Introduction

The intestinal epithelium is the most regenerative tissue in the human body and an essential interface between the microbial ecosystem and the underlying mucosa, orchestrating both immune-mediated and metabolic functions. Mitochondrial signaling and metabolism controls the phenotype and function of intestinal epithelial cells (IECs) and mitochondrial perturbation is associated with chronic inflammation. We hypothesize that disruption of microbial-metabolic circuits and impaired metabolic flexibility of IECs contribute to the initiation and progression of tissue injury underlying chronic inflammation.

Aims & Methods

To address the role of mitochondrial impairment in epithelial homeostasis, conditional deletion of Heat shock protein 60 (Hsp60) was induced in the epithelium of Hsp60^Δ/ΔIEC and Hsp60^Δ/ΔIEC;Il10^-/- mice under specific pathogen free and germfree conditions. Blinded histological analysis was used to assess metabolic inury and tissue inflammation. Additional 16S rRNA and shallow shotgun sequencing as well as metaproteomic analysis were performed to identify microbiome changes at the compositional and functional levels. Nanostring analysis and single-cell RNA sequencing (scRNA-seq) were used to identify epithelial cell population-specific transcriptional responses and to validate these gene signatures in resected tissues from Crohn’s disease patients.

Results

Hsp60 deletion in IECs leads to the disruption of mitochondrial metabolism and the development of irregular crypt architecture, referred to as metabolic injury. Tissue lesions and IBD-related colitis are accelerated in Hsp60^Δ/ΔIEC;Il10^-/- mice. Germfree mice are protected from injury and inflammation, demonstrating a causal contribution of bacteria to metabolic injury. Mitochondrial perturbation in Hsp60^Δ/ΔIEC mice is associated with microbial dysbiosis, including an increased abundance of Bacteroides spp., which are maintained during sustained inflammation in Hsp60^Δ/ΔIEC;Il10^-/- mice. Consistently, B. caecimuris triggers tissue aberration in monocolonized-Hsp60^Δ/ΔIEC mice, supporting its deleterious role in tissue homeostasis. Furthermore, metaproteomic analysis revealed a metabolic adaptation of B. caecimuris in response to tissue injury. Importantly, the clinical relevance of Bacteroides spp. is confirmed in a combined analysis of three IBD cohorts (N=560 patients). Transcriptional profiling of the epithelium identified a gene signature in injury-associated sub-populations, including Ido1, Nos2 and Duox2. Remarkably, the identified metabolic injury gene signature discriminates inflamed (N=196) versus non-inflamed (N=147) mucosa in CD patients, thus validating the human relevance of epithelial mitochondrial disruption in IBD.

Conclusion

Bacterial presence is a key driver of intestinal injury and metabolic injury associates with dysbiotic changes, notably expansion of Bacteroides spp. and their metabolic adaptation. Furthermore, mitochondrial perturbation induces a metabolic injury signature, which differentiates inflamed versus non-inflamed mucosa in IBD patients, strengthening the hypothesis of unresolved metabolic injury as a novel concept in the pathogenesis of intestinal inflammation.

Introduction

Fecal Microbiota Transplantation (FMT) delivered through capsules is an effective therapy against recurrent Clostrdioides difficile infections (rCDI). Studies suggests that the viral part (mainly represented by bacteriophages) of donor stool plays an important role in FMT treatment effect[1]. Through filtration steps the viral fraction of donor stool can be separated from the bacterial part to produce material that can be capsulized and delivered as fecal virome transplantation (FVT) through capsules[2].
The goal of this study was to compare the effect of FVT capsules against FMT capsules as treatment of rCDI in a randomized controlled pilot trial.

Aims & Methods

In the VISION study treatment with FVT capsules was compared to the standard treatment of FMT capsules in 40 patients with first or second recurrence of C. difficile infection.
Participants were randomized 1:1 to receive either one dose of FMT or FVT capsule treatment preceded by approximately 10 days of Vancomycin 125 mg x 4 daily or Fidaxomycin 200 mg x 2 daily. The same four fecal donors were used to produce FMT and FVT material. The primary endpoint was clinical resolution defined as resolution of diarrhea with ≤ 3 daily bowel movements or persistent diarrhea with a negative C. difficile test result, eight weeks following treatment. Patients receiving antibiotics as treatment of other infections were treated with concurrent Vancomycin and were defined as treatment failures in the Intention-to-treat analysis but were excluded from the per-protocol analysis.

Results

Forty patients were randomized and received FMT or FVT capsule treatment with no significant difference between groups in baseline characteristics (Table 1). The primary outcome was achieved by 70 % (14/20) in the FVT group and 75% (15/20) in the FMT group with no significant difference between groups (p = 1). Three patients were omitted from the per-protocol analysis. Here the primary outcome was achieved by 73.7 % (14/19) in the FVT group and 83.3 % (15/18) in the FMT group with no significant difference between groups (p = 0.69).

Table 1. Baseline characteristics

Conclusion

FVT capsules were effective as treatment of rCDI and were non-inferior to FMT capsules. Larger trials are needed to further explore the efficacy of FVT capsules as treatment of rCDI.

References

[1] Liu Q, Xu Z, Dai M, Su Q, Leung Chan FK, Ng SC. Faecal microbiota transplantations and the role of bacteriophages. Clinical Microbiology and Infection 2023;29:689–94. https://doi.org/10.1016/j.cmi.2022.11.012.
[2] Rasmussen TS, Mao X, Forster S, Larsen SB, Von Münchow A, Tranæs KD, et al. Overcoming donor variability and risks associated with fecal microbiota transplants through bacteriophage-mediated treatments. Microbiome 2024;12:119. https://doi.org/10.1186/s40168-024-01820-1.

Disclosure

Frederik Cold declares support for attending meeting and/or travel from AbbVie and Orion Pharma, Andreas Munk Petersen declares support for attending meeting and/or travel from AbbVie, grants or contracts from Chr. Hansen A/S part of Novonesis and consulting fee from Genfit, Hengameh Chloe Mirsepasi-Lauridsen, Torben Sølbeck Rasmussen, Lars Hestbjerg Hansen, Sofie Ingdam Halkjær, Dennis Sandris Nielsen and Morten Helms declares no conflicts of interest.

Introduction

The therapeutic landscape for ulcerative colitis (UC) is rapidly evolving, with an increasing number of biologic agents available.

Aims & Methods

This systematic review and meta-analysis synthesised randomised controlled trials (RCTs) data on biologic therapies for achieving key endoscopic and histologic endpoints in moderate to severe UC. A systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science and grey literature was conducted through November 2024. Separate meta-analyses were performed for induction and maintenance. A random-effects model was used to estimate relative risks (RR), with 95% confidence intervals (CI) and confidence in estimates was evaluated with the GRADE approach (Grading of Recommendation Assessment, Development and Evaluation).

Results

We included 40 RCTs (13 therapies , 14,369 patients). Thirty-two trials provided data in induction phase and twenty-eight in maintenance phase. During induction phase, all biologic therapies except for mirikizumab and filgotinib 100 mg demonstrated superiority over placebo (RR 2.02, 95% CI:1.76–2.31, I²=72%) for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 5.53, 95% CI: 3.78-8.09). In biologic-naive patients and in patients with no previous biologic failure status upadacitinib 30mg had the highest efficacy (RR 4.07, 95% CI:2.69-6.16). In biologic-exposed patients or those with previous biologic failure, upadacitinib 30mg also showed the greatest benefit (RR 10.52, 95% CI:4.55-24.34). For induction of mucosal healing, all interventions were superior to placebo (RR 2.95, 95% CI:2.11–4.13,I²=61%), except for filgotinib 100 mg. Risankizumab showed the highest efficacy (RR 10.25, 95% CI:2.49-42.11). In maintenance phase, all therapies showed superiority over placebo for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 4.18, 95% CI: 2.79–6.27). In biologic-naïve patients or those without prior biologic failure, all interventions—except filgotinib 100 mg and vedolizumab—were significantly superior to placebo, with etrasimod showing the highest efficacy (RR 3.12, 95% CI: 1.79–5.43). Among biologic-exposed patients or those with prior biologic failure, upadacitinib, mirikizumab, ustekinumab, etrasimod, tofacitinib, and risankizumab 180 mg were significantly superior to placebo. Upadacitinib showed the highest efficacy (RR 7.58, 95% CI: 3.42–16.8). For mucosal healing all therapies were superior to placebo, except for risankizumab. Upadacitinib showed the highest efficacy (RR 4.01 ,95% CI: 1.81–8.87). In biologic-naïve patients or those without prior biologic failure, only etrasimod, mirikizumab, upadacitinib 30 mg and subcutaneous infliximab were significantly superior to placebo, with upadacitinib showing the highest efficacy (RR 3.02, 95% CI: 1.18–7.71). Among biologic-exposed patients or those with prior biologic failure, only etrasimod, mirikizumab, and upadacitinib were significantly superior to placebo, with etrasimod demonstrating the highest efficacy (RR 9.45, 95% CI: 1.31–68.36).

Conclusion

Biologic and small-molecule therapies demonstrated substantial efficacy in achieving key endoscopic and histologic endpoints in moderate to severe UC. Upadacitinib consistently showed the highest efficacy across both induction and maintenance phases. Stratified analyses revealed enhanced response rates in biologic-naïve patients, supporting early initiation of advanced therapies. Our findings highlight the importance of individualised treatment strategies and the urgent need for standardised endpoint definitions to enhance comparability across future trials.

Introduction

Early detection of gastric neoplasms in esophagogastroduodenoscopy (EGD) remains challenging due to the subtle and indistinct appearance of the lesions. In addition to white light imaging (WLI), image-enhanced endoscopy techniques, such as linked color imaging (LCI), are commonly used to detect such lesions. Recently, a computer-aided detection (CADe) system compatible with WLI and LCI (CAD EYE; Fujifilm Co., Tokyo, Japan) has been developed. However, evidence of its effectiveness in real-world clinical settings remains limited.

Aims & Methods

We conducted a multicenter, non-randomized confirmatory trial to evaluate the performance of CAD EYE in detecting gastric neoplasms. Between July 2023 and January 2024, patients undergoing EGD for known early gastric neoplasms were recruited at four institutions in Japan. While systematically observing the entire stomach with WLI and LCI, we investigated whether these lesions were detected by CAD EYE. The primary outcome was the sensitivity of CAD EYE (WLI-CADe and LCI-CADe) in detecting tumors. Secondary outcomes included identifying tumor characteristics and factors associated with missed detections by CAD EYE. To determine the sample size, we presumed the sensitivity of CAD EYE to be 95% based on pre-approval data, with a threshold set at 90%. The number of lesions required was calculated to be 150, ensuring that the lower limit of the 95% confidence interval (CI) exceeded the threshold of 90%. Assuming one lesion per patient and accounting for a 5% dropout rate, we recruited a total of 160 patients.

Results

A total of 174 lesions from 162 patients (mean age: 73.7±9.5 years, male: 69.7%) were analyzed. Current or past history of Helicobacter pylori (H. pylori) infection was observed in 158 patients (97.5%). The mean tumor diameter was 15.1 ± 11.3 mm, and the morphology consisted of 6 protruded, 51 flat elevated, and 117 flat types. Histology included 151 differentiated adenocarcinoma, 20 undifferentiated adenocarcinoma, 2 adenocarcinoma of fundic-gland type, and 1 tubular adenoma. The sensitivities of WLI-CADe and LCI-CADe in detecting tumors were 92.0% (95% CI: 86.9%–95.5%) and 96.5% (95% CI: 92.6%–98.7%), respectively. The sensitivity of LCI-CADe met expectations, as the lower limit of the 95% CI exceeded the threshold of 90%; however, WLI-CADe failed to meet the same standard. In WLI-CADe, lesions located on the anterior/posterior wall were missed significantly more often than those on the greater/lesser curvature (13.9% [11 of 79] vs. 3.2% [3 of 95]; P = 0.020); whereas no difference was observed in LCI-CADe. Other factors, such as H. pylori infection status, tumor morphology, location, and histology, showed no differences between lesions detected and missed by WLI-CADe and LCI-CADe.

Conclusion

The use of CADe with LCI demonstrated satisfactory sensitivity in detecting gastric neoplasms in real-world clinical settings, suggesting its potential to assist endoscopists in tumor detection. However, CADe with WLI did not meet the expected standards, possibly due to limitations, such as detecting lesions located on the anterior/posterior wall.

Disclosure

CAD EYE was temporarily provided by Fujifilm Co. Osamu Dohi has received a research grant, not related to this study, from Fujifilm Co. The remaining authors declare no conflicts of interest.

Introduction

Acute Severe Ulcerative Colitis (ASUC) is a serious, potentially life-threatening condition. Hospital admission and prompt medical therapy with intravenous steroids is crucial, but rescue medical therapy with infliximab is frequently needed. Despite its frequency and relevance, there is no clear evidence about the optimal infliximab (IFX) dosing and timing in this context.

Aims & Methods

In a prospective multicentre, international cohort study, consecutive patients hospitalized for ASUC between 2/2019-1/2020 were included. The primary outcome was surgery during the first 90 days after admission (failure of medical treatment). For this analysis we identified and analyzed all patients receiving IFX as rescue therapy during the index admission. We used descriptive statistics along with non-parametric tests to determine patient characteristics and outcomes between IFX usage patterns.

Results

A total of 823 patients from 123 centers in 32 countries in five continents were included (median age 39 years [IQR, 28-54], 56% male, 64% non-smokers). IFX was started in 159 patients (19%) after a median of 6 days (IQR, 4-8) after starting steroids, with 27% after >7 days. The initial IFX dose was mostly 5 mg/kg (74%), followed by 10 mg/kg (23%). The overall response was considered adequate in 74%, this was numerically superior among those receiving 10 mg/kg (83% vs 74%, p=0.5). In 41 patients a second dose of IFX (26%) was administered during the admission. After a first dose of IFX 5 mg/kg or 10 mg/kg, most patients received a subsequent infusion with the same dosing (92% and 79%, respectively). Colectomy was performed in 35 patients (22%), without statistically significant differences between those with an initial dose of 5 or 10 mg/kg (23% vs 19%, p=0.6).

Conclusion

IFX is a relevant rescue therapy, required in around one in five patients with ASUC. Most patients receive 5 mg/kg, and this is usually followed by the same dosage. Still a proportion of patients receive higher doses with 10 mg/kg, but colectomy risk remains similar between both groups.