Introduction

Multiple recent studies suggest that COVID-19 (COVID) infection may increase risk of developing Disorders of Gut-Brain Interaction (DGBI). However, the extent of this effect on a population level, and how directly it is related to COVID illness, remains poorly understood.

Aims & Methods

We aimed to test in a multi-national sample the a priori hypotheses that IBS and FD prevalence rates (1) have increased after the COVID-19 pandemic, and are higher in individuals (2) who were more ill with their COVID infection, (3) who have long COVID, and (4) who were not vaccinated for COVID. A population-based Internet survey with pre-defined demographic quotas to obtain equivalent sex and age distribution across countries was conducted nationwide in 9 countries (Canada, China, Germany, Japan, Mexico, Poland, Romania, Spain, United States) in late 2023, and included demographic questions, Rome IV IBS and FD diagnostic questions, and questions about history of COVID infection and illness. Group prevalence was compared with Chi-Square tests to test the 4 hypotheses. For hypothesis 1, the total sample was compared to a pre-pandemic Rome Foundation Global Epidemiology Study (RFGES; Sperber et al. Gastroenterology 2021;160(1):99-114) sample from the same 9 countries, surveyed with comparable methodology in 2017-2018, using weighting to equalize country sample sizes.

Results

The survey was completed by 17,663 participants (50.2% females; mean age 46.3 years, range 18-96). People in the current sample had higher prevalence of both Rome IV IBS [% and 95% CI: 7.9% (7.5, 8.3) vs. 3.8% (3.5, 4.1); p<0.0001] and FD [12.7% (12.2, 13.2) vs. 7.0% (6.6, 7.4); p<0.0001] compared to the pre-COVID RFGES sample (N=19,669, 50.2% females, mean age 45.4 years, range 18-95) for the same countries. The post- vs. pre-pandemic prevalence of FD and IBS was numerically higher in all countries, and in all age and sex subgroups. In the current survey, people who reported having had test-confirmed COVID (41.3%) had higher IBS [9.4% (8.8, 10.1) vs. 6.8% (6.3, 7.2); p<0.0001] and FD [14.6% (13.8, 15.4) vs. 11.3% (10.7, 11.9); p<0.0001] prevalence than those without a COVID test-positive history. Those who were moderately or very ill during COVID infection had higher prevalence of IBS [12.0% (10.9, 13.0) vs. 6.8% (6.0, 7.7); p<0.0001] and FD [17.6% (16.4, 18.9) vs. 11.4% (10.4, 12.4); p<0.0001] compared to those with mild or no symptoms, and even higher if they had new-onset GI symptoms during their COVID illness (15.1% IBS, 21.3% FD). People with current lingering symptoms from past COVID infection (“long COVID”) had higher IBS [16.3% (14.4, 18.3) vs. 7.8% (7.1, 8.5); p<0.0001] and FD [22.9% (20.7, 25.1) vs. 12.6% (11.8, 13.5); p<0.0001] prevalence than fully recovered individuals. People who had not been vaccinated for COVID (19.4% of the sample) had higher prevalence of FD [14.3% (13.1, 15.4) vs. 12.3% (11.7, 12.8); p<0.0001] but not IBS [8.4% (7.4, 9.4) vs. 7.7% (7.3, 8.2); p=0.18] compared to the vaccinated.

Conclusion

Our findings indicate that both IBS and FD prevalence rates are significantly higher now among adults worldwide than before the COVID-19 pandemic. Greater illness severity during COVID infection and current long COVID status show striking associations with elevated prevalence of these DGBI. Although retrospective infection/illness self-report cannot prove causation, this pattern of findings strongly implicates COVID-related illness as a potent driver of subsequent vulnerability to having IBS and FD, leading to an increased population prevalence of these disorders.

Introduction

Aims & Methods

To systematically review genetic association studies (GAS) on GERD conducted from 2012–2024 and perform a meta-analysis to assess the relationship between specific genetic polymorphisms and GERD susceptibility.
A comprehensive literature search was conducted using PubMed, Cochrane, ScienceDirect, Scopus, DisGENET, GWASCatalog, and HuGE Phenopedia databases. Inclusion criteria focused on case-control studies reporting complete genotypic and allele frequency data. Meta-analytical methods were applied to pooled data for SNPs meeting analysis thresholds, calculating odds ratios (ORs) with 95% confidence intervals (CIs) under multiple genetic models (dominant, recessive, additive, codominant). Heterogeneity and publication bias were assessed using statistical tests and funnel plots.

Results

From an initial 9788 titles, 16 GAS involving 132 variants across 105 genes met the inclusion criteria. Meta- analysis was performed on four polymorphisms with sufficient data. Among these, the GNB3 rs5443 C>T polymorphism demonstrated a significant association with GERD (OR = 2.24; 95% CI: 1.56–3.21; p < 0.001), indicating a dominant genetic model with a two-fold increased risk of GERD. Polymorphisms in TNF, IL1B, and CYP2C19 genes showed no statistically significant associations. Notably, the GNB3 gene's role implicates its involvement in brain-gut signaling and inflammatory pathways, contributing to GERD pathophysiology. Heterogeneity was low across most analyses, and publication bias could not be definitively assessed due to the limited number of studies.

Conclusion

Disclosure

No Conflict of Interest

Introduction

Irritable bowel syndrome (IBS) is a multifactorial disorder characterized by recurrent abdominal pain associated with defecation or a change in bowel habits. The pathophysiology of IBS involves alterations in the epithelial barrier, but data on the intestinal vascular barrier are lacking.

Aims & Methods

The aims of this study were to investigate the morpho-functional integrity of the vascular barrier and to correlate barrier dysfunction with IBS symptoms. Forty-eight healthy subjects (AC) and 144 patients with IBS (61 IBS-D, 51 IBS-C and 32 IBS-M) were enrolled in the study. Rome IV criteria, Bowel disease questionnaire, Short Form 12, Hospital Anxiety Depression Scale were used to phenotype patients. Immunohistochemistry, western blot and electron microscopy were used to characterize the vascular barrier. Vascular permeability was evaluated by assessing two markers: plasmalemma vesicle–associated protein-1 (PV1) and vascular endothelial cadherin (VEC). A translational model based on HUVEC was used to evaluate permeability changes induced by mediators spontaneously released by mucosal biopsies, and to highlight the underlying molecular mechanisms. Correlation analyses between experimental and clinical data were performed.

Results

Mucosal vessel density was significantly increased by 1.5 fold in the colonic mucosa of IBS patients compared to AC (P<0.01). PV1 expression was increased (P<0.01) while VEC expression was decreased in the colonic mucosa of IBS patients compared to AC (P<0.05). Compared to AC, IBS mucosal mediators increased permeability in the HUVEC monolayer through the activation of protease-activated receptor (PAR)-2 and histone deacetylase (HDAC)11, resulting in VEC downregulation. PV1 expression significantly correlated with anxiety and depression scores and health-related quality of life reported by IBS patients.

Conclusion

The vascular barrier is impaired in IBS and contributes to clinical manifestations

Introduction

Serological diagnosis of coeliac disease (CeD) is accepted for pediatric patients in Europe [1]. Both the 2019 European guidelines and the 2023 American guidelines from the American College of Gastroenterology required a diagnostic biopsy in adults [2, 3]. In recent years we have seen several studies addressing the no-biopsy approach in adults [4-6]. Wide-spread implementation of no-biopsy approach demands precise instructions on how the diagnosis can be made and by whom.

Aims & Methods

We aimed at investigation the acceptance among clinicians for a no-biopsy approach, and how they follow current guidelines. A digital survey was sent in November 2023 to members of the Norwegian Society for Gastroenterology. It was sent out once, no reminder, and was open for one month. Replies were collected anonymously. The Society has 452 members including 256 gastroenterologists. Almost all specialists are members of this Society.

Results

We received 72 replies. Of the respondents, 48 were male and 22 female, 1 not-binary and 1 did not answer. Five of them were not clinically active. Fifty-eight of 72 adhered to guidelines and routinely took biopsies both from the bulb and the distal duodenum. Forty-five took 4 biopsies from the distal duodenum, only five of them 2 biopsies. Negative serology was considered insufficient to exclude CeD by 52 respondents. All used IgA-TG2 for diagnosis, 41 also IgG-DGP, whereas 6 used endomysium test (EMA) and 4 also anti-gliadin antibodies. We initially asked if positive serology alone could diagnose CeD and received mixed response; 26 supported the notion, 37 did not and 9 did not know. We thereafter provided information on no-biopsy diagnosis for children. With this information, fourty responders supported serological diagnosis without biopsy, 10 were negative and 21 uncertain. The majority (32) requested 2 strongly positive (more than 10 x ULN) IgA-TG2, whereas 14 considered a single strongly positive test as sufficient. Specialists deemed capable of setting the diagnosis was gastroenterology (48 votes), general practitioner (22 votes), internists (21 votes) any doctor (10 votes). However, half of the respondents considered it not necessary to personally meet the patient to make a diagnosis.

Conclusion

The no-biopsy approach receives support; but the precise set-up is not clear. If a no-biopsy approach is agreed upon, we should decide on single or repeated tests, on the use of EMA or rely on only IgA-TG2, and if IgG-DGP has a role. The coeliac community should agree on precise guidelines to minimize misdiagnosis and provide the patients with a clear and definite diagnosis.

References

1. Husby, S., et al., European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr, 2020. 70(1): p. 141-156.
2. Al-Toma, A., et al., European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J, 2019. 7(5): p. 583-613.
3. Rubio-Tapia, A., et al., American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am J Gastroenterol, 2023. 118(1): p. 59-76.
4. Penny, H.A., et al., Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts. Gut, 2021. 70(5): p. 876-883.
5. Ciacci, C., et al., Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected coeliac disease without IgA deficiency (Bi.A.CeD): a multicentre, prospective cohort study. Lancet Gastroenterol Hepatol, 2023. 8(11): p. 1005-1014.
6. Fuchs, V., et al., Serology-based criteria for adult coeliac disease have excellent accuracy across the range of pre-test probabilities. Aliment Pharmacol Ther, 2019. 49(3): p. 277-284.

Introduction

Chronic Intestinal Pseudo-Obstruction (CIPO) is a rare disease characterized by a severe impairment of intestinal propulsive activity resulting in a clinical picture mimicking a mechanical intestinal obstruction despite the absence of any physical obstruction. Velusetrag (VEL) is a highly selective oral 5-hydroxytryptamine type 4 receptor (5-HT4R) agonist that enhances peristalsis, stimulates intestinal secretion and inhibits gastrointestinal visceral sensitivity via acetylcholine and calcitonin gene-related peptide released from motor and sensory neurons, respectively. This phase II, multicenter, double-blind, placebo-controlled, 2 treatments, 4 periods, multi-crossover (N-of-1) trial investigates the efficacy and safety of VEL in CIPO patients.

Aims & Methods

Seventeen patients with idiopathic or secondary (to primary neurodegenerative disorders) CIPO with at least 30% of their daily caloric intake from oral nutrition were treated for 4 periods of 4 weeks each with either VEL 15 mg once daily or placebo (PLA), with a washout period of 2 weeks between treatment periods. Each cycle with two periods assigned to either VEL or PLA is considered as a pair of observations. Analysis was performed on the evaluable pairs (i.e., evaluation available both for VEL and PLA within cycle). Each subject could be evaluated twice, once for each cycle, thus, each subject could contribute to 0, 1 or 2 observations for each treatment. The present analysis was performed on 15 patients, assessed as responders or naïve to 5-HT4R agonists. The number of pseudo-obstructive episodes and stool type (Bristol stool scale) were assessed during the entire study.

Results

A 50% reduction in the number of pseudo-obstructive episodes in VEL (n=4) vs PLA (n=8) was detected in 30 evaluable pairs of observations. During VEL treatment, pseudo-obstructive episodes occurred once in 2 patients and twice in 1 patient; during PLA treatment 7 patients experienced 1 episode and 1 during wash-out period after PLA. Complete normalization of constipation was observed only with VEL. In 23 evaluable pairs, all 4 observations with constipation on VEL at pre-treatment had normal stools at end of treatment (from Bristol stool type 1-2 to 3-4); additionally, observations with normal stools increased from 3 (pre-treatment) to 6 (end of treatment). In contrast, all 3 observations with constipation on PLA at pre-treatment remained constipated at end of treatment and other 2 observations with diarrhea at pre-treatment shifted to constipation at the end of treatment (Tab. 1). These results did not reach statistical significance due to limited sample size. The number of subjects with treatment emergent adverse events was similar between VEL and PLA. No cardiovascular adverse reactions or serious treatment emergent adverse events were observed in both treatment groups.

Conclusion

​​​​​​​​A VEL prokinetic effect was confirmed by a decreased number of pseudo-obstructive episodes and a normalization of constipation, two main clinical features of CIPO. VEL was also well-tolerated and safe, with no serious drug-related adverse event reported.

Disclosure

Publications management support was provided by PharmaGenesis London, London, UK, and was funded by Alfasigma S.p.A.

This study was sponsored by Alfasigma S.p.A.

Stanghellini V is a member of advisory boards and/or is a speaker for Alfasigma, Bayer, GE Healthcare and Vibrant Pharma; and receives research support from Alfasigma.

Tack J and Malagelada C have relevant financial relationship(s) to disclose: Alfasigma S.p.A.; consultancy and honoraria.

Grimaldi M, Giovannini R, Gentile E, Scuderi V, Manzoni S, Pasquali E, Costantini C, Barone M and Pellacani A have relevant financial relationship(s) to disclose: Alfasigma S.p.A.; employees.

All other authors declare that they have no relevant conflicts of interest to disclose.