Introduction

Irritable bowel syndrome (IBS) is defined as a disorder of gut-brain interaction (DGBI) and is characterised by intestinal immune activation, increased intestinal permeability, and structural and functional brain alterations. DGBI patients have a higher prevalence of psychological comorbidities. Nevertheless, the exact pathophysiological link between these factors and the sequence of events is unknown. Gut alterations have been suggested to induce brain neuroinflammation in DGBI, but scientific evidence is lacking.

Aims & Methods

The present study aims to assess whether GI alteration induces brain neuroinflammation, alters brain function, and, consequently, induces psychological comorbidities. A unique longitudinal study was conducted from 30 to 220 days of age to establish the chronological sequence of intestinal and neurological changes. For this, we utilised the BioBreeding diabetes-prone (BBDP) rat model, which spontaneously develops intestinal inflammation, increased permeability, and colonic hypersensitivity^{1, 2}and has been employed as a model of DGBI. The BioBreeding diabetes-resistant (BBDR) was used as control. Anxiety-like behaviour was assessed using the elevated plus maze. Intestinal permeability was assessed in vivo by measuring the passage of 4 kDa and 70 kDa dextrans into the blood, thereby evaluating paracellular and transcellular permeability, respectively. The appearance of red colour, given by the mixture of the dextrans in the stools, was used to assess overall intestinal motility. The blood-brain barrier (BBB) integrity and brain metabolic profile were assessed using contrast-enhanced magnetic resonance imaging (0.25 mL/100g weight of 0.05 mM, gadolinium) and proton magnetic resonance spectroscopy, respectively.

Results

BBDP rats exhibit an increased colonic permeability starting from 90 days, and reduced GI motility at 90 and 160 days. Interestingly, this increased permeability is accompanied by an increased BBB permeability at 220 days only in the anterior cingulate cortex (ACC) but not in the hippocampus, insula, amygdala, or thalamus. BBDP rats showed a slight increase in total choline and myoinositol concentrations in the ACC and the insula at late time points, which may indicate increased neuroinflammation. BBDP rats also have higher concentrations of glutamine-glutamate in the insula and N-acetyl aspartate in the ACC. Moreover, BBDP rats develop anxiety-like behaviour at 160 and 220 days.

Conclusion

The BBDP rat model supports the current hypothesis that increased gut permeability can lead to brain neuroinflammation, altered function, and, consequently, to psychological comorbidities.
EU-funded DISCOvERIE project (No. 848228).

References

1. Meleine M, Accarie A, Wauters L, et al. Colonic hypersensitivity and low-grade inflammation in a spontaneous animal model for functional gastrointestinal disorders. Neurogastroenterol Motil 2019;31:e13614.
2. Vanuytsel T, Vanormelingen C, Vanheel H, et al. From intestinal permeability to dysmotility: the biobreeding rat as a model for functional gastrointestinal disorders. PLoS One 2014;9:e111132.

Introduction

Genome-wide association studies (GWAS) have identified more than 250 risk variants linked to inflammatory bowel disease (IBD). Most genetic variants increase the risk of disease onset, and their impact on clinical presentation is limited.^1,2,3 Variants in NOD2 and IL23R not only modulate the risk of disease onset, but also influence disease behaviour and localisation. Their role in predicting treatment response remains unclear.^3,4
A variant in an intron of TNRC18 (rs7486781, allele frequency 3.6%) was recently identified as having a strong risk-increasing effect (OR 3.2, p=2.4x10-61) for IBD in the FinnGen biobank study. The same allele was also associated with a risk for ankylosing spondylitis (AS), uveitis and psoriasis.⁵ The functional effect of rs7486781 is not yet fully established.⁶

Aims & Methods

The FinnGen biobank study includes the genotype data of 520 000 individuals and their longitudinal register data from national health registers, including 11 298 individuals with verified diagnosis for IBD. The data also include drug purchases, procedure codes and laboratory measurements of the individuals.
Our aim was to study the impact of the TNRC18-variant on IBD phenotype, particularly disease behavior. We assessed established aspects of disease severity⁷: use of immunosuppressants and advanced therapies, necessity to switch medications, frequent use of corticosteroids and risk of procedures. We also evaluated the presence of extraintestinal manifestations (EIM) and other disease complications.

Results

Regarding disease severity, the use of therapies beyond 5-ASA was more common among variant carriers; the use of thiopurines and other immunosuppressants (OR 1.21-1.27, p-values 1.35x10^-5 - 0.00849), ustekinumab and other IL-inhibitors (OR 1.46-1.48, p-values 0.00324 - 0.00286) and TNF-α-inhibitors (OR 1.26, p=0.00753) was more frequent.
In addition, perianal and anal canal operations were more prevalent with TNRC18 variant carriers (OR 2.44, p=1.41x10^-4), indicating perianal disease.
Assessing EIM, we observed that diagnoses for AS and uveitis (OR 1.62-1.67, p=1.3x10^-5 - 1.55x10^-4) were more frequent within IBD in patients with rs7486781.
Interestingly, a reduced risk of primary sclerosing cholangitis (PSC) was implicated by lower number of cholangitis (K83.0) diagnoses (OR 0.617, p=0.00221) and fewer purchases of ursodeoxycholic acid (OR 0.55, p=2.83x10^-5), in addition to lower levels of ALP (mean 75 vs 82, p=0.00296), IgG4 (mean 0.45 g/l vs 0.81 g/l, p=4.81x10^-5) and IgM (0.12 vs 0.15, p=0.00115) among variant carriers. All events survived the false discovery rate–adjusted p threshold of 0.05.
Our results also suggest that the cumulative risk for IBD related procedures⁸ (patients with procedures n=2209) from diagnosis and birth were elevated in TNRC18 variant carriers (HR=1.12 and HR=1.14, p=0.050 and p=0.023, assuming additive effect) using a Cox regression model.
Finally, our results in ulcerative colitis indicate that TNRC18 variant carriers are at higher risk of transitioning from 5-ASA/immunomodulators to biologics/JAK-inhibitors (HR=1.38, p=0.016). Variant carriers receiving immunomodulators or advanced therapies were not, however, in increased risk of colectomy (HR~0.97-1.34, p~0.86-0.37).

Conclusion

TNRC18 variant was associated with greater risk of operative treatment, the need of more advanced medication and perianal disease. AS and uveitis were more common EIMs, but PSC appeared less infrequent. Our preliminary results indicate that TNRC18 variant carriers might benefit from early intervention with immunomodulators or advanced therapies.

References

1. Chang, J. T. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med 383, 2652–2664 (2020).

2. Cleynen, I. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387, 156–167 (2016).

3. Atreya, R. & Neurath, M. F. Biomarkers for Personalizing IBD Therapy: The Quest Continues. Clin Gastroenterol Hepatol 22, 1353–1364 (2024).

4. Kayali, S. et al. NOD2 and Crohn’s Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired. Inflamm Bowel Dis 31, 552–562 (2025).

5. Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).

6. Rahimov, F. et al. A genome-wide CRISPR screen supported by human genetics identifies the TNRC18 gene locus as a novel regulator of inflammatory signaling. bioRxiv 2023.10.04.560902 (2023) doi:10.1101/2023.10.04.560902.

7. Swaminathan, A. et al. The Disease Severity Index for Inflammatory Bowel Disease Is a Valid Instrument that Predicts Complicated Disease. Inflamm Bowel Dis 30, 2064–2075 (2024).

Disclosure

Anna Aarni: Speaker fee from Abbvie, Clinic visit: travelling expenses from Tillots Pharma

Pauliina Molander: Speaker, consultancy and advisory board member fees from Abbvie, Johnson & Johnson, Lilly, Pfizer and Takeda. Clinic visit: traveling expenses from Tillots Pharma

Jukka Koskela: Pfizer-FinnGen genetic advisory board, traveling, clinic and congress visits: FinnGen partners, Tillots Pharma, Takeda, consulting: Pfizer

Introduction

Eosinophilic esophagitis (EoE) is a chronic, progressive, esophageal disease driven by type 2 inflammation.

Aims & Methods

The aim of this analysis was to determine the histopathologic effect of dupilumab on esophageal inflammation in patients aged 1–11 years with eosinophilic esophagitis (EoE) from the phase 3 EoE KIDS trial. In Part A, patients were randomized to receive weight-tiered dupilumab or placebo for 16 weeks. In Part B, all patients received weight-tiered dupilumab for 36 weeks. Biopsies from proximal, mid, and distal esophageal regions were analyzed. Peak eosinophil count (PEC) and EoE Histologic Scoring System (HSS) grade/stage scores were assessed at baseline, Week 16, and Week 52.

Results

At Week 16, dupilumab vs placebo treatment resulted in significantly greater improvements in PEC (least squares mean percent change -86.09% vs 20.98%, respectively; P<0.0001) and improvements from baseline were observed in EoE-HSS grade and stage total scores, and inflammatory and architectural sub-scores (Table). Improvements were maintained at Week 52 with continued dupilumab. For those who switched from placebo at Week 16, improvements were observed at Week 52. Improvements in individual component scores were also observed.

Table. Mean percent change from Part A baseline in EoE-HSS scores at Weeks 16 and 52.

Conclusion

Dupilumab treatment improved a range of histopathologic aspects of EoE through 52 weeks versus placebo in children aged 1–11 years with EoE.

Disclosure

Collins MH: Arena, Pfizer, AstraZeneca, Calypso Biotech, EsoCap Biotech, GSK, Receptos, Celgene, Bristol Myers Squibb, Regeneron Pharmaceuticals Inc., Robarts Clinical Trials Inc. Alimentiv, Inc., Sanofi, Shire, a Takeda company – advisory board/consultancy fees.
Lerner D: Regeneron Pharmaceuticals Inc. – educational board fees.
Pesek RD: Regeneron Pharmaceuticals Inc. – advisory board/consultancy fees.
Zevit N: AstraZeneca, Rafa Inc., Regeneron Pharmaceuticals Inc., Sanofi, Takeda – advisory board/consultancy fees. Adare Pharmaceuticals, Dr. Falk Pharma – advisory board/consultancy fees. Dr. Falk Pharma, Rafa Inc., Regeneron Pharmaceuticals Inc., Sanofi – speaker fees. Rome Foundation – honoraria.
Xia C, Raphael BP, Radwan A: Regeneron Pharmaceuticals Inc. – employees and shareholders.
Zaghloul S, Angello JT: Sanofi – employees, may hold stock and/or stock options in the company.

Introduction

Corpus atrophic gastritis (CAG) requires endoscopic-histological surveillance due to the risk of developing gastric neoplastic lesions (GNL). This study aimed to identify variables associated with GNL development at long-term follow-up using a feature ranking method based on a novel One-Class Support Vector Machine (SVM) model.

Aims & Methods

A dataset containing clinical, endoscopic, and histological variables from consecutive CAG patients (2001-2023) adhering to a surveillance program was considered. GNL presence at the longest available follow-up was recorded. Gastric biopsies and histological evaluations were conducted according to the updated Sydney system. CAG patients with any missing data or a GNL diagnosis at the baseline gastroscopy were excluded from the final analysis. A Fisher score-based feature ranking method and One-Class SVM were used to select the optimal subset of baseline variables associated with GNL development, aiming to achieve average sensitivity (Se) and specificity (Sp) above 80%.

Results

Overall, 355 CAG patients were initially considered. Of these, 36 were excluded due to the presence of GNL at baseline gastroscopy, and 216 for missing data. Thus, a total of 103 patients were considered and grouped into: CAG patients with [22 patients (F 68.1%), median age 68 (35-83) years] and without GNL at follow-up [81 patients (F 72.8%), median age 59(26-84) years]. After a median follow-up of 60 (12-192) months, 13 epithelial GNL (gastric adenocarcinoma or high/low-grade dysplasia) and nine type-1 gastric-neuroendocrine-tumors (T1gNET) were recorded. Parietal-cell-antibodies and pepsinogen-I < 30 μg/l were associated with both epithelial GNL and T1gNET. Antral inflammation and age > 60 were linked to epithelial GNL, while anti-thyroperoxidase-antibodies, smoking, and dyspeptic symptoms at CAG diagnosis were linked to T1gNET. Low-dose aspirin and H. pylori eradication therapy showed inverse associations with epithelial GNL and T1gNET, respectively.

Conclusion

This is the first study in which an AI model simultaneously considers clinical, endoscopic, and histological characteristics from a dataset of CAG patients, showing good sensitivity and specificity in identifying those variables associated with developing GNL. Nonetheless, we acknowledge the need for improved variable standardization and data balancing between groups to enhance model performance further.