Introduction

Ulcerative colitis (UC) is a refractory disease and tends to affect younger individuals. The current treatment of UC aims to reduce inflammation and achieve endoscopic remission. However, histological abnormalities such as goblet cell depletion and crypt distortion, often persist. Previous research suggests that persistent histologic abnormalities without inflammation might be a stricter indicator of relapse than endoscopic appearance alone. We have found that telomerase activator, Centella asiatica (CA), can normalize the epithelium of human colonic organoids in an UC model. CA is a traditional herb and has been sold as a supplement. Thus, CA could be a novel candidate for UC treatment.

Aims & Methods

There have been no clinical studies on CA for patients with UC. We therefore aimed to evaluate the safety and efficacy of CA in a phase I clinical trial. This study was conducted according to Japanese Clinical Trials Act (jRCTs031220305). Ten patients with mild UC were recruited for this study. Patients were administered orally 500mg of CA extract tablets once daily for 12 weeks. Safety and tolerability during the medication were monitored. The efficacy based on clinical manifestations, biomarkers, endoscopic findings, histopathological findings were evaluated. A telomere-lengthening effect in colonic epithelial cells of rectum by CA was assessed.

Results

Among 10 patients, half were female, with a median age of 48.5 years old and a median disease duration of 6 years. One patient withdrew from this trial due to disease progression. A total of nine patients received the experimental treatment. No adverse events were observed. After 12 weeks of treatment, one of the nine patients demonstrated a Partial Mayo Score (pMayo) decreased from 1 to 0 while the eight showed a pMayo remained at 0 before and after treatment. Two of the nine patients showed a decreased in Mayo Endoscopic Subscore (e Mayo) by 1, with a median eMayo score of 1 (range: 1–2) before treatment and 1 (range: 0–2) after treatment (p = 0.500). Two of the nine patients showed a 2-point decrease in UCEIS, and another two patients showed a 1-point decrease, the median UCEIS before treatment was 1 (range: 1-3), and after treatment was 1 (range: 0-2), (p = 0.125). Two of the nine patients showed histological improvement, the median Geboes score before and after treatment was 2 (range: 1-5), (p = 0.500). The median CRP before and after treatment was 0.03 mg/L (range: 0.03-0.06 mg/L) and 0.03mg/L (range: 0.03-0.05 mg/L), respectively (p = 0.500). The median Leucine-rich alpha 2 glycoprotein (LRG) level before treatment was 10.0 μg/mL (range: 7.2-16.4 μg/mL), and after treatment was 8.7 μg/mL (range: 7.1-17.6 μg/mL), (p = 0.3125). Among five patients, the median relative telomere length of rectum before and after treatment was 0.96 (range: 0.44-3.28) and 0.81 (range: 0.54-3.58), respectively (p = 0.625). A patient exhibited telomere elongation in rectal epithelial cells, with a decrease of Mayo and UCEIS score.

Conclusion

CA is a safe candidate for patients with UC. One patient exhibited a decrease in endoscopic and histological scores with telomere elongation in rectum. This study providing a foundation for further clinical trials in the future. Longer treatment duration and larger participants pools will be needed to assess the efficacy of CA for histological healing with crypt normalization in the future.

References

1. Watanabe S, Hibiya S, Katsukura N, et al. Importance of telomere shortening in the pathogenesis of ulcerative colitis: a new treatment from the aspect of telomeres in intestinal epithelial cells. J Crohns Colitis 2022;16(1):109-121.
2. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology 2021;160(5):1570-1583.

Introduction

The Mayo Endoscopic Subscore (MES) is widely used in clinical trials and daily practice to assess disease activity and response to treatment in UC.

Aims & Methods

The objective of this study was to identify any nuances in patients with MES > 1 treated with non-TNF biologics and targeted oral therapies. The Ipsos UC Therapy Monitor, a multi-centre online medical chart review study of patients with UC, was conducted between July and September 2024 among gastroenterologists practicing across hospital and private practices in the UK, France, Germany, Italy, and Spain. Physicians were screened for practice duration and patient volume. Charts of patients prescribed advanced therapy were included in the analysis.

Results

205 sampled physicians collectively reported 820 UC patients. Of the reported patients with MES > 1, 62 were treated with non-TNF biologics and 62 were treated with novel oral therapies. Among the patients treated with non-TNF biologics, a higher proportion were female vs those receiving oral therapy (48% vs 31%); they were also older in age (mean years: 43 vs 38).
The patients treated with non-TNF biologics had a higher prevalence of comorbidities, including depression/anxiety (24% vs 19%), cardiovascular disease (8% vs 0%), and dyslipidemia/hyperlipidemia/hypercholesterolemia (11% vs 7%), compared to those treated with novel oral therapy.
Mean CRP levels were higher in the oral therapy group (10.2 mg/L vs 9.1 mg/L), while mean Mayo scores were slightly lower (4.7 vs 5.2). Fecal calprotectin levels were elevated in patients treated with non-TNF biologics vs oral therapy group (441 µg/g vs 503 µg/g).
When analysing reasons for prescribing selected advanced therapy between the two patient groups, a greater proportion of patients treated with non-TNF biologics had safety reasons specified more frequently by the sampled physicians.

Table 1: % of reported UC patients receiving advanced therapy for specific cited reasons

Conclusion

This study highlights key differences in patient characteristics and treatment considerations among UC patients with MES > 1 treated with non-TNF biologics compared to those treated with targeted oral therapies. Patients on non-TNF biologics tend to be older, more often female, and have a higher prevalence of comorbidities. Physicians prescribing non-TNF biologics prioritize safety, while those prescribing oral therapies focus on rapid symptom control. These findings highlight the importance of considering patient characteristics and treatment goals when selecting advanced therapies for UC patients with MES > 1. Further investigation using comparator cohort is warranted.

Introduction

The pathogenesis of ulcerative colitis (UC) involves complex immune responses, including Th1, Th2, and Th17 pathways, and is characterized by substantial heterogeneity. Cytokine profiling may contribute to understanding individual disease mechanisms and guiding personalized therapeutic strategies; however, its clinical application remains limited due to technical complexity. This study aimed to investigate whether endocytoscopic and histopathological findings correlate with mucosal cytokine expression levels and could serve as surrogate markers.

Aims & Methods

Thirty-five patients with UC receiving treatment at our institution were enrolled. Endocytoscopy (ultra-magnifying endoscopy) was performed in all patients, and the findings were classified according to the Endocytoscopic Classification system (EC classification: EC-A, EC-B, EC-C, EC-D). Mucosal biopsies were obtained from the most inflamed areas identified during endocytoscopy. Histological evaluation included the Matts histological grade and assessments of neutrophil, eosinophil, and lymphocyte infiltration; goblet cell depletion; crypt distortion; and epithelial damage, each graded on a four-point scale (absent, mild, moderate, severe). mRNA expression levels of cytokines (IFN-γ, TGF-β1, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, and IL-23) were quantified using RT-PCR. Statistical analyses were performed to assess correlations between endocytoscopic/histopathological findings and cytokine expression levels.

Results

The median age of participants was 44 years (IQR: 35–57), with 24 males and 11 females. Disease types included pancolitis (n = 16), left-sided colitis (n = 14), and proctitis (n = 5). The median Mayo score was 1 (IQR: 0–5). EC classification scores showed significant positive correlations with the expression levels of IL-1β, IL-6, IL-8, IL-13, IL-17, and IL-23 (Spearman’s rank correlation, p < 0.05; r = 0.555, 0.526, 0.584, 0.441, 0.422, and 0.449, respectively). Similarly, Matts histological grades were significantly correlated with the expression of IFN-γ, IL-1β, IL-6, IL-8, IL-13, IL-17, and IL-23 (p < 0.05; r = 0.493, 0.756, 0.692, 0.730, 0.656, 0.623, and 0.448, respectively). Histopathological features—including neutrophil and lymphocyte infiltration, goblet cell depletion, epithelial damage, and crypt distortion—were significantly associated with the expression of IFN-γ, IL-1β, IL-6, IL-8, IL-13, IL-17, and IL-23. Additionally, eosinophil infiltration was positively correlated with the expression levels of IL-1β, IL-5, and IL-13.

Conclusion

This study demonstrates that endocytoscopic and histopathological indicators of inflammation are associated with mucosal expression levels of several cytokines—particularly inflammatory and Th17-related cytokines—in patients with ulcerative colitis (UC). These findings suggest that such evaluations may serve as surrogate markers, potentially improving disease assessment and informing therapeutic decision-making.

Introduction

The Mayo Endoscopic Subscore (MES) is the most widely used endoscopic index for assessing disease activity in ulcerative colitis (UC). Although artificial-intelligence　(AI)–assisted colonoscopy is expected to reduce inter-observer variability, the MES 4-point scale (0–3) lacks sufficient sensitivity to detect subtle changes in mucosal activity, limiting its ability to capture incremental improvement or deterioration. Moreover, because MES focuses on qualitative features—such as bleeding and erosions—without considering the extent or surface area of inflammation, it provides an incomplete estimate of a patient’s overall inflammatory burden.

Aims & Methods

We sought to develop and validate a quantitative, AI–driven colonoscopic score—Quantitative Ulcerative Colitis Assessment using Deep-learning (QUAD)—and to determine whether it predicts clinical relapse in patients with UC. The QUAD system was trained on 84 743 colonoscopic images from 998 UC patients at three centers and comprises three main functions: i) Image filtering: Automatic exclusion of low-quality images that are unsuitable for analysis owing to light saturation (halation), inadequate insufflation, excessive proximity to the mucosa, chromoendoscopy, or virtual chromoendoscopy. ii) Frame-level scoring: Each frame is divided into four quadrants; inflammation in each quadrant is graded from 0 to 3, and the quadrant scores are summed to yield a QUAD score of 0–12. iii) Video-level aggregation: Full-length withdrawal videos are processed to generate (i) an Entire QUAD score (0–60), representing pan-colonic inflammation, and (ii) a Distal QUAD score (0–12) for the rectosigmoid segment (final 20 % of the video).
The QUAD system contains mainly three function: i) automatically exclude low quality images that is ineligible for analysis in cases of halation, inadequate air de­livery, proximity to mucosa, chromoendoscopy, and virtual chromoendoscopy; ii) fully auto­mated twelve-class score output based on frame analysis: Each frame was divided into four quadrants; inflammation in each quadrant was graded 0–3 and summed to yield a QUAD score of 0–12; and iii) full-length withdrawal videos were processed to generate (I) an Entire QUAD (0–60) for considering whole-colon inflammation status and (II) a Distal QUAD (0–12) for the distal rectum–sigmoid segment (final 20 % of the video). An open-label cohort of adults with quiescent UC (partial Mayo score ≤ 2 for ≥6 months) was prospectively enrolled at a single center (August 2022–February 2023), and followed for 24 months after baseline colonoscopy; clinical relapse was defined as partial Mayo score > 2. The predictive value of QUAD scores for relapse was evaluated.

Results

Frame-level QUAD scores correlated strongly with expert-assigned MES values (Spearman r = 0.68, p < 0.01). Among 156 participants (median age, 51 years; 49 % male), 22 experienced relapse during follow-up. Relapse occurred in 19.4 % (19/98) of patients with a QUAD score > 3 versus 5.2 % (3/58) with a score ≤ 3 (log-rank p = 0.01).
In video analysis, an Entire QUAD > 6 did not significantly stratify relapse risk (16.8 % [17/101] vs 9.1 % [5/55]; log-rank p = 0.17). In contrast, a Distal QUAD > 3 was strongly associated with relapse (43.8 % [7/16] vs 10.7 % [15/140]; log-rank p < 0.01).

Conclusion

AI-generated QUAD provides a sensitive, fully quantitative measure of mucosal inflammation and stratifies relapse risk in clinically quiescent UC. In particular, the automatically derived Distal QUAD—focused on the distal colon and independent of operator image selection—offers a practical, objective tool for longitudinal monitoring and treatment tailoring in UC.

Introduction

Crohn’s disease (CD) is a human immune-mediated inflammatory disease (IMID) of unknown etiology that affects the gastrointestinal (GI) tract. CD is now a global health issue due to its lifelong nature and significant burden on patients and public health [1]. Phase III clinical trials have shown that treatment with oral Janus Kinase (JAK) inhibitors can alleviate disease in patients with CD. However, the United States (US) Food and Drug Administration (FDA) has issued warnings about side effects for this class of oral drugs which target JAKs systemically in the human body. Therefore, new targeted delivery approaches are needed to block JAK activity selectively in the GI tract. The JAK1/2-STAT1 intracellular signaling pathway is activated by the Th1 cytokine IFN-γ alone or in synergy with another Th1 cytokine, TNF-α, and SOSC1 is an endogenous negative regulator of JAK1/2. This pathway activates the expression of inflammatory genes in multiple cell types typically associated with active or inflamed CD [2]. RNA interference (RNAi) mediated gene silencing using small interfering RNA (siRNA) targeting JAK1/2-STAT1 and SOCS1 overexpression using exogenous SOCS1 mRNA are promising methods to reduce the JAK-STAT pathway activation.

Aims & Methods

The GENEGUT project aims to develop oral RNA-based therapies for ileal CD. In this study, we have developed new approaches to deliver siRNAs targeting JAK1, JAK2, and STAT1 into relevant cell models, including human intestinal epithelial cell (IEC) lines. Epithelial cell models that replicate the inflammatory microenvironment in CD were used by exposing IECs to inflammatory cytokines IFN- γ/TNF- α, leading to increased cytokine production and cell death.

Results

Selected siRNAs effectively blocked JAK1, JAK2 and STAT1 expression and activity, preventing the downstream activation of inflammatory and cell death pathways. SOCS1 overexpression also suppressed JAK1/2-STAT1 pathway activation and enhanced cell survival.

Conclusion

Ongoing work is focused on optimizing the delivery of siRNA and mRNA into differentiated epithelial monolayers, co-cultures and patient-derived organoids to advance translational applications.

References

1. Dulai PS, Singh S, Vande Casteele N, Boland BS, Rivera-Nieves J, Ernst PB, Eckmann L, Barrett KE, Chang JT, Sandborn WJ. Should We Divide Crohn's Disease Into Ileum-Dominant and Isolated Colonic Diseases? Clin Gastroenterol Hepatol. 2019 Dec;17(13):2634-2643. doi: 10.1016/j.cgh.2019.04.040. Epub 2019 Apr 19. PMID: 31009791; PMCID: PMC6885453.
2. Cordes F, Foell D, Ding JN, Varga G, Bettenworth D. Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn's disease. World J Gastroenterol. 2020 Jul 28;26(28):4055-4075. doi: 10.3748/wjg.v26.i28.4055. PMID: 32821070; PMCID: PMC7403801.

Disclosure

Funded by the European Union (GA 101057491) and supported the Swiss State Secretariat for Education, Research and Innovation (SERI) under contract number 22.00119. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HaDEA). Neither the European Union nor the granting authority can be held responsible for them. UK participants in Horizon Europe Project GENEGUT are supported by UKRI grant number 10042451 (Bangor University).

Introduction

Prevalence of MASLD in patients with Inflammatory Bowel Disease (IBD) has been and 21.6% in a previous cross-sectional study from our center. However, data on the progression of MASLD in IBD patients are scanty. reported 24.4% in a recent metaanalysis

Aims & Methods

We aimed to investigate the prevalence and the progression of MASLD, diagnosed by non-invasive tools, in a homogeneous cohort of patients with IBD followed in our referral center.
Consecutive IBD patients without known chronic liver disease were retrospectively enrolled and prospectively followed between 2020 and 2024. MASLD was defined as Controlled Attenuation Parameter (CAP) ≥275 dB/m. Significant fibrosis was defined as Liver Stiffness (LSM) ≥8 kPa by FibroScan. Demographic, metabolic and biochemical data were collected at baseline and at the last follow-up visit. All patients were genotyped for PNPLA3 rs738409 C>G by Taqman assay. Appropriated statistical analysis were performed to identify risk factors associated with the prevalence of MASLD and its progression.

Results

230 patients (mean age was 46.1±13.4 years, 49.2% were males, 50.8% had Crohn’s disease, mean disease duration was 9.4±7.5 years) were recruited. 14.8% of them were obese (BMI > 30 kg/m2), 9.8% diabetic. 49.2% were PNPLA3 rs738409 CG/GG. 116 out of 230 patients had complete metabolic and biochemical assessment at follow-up. Mean follow-up time was 4 years. At baseline, 25% (29/116) had MASLD. 18% (16/87) of patients without steatosis at baseline, developed steatosis at follow-up; while 44 % of those having steatosis at baseline, did not show steatosis at follow-up. 13.5% developed obesity. Obesity was significantly associated with the prevalence of MASLD both at baseline (p=0.040) and on follow-up (p<0.001) and was a predictor of steatosis progression (p<0.001); no association was found in relation to sex, PNPLA3 polymorphism, disease characteristics and the use of biologics. Diabetes was not significantly associated with MASLD in our cohort, but the number of patients was low. The Biologics use was significantly associated with the steatosis regression (p=0.038).

Conclusion

One third of IBD patients had MASLD and obesity was the main predictor of its prevalence and progression, highlighting the relevance of active surveillance of MASLD and appropriate nutritional and lifestyle counselling especially in obese IBD patients. Further studies needed to confirm our results and to identify other risk factors for MASLD in larger populations

Introduction

Vedolizumab (VDZ), an α4β7 integrin receptor antagonist monoclonal antibody, reduces inflammation and induces clinical remission in the treatment of Inflammatory Bowel Disease (IBD) patients with high efficacy and safety. The effect of this treatment on the gut microbiome and its relationship with clinical outcomes are still underexplored in IBD patients.

Aims & Methods

In this study, the effect of VDZ treatment on changes in gut microbiota composition of IBD patients was explored and correlated with clinical data and colonic epithelial barrier integrity.23 IBD patients undergoing VDZ treatment and 16 healthy controls (HC) were enrolled. Crohn's disease (CD) and ulcerative colitis (UC) patients were evaluated for clinical remission and response using the Harvey-Bradshaw Index (HBI) and the Partial Mayo Score (PMS), respectively, at three time points: before treatment (T0), after 24 weeks (T1), and after 52 weeks (T2). Clinical response to VDZ treatment was defined as a reduction in the Harvey-Bradshaw Index (HBI) score > 2 for CD and a decrease in the Partial Mayo Score (PMS) > 2 for UC, along with either a rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1. During each endoscopy, 8 colonic biopsies were collected for immunohistochemical analyses, permeability assessment using the Ussing Chambers system and for microbiota analysis via MiSeq 16S rRNA gene sequencing. Immunohistochemical analysis of integrin α4β7 and tight junction (TJ) complex system proteins was performed.

Results

A significant reduction in PMS (p<0.0001) and HBI (p<0.01) was observed in the IBD population at T2 compared to T0. A significant increase in Roseburia, Collinsella, Tidjanibacter, and a decrease in Enterocloster and Clostridium were observed in IBD patients at T2 compared to T0 in fecal microbiota. The mucosal microbiota of IBD patients at T2 demonstrated significant enrichment of Proteobacteria and Acidaminococcus compared to T0. When stratifying the IBD patients into clinical responders (RSPs) and non-clinical responders (nRSPs) at T2, an increase in Firmicutes, Actinobacteria, and Proteobacteria was observed in RSPs at T0 compared to nRSPs in the fecal microbiota, with an enrichment in Bifidobacterium highly associated with response to VDZ. Interestingly, a significant enrichment of Prevotella at T0 and of Akkermansia at T2 was found in the mucosal microbiota of RSPs. Finally, at T2, a negative correlation was identified between Clostridium and TEER values (p=0.0048) and between Ruminococcus and FD-4 permeability values (p=0.0001). Immunohistochemistry data showed an enhanced expression of integrin α4β7 at T0 compared to controls; a significant reduction was observed at T1 and T2. Concurrently, the expression of TJ complex system proteins was significantly reduced before treatment (T0) compared to controls, with a significant increase after 24 weeks; this increase was maintained following 52 weeks.

Conclusion

These findings suggest that VDZ, by reducing leukocyte trafficking and mucosal inflammation, may positively impact intestinal barrier integrity and address intestinal dysbiosis in IBD patients. Further studies are needed to identify specific biomarkers advancing the approach toward personalized medicine.

References

1. Lo Presti A, Zorzi F, Del Chierico F, Altomare A, Cocca S, Avola A, De Biasio F, et al. Fecal and Mucosal Microbiota Profiling in Irritable Bowel Syndrome and Inflammatory Bowel Disease. Front Microbiol. 2019
2. Cicala M, Gori M, Balestrieri P, et al. Colonic Epithelial Permeability to Ions Is Restored after Vedolizumab Treatment and May Predict Clinical Response in Inflammatory Bowel Disease Patients. Int J Mol Sci. 2024
3. Ananthakrishnan AN, Luo C, Yajnik V, et al. Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 2017
4. Schneider I, Allner C, Mühl L, et al. Expression and function of α4β7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease. Transl Res. 2023;253:8-15.