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

Irritable Bowel Syndrome (IBS) is a prevalent and chronic gastrointestinal disorder that affects approximately 85 million Europeans. It predominantly impacts women and significantly impairs quality of life, presenting with recurrent abdominal pain and altered bowel habits in the absence of identifiable structural abnormalities. Beyond its gastrointestinal symptoms, IBS frequently co-occurs with mental and somatic conditions such as anxiety, depression, fibromyalgia (32.5%), and chronic fatigue syndrome (14%). Up to 60% of IBS patients experience mental comorbidities, highlighting the complex interplay between gut and brain—often referred to as dysregulation of the gut–brain axis. This dysregulation manifests in altered intestinal motility, increased gut permeability, visceral hypersensitivity, and significant shifts in gut microbiota composition.

Aims & Methods

We present the DISCOVERIE project (Development, dIagnostic and prevention of gender-related Somatic and mental COmorbitiEs in iRritable bowel syndrome In Europe), an international, multi-centre initiative aimed at characterizing IBS and its associated comorbidities, with a particular focus on sex- and gender-related differences. To this end, we generated a comprehensive multi-omics dataset from 743 individuals, including shotgun quantitative microbiome profiling and untargeted metabolomics. These molecular data were complemented by in-depth clinical phenotyping, capturing information on anxiety, depression, fibromyalgia, and chronic fatigue syndrome. Particular attention was given to age, sex/gender, lifestyle factors, and systemic inflammatory markers. Multivariate statistical models were applied, correcting for common microbiome confounders, to analyze the multi-omics layers and identify microbiome-related signatures and mechanistic links across IBS and its comorbid subgroups.

Results

Our microbiome analysis revealed that IBS subjects exhibit features of a dysbiotic bacterial community, characterized by an increased prevalence of the Bacteroides 2 enterotype (17–26% in IBS participants across comorbid groups vs. 17% in the general population and only 2% in the healthy control group; chi-squared test, FDR < 0.05), a reduced butyrate synthesis capacity, and increased levels of opportunistic taxa compared to non-IBS controls.
Interestingly, IBS individuals—regardless of comorbidities—showed enrichment of bacterial metabolic modules involved in the degradation of amino acids that serve as precursors for neurotransmitters. Specifically, we observed an increase in pathways associated with GABA degradation and a decrease in modules responsible for glutamate biosynthesis. This dysregulation of gut neurotransmitter metabolism may contribute to hallmark IBS symptoms.
Strikingly, pro-inflammatory IL-6 levels were strongly associated with specific bacterial genus (FDR < 0.05), as well as with a metabolic module responsible for the degradation of gamma-hydroxybutyric acid (GHB), a neurotransmitter and central nervous system depressant, suggesting a potential mechanistic link between low-grade inflammation and depressive symptoms in IBS.

Conclusion

The results from this large-scale, multi-center international study reveal a dysregulation of gut neurotransmitter metabolism that may contribute to IBS symptoms and associated comorbidities. These findings underscore a potential link between elevated IL-6 levels, microbial metabolism, and the gut–brain axis, offering new insights into the complex interplay between microbiota composition, host physiology, and IBS-related comorbidities.

Introduction

Immune checkpoint inhibitor (ICI) mediated enterocolitis (IMC) may lead to treatment discontinuation. Corticosteroids for IMC is associated with serious side effects and might affect cancer progression in addition to preclude continued ICI treatment. We hypothesized that vedolizumab, a gut selective α4β7 integrin inhibitor, is effective as a first-line treatment and investigated whether vedolizumab reduces corticosteroid exposure and facilitate ICI resumption.

Aims & Methods

We conducted a single center, open-label, explorative phase 2 trial including patients treated with ICI who developed IMC. Patients were randomized 1:1 ratio to receive vedolizumab (300 mg) or standard treatment with corticosteroids, with infliximab used as recue therapy for corticosteroid failure. The primary outcome was cumulative corticosteroid dose at week 30. Key secondary outcomes included cumulative corticosteroid dose at week 10, corticosteroid free remission at week 10 and ICI resumption rates.

Results

Twenty-two patients received vedolizumab, and 19 patients received standard treatment. At week 10, the mean cumulative corticosteroid use was significantly lower in the vedolizumab arm (1157 mg vs. 2207 mg). By week 30, the mean corticosteroid use remained lower but not statistically significant (1378 mg vs. 2390 mg, estimated difference 1012 mg, 95% CI -229 to 2253, p=0.107), Among patients with less severe IMC, who did not need corticosteroids during screening, vedolizumab-treated patients used in average 1729 mg less corticosteroid (95% CI 631 to 2827). Corticosteroid-free remission at weeks 2 and 10 was more common with vedolizumab. Seven patients (33.3%) in the vedolizumab group resumed with ICI compared to three (16.7%) in the standard arm. In patients with severe colitis, who required upfront corticosteroid treatment, a trend towards longer hospitalization in the vedolizumab arm was observed.

Conclusion

For patients with less severe colitis, not needing corticosteroids during screening, vedolizumab may be a viable corticosteroid-sparing option, enabling faster remission and ICI resumption.

Disclosure

The study was funded by Aage og Johanne Louis-Hansens Fond, National Research grants. Takeda Pharma provided the study drug vedolizumab.

Introduction

Irritable bowel syndrome (IBS) is defined as a disorder of gut-brain interaction (DGBI) and is characterised by intestinal immune activation, increased intestinal permeability, and structural and functional brain alterations. DGBI patients have a higher prevalence of psychological comorbidities. Nevertheless, the exact pathophysiological link between these factors and the sequence of events is unknown. Gut alterations have been suggested to induce brain neuroinflammation in DGBI, but scientific evidence is lacking.

Aims & Methods

The present study aims to assess whether GI alteration induces brain neuroinflammation, alters brain function, and, consequently, induces psychological comorbidities. A unique longitudinal study was conducted from 30 to 220 days of age to establish the chronological sequence of intestinal and neurological changes. For this, we utilised the BioBreeding diabetes-prone (BBDP) rat model, which spontaneously develops intestinal inflammation, increased permeability, and colonic hypersensitivity^{1, 2}and has been employed as a model of DGBI. The BioBreeding diabetes-resistant (BBDR) was used as control. Anxiety-like behaviour was assessed using the elevated plus maze. Intestinal permeability was assessed in vivo by measuring the passage of 4 kDa and 70 kDa dextrans into the blood, thereby evaluating paracellular and transcellular permeability, respectively. The appearance of red colour, given by the mixture of the dextrans in the stools, was used to assess overall intestinal motility. The blood-brain barrier (BBB) integrity and brain metabolic profile were assessed using contrast-enhanced magnetic resonance imaging (0.25 mL/100g weight of 0.05 mM, gadolinium) and proton magnetic resonance spectroscopy, respectively.

Results

BBDP rats exhibit an increased colonic permeability starting from 90 days, and reduced GI motility at 90 and 160 days. Interestingly, this increased permeability is accompanied by an increased BBB permeability at 220 days only in the anterior cingulate cortex (ACC) but not in the hippocampus, insula, amygdala, or thalamus. BBDP rats showed a slight increase in total choline and myoinositol concentrations in the ACC and the insula at late time points, which may indicate increased neuroinflammation. BBDP rats also have higher concentrations of glutamine-glutamate in the insula and N-acetyl aspartate in the ACC. Moreover, BBDP rats develop anxiety-like behaviour at 160 and 220 days.

Conclusion

The BBDP rat model supports the current hypothesis that increased gut permeability can lead to brain neuroinflammation, altered function, and, consequently, to psychological comorbidities.
EU-funded DISCOvERIE project (No. 848228).

References

1. Meleine M, Accarie A, Wauters L, et al. Colonic hypersensitivity and low-grade inflammation in a spontaneous animal model for functional gastrointestinal disorders. Neurogastroenterol Motil 2019;31:e13614.
2. Vanuytsel T, Vanormelingen C, Vanheel H, et al. From intestinal permeability to dysmotility: the biobreeding rat as a model for functional gastrointestinal disorders. PLoS One 2014;9:e111132.

Introduction

Infectious mononucleosis (IM) is a largely self-limiting syndrome mainly affecting adolescents and young adults but can present as a severe disease requiring hospitalisation. The infectious agent most commonly causing IM, Epstein-Barr virus (EBV), has been associated with the development of several immune-mediated and inflammatory diseases¹. Recent epidemiological studies have also identified a potential association with IM and inflammatory bowel disease (IBD)^2,3.

Aims & Methods

We therefore aimed to investigate the risk of IBD diagnosis following hospitalisation with IM using Danish nationwide registry data. We identified severe IM patients (those hospitalised with infectious mononucleosis) and matched these by sex-, age- and residence municipality to non-severe IM controls, from 1st January 1977 to 31st December 2021. We undertook Cox regression modelling to assess the hazards (HR) and 95% CI of IBD diagnosis, including Crohn’s disease (CD) and ulcerative colitis (UC), following severe IM. Analyses were stratified by sex, age at, and calendar year of IM hospitalisation.

Results

We identified 39,684 patients with severe IM who were sex-, age-, and municipality-matched to 396,840 non-severe IM controls. Severe IM was significantly associated with the development of IBD (HR:1.35; 95% CI: 1.22-1.49) and this was seen particularly in CD (HR: 1.56; 95% CI: 1.34-1.83) and to lesser extent in UC (HR: 1.23; 95% CI: 1.08-1.40). Sex at severe IM diagnosis was not found to be a significant modifier to the risk of IBD diagnosis, with risk increased in both females (HR: 1.36; 95% CI: 1.20-1.55) and males (HR: 1.34; 95% CI: 1.17-1.54). Only those receiving a severe IM diagnosis at 10-16 years (HR: 1.42; 95% CI:1.22-1.64) or 17-29 years (HR: 1.34; 95% CI:1.15-1.56) had a significantly increased risk of IBD diagnosis. Finally, this increased risk remained present across calendar year of IM diagnosis, from 1977 to 2022.

Conclusion

This study demonstrated an association between IM hospitalisation and later IBD diagnosis, indicating an association between severe EBV disease and IBD development. Further exploration of the potential factors contributing to IBD susceptibility following EBV infection is warranted.

References

1. Houen G, Trier NH. Epstein-Barr Virus and Systemic Autoimmune Diseases. Front Immunol 2021;11.
2. Loosen SH, Kostev K, Schöler D, et al. Infectious mononucleosis is associated with an increased incidence of Crohn’s disease: results from a cohort study of 31 862 outpatients in Germany. Eur J Gastroenterol Hepatol 2023;35:255–260.
3. Nandy A, Petralia F, Torres J, et al. 463: EPSTEIN BARR VIRUS (EBV) EXPOSURE PRECEDES CROHN’S DISEASE DEVELOPMENT. Gastroenterology 2022;162:S-105.