Introduction

Diabetic gastroenteropathy is a condition that can cause debilitation symptoms such as vomiting, intense nausea, bloating, abdominal pain, constipation, diarrhea and faecal incontinence. These symptoms not only impact the patient’s morbidity but also significantly reduce their quality of life. The condition occurs due to damage to the nerves of the sympathetic, parasympathetic and enteric nerve systems. Treating the condition can be difficult since many available therapies have limited effectiveness or pose long-term safety concerns. Consequently, this leaves the patients with few alternatives beyond general dietary advice, broad-spectrum antibiotics, or prokinetic laxatives. Faecal microbiota transplantation (FMT) involves transferring minimally processed faeces from a healthy donor to a recipient. This leads to the establishment of a donor-like microbiota in the recipient. By restoring the intestinal microbiota, FMT holds the potential for a safe and effective means to alleviate gastrointestinal symptoms and enhance the quality of life in patients with type 1 diabetes.

Aims & Methods

We conducted a pilot trial that was randomised, double-blinded and placebo-controlled. We enrolled adults who had type 1 diabetes and moderate to severe gastrointestinal symptoms. The patients were randomly assigned to receive either encapsulated FMT or placebo in a 1:1 ratio. After six weeks, all patients received encapsulated FMT as a second intervention. Our primary endpoint was the occurrence of adverse events of severity grade 2 or higher, assessed by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5) during the initial intervention. Secondary endpoints included assessing gastrointestinal symptoms and quality of life. The trial is registered with ClinicalTrials.gov, NCT04749030.

Results

From June 2021 to May 2023, we conducted a screening of 23 patients, out of which ten were randomly selected for FMT and ten for placebo. During the first intervention, we registered 26 adverse events of severity grade 2 or above. Out of these, four patients who received FMT reported seven adverse events, while five patients who received placebo group reported 19 adverse events. None of the adverse events related to the treatment were serious. The most commonly reported adverse events were diarrhea, bloating, and abdominal pain. Patients who received FMT experienced a significant reduction in their median Gastrointestinal Symptom Rating Scale – Irritable Bowel Syndrome (GSRS-IBS) score from 58 at baseline to 35, while patients receiving placebo had only a slight increase in the median score from 64 to 56 (p=0.01). The Irritable Bowel Syndrome Impact Scale (IBS-IS) score also improved from 108 to 140 points in the FMT group compared with an increase from 77 to 92 points in the group of patients receiving placebo (p=0.02). The Patient Assessment of Gastrointestinal Symptom Severity Index (PAGI-SYM) also showed improvement with patients who received FMT reducing their median score from 42 points at baseline to 25, while the score of patients receiving placebo was reduced from 47 to 41 (p=0.03).

Conclusion

This study is the first randomised trial of FMT for patients with type 1 diabetes and symptoms of severe diabetic gastroenteropathy. As far as we know, this study shows the most promising clinical effect of FMT beyond C. difficile infection. This study demonstrates that FMT is safe and markedly improves clinical outcomes for patients with type 1 diabetes who suffer from debilitating bowel symptoms.

Disclosure

The study was funded by a Steno Diabetes Collaborative Grant. They had no influence on the design, analysis, or reporting of the study.

Introduction

An important issue for unresectable advanced stage hepatocellular carcinoma (uHCC) patients with Child-Pugh class B liver cirrhosis (CP-B), is lack of safe treatment options that show therapeutic efficacy, thus it is considered to be an unmet need. Atezolizumab plus bevacizumab (At/Bv) and durvalumab plus tremelimumab (Dur/Tre) have each been used as first-line systemic immunotherapy for uHCC.

Aims & Methods

The present study aimed to elucidate clinical outcomes of uHCC patients with CP-B treated with those combination treatments. The records of 169 uHCC patients with CP-B in Japan, treated with At/Bv or Dur/Tre as first-line systemic therapy from 2020 to 2024 at participating institutions were examined (median age: 73 years, males: 143, Child-Pugh score 7:8:9 = 121:43:5, BCLC stage B:C = 65:104, At/Bv:Dur/Tre = 131:38). Each regimen was analyzed for therapeutic efficacy and safety, and the results compared, in a retrospective manner.

Results

Using RECIST, ver. 1.1, the objective response rate (ORR) was shown to be 25.9% in the At/Bv group, and 18.4% in the Dur/Tre group (p=0.08). Disease control rate (DCR) was significantly higher in the At/Bv group (64.9% vs. 39.5%, p=0.01). There were no significant differences between the groups for progression-free survival (PFS) [At/Bv vs. Dur/Tre=5.3 vs. 3.5 months (95% CI: 3.9–6.5 and 2.3–7.2, respectively), p=0.90], overall survival (OS) [10.5 vs. 12.5 months (95% CI: 9.1–13.3 and 7.9–NA, respectively), p=0.58], or post-progression survival (PPS) [4.9 vs. 7.5 months (95% CI: 3.7–7.5 and 2.2–NA, respectively), p=0.60]. The rate of incidence of immune-related adverse events (irAEs) of any grade was 11.5% in the At/Bv group and 23.7% in the Dur/Tre group (p=0.07), while irAEs of grade 3 or higher were noted in 3.1% and 15.8%, respectively (p=0.02) significantly greater in the Dur/Tre group).

Conclusion

The incidence rate of irAEs in each group was similar to that observed in clinical trials previously performed for these regimens. uHCC patients with CP-B, who received Dur/Tre had a greater rate of incidence of high-grade irAEs, while the At/Bv group had a better DCR, though there were no significant differences for PFS, OS, or PPS between the groups. Neither treatment was found to sufficiently improve the prognosis of uHCC patients with CP-B. Development of safe and effective treatment options for patients affected by uHCC, that can be administered even to those with CP-B remains necessary.

Disclosure

Atsushi Hiraoka: lecture fee Chugai, AstraZeneca, and Lilly.

Introduction

Very early onset inflammatory bowel disease (VEO-IBD) is often associated with a severe disease course and unique characteristics including an underlying monogenic defect. In this study, we identified new pathogenic mutations in CGNL1 associated with VEO-IBD and other inflammatory GI disease. CGNL1 (Cingulin Like 1) encodes an epithelial junctional protein whose function was previously unknown in the gastrointestinal tract.

Aims & Methods

Whole exome sequencing (WES) was performed on the affected patient with VEO-IBD and all first-degree relatives with IBD and other inflammatory disease. Intestinal epithelial organoids (IEOs) were generated from the affected patient and were characterized by transepithelial electrical resistance (TEER), FITC-dextran permeability assay on epithelial cell monolayer, immunostaining, RNA sequencing, and transmission electron microscopy (TEM). In addition, we generated a new Cgnl1^-/- mouse model, which was characterized using FITC-dextran permeability assay, TEM, dextran-sodium sulfate (DSS)-induced colitis, and infections by Citrobacter rodentium and Clostridioides difficile. Single-cell datasets were analyzed to determine CGNL1 expression in IBD, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH).

Results

In the affected patient with VEO-IBD who required early total colectomy and pouch formation with coexistent PSC and celiac disease, WES identified two rare, new, pathogenic variants in the CGNL1 gene. Both pathogenic variants were also present in the patient’s younger sister, who has a similar history including early-onset, fulminant ulcerative colitis requiring total colectomy with ileostomy and PSC-AIH overlap syndrome. Furthermore, multiple relatives of the patient suffer from IBD and other inflammatory conditions including celiac disease, eosinophilic esophagitis, and type-1 diabetes. The RNA and protein levels of CGNL1 were significantly diminished in the patient’s intestinal epithelial cells compared to that of healthy individuals and other IBD patients by RNA-seq, immunoblotting, and immunostaining. The patient’s IEOs from pouch body and pre-pouch ileum formed smaller 3D spheroids with altered cell composition and significantly impaired barrier function compared to those from healthy controls and other IBD patients. Immunofluorescence and TEM demonstrated that CGNL1 is required for the assembly of junctional complexes in human IEOs and an epithelial cell line. Similarly to findings from the patient, impaired junctional complexes in intestinal epithelial cells and elevated intestinal permeability were present in Cgnl1^-/- mice at steady state. Cgnl1^-/- mice showed substantial vulnerability to DSS-induced colitis and bacterial infections that directly compromise the epithelial barrier. In addition, 6-month-old Cgnl1^-/- mice exhibited spontaneous inflammation in the colon and terminal ileum due to disrupted intestinal barrier, which was microbiome-dependent. Furthermore, single-cell analysis revealed diminished expression of CGNL1 in the intestinal and hepatic epithelial cells from patients with IBD or PSC/AIH, respectively.

Conclusion

The pathogenic CGNL1 variants contribute to VEO-IBD by disrupting gut barrier integrity, as demonstrated by patient’s cells and novel murine models. This study expands our understanding of epithelial barrier impairment in the pathogenesis of VEO-IBD, and highlights intestinal epithelium as a therapeutic target in some IBD patients.

Introduction

Functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome (IBS) and functional dyspepsia, are prevalent conditions within the field of Neurogastroenterology. These disorders have a profound impact on patients’ quality of life and demand a comprehensive biopsychosocial approach to care. Despite evidence in favor of integrated care, treatment remains largely pharmacological. To address this gap, our hospital established a dedicated Functional Neurogastroenterology Unit by incorporating a nurse trained in health coaching and Neuro-Linguistic Programming (NLP) supported by a custom GPT-based artificial intelligence (AI) tool aimed at enhancing patient communication and clinical decision-making.

Results & Findings

A descriptive observational study was conducted on nurse-led consultations between September 2024 and April 2025. The intervention integrated coaching sessions, Neuro-Linguistic Programming (NLP), and the use of a customized GPT-based system to support communication and care planning. Data collected included demographic characteristics, presenting symptoms, and referral patterns. Additionally, each patient was invited to write a personal narrative reflecting on their experience throughout the intervention.

Summary & Discussion

Forty-eight patients were attended during the study period (mean age: 38.6 years; 68.7% female). The most common diagnoses were functional dyspepsia, irritable bowel syndrome, and nonspecific digestive disorders. Frequently reported symptoms included bloating, epigastric pain, early satiety and burning. 20.8% of patients were referred to psychology services and 2.1% to psychiatry. Patient narratives revealed improvements in emotional self-regulation, greater sense of empowerment, and high levels of satisfaction. AI reduced administrative burden, improving focus on direct care, interdisciplinary communication, and adherence to treatment.

Conclusion

Coaching, NLP and AI are effective tools to address FGIDs from nursing, promoting personalized care and improving the patient's emotional well-being.

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