Introduction

With the recent rise in the occurrence of esophageal adenocarcinoma (EAC) in Western nations, there is an escalating worry regarding Barrett’s esophagus (BE). In contrast, Asian countries exhibit a lower prevalence of BE compared to their Western counterparts. Given the annual increase in chronic gastroesophageal reflux disease (GERD) cases, there is an expectation of a concurrent rise in the prevalence of BE. Consequently, we are embarking on a multicenter prospective study to assess the current prevalence of BE and pinpoint its risk factors in Taiwan.

Aims & Methods

Aim: to evaluate current prevalence and risk factors of Barrett's esophagus in Taiwan.
Methods: We carried out a prospective multicenter study involving consecutive outpatients who underwent upper gastrointestinal endoscopy for various upper gastrointestinal symptoms. Biopsies were taken from endoscopically suspected esophageal metaplasia (ESEM), clearly visible at least 1 cm above the gastroesophageal junction during endoscopy. The biopsy procedure involved obtaining standardized random samples, with four pieces taken every 2 cm from the four quarters of the esophagus exhibiting the ESEM lesion. BE was defined based on the histological confirmation of specialized intestinal metaplasia in the metaplastic esophageal epithelium.

Results

A total of 8925 subjects were enrolled in this study. The prevalence of BE was 2.6%. A total of 228 subjects with BE were detected among 751 ESEM subjects. Short segment BE (78.1 % , n = 178) was more prevalent than long segment BE (22.9 % , n = 50). The prevalence of GERD symptoms, erosive esophagitis (EE), and hiatal hernia (HH) was 52.5%, 27.3% and 7.85%, respectively. Multivariate analysis disclosed that old age [odds ratio (OR) = 1.59; 95% CI, 1.20-2.11; P <0.01], male gender (OR = 2.27; 95%CI, 1.65-3.11; P < 0.01),alcohol consumption (OR = 1.70, 95%CI, 1.19-2.44; P< 0.01), GERD symptoms (OR = 1.45, 95%CI, 1.10-1.92; P< 0.01), EE (OR = 1.94, 95%CI, 1.47-2.56; P< 0.01) and presence of hiatal hernia (OR = 2.49; 95%CI, 1.78-3.47; P < 0.001) were significant risk factors predicting BE.
Risk factors for Barrett esophagus: multivariable analysis.

Conclusion

The prevalence of BE was identified as 2.6%. Notably, advanced age (>50), male gender, alcohol consumption, symptoms of gastroesophageal reflux disease (GERD), erosive esophagitis, and the presence of hiatal hernia emerged as independently significant risk factors for Barrett's esophagus.

References

1. Sharma P. Barrett Esophagus: A Review. Jama. 2022;328(7):663-71.
2. Marques de Sá I, et al. The global prevalence of Barrett's esophagus: A systematic review of the published literature. United European Gastroenterol J. 2020;8(9):1086-105.
3. Chang CY, et al. Current status of Barrett's esophagus research in Asia. J Gastroenterol Hepatol. 2011;26(2):240-6.
4. Shiota S, et al. Prevalence of Barrett's Esophagus in Asian Countries: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2015;13(11):1907-18.
5. Chang CY, et al. The application of Prague C and M criteria in the diagnosis of Barrett's esophagus in an ethnic Chinese population. Am J Gastroenterol. 2009;104(1):13-20.
6. Fock KM, et al. Asia-Pacific consensus on the management of gastro-oesophageal reflux disease: an update focusing on refractory reflux disease and Barrett's oesophagus. Gut. 2016;65(9):1402-15.
7. Eusebi LH, et al. Global prevalence of Barrett's oesophagus and oesophageal cancer in individuals with gastro-oesophageal reflux: a systematic review and meta-analysis. Gut. 2021;70(3):456-63.
8. Akiyama T, et al. Alcohol consumption is associated with an increased risk of erosive esophagitis and Barrett's epithelium in Japanese men. BMC Gastroenterol. 2008;8:58.
9. Andrici J,et al. Hiatal hernia and the risk of Barrett's esophagus. J Gastroenterol Hepatol. 2013;28(3):415-31.

Introduction

Persulfidation of proteins (PSSH) appears functionally significant, e.g. in aging, preventing cellular oxidation, but its role in GI diseases remains clinically elusive. This posttranslational proteins modification relies on endogenous hydrogen sulfide (H₂S) signaling. GERD induces oxidation in esophageal squamous cells. However, the contribution of persulfidation and H₂S bioavailability in etiology, diagnosis or treatment of Barrett’s esophagus (BE) is unknown. We hypothesized that GERD-induced pathway-specific PSSH impairments underlie BE pathogenesis. We explored whether restoration/depletion of esophageal H₂S impacts persulfidation-sensitive, BE-associated targets and BE development.

Aims & Methods

We clinically performed a wide-scale analysis of persulfidated proteins (normalized to total proteins levels) in three-sets of endoscopic biopsies representing BE or squamous segments +/- GERD (n=4-5 each), using the recent chemoproteomic method. We used the microsurgical rat model of GERD/BE (esophago-gastroduodenal anastomosis) +/- i.g. pharmacological treatments to up-/downregulate esophageal H₂S levels over 10 weeks. In parallel, we employed in vitro model of chronic GERD +/- H₂S donors using human esophageal squamous cell lines with (NES-G2T) or without (EPC2) clinical GERD and a Barrett’s cells (BAR-T). CRISPR-Cas9 was used to knockout H2S-producing enzymes.

Results

Global persulfidation level (reflecting H₂S bioavailability) was decreased in clinical BE vs GERD-exposed squamous biopsies. GERD induced statistically significant pathway-specific PSSH changes of ≈90 proteins in squamous segments compared to patients w/o GERD. These persulfidomic alterations further increased in BE where >900 targets were deregulated. IL-1b, prostaglandin (PG)E2 pathways or mTOR-associated proteins, but not exclusively, showed persulfidation shift (e.g. PSSH fall of IL-1b-receptor antagonist (IL-1RA)). H2S-decrease was noted in vitro or in vivo after long-term GERD in rats with chronic esophageal lesions and in human squamous, but not BAR-T cells. In cells and/or rats, treatment with NaSH or GYY4137 to restore H2S induced IL-1RA and inhibited IL-1b/PGE2/mTOR signaling, RNA oxidation, limiting molecular or morphological BE development. H₂S-enzymes inactivation promoted BE-related events in both models.

Conclusion

BE is preceded by GERD-induced, pathway-specific persulfidation shifts, initiated early in squamous epithelium and enhanced in metaplasia. Decreased but stable biosynthesis of H2S reflects the adaptative resistance of the metaplastic cells to GERD. Restored H2S signaling counteracts BE development by interfering in oxidative balance and BE-associated IL-1β, PGE2 and mTOR pathways activation. These findings suggest that BE is a mechanistic outcome of reduced esophageal H₂S caused by GERD. [Funding: National Science Centre (Poland): 2016/23/D/NZ4/01913, 2019/33/B/NZ4/00616, 2023/07/X/NZ4/01052]

Introduction

Lifestyle factors are significant contributors to fatigue, which affects approximately 45% of patients with Inflammatory Bowel Disease (IBD) in remission.

Aims & Methods

In this study, we evaluated the effect of a digital multimodal lifestyle intervention on fatigue in patients with IBD. Patients with IBD in biochemical remission (fecal calprotectin <150 mg/kg) were enrolled in a multicenter, non-randomized, controlled interventional study. The intervention group participated in a 12-month lifestyle program—provided by the non-profit organization Voeding Leeft—that included digital group meetings with a nutritionist and a lifestyle coach focusing on gradual and sustainable behavior change regarding nutrition, physical activity, sleep, and stress management. In addition, the program encouraged patients to exercise more self-control over their personal health. Following the initial six months, attendance at online sessions was not mandatory; however, patients could attend online sessions every six to 12 weeks to stay motivated and foster the lifestyle habits they acquired throughout the course. Patients in the control group received standard care that included an informational leaflet about the potential causes of fatigue in IBD, the leaflet also included basic lifestyle information and advice to exercise more, eat a healthier diet, stop smoking, reduce alcohol intake, improve sleeping habits, and manage stress. The allocation to a study group was determined by the availability within the group and participant’s ability to attend the scheduled intervention. Clinical data and patient-reported outcomes were collected. Fatigue was measured with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); any increase in FACIT-F after six months was considered a positive response to the intervention. The Minimal Clinically Important Difference (MCID) for fatigue was at least a four-point increase in the FACIT-F score¹. Inverse probability treatment weighting was used to correct confounding by indication.

Results

Thirty-six patients in the intervention group and 32 in the control group were compared. After six months, more patients in the intervention group (82.1% of patients) than in the control group (54.2% of patients) experienced improvement in fatigue, P = 0.029. Likewise, significantly more patients in the intervention group (71.4% of patients) than the control group (33.3% of patients) achieved a MCID regarding fatigue; P = 0.006. The improvements in fatigue were sustained throughout the study period in the intervention group. Acceptance of the health status was a significant factor for improvement in fatigue (β 7.813, SE 1.908, P < 0.001). Compared to the control group, quality of life improved in the intervention group; these patients gained 0.05 more quality-adjusted life years throughout the study. Last but not least, significant improvements in dietary quality were observed as early as three months after the baseline in the intervention but not the control group; these improvements in the intervention group were sustained throughout the study period.

Conclusion

Multimodal lifestyle intervention improves fatigue, quality of life, and dietary quality in patients with IBD who are in remission. Acceptance of the health status appears essential for fatigue improvement; instruments evaluating acceptance could help to personalize treatment and maximize its effectiveness.

References

1. Cella D, Yount S, Sorensen M, et al. Validation of the Functional Assessment of Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol 2005;32:811-9.

Disclosure

AEvdMdJ received unrestricted research grants from Galapagos, Norgine, Vedanta, Nestle, including speaker’s fees from Galapagos, Tramedico, Takeda, Ferring, and Janssen Pharmaceuticals. PWV has received speaker fee from Galapagos and Takeda and served on the advisory board of Lilly, Galapagos, Janssen, BMS, Takeda, and Abbvie. RL has received travel expenses from Galapagos and Cablon Medical and served on the advisory board at Cablon Medical. NW and MJHB are employed by the non-profit organization Voeding Leeft and were a part of the team that guided participants in the intervention group. All other authors have no conflicts of interest to declare.

Introduction

Colorectal cancer, with an estimated two million new cases each year worldwide, poses a significant socioeconomic burden on modern society. It is the second leading cause of cancer-related deaths, accounting for nearly one million premature deaths annually.

Aims & Methods

The role of Signal Transducer and Activator of Transcription 2 (STAT2) in this context is not yet understood, and no therapies targeting this transcription factor are currently being pursued. We explored the function of STAT2 in colorectal cancer by employing experimental mouse models, as well as conducting functional assays with three-dimensional tumoroids in the context of anticancer therapy.

Results

In vivo studies showed that Stat2KO mice were more resistant to developing tumors in both inflammation-driven and inflammation-independent models of experimental colorectal cancer. This unexpected outcome could not be reconciled with the known role of STAT2 in inducing cell death downstream of type I interferon signaling. We consequently performed ex vivo experiments with tumoroids derived from Stat2KO mice carrying the multiple intestinal neoplasia (Min) mutant allele of the adenomatous polyposis coli (Apc) gene. These tumoroids exhibited slower growth, were generally smaller in size, and showed a higher degree of differentiation compared to those derived from ApcMin/+ wildtype mice. Remarkably, when treated with anti-tumor agents that induce cell death through various mechanisms, tumoroids derived from ApcMin/+ Stat2KO mice were found to be highly sensitive. Additional functional studies indicated that the underlying mechanism might involve a STAT2-dependent disruption of innate immune DNA sensing.

Conclusion

Our results establish STAT2 as a promoter of colorectal cancer and a contributor to resistance against anti-tumor therapy. These findings suggest that targeting STAT2-dependent signaling could be a promising therapeutic strategy for patients with colorectal cancer.

Introduction

Irritable bowel syndrome (IBS) is a highly prevalent and challenging condition with limited therapeutic options. Chitin-glucan (CG) is a novel dietary prebiotic considered as a safe food ingredient by EFSA. To provide an alternative approach to the management of IBS patients, we evaluated in preclinical studies the roles of CG on visceral analgesia, intestinal inflammation and barrier function and performed an open-label trial in IBS patients.

Aims & Methods

Analgesic effect of CG used at a human equivalent dose (HED) of 1.5-3 g/d was evaluated in rats and compared to negative-tap water and positive-phloroglucinol control groups. Mice with DSS-induced colitis were used to analyze the anti-inflammatory properties of CG. Molecular mechanisms underlying analgesic, anti-inflammatory, and intestinal barrier-strengthening functions of CG were evaluated in human intestinal HT-29 epithelial cells. CG molecular modeling was developed to study its interactions with microbial cell walls.
A multicenter open-label trial was conducted in 120 patients with IBS (Rome IV criteria) treated with CG 1.5 g/d and simethicone 0.75 mg/d for 4 weeks. The primary endpoint was the responder rate, defined as the number of patients whose abdominal pain score decreased by ≥30% from baseline at week (W) 4. The analysis was performed using the per-protocol set. Cardinal symptoms, impact of global symptoms on daily life, change in stool consistency, and improvement in defecatory disorders were evaluated.

Results

CG in animals was well tolerated. CG at 3g/d HED significantly decreased visceral perception by 14% after 2 weeks (p<0.01) and reduced inflammation by 50% promoting mucosal regeneration in DSS-induced colitis mice. CG at 1.5g/d HED reduced visceral pain perception by 20% after 5 weeks of treatment (p<0.01). At 3g/d HED, this analgesic effect was superior to phloroglucinol with a faster onset of action and a 50% inhibition of pain perception (p<0.0001). The molecular mechanisms contributing to these analgesic and anti-inflammatory effects of CG involved a significant induction of µ-opioid receptor (MOR), cannabinoid-2 (CB2) receptor, IL-10 and a significant decrease of pro-inflammatory cytokines IL-1b and IL-8 mRNA. CG also significantly up-regulated barrier-related genes like muc5AC, claudin-2 and ZO-2. CG molecular modelling revealed a new property of the molecule as a chelator of gram–negative lipopolysaccharide (LPS), gram–positive lipoteichoic acid (LTA) and phospholipomannan (PLM) in fungi.
Overall, 100 IBS patients were evaluated. At week 4, 67% were abdominal pain responders (score: 5.8 ± 2.4 vs. 2.9 ± 2.0, p<0.0001). Similar improvements were observed for bloating (8.0 ± 1.7 vs. 4.7 ± 2.9, p<0.0001; 60% responders), abdominal distension (7.2 ± 2.1 vs. 4.4 ± 3.1, p<0.0001; 53% responders), and impact of global symptoms on daily life (7.1 ± 2.0 vs. 4.6 ± 2.9, p<0.0001; 54% responders). Stool consistency improved in most patients (90% and 57% for patients with liquid and hard stools, respectively). Overall, 42% of patients with defecatory disorders reported very much/considerable improvements by 2 weeks. No severe adverse event occurred, and tolerability was rated “good” or “very good” by 93%.

Conclusion

CG decreased visceral perception and intestinal inflammation. It also impacted master genes regulation and direct binding of microbial products. CG-simethicone was well tolerated and improved IBS symptoms in an uncontrolled trial. A placebo-controlled trial with longer follow-up is now ongoing to confirm the benefits of CG in IBS patients.

Disclosure

Prof Pierre Desreumaux is President of the Scientific Board of BiOkuris SA
Prof Edouard Louis is member of the Scientific Board of BiOkuris SA

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms, such as gastrointestinal symptoms. Emerging evidence suggests that gut permeability and inflammation play a role in PD pathophysiology via the gut-brain axis. According to Braak’s theory, the pathological degeneration associated with PD may originate from the gut and subsequently develop in the brain through the vagus nerve.

Aims & Methods

The aims were to assess the relationship between gut permeability and neuroinflammation in a cohort of patients with PD and REM behavior disorder (RBD), a condition that often precedes the onset of PD. The study prospectively included 28 PD patients and 18 RBD patients both complaining of GI symptoms. No serious organic diseases or therapies potentially affecting GI motility were reported. Relevant demographic and clinical data were collected for all patients. There was the inclusion of 14 healthy controls (HCs). A serum ELISA assay of tumor necrosis factor (TNF), caspase-1, and lipopolysaccharide-binding protein (LBP) was performed in all participants to investigate systemic inflammatory status and gut permeability, respectively. In a total of 10 PD patients, 4 RBD patients and 9 HCs, multiple colic biopsies were obtained to assay tissue expression of inflammation markers by both western blot (WB) (i.e. caspase-1 and procaspase-1) and immunofluorescence (IF) (i.e. ASC and CD68). Data were expressed as mean ± SD, and ANOVA and Dunnett's tests were used to compare the three groups.

Results

All three groups were comparable in age and sex. Serum assays showed significantly increased LBP, in patients with PD (35.0 ± 0.25; p = 0.002) and RBD (32.2 ± 1.1; p = 0.009) compared with HCs. TNF (0.1 ± 0.02; p = 0.03) and caspase-1 (16.9 ± 9.4; p = 0.04) were significantly raised only in the PD group in comparison with HCs (Table 1). WB analysis showed significant differences in the expression of procaspase-1 (157.3 ± 17.8; p = 0.02) and caspase-1 (168.3 ± 23.3; p = 0.03) only in PD patients compared with HCs. IF showed a qualitative increase in both CD68+ macrophage infiltration and ASC expression in PD and RBD groups compared with HCs.

	PD	RBD	HCs	P-value
LBP (ng/ml)	35.0 ± 0.25	32.2 ± 1.1	23.1 ± 2.1	0.009 (RBD vs HCs) 0.002 (PD vs HCs)
Caspasi-1 (ng/ml)	16.9 ± 9.4	11.4 ± 2.1	9.9 ± 2.7	0.04 (PD vs HCs)
TNF (pg/ml)	0.1 ± 0.02	0.05 ± 0.02	0.04 ± 0.02	0.03 (PD vs HCs)

Conclusion

Our results show a bowel activation of NLRP3 inflammasome in PD, as demonstrated both by the levels of procaspase-1 and caspase-1 on WB analysis and by the increase of CD68+ macrophages and ASC in the lamina propria of colonic mucosa. Only a qualitative increase in NLRP3 activation at IF could be observed in RBD patients. However, findings from colonic biopsies, if related to elevated serum levels of TNF and caspase-1 in PD patients, and LBP in PD and RBD patients, suggest that bowel inflammation, sustained by increased gut permeability, may represent an early stage in the develop of RBD and PD.

Introduction

The detection of cancer within large non-pedunculated colorectal polyps (LNPCPs) is suboptimal in non-expert settings. Identification of 6 macroscopic (Blink) features (6BF) of deep submucosal invasive cancer (SMI) has shown significant improvement in the sensitivity of cancer detection by inexperienced endoscopists at the expense of decreased specificity. This study investigates the impact of endoscopic resection scars, which can resemble deep SMI, on the accuracy of non-expert endoscopists using the 6BF evaluation system known as Blink Impression.

Aims & Methods

An online survey was disseminated containing 20 overview images of LNPCPs (1 image/polyp). Images (randomized) were shown before, and after a 2-minute educational video (the intervention) introducing the 6BF - fold deformation, extra redness, depression, chicken skin mucosa, ulceration and spontaneous bleeding. Before and after the intervention participant Blink Impression was elicited (cancer/no cancer) and only after, the presence of the 6BF. Responses were analysed relative to histopathology (no vs superficial vs deep SMI) and expert opinion on the presence of the 6BF and endoscopic resection scars.

Results

7/20 LNPCPs contained cancer (3 superficial, 4 deep SMI), 3 contained scars. 191 participants from 21 countries completed 3,755 observations. 129/191 (67.5%) participants were inexperienced. Expert-identified scarred LNPCPs contained median 1.0 (IQR 2.0) BF vs 1.0 (IQR 2.0) for no cancer, 2.0 (IQR 2.0) for superficial SMI and 3.0 (IQR 2.0) for deep SMI (all P<.001). Presence of ≥2 BF therefore reliably identifies cancer within LNPCPs but not scars. Fold deformation was the only BF identified more commonly amongst scarred LNPCPs (44.6%) vs no cancer (22.5%, P<.001) and vs superficial SMI (33.0%, P<.001), but similar to deep SMI (44.6%, P=1.000). Depression, chicken skin mucosa and spontaneous bleeding were less commonly identified in scarred polyps (12.3%, 7.6% and 1.8%) than both no cancer (33.1%, 14.4% and 8.6%, all P<.001), superficially invasive (68.6%, 14.3% and 5.8%, all P<.001) or deeply invasive polyps (45.9%, 19.6% and 40.5%, all P<.001). Extra redness and ulceration were identified with similar frequency to no cancer in scars (26.4% vs 26.8%, P=0.891 and 10.2% vs 9%, P=0.441 respectively), but less commonly than superficial (64.2%, P<.001 and 15.7%, P<.001) or deep SMI (60.2%, P<.001 and 24.7%, P<.001) (Table 1).

Conclusion

The presence of ≥2BF reliably discriminates LNPCPs with cancer from non-cancer even in the presence of scarred lesions amongst non-expert endoscopists. Scarred LNPCPs exhibit fold deformation at a similar rate to LNPCPs with deep SMI but other BF are not present.

References

Debels LK, Smeets S, Poortmans PJ, Argenziano ME, Desomer L, Anderson J, Valori R, David J Tate. Identification of 6 key features of colorectal polyps increases the sensitivity of cancer detection and ability to discriminate deep submucosal invasion The basis of the Blink (first) impression? United European Gastroenterology Journal 2023; Vol.11