Introduction

Metaplasia refers to the emergence of cells not normally present in a given organ, typically as a result of chronic inflammation. While often linked to cancer development, its role in inflamed epithelium remains unclear. Paneth cell metaplasia (PCM) is a phenomenon in which Paneth cells, normally restricted to the small intestine, appear ectopically in the inflamed colonic epithelium of patients with ulcerative colitis (UC). However, the roles and characteristics of PCM in the inflamed colonic mucosa remain poorly understood. This study aimed to characterize the clinical and molecular features of colonic PCM and investigate its functional role in the inflamed epithelium.

Aims & Methods

We first analyzed the clinical characteristics of PCM using biopsy samples and clinical data from UC patients who underwent endoscopic evaluation at our institution. To elucidate the molecular features of colonic PCM, we employed spatial transcriptomics to compare PCM in the colon with Paneth cells in the small intestine from the same individuals. These findings were validated in a knockout mouse model, murine colonic organoids, and patient-derived human colonic organoids. This multi-model approach allowed us to investigate the mechanisms underlying PCM formation and assess its functional relevance in intestinal epithelial biology.

Results

PCM was predominantly observed in the left-sided colon and was associated with longer disease duration and the presence of pathological inflammation. Spatial transcriptomic HD analysis suggested that colonic PCM emerges within an inflammatory microenvironment distinct from that of the small intestine. Notably, the expression of the Wnt target genes HD5 and HD6, which are typically required for Paneth cell differentiation in the mouse small intestine, was reduced in colonic PCM. In contrast, expression of REG3A, a gene known to be induced by the inflammation-associated cytokine IL-22, was maintained. Consistent with previous reports highlighting the role of IL-22 in the differentiation and maturation of human Paneth cells, these findings suggest that IL-22 may contribute to the induction of PCM under inflammatory conditions. Mechanistically, IL-22 was shown to suppress Notch signaling in human colonic organoids, thereby promoting PCM formation and inducing REG3A expression in metaplastic cells. In vitro experiments using mouse colonic organoids demonstrated that Reg3a enhances epithelial cell proliferation and promotes wound healing. In vivo, Reg3a^ΔIEC mice exhibited impaired wound healing in both acute and chronic DSS-induced colitis models. Furthermore, REG3A treatment of human colonic organoids derived from UC patients stimulated epithelial proliferation and accelerated wound closure.

Conclusion

PCM contributes to epithelial protection in UC by promoting REG3A-mediated regeneration. These findings suggest that PCM may play a compensatory role in mucosal healing during colonic inflammation.

Introduction

Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass. Primary sarcopenia is associated with aging, while secondary sarcopenia is caused by various factors, including inflammatory conditions such as inflammatory bowel disease (IBD). The complex interaction between inflammation, intestinal dysbiosis, and malnutrition in IBD patients is referred to as the gut-muscle axis. High levels of cytokines and intestinal dysbiosis in IBD activate pathways that disrupt muscle protein synthesis. However, molecular and microbial mechanisms of sarcopenia in IBD are not extensively studied as well as therapeutic approaches.

Aims & Methods

A murine model of DSS-induced colitis was used. To detect sarcopenia, physical performance assessment on a rotarod was conducted. In this model, muscle was studied using immunohistochemistry, fiber counting per field, and cross-sectional area evaluation. Subsequently, intestinal microbiota and serum LPS detection were assessed. Additionally, an in vitro model of muscle cells was created using the immortalized murine cell line C2C12. Cells were exposed for 30 Min and 6 h to treatments including exposure to pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6), lipopolysaccharides (LPS), drugs (Infliximab, Upadacitinib, Tofacitinib), and probiotics (L. plantarum, L. rhamnosus).

Results

The murine model showed decreased body weight and muscle function alongside increased expression of muscle atrophy markers (myostatin and Murf-1) in colitic mouse muscle. Furthermore, there was an upregulation of the STAT3-pSTAT3 pathway associated with muscle wasting and a decrease in pAKT, a pathway associated with muscle growth. Surprisingly, DSS-induced colitis in mice resulted in intestinal dysbiosis characterized by reduced Roseburia genus and increased Sutterella, Turicibacter, and Bacteroides in the DSS group, as well as increased serum LPS levels.
In vitro, Upadacitinib and Tofacitinib, in the presence of inflammatory cytokines, reduced the expression of pathways associated with muscle atrophy (STAT3, pSTAT3, and NFκB) and increased pAKT expression, a protein associated with muscle synthesis. When cells were treated with LPS, NFκB expression did not decrease with the addition of the drugs, suggesting that LPS can activate NFκB independently of the JAK/STAT pathway.
Treatment with probiotics reduced STAT3 and pSTAT3 signals, suggesting potential positive modulation by all probiotics.

Conclusion

These data open new avenues for the gut-muscle axis as a promising research area for managing sarcopenia in IBD. Considering microbiota and LPS along with inflammatory cytokines may provide a more comprehensive understanding, especially as LPS-induced signaling appears to be only partially controlled by drugs and potentially positively influenced by probiotics.

Introduction

Gender diversity in scientific authorship is a progress indicator in various medical fields, including gastrointestinal (GI) endoscopy. The representation of women in academia reflects broader changes in professional roles and leadership. This study aims at analyzing trends in gender representation among authors of randomised controlled trials (RCTs) in GI endoscopy from the 1960s to the present, providing insights into the progression of gender equity in academic gastroenterology.

Aims & Methods

A PubMed search using the terms "digestive endoscopy" and "gastrointestinal endoscopy" was conducted on April 1st, 2024, yielding 5,944 studies filtered for RCTs. After excluding non-English articles, those unrelated to endoscopy, and studies without identifiable first authors, 4,357 RCTs were included. First and last authors' genders were identified using Genderize.io with ≥90% certainty. Descriptive and inferential statistics, including chi-squared tests, were used to analyze trends in gender representation over time.

Results

In total, there were 967 female first authors (21.7%), 3,415 male first authors (77.0%), and 57 unclassified first authors (1.3%). Out of 4173 last authors, 637 were female (15.3%), 3,203 were male (76.7%), and 333 were unclassified (8.0%) (p < 0.001). Female representation among last authors increased from 0% to approximately 20%, while first authors rose from 0% in the 1970s to about 30% by 2024 (p<0.05 for both trends). Multivariate regression confirmed that the increase in female first authorship was more significant compared to last authorship (p<0.001, R-square 0.90).Regarding specific topics, “non-IBD-related diagnostic lower GI endoscopy” showed the highest representation for female first authors at 25.5%, while “Obesity” and “Artificial Intelligence” had the lowest at 1.4% and 1.7%, respectively. For the last authorship, “non-IBD-related diagnostic lower GI endoscopy” led at 22.1%, followed by “Diagnostic upper GI endoscopy” at 14.0%. The lowest percentages among the last authors were “Obesity” at 1.4% and “Artificial Intelligence” at 0.6%. Statistical analysis revealed significant differences in gender representation across topics (p < 0.0001).Regional differences were noted, with female first authors more prevalent in Europe (36.2%) and Asia (31.0%), while female last authors were more common in Europe (34.2%) and North America (30.8%, p = 0.032), highlighting variations in gender dynamics within endoscopy research.

Conclusion

This study demonstrates a progressive increase in female representation in digestive endoscopy RCTs, particularly among first authors. However, gender disparities persist in senior roles, underscoring the need for continued efforts to support gender equity, especially in leadership positions within academic gastroenterology.

References

Liu CS et al. Am J Gastroenterol. 2024 Oct 1;119(10):2103-2106.
Genderize Data Roskilde, Denmark. Genderize.io (last access Nov 1st, 2024

Introduction

​​​​​PSC is chronic infammatory disease of bile ducts leading to strictures of bile duct and eventually to liver cirrhosis. Chronic inflammation is associated with markedly increased risk of cholangiocancer (CCA). In addition, gall bladder abnormalities are common in patients with PSC¹ such as cholecystitis, gallstones, polys and gallbladder carcinoma (GBCA). Increased fasting gallbladder volume has been reported with normal gallbladder emptying². Due to the increased risk of GBCA³ cholecystectomy is recommended in PSC with gallbladder polyps ≥8 mm and smaller polyps growing⁴. However, cholecystectomy has been associated with impaired PSC outcome. A study consisting of 11 PSC patients with cholecystectomy suggested protective role of gallbladder based on MRCP changes and elevated AST levels in patients with cholecystectomy. No significant difference in serum bile acids was observed in patients with or w/o cholecystectomy⁵. Another small study including five PSC patients with cholecystectomy showed that cholecystectomy was associated with worse Mayo scores and an elevated FIB4⁶. More than 50% of PSC have enlarged gallbladder which is suspected to be caused by hyperpressure in the biliary tract⁵. Cholecystectomy may thus eliminate this reserve function and lead to progression of bile duct strictures.

Aims & Methods

To evaluate the impact of cholecystectomy on liver enzyme levels, biliary bile acid composition, bile duct disease progression, and overall outcomes in a large PSC patient cohort, we analyzed data from 1,009 individuals enrolled in the prospective Helsinki PSC registry. Of these, 114 patients (11.3%) had undergone cholecystectomy—34 prior to and 80 following the PSC diagnosis. Patients with gallbladder cancer were excluded. Clinical and laboratory parameters were collected, along with data on disease progression based on sequential ERC examinations scored by the Helsinki ERC score⁷. Additionally, bile composition was analyzed in a subgroup of 157 patients receiving UDCA therapy, 32 of whom had undergone cholecystectomy.

Results

Demographics, liver function tests, and outcomes stratified by cholecystectomy, are presented in the table. We found no differences between the three groups (no cholecystectomy, cholecystectomy done prior or after PSC dg) regarding the progression of bile duct disease or its severity, liver function tests, development of biliary dysplasia or need for dilatation, Mayo- and MELD-scores. The cumulative incidence of the composite end point (= transplantation, liver related death, HCC or CCA) did not differ between groups. The molar-% of phospholipids were lower and cholic acid and deoxycholic acid (mg) elevated in bile in patients with cholecystectomy, whereas no differences were found in UDCA content.

Conclusion

In this large study investigating the impact of cholecystectomy on PSC outcomes, we found no effect on liver enzyme levels, prognostic indices, bile duct disease progression, or overall prognosis, regardless of whether the procedure was performed before or after the PSC diagnosis.

References

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2. Said K, et al. World J Gastroenterol 2009; 15: 3498-3503
3. van Erp LW, et al. Liver Int 2020; 40:382–92.
4. Chazouilleres O et al. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761–806
5. Cazzagon N, et al. JHEP Reports 2023. https://doi.org/10.1016/j.jhepr.2022.100649
6. Miyake N, et al. Cureus 17(3): e80184. DOI 10.7759/cureus.80184
7. Boyd S, et al. Endoscopy. 2016;48:432-9.