Introduction

Multiple studies report on the prevalence and characteristics of adult Rome IV irritable bowel syndrome (IBS), but reports in the young adult general population are in comparison few. Further, few have prospectively assessed childhood factors associated with Rome IV IBS in the young adult general population.

Aims & Methods

We aimed to describe the prevalence, characteristics and associated childhood factors of Rome IV IBS among young adults (age 24y) in the general population. We used data from a Swedish prospective population-based birth cohort study of 4089 children, with data on IBS at 24y and no diagnosis of inflammatory bowel disease or celiac disease in 2853 participants. IBS at 24y was assessed using select questions from the Rome IV diagnostic questionnaire. Multiple characteristics were assessed at baseline (age 2 months) and at follow-up at age 1y, 2y, 4y, 8y, 12y, 16y, and 24y and compared between IBS-positive and IBS-negative participants at 24y using univariate logistic regression models.

Results

The prevalence of Rome IV IBS at 24y was 10.0% (n=286). Characteristics associated with being IBS-positive vs IBS-negative at 24y were female sex (OR 3.7, 95% CI 2.7-5.0); having concurrent asthma (OR 2.3, 95% CI 1.7-3.0), allergic rhinitis (OR 1.3, 95% CI 1.0-1.7), or eczema (OR 1.6, 95% CI 1.1-2.1); a lifetime diagnosis of migraine (OR 2.1, 95% CI 1.4-3.2) or depression (OR 2.5, 95% CI 1.9-3.3); higher perceived stress (PSS-10 score), lower overall health-related quality of life (EQ VAS, EQ-5D index value) and reporting problems in four of five EQ-5D dimensions (all P <0.05). Childhood factors associated with being IBS-positive vs IBS-negative at 24y were exposure to furred pets at any time during childhood (OR 1.4, 95% CI.1-1.9); sleeping <7 hours/night at 16y (OR 1.6, 95% CI.1-2.3); food hypersensitivity at any time during childhood (OR 1.9, 95% CI 1.4-2.6); lower overall health-related quality of life (EQ VAS, EQ-5D index value) and reporting problems in four of five EQ-5D dimensions at 16y (all P<0.05); having parents reporting gastrointestinal symptoms at age 12y of the child (abdominal pain, OR 1.6, 95% CI 1.1-2.2; IBS-like symptoms, OR 2.0, 95% CI 1.3-3.0; any symptoms limiting daily life, OR 2.5, 95% CI 1.3-4.8); and having childhood abdominal pain (weekly abdominal pain at 12y, OR 2.5, 95% CI 1.5-4.3; weekly abdominal pain at 16y, OR 3.8, 95% CI 2.9-4.9; any Rome III abdominal pain-related disorder of gut-brain interaction at 16y, OR 4.6, 95% CI 3.4-6.2; Rome III IBS at 16y, OR 5.6, 95% CI 3.8-8.1), although only a minority of affected children were IBS-positive at 24y (20.9%, 21.8.%, 26.8%, and 33.6%, respectively).

Conclusion

The prevalence of Rome IV IBS among young adults in the Swedish general population is high and associated with female sex, multiple comorbidities, high stress levels, and impaired health-related quality of life. Multiple childhood factors are associated with being IBS-positive in the young adult general population, including growing up with parents with gastrointestinal problems and suffering from childhood health-related quality of life impairment or abdominal pain, although most children with abdominal pain do not suffer from IBS in young adulthood.

Introduction

Immune checkpoint inhibitors (ICIs) have marked a breakthrough in the management of a wide range of cancer types, leading to increased overall survival. However, this treatment is frequently associated with the onset of various immune-related adverse events (irAEs), including ICI-related diarrhea and colitis.¹ Current recommendations for patients with diarrhea or colitis grade 2 or higher (graded via CTCAE)² include the discontinuation of ICI and administration of immune suppressants (e.g. steroids or biologics), which may lead to worse outcomes in these patients.³ Therefore, alternative therapeutic strategies to manage irAEs are needed. The gut microbiota plays a pivotal role in the onset of gastrointestinal irAEs, but the role of its therapeutic modulation on these disorders is mostly unknown. ^4,5

Aims & Methods

Our aim was to evaluate the efficacy and safety of therapeutic microbiome modulation for gastrointestinal irAEs in cancer patients. We enrolled cancer patients affected by ICI-related diarrhea/colitis referred to our Microbiome Clinic from January 2023 to March 2025. After clinical evaluation, patients were stratified according to severity of diarrhea (graded via CTCAE)² and then received a microbiome-modulating therapy. Patients were followed-up for at least 8 week after the initiation of therapy. We collected data about patient demographics (age and gender), patient’s overall health status as assessed by the the Charlson Comorbidity Index (CCI)⁶, type of cancer, oncological therapy and its suspension, time in weeks from initiation of cancer therapy to onset of diarrhea, severity of diarrhea (graded via CTCAE)², time in weeks until resolution of diarrhea and resumption of oncological therapy

Results

We enrolled 42 patients in the study period (8 males, 34 females, mean age 58,3 years-old, mean CCI-index 5.8). All patients were treated with ICI (Pembrolizumab: n=25 , Dostarlimab: n=4, Nivolumab: n=4; Atezolizumab: n=3; Novulumab and Ipilumab: n=2, Cemiplimab: n=2; Mogamulizumab: n=1; Pertuzumab: n=1). Ten patients experienced G1 diarrhea (23,8%), 16 (38,1) G2, 15 (35,7%) G3 and one G4 (2,4%). As indicated by current European Guidelines³, 30 patients (71,4%) had to interrupt ICI due to diarrhea. Multi-strain probiotics were administered to 27 (64.3% ) patients, rifaximin to 22 (52,4%). Overall, 21 patients (50%) needed therapy with systemic steroids. Seven patients who experienced ICI-related colitis refractory to steroids and biologics were successfully treated with FMT. Twenty-eight patients (66.7% ) had a resolution of the diarrhea (G0) and 11 patients (26.2%) had diarrhea G1 at a mean time of 8 weeks. Upon resolution of diarrhea, nine of the 30 patients who had interrupted ICI (30%) were able to resume the treatment. None of the patients experienced any adverse event related to gut microbiota modulation as defined by CTCAE².

Conclusion

Therapeutic modulation of gut microbiota appears to be a promising safe and effective approach for treating ICI-related diarrhea and colitis. However, these preliminary findings need confirmation through more consolidated and well-designed studies.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009
3. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
4. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
5. Wang T, Zheng N, Luo Q, et al. Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.01235
6. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.

Introduction

The achievement of histological remission (HR) is a key treatment goal in ulcerative colitis (UC), as it is suggestive of better disease management and predicts response to therapy.
The absence of neutrophils in epithelium and lamina is crucial to define HR. However, the role of neutrophil number and localisation remains unclear. We aimed to develop a novel artificial intelligence (AI)-driven system to automate neutrophil detection, localisation, and quantification, supporting assessment of HR and enable the prediction of response to therapy.

Aims & Methods

We developed an AI-driven system by integrating two deep learning models to (1) segment whole slide images (WSIs) into epithelium, crypts and lamina propria and to (2) detect and quantify neutrophils. Outputs from these models were combined to compute neutrophil densities in the lamina propria, epithelium, and overall tissue. The optimal neutrophil density cut-offs to assess disease activity (Geboes score >2B.0) in UC patients were identified in the AMAC phase 2 Mirikizumab trial, and subsequently validated in the multicentre prospective PICaSSO cohort study. Cut-offs to determine treatment response at weeks 12 and 52 (histological improvement [HI; Geboes score ≤3.1] and histological remission [HR; Geboes score ≤2B.0]), were also evaluated.

Results

Table 1 shows the system diagnostic performance in assessing disease activity and predicting response to therapy at W12 and W52 in the Mirikizumab cohort.
303 WSIs from active UC patients from the multicentre, randomised, double-blind, parallel-arm, placebo-controlled phase 2 clinical trial of Mirikizumab were analysed. The model yielded a DICE SØrensen of 0.57 for segmentation, precision of 82.3% and recall of 77.0% for neutrophil detection. The system identified an overall optimal neutrophil density cut-off (cells/mm²) predictive of disease activity of >21.7.0 (>10.1 and >30.4 for epithelium and lamina propria, respectively), with an accuracy of 86% (85% and 85%, respectively). Further validation in the multicenter PICaSSO cohort yielded to similar results.
Moreover, the overall optimal cut-off to predict histological remission at W52 was <20.8 (<10.4 and <27.9 for epithelium and lamina propria, respectively), with an accuracy of 82.0% (81% and 80%, respectively).

Conclusion

Our novel AI-based system demonstrates strong potential as an automated tool to detect, localise, and quantify neutrophils to assess histological activity and predict response to therapy in a clinical trial UC cohort and real-world settings. This framework could be applied in clinical trials and routine clinical practice, offering objective guidance for personalised management in UC patients.

References

[1] Santacroce G, Meseguer P, Zammarchi I, et al. P406 A novel active learning-based digital pathology protocol annotation for histologic assessment in Ulcerative Colitis using PICaSSO Histologic Remission Index (PHRI). Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i843–i844
[2] Graham S, Vu QD, Jahanifar M, et al. CoNIC Challenge: Pushing the frontiers of nuclear detection, segmentation, classification and counting. Med Image Anal. 2024;92:103047.

Disclosure

MI received research grants and consultant fees from Olympus, Pentax, Eli Lilly, and Janssen. All other authors declare no competing interests.

Introduction

Immune checkpoint inhibitors (ICIs), a new class of immunotherapeutic agents, are the first-line treatment for many advanced epithelial cancers. Gastrointestinal irAEs, particularly diarrhea and colitis, affect approximately 40% of ICI-treated patients and often lead to therapy discontinuation.¹ High-dose corticosteroids represent the first-line treatment, but about one-third of patients show inadequate response and require second-line immunosuppressants such as Infliximab or Vedolizumab.² As the body of evidence about the role of gut microbiota in the pathogenesis of GI irAE grows, fecal microbiota transplantation (FMT) is emerging as a potential treatment for steroid- and biologic-refractory ICI-induced colitis.³ Although data are still preliminary, FMT represents a promising therapeutic strategy in this setting.

Aims & Methods

The aim of this study is to evaluate the safety and efficacy of FMT in patients referred to our Microbiome clinic for steroid- and biologic-refractory ICI-induced colitis. After clinical evaluation, patients were treated with FMT via colonoscopy from healthy donors. FMT was performed as already described, following international clinical guidelines.^4,5 Following the endoscopic procedure, patients were evaluated at 1, 4, 8, and 12 weeks. We collected data on: patient characteristics, cancer type, cancer treatment and its suspension, severity of diarrhea before FMT (graded via CTCAE)⁶, time in weeks from initiation of cancer therapy to onset of diarrhea, grade of diarrhea following treatment and resumption of ICI.

Results

Our cohort included 7 patients with steroid- and biologic-refractory ICI-induced colitis (grade 1: n=0 ; grade 2: n=1 ; grade 3: 5=x; grade 4: n=1). Four patients were affected by renal cell carcinoma, 2 by melanoma, 1 by pulmonary cancer. All patients were treated with PD-1/PDL-1 inhibitors or CTLA-4 ( Nivolumab: n= 3; Nivolumab and Ipilimumab: n=2; Durvalumab: n= 1; Pembrolizumab: n= 1) and 6 patients interrupted ICI due to gastrointestinal irAEs. All patients received single FMT from healthy donors via colonoscopy. Following FMT, diarrhea improved to grade ≤ 1 in 6 patients (85%) at week 1, 4, 8, and 12 after the procedure, suggesting a sustained effect of microbiome modulation in the medium term. One patient died during follow-up for reasons other than ICI-colitis.

Conclusion

Our preliminary findings suggest that FMT may be a promising therapeutic strategy for refractory ICI-colitis. Further, larger and randomized studies are warranted to confirm our data.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
3. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
4. Cammarota G, Ianiro G, Kelly CR, et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019;68(12):2111-2121. doi:10.1136/gutjnl-2019-319548
5. Ianiro G, Rossi E, Thomas AM, et al. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma. Nat Commun. 2020;11(1):4333. doi:10.1038/s41467-020-18127-y
6. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.