Introduction

The low-FODMAP diet (LFD) is the most well-documented diet intervention for significantly improving irritable bowel syndrome (IBS) symptoms. The Mediterranean diet (MED), with plant-based foods, olive oil, fruits, herbs, wine, and lean proteins, has antioxidant properties that might ameliorate the low-grade inflammation characterizing the syndrome. The efficacy of the two diets combined in IBS is unknown.

Aims & Methods

Our primary aim was to examine the efficacy of combining LFD with MED diet components (MED-LFD) compared to the nutritional recommendations of the British National Institute for Health and Care Excellence (NICE) for managing non-constipation IBS.
Single-center, randomized, parallel groups design, single-masked, controlled study with six months of follow-up. We enrolled patients fulfilling Rome IV criteria with Bristol Stool Form Scale 3-7, IBS-SSS > 175, normal TSH, negative tTg-IgA/IgG, without either chronic systemic disorder or probiotic and/or antibiotic administration within a month before enrolment. Patients were randomized to either MED-LFD that included swapping high FODMAP for low FODMAP alternatives (1st phase), gradual introduction of foods rich in FODMAPs to test tolerance (2nd phase), and individualized diet based on personal tolerance (3rd phase) or a diet according to their energy needs adjusted to NICE recommendation for IBS. Patients were evaluated at baseline and follow-ups (1stFU: 4 weeks after initiation of intervention for NICE and at the end of phase 2 for MED-LFD, 2ndFU: at six 6 months) with: IBS-SSS (intervention responder: drop of >50 points), IBS-QOL, SF-12, modified for lower GI symptoms burden GSRS, and HADS.

Results

From July 2019 to April 2023, 108 patients (77.8% females, 40±11 yrs) were randomized (1:1) to MED-LFD or NICE diet groups. 92 (85.2%) patients completed the study. Primary endpoints: 1. Responders' rate was significantly higher in the MED-LFD group in the ITT and PP analysis at the 1st (81.5% vs. 57.4%, p=0.007 and 84.6% vs. 60.8%, p=0.007) and 2nd (68.5% vs. 40.7%, p=0.004 and 80.4% vs. 51.2%, p=0.004) FUs, respectively. 2. At both FUs, the MED-LFD group showed significantly greater improvement in symptom severity (IBS-SSS: 159±80 vs. 253±94 and 168±117 vs. 245±98). For all secondary endpoints (Table 1), patients in the MED-LFD group showed significantly higher improvement than the NICE group at each FU. Adherence rate was significantly higher in the MED-LFD group at both FUs (75% vs. 41% and 45% vs. 7%). No patient discontinued the intervention due to an adverse event. Eighteen (10 and eight in the MED-LFD and NICE groups, respectively) patients reported the use of rescue medication 26 times (12 and 14 in MED-LFD and NICE groups, respectively) during the intervention, including paracetamol (n=10), loperamide (n=14) and a combination of the two medications in two cases.

Table 1. Secondary endpoints: * denotes significant difference over baseline score at the different time points; $ denotes significant difference over comparator score at the FU.

Conclusion

Low-FODMAP diet combined with Mediterranean diet components is superior to the NICE nutritional recommendations for amelioration of IBS symptoms and improvement of quality of life of non-constipated IBS patients. The results are sustainable for six months

References

ClinicalTrials.gov identifier: NCT03997708

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.