Introduction

Opioids used to manage severe pain in acute pancreatitis might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, may counteract these effects without changing analgesia.

Aims & Methods

This multicentre, double-blind, randomised, placebo-controlled, investigator-initiated trial included adult patients with predicted moderately severe or severe acute pancreatitis at four Danish pancreatitis referral centres. Patients having chronic pancreatitis, contraindications to methylnaltrexone, or renal insufficiency were excluded. Participants were randomised to receive 5 days of continuous intravenous methylnaltrexone (0.15mg/kg/day) or placebo added to the standard of care, including intravenous fluids, analgesics, and nutrition. The primary endpoint was the Pancreatitis Activity Scoring System score after 48 hours of treatment. Main secondary outcomes included pain questionnaire scores, use of opioids and laxatives, admission length, disease severity (revised Atlanta classification), and mortality.

Results

In total, 105 patients (54% males; median age 57 [IQR, 45-69]) were randomised to methylnaltrexone (n=51) or placebo (n=54). After 48 hours, the Pancreatitis Activity Scoring System score was 134.3 points in the methylnaltrexone group and 130.5 points in the placebo group (difference, 3.8 points [95% CI, -40.1 to 47.6]; P=0.87). At 48 hours, we found no differences between groups in pain severity (difference, 0.0 [95% CI, -0.8 to 0.9]; P=0.94), pain interference (difference, -0.3 [95% CI, -1.4 to 0.8]; P=0.55), and morphine equivalent doses (difference, 6.5 mg [95% CI, -2.1 to 15.2]; P=0.14). Compared to placebo, methylnaltrexone did not affect the median admission length (difference, -23 hours, [95% CI, -85 to 39]); P=0.47). Methylnaltrexone also did not affect the risk of laxative use (risk difference, -15% [95% CI, -34 to 2]; P=0.10), moderately severe or severe disease according to the Atlanta classification (risk difference, 8% [95% CI, -11 to 28]; P=0.38), 30-day mortality (risk difference, 6% [95% CI, -1 to 12]; P=0.11), or adverse events (risk difference, 10% [95% CI, -9 to 29]; P=0.30).

Conclusion

Methylnaltrexone treatment did not change the outcome of acute pancreatitis. Indirectly, the study supports that short-term opioid use is safe for pain control in acute pancreatitis.

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

The interplay of diet and the intestinal microbiome plays a key role in developing colorectal cancer (CRC), with westernization of diets, e.g., an increase in fat and sugar and a decrease in fiber content, being the main contributor. We recently demonstrated that the endoplasmic reticulum unfolded protein response (ER-UPR) effector activating transcription factor 6 (ATF6) is associated with early and late onset of CRC in patients. Furthermore, the overexpression of ATF6 observed in a subset of CRC patients is associated with the presence of certain gut bacteria. The specific expression of activated ATF6 (nATF6) in mouse intestinal epithelial cells (nATF6^IEC) induces spontaneous development of colonic tumors in a microbiota-dependent manner, highlighting the functional relevance of ATF6 as a novel oncogenic driver.

Aims & Methods

To elucidate the adverse role of dietary fat, sugar, and fiber in tumorigenesis, we exposed nATF6^IEC mice under SPF conditions to control (chow) and westernized diets for 7 weeks after weaning. Microbial and metabolite profiles were assessed through deep metagenomic sequencing and targeted/untargeted mass spectrometry (LC-MS) analysis. Microbiota transfer of diet-exposed mice into germ-free recipients was conducted to verify the microbiota-dependent transmissibility of tumor formation. Bismuth(II)subsalicylate (BSS) was used as a dietary additive to validate the impact of bacteria-produced H₂S on tumorigenesis.

Results

Westernized high lard (HL) diet, enriched in fat and sugar and depleted in fermentable fiber, increased tumor burden in biallelic nATF6^IEC mice. Unexpectedly, HL induced de novo tumorigenesis in otherwise tumor-free monoallelic nATF6^IEC mice. Surprisingly, modifying the HL diet by supplementing dietary fiber or lowering fat content failed to protect the HL-induced tumorigenic phenotype. Metabolite profiling clearly differentiated westernized from control diets and tumor bearing from control mice. Transferring microbiota from diet-exposed mice into germ-free nATF6^IEC mice was sufficient to trigger tumorigenesis. Metagenomic profiles of westernized diet-exposed mice identified an increased relative abundance of H₂S-producing Desulfovibrio species and genes related to dissimilatory sulfate reduction. Supplementing westernized diets with the H₂S-scavenger BSS resulted in a drastic change in microbial communities as well as the prevention of tumor formation in monoallelic nATF6^IEC mice.

Conclusion

These results highlight the ability of westernized diets to enhance nATF6-related tumorigenesis while altering metabolite and microbial profiles. Westernized diets favor the growth of sulfate-reducing Desulfovibrionaceae, possibly resulting in increased H₂S production. H₂S scavenging significantly reduces diet-induced colonic tumor susceptibility, clearly demonstrating the impact of diet in shaping cancer-related microbiome alterations.