Introduction

Prophylactic total gastrectomy (PTG) is the definitive treatment for hereditary diffuse gastric cancer syndrome (HDGC). Endoscopic surveillance informs the requirement and optimal timing to surgery. However, endoscopic recognition of early signet ring cell carcinoma (SRCC) remains challenging. In this study, we aimed to develop and prospectively validate a user-friendly diagnostic framework with machine-learning to support endoscopists in accurate identification of early SRCC during surveillance in HDGC individuals.

Aims & Methods

We retrospectively analysed 147 HDGC individuals undergoing endoscopic surveillance to evaluate the diagnostic accuracy of endoscopic criteria (Cambridge criteria), develop a clinical decision tree (cDT) to better apply the criteria based on machine leaning, and investigate its clinical significance. We then prospectively validated cDT in 66 CDH1 pathogenic-variant carriers. The inter-observer agreement and diagnostic accuracy of Cambridge criteria and cDT were assessed through multi-reader multi-case study.

Results

Retrospective analysis of 537 endoscopies showed Cambridge criteria achieved 82.8% (48/58) sensitivity and 78.2% (140/179) specificity for SRCC diagnosis. The presence and number of neoplastic pale areas are independent predictors of higher cancer burden in HDGC individuals. In prospective study, cDT had 77.8% (21/27) sensitivity and 90.7% (49/54) specificity. The cDT significantly improved average sensitivity among non-experts from 66.7% to 72.5% and 87.5%, and among experts from 74.1% to 80.0% and 91.7% (P = 0.03).

Conclusion

We developed and validated a practical endoscopic framework to enhance SRCC assessment during HDGC endoscopic surveillance.

Introduction

Hepatobiliary disorders are recognised extraintestinal manifestations in inflammatory bowel disease (IBD). Up to 30% of patients exhibit abnormal liver function tests and 5% will develop chronic liver disease (1). IBD-associated liver diseases (IBDALD), comprising primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) and AIH/PSC overlap syndrome carry significant morbidity through progressive hepatobiliary damage and increased cancer risk. Early recognition is challenging due to non-specific biochemical derangement and heterogeneous presentation. No validated stratification tools exist for prospective risk identification. This study investigated whether routinely collected biomarkers convey predictive value for IBDALD, leveraging large-language model (LLM) refined phenotyping.

Aims & Methods

We analysed 1,571 paediatric and adult-onset IBD patients recruited to the “Genetics of IBD” study (Southampton, UK; 2010–). IBDALD cases were identified through LLM-assisted (Llama 3.1-70B-Instruct) structuring of 32,041 free-text imaging and histopathology reports, followed by clinician verification (2). Participants diagnosed with IBDALD prior to IBD were excluded from further analysis. Examined biomarkers included ALT, ALT and ESR (n=335,605 datapoints for the examined cohort). For each biomarker, patient-level medians were calculated from all available results within ±6 months of IBD diagnosis. A 1:4 individual matched case-control design was applied (matched on age at IBD diagnosis, gender, and IBD subtype) in R. Conditional logistic regression models assessed associations between IBDALD and biomarker values, treated as both continuous (patient-level medians) and binary – normal versus abnormal - (age- and sex-adjusted lab range flags) variables. Longitudinal biomarker trajectories were explored using LOESS and linear mixed-effects models.

Results

Thirty-five cases of IBDALD were identified (27 post-IBD diagnosis). Median follow-up duration was 11.5 (0.5–59.5) years and median 4.5 years (0.4–39.1) from IBD diagnosis to liver disease onset. In whole cohort analyses, ALT, ALP, and ESR were significantly elevated in IBDALD at diagnosis of IBD (p < 0.01). In matched case-control models, higher median ALT (OR = 1.04 per U/L increase, 95% CI: 1.01–1.07, p = 0.012), ALP (OR = 1.01, 95% CI: 1.00–1.02, p = 0.014), and ESR (OR = 1.05, 95% CI: 1.00–1.09, p = 0.034) were each associated with IBDALD. In a combined model including all three biomarkers, none retained statistical significance. When analysed as binary (normal/abnormal) variables, ALT and ALP remained significantly associated with IBDALD (ALT: OR = 5.10, 95% CI: 1.57–16.59, p<0.01; ALP: OR = 15.33, 95% CI: 1.87–125.77, p<0.05). ESR did not reach significance (OR = 3.71, 95% CI: 0.75-18.32 p=0.107). Longitudinal modelling supported distinct ALT and ALP trajectories in the IBDALD group and distinct trends over time were visualised for ALT, ALP and ESR in LOESS scatterplots.

Conclusion

These data suggest that routinely measured biomarkers may carry early predictive signals for IBD-associated liver disease, identifiable at the time of IBD diagnosis. The use of LLM-assisted phenotyping enabled high-fidelity case definition within real-world data. These findings should be interpreted cautiously given the rarity of IBDALD and potential overfitting in multivariable models. Future prospective studies are warranted to validate predictive models and support integration into IBD care pathways.

References

1. Scott JA, Mysko C, Purssell H, et al. Investigation of abnormal liver blood tests in patients with inflammatory bowel disease. Frontline Gastroenterology 2024;15:516-522.
2. Kadhim A, Green Z, Nazari I, et al. Application of Generative Artificial Intelligence to Utilise Unstructured Clinical Data for Acceleration of Inflammatory Bowel Disease Research. Article in PrePrint medRxiv 2025.03.07.25323569; doi: https://doi.org/10.1101/2025.03.07.25323569

Disclosure

JJA is a SAB member for Orchard Therapeutics.

Introduction

The intestinal mucosa undergoes constant renewal, with epithelial and immune cells routinely shed into the gut lumen. Recent findings suggest that these shed cells remain viable and retain transcriptomic signatures relevant to bowel pathology. Analysis of luminal content obtained during colonoscopy indicates that Fecal Host Transcriptomes (FHT) mirror histologic inflammation in IBD. This study aimed to evaluate whether sequencing of stool samples can noninvasively reflect the presence of intestinal inflammation in patients with IBD, predict the location of inflammation within the bowel and distinguish between IBD type; Crohn’s Disease and Ulcerative Colitis.

Aims & Methods

Our aim was to investigate whether transcriptomic analysis of stool samples that are taken ambulatory or at home could reveal the inflammation signature of inflamed IBD patients.
Bulk RNA sequencing of stool samples from 71 IBD patients and healthy controls was used to generate FHTs. Each sample was paired with an endoscopic assessment and clinical data to capture a time-matched view of intestinal inflammation. Three random forest classifiers were trained to: (1) distinguish active inflammation from remission; (2) predict inflammation location in Crohn’s disease (colon vs. small intestine). and (3) classifier based on gene modules expression was used to differ between CD and UC in patients with active inflammation.

Results

Fecal RNA quality was high, with a median of 2,140 human genes detected per sample. The FHT test demonstrated robust performance across all tested applications. The first model, designed to distinguish active inflammation from remission (n = 71), achieved a sensitivity of 85% and a specificity of 92%. The second model, which predicted the location of inflammation in Crohn’s disease patients (n = 21), achieved 100% sensitivity and 100% specificity. The third model, aimed at differentiating Crohn’s Disease from Ulcerative Colitis (n = 35), reached a sensitivity of 83% and a specificity of 100%. These findings underscore the potential of FHTs as a non-invasive tool for comprehensive inflammation profiling in IBD.

Conclusion

Fecal shed cell transcriptomics offers a novel, non-invasive approach for assessing mucosal inflammation at the endoscopic level in IBD patients. This approach enables differentiation between disease activity states, anatomical localization of inflammation, and IBD subtype classification. Ongoing studies aim to evaluate its utility in grading inflammation severity and predicting therapeutic response.

References

Dan et al., CMGH 2023
Ungar et al., GUT 2022

Introduction

Vedolizumab (VDZ) is a monoclonal antibody therapy approved in China in 2020 for the treatment of patients with inflammatory bowel disease (IBD; Crohn's disease [CD] and ulcerative colitis [UC])² who were intolerant to conventional therapies.¹ VDZ has a unique, gut-selective, anti-lymphocyte trafficking (GSALT) mechanism of action.³ However, data on the efficacy and safety of VDZ in Chinese patients with IBD in the real-world setting are limited.⁴ This study evaluated the safety of VDZ in adult patients with IBD.

Aims & Methods

VALUE (NCT04872491) was a multicenter, single-arm, prospective, observational study to evaluate the safety of VDZ in adult Chinese patients with IBD (N=500) over a maximum observation period of 72 weeks. Incidence of adverse events (AEs), serious AEs (SAEs), treatment-related adverse drug reactions (ADRs), and AEs of special interest (AESIs) was evaluated. This was the final analysis of the VALUE study conducted in patients with IBD.

Results

A total of 500 patients (UC: n=409; CD: n=91) received VDZ 300 mg. Mean (±standard deviation) age of patients was 44.3 (±15.2) years, and 61.4% (n=307) were male. The mean duration for VDZ exposure was 414 days (UC: 416 days; CD:407 days). A total of 500 patients developed 674 AEs (Table), and the most frequent AEs were infections and infestations (I&I; UC: 115 [28.1%]; CD: 24 [26.4%]), followed by gastrointestinal disorders (GIDS; UC: 87 [21.3%]; CD: 18 [19.8%]). Incidence rates of AEs (/patient-years) were 1.2 and 1.0 in patients with UC and CD, respectively. Overall, 13 (3.2%) patients with UC and 10 (11.0%) with CD had AEs leading to study discontinuation. SAEs were observed in 78 patients with UC and 18 with CD (Table). A total of 19 AESIs were reported by patients with UC and 9 AESIs by those with CD, with the most common AESIs being I&I (UC: 13 [3.2%]; CD: 4 [4.4%]) and malignancy (UC: 3 [0.7%], CD: 2 [2.2%]). The most common I&I disorders reported by patients with UC and CD were Clostridium difficileinfection (4 [1.0%]) and pneumonia (1 [1.1%]), respectively. Overall, 17 (4.2%) patients with UC and 7 (7.7%) with CD had at least 1 AESI. A total of 91 and 15 treatment-related ADRs were observed in patients with UC and CD, respectively; I&I were the most frequently documented ADRs to VDZ treatment (Table). A total of 10 (UC: 5 [1.2%]; CD: 5 [5.5%]) patients treated under concomitant IBD advanced therapy (CIBDAT) experienced a total of 16 AEs (UC: 9; CD: 7), with the most common AEs being I&I (UC: 1 [20.0%]; CD: 2 [40.0%]) and GIDS (UC: 3 [60.0%]; CD: 1 [20.0%]) with CIBDAT. No deaths were reported during the study.

Conclusion

The VALUE study indicated that VDZ was well tolerated in Chinese patients with IBD, with no new safety concerns.

References

1. Scribano ML. World J Gastroenterol. 2018; 24: 2457-2467.
2. Yamamoto S et al., Cureus. 2024;16: e59691.
3. Soler D et al. J Pharmacol Exp Ther. 2009; 330: 864-875.
4. Baili C et al. Am J Gastroenterol. 2023; 118: S213-S214.

Disclosure

This study was funded by Takeda (China) International Trading Co. Ltd. Li Li, Haiyan Zhang, Chengxia Liu, and Xiaomei Sun have no conflicts of interest. Xiaoyu Qian and Fang Zhou are Takeda employees and hold Takeda stock options. Minhu Chen received speaker honorariums from Takeda China, AstraZeneca China, Xian Janssen, and Eisai China.
Medical writing support for the development of this abstract under the direction of the authors was provided by Vibhuti Singh, Ph.D., of Cactus Life Sciences (part of Cactus Communications), funded by Takeda (China) International Trading Co., Ltd.

Introduction

Chemotherapy-induced diarrhea (CID), a dose-limiting toxicity impairing treatment adherence and anticancer efficacy, lacks targeted prophylaxis. While short-acting glucagon-like peptide-2 (GLP-2) analog was approved for short bowel syndrome (SBS), the mucosal regenerative properties of GLP-2 suggest therapeutic potential for CID prevention. GLP-2 can also enhance the intestinal mucosal barrier and may provide a new treatment option for inflammatory bowel disease (IBD). In this study, we developed FT1, a long-acting GLP-2 analog engineered for sustained exposure, and reported first-in-human phase I trial data of FT1 in Chinese healthy adults.

Aims & Methods

This randomized, double-blind, placebo-controlled, single-center phase I study (NCT06610487) evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of FT1 to establish dosing rationale for the future CID trials. Single ascending dose (SAD: 0.05-0.4 mg/kg) and multiple ascending dose (MAD: 0.1-0.2 mg/kg, once weekly for 3 weeks) were administered subcutaneously. Participants were randomized 3:1 (SAD; except for 0.05 mg/kg: 2:1) or 4:1 (MAD) to receive FT1 or placebo. Plasma citrulline, a validated biomarker of enterocyte mass, served as the primary PD endpoint. Safety, PK, PD, and immunogenicity were assessed up to 28 days post-dose.

Results

Currently available analyzed data (n=50) revealed:
1. PK: FT1 exhibited dose-proportional exposure (C_max/ AUC_0-inf) across SAD doses (0.05-0.4 mg/kg). Median T_max was 24 h with prolonged t_1/2 = 67.6-69.1 h. MAD regimens showed moderate accumulation (1.42- 1.73-fold post-3rd dose).
2. PD: Citrulline elevation was dose- and regimen-dependent. SAD 0.4 mg/kg achieved maximal change in plasma citrulline (ΔE_max) = 3,340 ng/mL (baseline: 5,125 ng/mL) at 8.5 days post-dose. After weekly administration of FT1, the citrulline level was further enhanced. MAD 0.2 mg/kg induced 33% greater ΔE_max vs MAD 0.1 mg/kg (4,512 vs 3,390 ng/mL; both post-3rd dose), exceeding SAD 0.4 mg/kg response.
3. Safety: All adverse events were Grade 1-2 (CTCAE v5.0) with no dose-limiting toxicities or immunogenicity signals.

Conclusion

FT1 demonstrated favorable safety and linear PK up to 0.4 mg/kg (SAD) and 0.2 mg/kg weekly×3 (MAD) in healthy participants. The 0.2 mg/kg MAD regimen achieved superior enterotrophic effects (citrulline ΔE_max) versus lower doses while maintaining tolerability, supporting it as a priority candidate for further clinical evaluation in patients with once-weekly dosing.

References

1. McQuade RM, et al. Chemotherapy-induced constipation and diarrhea: pathophysiology, current and emerging treatments. Front. Pharmacol. 2016, 7:414.
2. Barzał J, et al. Plasma citrulline level as a biomarker for cancer therapy-induced small bowel mucosal damage. Acta Biochim Pol. 2014; 61(4):615-31

Disclosure

Chengyong Tang, Mingxue Zhu, and Lei Wan have no conflicts of interest that are directly relevant to the content of this article. Kai Fan, Qing Chen, and Yanmin Bai are Chongqing Peg-Bio Biopharm Co., Ltd employees.

Introduction

Mitochondrial dynamics refers to coordinated cycles of mitochondrial fission and fusion that allow mitochondrial networks to re-model their shape, distribution and size. These transient processes are involved in multiple cellular functions and the perturbation of mitochondrial dynamics is reported in models of Inflammatory Bowel Diseases (IBD). The role of Dynamin-related protein 1 (Drp1), a critical GTPase for mitochondrial fission, remains understudied in an intestinal disease context.

Aims & Methods

This research aims to examine how mitochondrial networks are altered in mouse and cell culture-based models of intestinal injury and IBD. Cell culture-based assays were performed with the MODE-K intestinal epithelial cell line to explore the role of mitochondrial dynamics in vitro. A Drp1-specific knockout (Drp1 KO MODE-K) was generated using CRISPR-based approaches . Mitochondrial fission was also targeted pharmacologically using P110 and Mdivi-1 fission inhibitors. Intestinal tissue from IBD-related mouse models including TNF^ΔARE (ileitis), Il10^-/- (colitis), Hsp60 ^Δ/ΔIEC (metabolic injury) and Hsp60 ^Δ/ΔIEC;Il10^-/- (metabolic injury/colitis) mice were used for histological analyses and ex vivo organoid cultures. TOM20 was used to stain mitochondrial networks. A novel IBD mouse model with a Drp1 intestinal epithelial cell specific knockout Drp1 ^Δ/ΔIEC;Il10^-/- was generated to assess the role of Drp1-mediated mitochondrial fission in vivo.

Results

TOM20 immunofluorescence staining of mouse tissue sections show that mitochondrial morphology, localisation and mass are diverse under different inflammation and injury-based conditions. The colitis susceptible Il10^-/- mice typically show more fragmented, rounder mitochondria with a decrease in mitochondrial mass compared to Il10^+/+ controls. Hsp60^Δ/ΔIEC mice have a conditional deletion of the Heat shock protein 60 (Hsp60) in the epithelium which results in metabolic injury, a transient tissue injury with irregular tissue architecture and altered mitochondrial metabolism. This Hsp60 loss further accelerates Il10^-/- pathology in Hsp60 ^Δ/ΔIEC;Il10^-/- mice. At day 4 (D4) post tamoxifen treatment, before the onset of crypt loss, Hsp60 ^Δ/ΔIEC;Il10^-/- mice show an increase in a phosphorylated form of Drp1 (pDrp1^Ser616) indicating increased mitochondrial fission. At day 8 (D8), during peak metabolic injury, both Hsp60 ^Δ/ΔIEC;Il10^+/+ and Hsp60 ^Δ/ΔIEC;Il10^-/- mice show a significant increase in mitochondrial mass compared to controls. Furthermore, co-stimulation of ex vivo wild-type organoids with the inflammatory cytokine Tnf and the Drp1-specific inhibitor P110 increases mitochondrial unfolded protein response (UPR) markers at the mRNA level, highlighting the interplay between mitochondrial dynamics and stress responses in injury-based inflammatory conditions. Drp1 KO MODE-K cells also show a noticeable increase in dense, peri-nuclear TOM20 staining when compared to control cells. In extension, the novel Drp1 ^Δ/ΔIEC;Il10^-/- model has proved viable and preliminary data indicates that Drp1 ^Δ/ΔIEC;Il10^+/+ mice have reduced body weights compared to Drp1 ^flox/flox;Il10^+/+ mice. Further characterisation will provide insight into the interplay between Drp1, mitochondrial dynamics and intestinal disease development.

Conclusion

Mitochondrial networks are altered in response to different types of inflammation or injury in models of IBD. Regulated mitochondrial fission and fusion is important for intestinal epithelial cell homeostasis and Drp1 loss or inhibition affects intestinal epithelial cell responses.

Introduction

Clostridioides difficile infection (CDI) is the most common cause of nosocomial diarrhoea, and
during the last decades its incidence has significantly increased, not only in the hospital setting but
also in the community (1). CDI includes severe clinical pictures of disease. Fecal microbiota
transplantation (FMT) is an established treatment for recurrent CDI, but its role in severe clinical
pictures of CDI is still not well defined.

Aims & Methods

Our aim is to report efficacy and safety of FMT in a large cohort of patients with severe and severe-
complicated CDI. We included patients with severe CDI treated with FMT at our center from June
2013 to August 2024. Severe and severe-complicated CDI were defined according to international
guidelines. Data was collected on patient demographics, CDI characteristics, including disease
severity, risk factors and concomitant diseases. Enrolled patients were followed up at 12 weeks after
the last FMT. The primary outcome was the clinical resolution of CDI at 8 weeks after FMT, while
the secondary outcomes were the overall survival at 90 days and the safety of FMT. Donor stools
were screened following international guidelines. Prior to fecal infusion, all patients underwent a 3-
day antibiotic pre-treatment regimen with oral vancomycin or fidaxomicin, as well as bowel
cleansing. FMT procedures were carried out by colonoscopy using a single-donor solution of at
least 50 grams of fresh or frozen feces. A sequential FMT approach was planned in patients with
pseudomembranous colitis (PMC), until the disappearance of pseudomembranes, or in patients who
experienced diarrhea after the initial FMT with a persistence of C. difficile toxin on stool samples.

Results

125 patients were enrolled (60.8% female, mean age 71 years). One-hundred and ten patients had
severe CDI (88%), 15 had severe complicated CDI (12%). Of them, 73 patients had
pseudomembranous colitis (58.4%). The median number of CDI recurrences was 2. A sequential
FMT protocol was performed in 62 patients (49.6%), for a total of 235 FMT procedures. Regarding
risk factors, the most frequent were hospitalization (107 patients – 85.6%), antibiotic use in the 30
days prior to infection (94 patients – 75.2%), chronic therapy with proton pump inhibitors (74
patients – 59.2%) and enticement (39 patients – 31.2%). The median Charlson Comorbidity Index
(CCI) was 5. Overall, 108 patients (86.4%) experienced resolution of CDI (97 with severe CDI and
11 with severe-complicated CDI). 18 patients (14.4%) died within the follow-up period. No deaths
were attributable to FMT. Severe adverse events occurred in 11 (8.8%) patients and 6 were
potentially associated with FMT and/or failure to cure CDI.

Conclusion

In our cohort of patients, FMT was a highly effective and safe treatment for severe and severe-
complicated CDI.

References

1 - Liu C, Monaghan T, Yadegar A, Louie T, Kao D. Insights into the Evolving Epidemiology of
Clostridioides difficile Infection and Treatment: A Global Perspective. Antibiotics (Basel). 2023 Jul
1;12(7).