Introduction

Increased mesenteric blood flow in inflammatory bowel disease (IBD) alters biomechanical forces acting on intestinal vascular endothelial cells (ECs). These cells sense mechanical stimuli through the mechanosensitive ion channel Piezo1, which transduces these forces into pro-inflammatory signaling, thereby aggravating inflammation. Moreover, lactate contributes to immune regulation by influencing macrophage polarization. However, the precise role of Piezo1 in governing endothelial lactate metabolism during IBD pathogenesis remains insufficiently understood.

Aims & Methods

To elucidate the role of Piezo1 in IBD, single-cell RNA sequencing was conducted on colonic tissues from IBD patients and healthy controls to evaluate Piezo1 expression and its association with lactate metabolism. Endothelial cell-specific Piezo1 knockout (Piezo1^ΔEC/ΔEC) mice were generated and subjected to DSS-induced colitis to assess inflammation severity, lactate levels, and macrophage polarization. CRISPR-Cas9 technology was employed to knock out Piezo1 in human umbilical vein endothelial cells (HUVECs). The involvement of the HIF-1α-mediated glycolysis pathway and monocarboxylate transporter 1 (MCT1) in Piezo1-dependent lactate regulation was also investigated.

Results

Piezo1 expression was significantly upregulated in intestinal ECs from active IBD patients and DSS-induced colitis mice compared to controls. Single-cell sequencing further confirmed the enrichment of Piezo1 in intestinal ECs during active inflammation. In DSS-induced colitis, Piezo1^ΔEC/ΔEC mice exhibited decreased levels of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β), a reduced M1/M2 macrophage ratio, and lower lactate concentrations in both endothelial cells and plasma. Piezo1 activation promotes aerobic glycolysis through the Ca²⁺-induced CaMKII-HIF1α axis. Moreover, the Piezo1/HIF-1α pathway upregulated MCT1 expression in ECs, enhancing lactate transport across mesenteric vessels. Deletion of Piezo1 suppressed MCT1 expression, normalized plasma lactate levels, attenuated M1 macrophage activation, and ameliorated colitis severity in Piezo1^ΔEC/ΔEC mice.

Conclusion

These findings demonstrate that mechanical forces activate Piezo1 in intestinal ECs, driving lactate metabolism through the Piezo1-HIF-1α-MCT1 axis and promoting M1 macrophage differentiation, which subsequently contribute to intestinal inflammation in IBD. Targeting Piezo1 may represent a promising therapeutic strategy for the treatment of IBD.

Introduction

Tyrosine kinase 2 (TYK2) inhibitors block signaling downstream of multiple pro-inflammatory cytokines involved in immune-mediated inflammatory diseases, including inflammatory bowel disease, and may have an improved safety profile relative to Janus kinase inhibitors. Phase 2 studies of the highly selective and potent TYK2 inhibitor zasocitinib in Crohn’s disease (CD; NCT06233461) and ulcerative colitis (UC; NCT06254950) are ongoing.^1,2 Here, we describe the design of a combined open-label extension trial (NCT06764615), which will include patients from both parent trials who are responsive to treatment.

Aims & Methods

Patients are eligible for the phase 2 parent studies in CD and UC if they are aged 18–75 years with moderately to severely active disease, and have inadequate or loss of response to, or intolerance of, ≥ 1 standard or advanced therapy. Patients who have failed treatment with ≥ 3 classes of advanced therapy are excluded. Patients are randomized to one of three (CD) or two (UC) doses of zasocitinib, or placebo, for a 12-week double-blind induction phase followed by a 40-week sponsor-open (CD) or open-label (UC) maintenance period. At the end of the parent trials, patients will be eligible for the combined open-label extension if they are clinical (CD) or symptomatic (UC) responders at Week 52, defined as: (1) CD: a ≥ 30% decrease in average daily very soft or liquid stools and/or a ≥ 30% decrease in average daily abdominal pain from baseline; and (2) UC: a ≥ 1-point and ≥ 30% decrease from baseline in partial modified Mayo score, and a ≥ 1-point decrease from baseline in rectal bleeding (RB) subscore or achievement of an absolute RB subscore of ≤ 1. All enrolled patients will receive the same dose of open-label, oral, once-daily zasocitinib for a maximum of 108 weeks, with study visits every 12 weeks, followed by a 4-week safety follow-up period. Data analysis will be descriptive, with no formal statistical comparisons performed.

Results

The primary objective of the study is to determine long-term safety and tolerability, assessed through the incidence of treatment-emergent adverse events or adverse events of special interest. Secondary endpoints will assess the long-term efficacy of zasocitinib, including clinical, symptomatic, or endoscopic response or remission by visit or at Weeks 48 and 108, according to indication, and effects on patient-reported outcomes, including fatigue, bowel urgency, abdominal pain, and disease-specific health-related quality of life.

Conclusion

This open-label extension trial will provide data on the long-term safety of zasocitinib, as well as durability of treatment response among patients with CD or UC who experience treatment benefit in the phase 2 parent studies.

References

1. Jairath V et al. UEG Journal 2024;12(S8):1033.
2. Peyrin-Biroulet L et al. UEG Journal 2024;12(S8):1041.

Disclosure

GP reports receiving personal payments, honoraria, or speaker fees from AbbVie, Allergan, BMS, Celltrion, Ferring, Galapagos, Janssen, Pfizer, Sorriso, Takeda, and Tillotts, travel grants or fellowships from AbbVie, Celltrion, Ferring, Janssen, Takeda, and Tillotts, and is a Director and shareholder in Ampersand Health. SGR, LZ, VAN, LA, FN, TF, LS, and NS are employees and shareholders of Takeda.

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

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

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

Artificial intelligence tools for endoscopic assessment of Ulcerative Colitis remain limited due to suboptimal agreement with expert readers and reliance on small, inconsistently labeled datasets. We developed a novel computer vision model (DovaVision) trained on a large-scale, expert-annotated video dataset to assess UC activity using detailed frame-level features.

Aims & Methods

DovaVision was pre-trained using DINOv2 self-supervised learning on 845 colonoscopies and millions of GI images, then significantly refined using annotations collected via a proprietary platform. 15 IBD central readers (CRs) scored video frames for five UC features (vascular pattern, bleeding, ulcers/erosions, friability, erythema) across multiple severity levels. Annotators underwent standardized onboarding to ensure high inter-rater reliability. The model comprises two vision transformer architectures: a Quality Control (QC) module to exclude low-quality/non-diagnostic frames, and a Scoring module that outputs feature-specific severity grades. Model outputs include burned-in heatmaps (for mapping of disease activity to specific timepoints) and structured JavaScript Object Notation (JSON) files.

Results

A total of 83.8 million frames from 200 colonoscopy videos were labeled by 3 expert CRs across 7 categories per video, yielding 16.9 million merged labels by majority vote. Inter-rater agreement on modified Mayo Endoscopic Score (MES) showed strong reliability (ICC = 0.86; QWK = 0.88). On a 31-video validation set from 3 separate data sources, DovaVision showed equivalency with the gold standard of CR consensus (2+1 majority vote), achieving a QWK of 0.904 and ICC of 0.907. In comparison, the pool of 3x CRs assigned/video on this same set showed ICC of 0.905. On friability assessment—a challenging feature-- DovaVision showed 90% agreement and 0.811 ICC when compared to gold standard (3x CR majority vote), while the agreement for 3 CRs per video was only 0.447 ICC on the same set. The average model inference time was short at 3.5 minutes per video. The model also outputs continuous “frame-by-frame” level information on the sub-score characteristics. The model is an entire data processing pipeline deployed on a cloud architecture with an API for secure authentication, bulk data upload, and secure results storage/retrieval.

Conclusion

DovaVision is a validated AI-based model for automated grading of UC severity on endoscopy. Its high concordance with expert readers, detailed feature-level (sub-score characteristics) analysis, and rapid inference support real-world integration into clinical and research workflows. Although further validation with additional datasets is required.

Disclosure

Dr. Michael Byrne is the Chairman, Founder and CMO at Dova Health Intelligence

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.