Introduction

Celiac disease (CeD) may affect the interplay between the duodenal mucosa and exocrine pancreatic function as a consequence of intestinal inflammation, and could potentially increase the risk of acute pancreatitis (AP). However, the association between these two conditions remain largely unexplored.

Aims & Methods

This Swedish nationwide cohort study in ESPRESSO aimed to investigate the risk of incident AP in patients with CeD without previous pancreatic disease. Patients with biopsy-confirmed CeD were identified between 1969 and 2023 (n=57,221) and were individually matched with ≤5 general population reference individuals (n= 279,126) by sex, birth year, calendar year, and county of residence. Included individuals were followed until 31 August 2024. The primary outcome was any incident AP. Secondary outcomes included (1) specific AP types (i.e., gallstone-related, non-gallstone-related, potential alcohol-related AP); (2) severe AP, defined as (i) any hospitalization for AP that lasts for ≥14 days or being combined with diagnostic or procedural code implying a complicated episode, or (ii) all-cause death <90 days after being discharged for AP); as well as (3) second episode of any AP that occurred ≥90 days after being discharged for incident AP. Flexible parametric survival models were used to estimate the adjusted hazard ratios (aHRs) for investigated outcomes. Familial risk factors were additionally accounted for in the comparison with CeD-free full siblings (n=70,016).

Results

During a median follow-up of 15.5 years, incident AP was observed in 549 patients with CeD (incidence rate (IR)=59 per 100,000 person-years) and 1,732 reference individuals (IR=38). Patients with CeD had a higher hazard of developing any AP than reference individuals (aHR=1.50, 95% confidence interval:1.35 to 1.67). The hazard elevation remained significant for more than 25 years after the diagnosis of CeD, resulting in one extra AP event per 185 CeD patients until then. CeD was significantly associated with gallstone-related AP (aHR=1.31 [1.12 to 1.54]), non-gallstone-related AP (aHR=1.65 [1.41 to 1.93]), severe AP (aHR=1.68 [1.32 to 2.14]), but not with potential alcohol-related AP (aHR=1.22 [0.89 to 1.67]). The association between CeD and any AP was attenuated but remained significant in the sibling comparison and in sensitivity analyses that respectively accounted for the potential influence of cancer, medications that may induce AP (i.e., steroids, mesalamine, and immunosuppressants), and the COVID-19 pandemic.
Restricting our data to patients who had experienced a first AP, the risk of second-time AP was not higher in patients with CeD (aHR=0.81 [0.61 to 1.07]) than in reference individuals.

Conclusion

Patients with CeD were at an increased risk of incident AP, especially non-gallstone-related AP, for more than 25 years after diagnosis. However, the risk was no longer elevated beyond the first AP episode. Further research is needed to investigate the underlying mechanism linking CeD to AP.

Disclosure

All authors have completed the ICMJE uniform disclosure form and declare:
FE has served as an advisory board member for Boehringer Ingelheim.
DAL is an employee of Takeda Pharmaceuticals and owns stock in this company.
JFL has coordinated a study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen Corporation. JFL has also received financial support from MSD/Merck developing a paper reviewing national healthcare registers in China, and for a collaboration on inflammatory bowel disease. JFL also has a research collaboration on celiac disease with Takeda.
The other authors report no disclosures relevant to the manuscript.

Introduction

Underwater endoscopic mucosal resection (UEMR) is an alternative to conventional EMR (CEMR) offering consistent negative horizontal margins. However, UEMR does not involve submucosal injection; thus, its ability to achieve a sufficient resection depth comparable to that of CEMR remains uncertain. This randomized controlled trial (RCT) aimed to compare UEMR and CEMR in terms of resection depth.

Aims & Methods

This multicenter, parallel two-arm, open-label, noninferiority RCT was conducted across four Japanese institutions enrolling patients with colorectal tumors measuring 10–20 mm. Participants were randomly assigned in a 1:1 ratio to either to UEMR or CEMR group, using a computerized random-number generator. The primary outcome was the resection depth, which is the distance from the lower edge of the muscularis mucosa to the deep margin of the resected specimen, analyzed based on per-protocol (PP) principles (noninferiority margin of 400 µm).

Results

This study screened 217 patients from September 21, 2022, to December 2, 2024, and randomly assigned them to the UEMR (n =109) or CEMR (n =108) group. The PP analysis revealed that the mean resection depths of the UEMR and CEMR groups were 1688.9 ± 1510.0 µm and 1432.3 ± 1294.2 µm, respectively (mean difference: 256.6 µm, 95% confidence interval: -119.9 µm to 633.1 µm; P = 0.18), indicating the noninferiority of UEMR compared with CEMR in terms of resection depth. Subgroup analyses revealed that the resection depth of lesions by UEMR, especially at the cecum/ascending colon (1822.4 ± 1469.7 µm vs. 1096.5 ± 1007.6 µm; P = 0.01), and those with superficial morphology (1238.7 ± 862.2 µm vs. 731.6 ± 376.1 µm; P < 0.01), was significantly deeper than that achieved by CEMR. Moreover, even for nonexperts, UEMR tended to provide adequate resection depth compared with CEMR, approaching the proficiency level exhibited by experts (1786.6 ± 1471.6 µm vs. 1192.4 ± 1074.7 µm; P = 0.07). There were no significant differences in adverse events between the two groups, including one case of intraoperative perforation (0.9%) in the CEMR group and one case of delayed bleeding (0.9%) in the UEMR group. No EMR-related deaths were reported.

Conclusion

UEMR maintains the equivalent resection depth as CEMR and could become the gold standard endoscopic resection technique for intermediate-size colorectal tumors. UEMR is strongly recommended, especially for lesions at the cecum, ascending colon, and superficial lesions, because it could resect significantly deeper than CEMR. Furthermore, UEMR is recommended for nonexperts as a resection method that provides sufficient resection depth (Clinical trial registration number: UMIN000047432).

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

Current therapies for inflammatory bowel disease (IBD) suppress inflammation rather than inhibiting underlying microbial drivers. Treatment failures of frontline interventions, including corticosteroids, can lead to dose escalation and risk of adverse effects.^1,2 Bacteria with pro-inflammatory potential, like adherent-invasive Escherichia coli (AIEC), have been postulated as a possible microbial driver in Crohn’s disease (CD), however, targeting these bacteria with precision in IBD remains challenging.^3,4 Most antibiotics have broad-spectrum activity and disturb the background microbiome, which may exacerbate inflammation.⁵ Attention has shifted towards bacteriophages, yet their underlying mechanisms of treating IBD, and how they may work as an adjunctive therapy, remains elusive.

Aims & Methods

We aimed to assess whether and how phage therapy, specific for a CD-associated bacterium, reduces colitis severity using gnotobiotic mouse models.
In vitro kill curves and biofilm challenges were used to identify lytic phage candidates. Adult germ-free C57BL/6 mice were colonized with altered Schaedler-flora (ASF) and E. coli NRG857c (NRG), a CD-associated isolate. After 3 weeks, mice were treated with an NRG-specific lytic phage (1x10⁹ PFU/dose; daily or TIW) or vehicle (PBS) for 2 weeks (n=6/group) and then exposed to 1 cycle of dextran sulfate sodium (2%; DSS) in drinking water. PBS-treated mice (n=6) not exposed to DSS served as controls. Phage treatment was also tested in a spontaneous model of colitis using C57BL/6NTac-Il10^em8Tac (IL-10^-/-) mice, treated weekly. Mice were monitored daily for weight, stool consistency, and occult blood. Fecal contents were cultured to determine bacterial load, and the expression of NRG fimS was quantified using qPCR as an assessment of virulence. At endpoint, colon tissues were collected for histological and immunohistochemistry analysis to quantify colitis severity and NRG infiltration, respectively. Additional C57BL/6 mice were colonized and treated as previously described. During colitis induction, mice received a low-dose of budesonide (2μg/day)⁶ (n=5) or vehicle (n=5) until endpoint. Mice were monitored daily for disease activity and colon tissues were collected for histological analysis. HPLC was used to determine active budesonide levels.

Results

HER259 was identified as a lytic phage against CD-associated AIEC NRG. In ASF and NRG colonized mice, HER259 reduced clinical symptoms (p< 0.001, p< 0.001) and histological scores (p< 0.0001, p< 0.001) in chemical induced and spontaneous colitis, respectively. A 1-log reduction in NRG bacterial load was observed in HER259-treated mice (p< 0.001). Reisolated NRG exhibited a reduced FimS ON/OFF ratio (p-value < 0.01). Immunohistochemistry revealed reduced infiltration of NRG into the lamina propria following HER259 treatment, with greater accumulation in the epithelium. HER259 treatment increased the efficacy of a sub-therapeutic dosing regimen of budesonide (p< 0.001), which was independent of microbial-based drug metabolism as determined by HPLC.

Conclusion

Our results demonstrate that lytic phage targeting a CD-associated bacterium attenuates colitis in two gnotobiotic mouse models. The intervention did not lead to complete eradication of the disease-driving agent, but instead modulated bacterial virulence mechanisms and enhanced responses to corticosteroid therapy. The data suggests that alternative mechanisms should be considered when translating phage therapy to treat IBD in clinical trials.

References

1. Yan, Y. et al. Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability. Cell Rep Med 4, 101153 (2023).
2. Nagayama, M., Gogokhia, L. & Longman, R. S. Precision microbiota therapy for IBD: premise and promise. Gut Microbes 17, 2489067 (2025).
3. Darfeuille-Michaud, A. et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127, 412–421 (2004).
4. A, D.-M. et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology 115, 1405–1413 (1998).
5. Nelson, R. L., Suda, K. J. & Evans, C. T. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev 3, (2017).
6. Bercik, P. et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139, (2010).