the prepared solution were administered into the submucosa of the gastric antrum, body and fundus in a circular direction with 1-3cm intervals, using a standard 6mm sclerotherapy needle of 23 gauge. We incorporated liraglutide and gastric BTX-A with a reduced calorie diet and increased physical activity. The primary outcome of the study was to evaluate the effect of the combined treatment on weight loss (in kilograms, kg) in obese and overweight patients, based on measurements taken during patient follow-up at 3 and 6 months after treatment. The efficacy of the treatment was further assessed based on measurements of body mass index-BMI (kg/m²) and visceral fat (%) taken at the aforementioned time points.

Results

Between September 2022 and April 2023, a total of 60 patients(81.7% female) received combined treatment and completed the 3 and 6-month follow-up. The baseline mean(± standard deviation) weight and BMI were 94.5±16.9kg and 33.7±4.7kg/m², respectively. Following intragastric BTX-A and liraglutide treatment, body weight and BMI decreased significantly: by 8.3±4.3kg and 3±1.6kg/m² at 3 months, and by 12±6.2kg and 4.2±2.2kg/m² at 6 months(all P < 0.001). At 3 months, BMI was reduced by 8.9±4.5% and body weight by 8.8±4%. At the same time-point, 65% of subjects had already lost more than 7% of their baseline body weight. Regarding BMI, 55% and 36.7% of patients experienced a reduction of more than 8% and 10% of their baseline BMI, respectively. The reduction in weight, BMI, and visceral fat did not differ significantly between genders or between overweight and obese patients. However, patients with moderate obesity appeared to benefit more in terms of weight loss(12±5.4 kg) and BMI reduction(4.3±1.9 kg/m²) compared to overweight patients (6.7±2.9kg, p=0.002) and those with mild obesity(6.9±2.7 kg, p=0.001). After 6 months, visceral fat decreased significantly by 2.3±3.8%(P=0.002). Among all patients, 19% experienced mild side effects, including constipation (9%), headache (4%), diarrhea(3%), and nausea(3%).

Conclusion

This is the first study that combined gastric BTX-A with liraglutide for weight management. Results revealed noteworthy reductions in weight, BMI, and visceral fat, without any severe side-effects. To confirm these findings and establish the efficacy of this approach, randomized clinical trials are required.

References

1.https://www.who.int/europe/publications/i/item/9789289057738#:~:text=Overweight%20and%20obesity%20affect%20almost%2060%25%20of%20adults,after%20high%20blood%20pressure%2C%20dietary%20risks%20and%20tobacco.
2. Stimac D, Klobucar Majanovic S, Belancic A. Endoscopic treatment of obesity: from past to future. Dig Dis. 2020:1–13
3. Garcia-Compean D, Maldonado GH. Intragastric injection of botulinum toxin for the treatment of obesity. Where are we? World J Gastroenterol. 2008;14:1805–9
4. Pero R, Coretti L, Lembo F. Botulinum toxin A for controlling obesity. Toxins. 2016;8:281.

Introduction

Chronic anal fissure is a frequent cause of referral to the proctology clinic and is associated with significant morbidity. In cases refractory to conservative measures, botulinum toxin (BT) is an alternative to a surgical approach, without the risk of permanent damage to the internal anal sphincter.

Aims & Methods

The aim of this study was to assess the efficacy of BT in anal fissure healing and to identify predictors of non-response. This was a retrospective, single-centre, observational study. Patients with chronic anal fissure who underwent TB between 2019 and 2023. Patients with a follow-up of less than 3 months or inflammatory bowel disease were excluded. On clinical reassessment, patients were categorised as complete, partial or refractory.

Results

Of the 118 patients selected, 80 were included. The average age was 49.1 ± 14.9 years, with 73.8% (n=59) of the patients female. The overall TB response rate was 62.0%. More than one TB session was carried out on 40.0% (n=32) of the patients, with an average of 1.5±0.6 per patient, with an interval between sessions of 3.4 ± 5.8 months. On reassessment after the first application, 30.0% (n=24) showed a complete response, 56.3% (n=45) a partial response and 13.8% (n=11) were refractory. Of the partial or refractory responders, after completing the treatment cycle, 56.5% (n=13) showed a complete response, 26.1 (n=6) a partial response and 17.4% (n=4) were refractory. During a median follow-up of 10.0 [3-48] months, 7 patients became asymptomatic and 2 patients had a recurrence of the cleft. 21 patients (26.3%) were referred for surgery. The duration of symptoms was an independent predictor of TB treatment failure and the need for surgery (OR 4.895; p=0.049).

Conclusion

TB has a satisfactory response rate in the treatment of patients with chronic anal fissure, making it possible to avoid surgery in patients, specially with a short duration of symptoms.

Introduction

Anti-TNF are the first biologic treatment option in inflammatory bowel diseases (IBD). Few data is available on the long term risk of relapse after anti-TNF withdrawal in paediatric-onset IBD, especially at the population level.

Aims & Methods

All paediatric-onset (<17 years) IBD diagnosed between 1988 and 2011 were included in a prospective population-based study and were retrospectively followed until 2013. Among patients treated with first-line anti-TNF, the cumulative probability of relapse after anti-TNF withdrawal was evaluated using a composite outcome (intestinal resection, and/or flare-related hospitalization, and/or IBD treatment initiation, and/or active disease). Factors associated with relapse were investigated with a Cox model.

Results

Among a total of 1,344 patients (Crohn’s disease (CD): n=1,007; Ulcerative colitis (UC): n=337), 562 were treated with anti-TNF. Anti-TNF was stopped in 73 patients (CD: n=66; UC: n=7) during remission defined by Harvey-Bradshaw score < 4 in CD and Mayo score ≤ 2 in UC. Among them, median time to anti-TNF initiation was 1.6 years (IQR, 0.7-4.0) and median duration of treatment was 1.0 year (0.3-1.7). The first line anti-TNF therapy was infliximab in 68 (93%) patients. At anti-TNF withdrawal, 47 (64%) patients received immunosuppressant. The cumulative probability of relapse after anti-TNF withdrawal at 1, 3 and 5 years was respectively 62%, 85% and 93%. Median delay of relapse was 9.5 months (7.5-12.0). The cumulative probability of flare-related hospitalization at 1, 3 and 5 years was respectively 7%, 7% and 8%. No patient required intestinal resection after a median follow-up of 8.7 (5.8-13.8) years. In multivariate analysis, median time to anti-TNF initiation >1 year was the only factor associated with the risk of relapse (HR 0.58, CI95% [0.35-0.97], p=0.036). Among relapsers, 46 (63%) were retreated with anti-TNF. Retreatment with anti-TNF was effective in 45 (98%) patients after a median delay of 3.9 months (3.5-10.0). Infusion reaction occurred in only 2 patients.

Conclusion

In a population-based cohort of paediatric-onset IBD, the risk of relapse after anti-TNF withdrawal was high, but was not associated with major complication. Retreatment with anti-TNF was effective and well tolerated.

Disclosure

Consultant fees from Sandoz and AbbVie

Introduction

Barrett’s esophagus (BE), the major precursor of esophageal adenocarcinoma (EAC), is a condition where the normal stratified squamous esophageal epithelium undergoes transdifferentiation into the specialized, intestinal-like epithelium. This reprogramming, also termed ‘paligenosis’, is predominantly caused by gastroesophageal reflux disease (GERD)¹. On the other hand, hydrogen sulfide (H₂S) next to carbon monixide (CO) is an important endogenous gaseous mediator. H₂S is biosynthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). Both, H₂S and CO have been shown to maintain gastrointestinal (GI) integrity^2,3,4. However, the contribution of gaseous mediators signaling to esophageal transdifferentiation process is overlooked.

Aims & Methods

Thus, in this study we aimed to explore the role of H₂S bioavailability in mTOR-dependent paligenosis induced by chronic epithelial injury. Furthermore, we evaluated the relationship between GERD, the barrier function of cultured cells, and the pattern of selected components involved in the formation of the tight junctions (TJs) and responsible for epithelial barrier integrity.
We implemented an animal model of GERD, based on Male Wistar rats with esophagogastroduodenal anastomosis (EGDA) treated i.g. for 8 weeks with vehicle or with H₂S- releasing chemicals: GYY4137 (5.0 mg/kg)/NaHS (1.0 mg/kg) or CTH/CBS inhibitors: PAG (15 mg/kg)/AOAA (11 mg/kg). In parallel, we employed optimized in-vitro GERD model based on human-derived esophageal epithelial (EPC2) cells +/- CRISPR-Cas9-induced knockout of H₂S-producing enzymes that were treated with acidified bile mixture (BM) or with GYY4137/NaHS (100 µM). We evaluated activation of AKT/mTOR pathway by multiplex microbeads fluorescent assay and an expression of TJ-associated protein (ZO-1) and occludin by capillary immunoblotting. The barrier function of cultured cells was evaluated by measurement of transepithelial electrical resistance (TER).

Results

We observed that either chronic reflux in EGDA-rats and/or treatment of human esophageal cells with BM led to a slight or a significant activation of AKT/mTOR signaling pathway and its down-stream effector - p70S6K. Additionally, we observed that pharmacologically-derived H₂S reversed this effect, while inhibition of endogenous H₂S biosynthesis (pharmacological or induced by knockout of H₂S-producing enzymes) had either no effect or increased GERD-induced phosphorylation of AKT/mTOR pathway components. Moreover, we showed that ZO-1 is highly expressed in BM treated EPC2 cells and this was reflected by the increase in TER measurment. Level of occludin remained unchanged. We did not observe any changes in expression of ZO-1 and occludin after GYY4137 treatment; however, TER measurment decreased in comparison to BM treated cells. Selective knockout of H₂S-producing enzymes led to a decrease in ZO-1 protein content in comparison to wild-type cells.

Conclusion

We conclude that interventional enhancing or decreasing of H₂S bioavailability in esophageal epithelium respectively delay or accelerate the GERD-induced paligenosis process via regulation of the mTOR pathway. H₂S-prodrugs may provide a protective effect on the esophageal epithelium by substituting the phisiological defensive response of the tissue against GERD, which is reflected by an increase in the expression of ZO-1 and tightening of the cellular barrier.

References

1. Souza RF, Spechler SJ. Mechanisms and pathophysiology of Barrett oesophagus. Nat Rev Gastroenterol Hepatol 2022.
2. Fiorucci S, Distrutti E, Cirino G, Wallace JL. The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology 2006.
3. Magierowska K, Korbut E, Wójcik-Grzybek D, Bakalarz D, Sliwowski Z, Cieszkowski J, Szetela M, Torregrossa R, Whiteman M, Magierowski M. Mitochondria-targeted hydrogen sulfide donors versus acute oxidative gastric mucosal injury. J Control Release 2022.
4. Magierowska K, Brzozowski T , Magierowski M. Emerging role of carbon monoxide in regulation of cellular pathways and in the maintenance of gastric mucosal integrity. Pharmacol Res 2018.

[Funding: National Science Centre, Poland (UMO-2016/23/D/NZ4/01913, UMO-2019/33/B/NZ4/00616) and Statutory Grant (N41/DBS/000874), Jagiellonian University Medical College].

Introduction

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder with recurrent symptoms but without any known radiological feature or biomarker test to diagnose it. Intestinal ultrasound (IUS) has been used to measure the bowel wall thickness (BWT) of the colon with a cut-off value >3mm indicating active inflammation (1). IUS has increased sensitivity and specificity for detection of disease activity when combining BWT with fecal calprotectin measurements (2).

Aims & Methods

The aim was to measure BWT of the colon in patients with diarrhea-predominant irritable bowel syndrome (IBS-D) using ultrasound and to correlate it with fecal calprotectin measurement during IBS exacerbation. The study included 50 IBS-D patients (25 females and 25 males) according to Rome IV criteria. The patients were examined with a 10 MHz linear array ultrasound transducer to measure the BWT in the ascending and descending colon and to assess bowel wall vascularity using color Doppler ultrasound where Limberg score 2 or above is considered abnormal (3). Blood test and stool analysis with culture were performed. Fecal calprotectin was measured during the same day of the ultrasonographic examination. Colonoscopy with colon biopsy samples was performed within 48 hours to rule out any pathology.

Results

The IBS severity scoring system (mean±SEM) was 285±15. The value for fecal calprotectin was 260±46. Blood test and stool analysis with culture were normal. Colonoscopy was normal macroscopically but showed edematous lamina propria microscopically. Intestinal ultrasound showed that the BWT of the descending and ascending colon in millimeters (mean±SEM) were 3.0±0.11 and 1.2±0.08, respectively, with a significant difference (P<0.0001) between them. Significant correlation was found between fecal calprotectin and BWT of descending colon (r 0.45, P 0.0012) but not between BWT of ascending colon (r 0.18, P 0.3). Further measurements of the layers of the descending colon showed a significant correlation (r 0.50, P 0.0005) between fecal calprotectin and thickness of the submucosal layer (1.4±0.09) but not the other layers (mucosa and proper muscle). Color Doppler ultrasound showed no mural flow of the thickened bowel wall, assessed as grade 1 of the Limberg score.

Conclusion

Patients with IBS-D during symptom exacerbation with elevated fecal calprotectin exhibit thickened BWT in the descending colon without increased vascularity. Fecal calprotectin correlated with wall thickening of the descending colon especially of the submucosal layer.

References

(1) Fraquelli M, Colli A, Casazza G, et al. Role of US in detection of Crohn disease: meta-analysis. Radiology. 2005;236:95–101.
(2) Zaid S Ardalan, Antony B Friedman, Danny Con, et al. Accuracy of Gastrointestinal Ultrasound and Calprotectin in the Assessment of Inflammation and its Location in Patients with an Ileoanal Pouch, Journal of Crohn's and Colitis. 2022;16(1):79–90.
(3) Limberg B, Osswald B. Diagnosis and differential diagnosis of ulcerative colitis and Crohn's disease by hydrocolonic sonography. The American journal of gastroenterology. 1994;89(7):1051–7.

Introduction

Individuals with disorders of brain gut interaction (DBGI) such as irritable bowel syndrome (IBS) and functional dyspepsia (FD) have symptoms that generally originate either first in the GI tract (e.g. fullness, pain: gut to brain) or brain (e.g. anxiety: brain- to –gut). It is unclear however what risk factors may moderate the order of incidence of either a DBGI or psychological diagnosis.

Aims & Methods

This study aimed to determine the proportion of individuals in general practice with a diagnosis of a DBGI (IBS and/or FD, IBS only, FD only, overlap IBS/FD) prior to a mood or anxiety disorder (gut to brain), and vice versa (brain to gut) and whether specific factors moderate the order of incidence of the diagnosis. Data was collected from a retrospective study of 152,674 patients diagnosed with a DBGI (excluding inflammatory bowel disease, coeliac disease, peptic ulcer disease, colorectal and gastric cancer) and psychological disorder (mood or anxiety disorder) at general practices in the United Kingdom over an average period of 16 years (SD=7 years). Information on which diagnosis appeared first was recorded (January 1994 to end 2022, inclusive). Multiple logistic regression was performed to compare a diagnosis of a DBGI (IBS and/or FD) first versus psychological diagnosis first on a range of sociodemographic factors (age, gender), medical conditions (allergy, eczema, Helicobacter pylori, Type 1 and Type 2 diabetes, autoimmune disease, rheumatoid arthritis, lupus, scleroderma, alcohol related diseases and prior gastrointestinal infection) and medication usage (antibiotics, proton pump inhibitors (PPI) and non-steroidal anti-inflammatory drugs (NSAIDs)) ever and prior to a diagnosis of either a DBGI or psychological disorder. Only individual moderators that reached the criterion of p<0.01 are included in the multivariate model.

Results

Of the 152,674 eligible individuals in the UK GP data set, just over half (56.2% n=85843) were diagnosed with a mood or anxiety disorder first compared with (42.9%, n=64739, 55.43%) a DBGI first. In a multivariate model being female, prior GI infection and prior PPI, antibiotic and NSAID use significantly increased the odds of being diagnosed with a DBGI first, whereas alcohol related diseases, asthma and ever having PPI and NSAID use significantly reduced the odds of having a DBGI diagnosis first (Table 1). Of clinical relevance people diagnosed with a DBGI first were twice as likely to have had prior PPI use compared with those with a psychological diagnosis first (OR=2.0, 95%CI 1.94, 2.06; P=0.000). These results were similar for IBS only, FD only and overlap DBGI.

Table 1. Multivariate model of predictors of a DBGI prior to a mood or anxiety disorder

Conclusion

In a large sample of primary care patients, prior PPI use was associated with an increased probability of a gut to brain pathway. While PPI use may indicate the presence of a upper gut DGBI, the data may equally point towards the possibility that PPI use may cause changes in the gut microbiome including reduced bacterial richness.