Personalized Anti-Inflammatory Fibres in Ulcerative Colitis

Official title

Clinical Profiling of Anti-inflammatory Fibre Supplements in Patients With Ulcerative Colitis: Towards Personalized Complementary Strategies.

Overview

The goal of this clinical trial is to determine the clinical effects of two different dietary fibre supplements, acacia gum (AG) and microcrystalline cellulose (MCC), in patients with ulcerative colitis. The main question it aims to answer is: Can the fibre supplements reduce gut inflammation (fecal calprotectin)? Researchers will compare AG and MCC to a placebo (a look-alike substance that contains no fibre) to see if the fibre supplements improve inflammation in ulcerative colitis. Participants will add their assigned fibre supplement or placebo to their usual diet daily for 6 weeks. They will visit the clinic at baseline, week 3, and week 6 to provide samples (stool, blood) and complete various questionnaires.

Detailed description

Prevalence and incidence of inflammatory bowel diseases (IBD), including ulcerative colitis (UC), is rising rapidly in Canada and the rates are amongst the highest globally (Crohn's and Colitis Canada, 2023). UC is a chronic disease characterized by colonic inflammation, often inadequately managed in the long-term with immunosuppressive medications that can increase risk of infections and malignancies (Kayal \& Shah, 2019). Alternative, complementary strategies are, therefore, necessary to improve patient outcomes.

A potential target for such strategies may be the gut microbiome, which can predict failure of standard therapy in pediatric UC (Michail et al., 2012). Putative, pro-inflammatory microbes are enriched in patients with IBD compared to healthy controls and disease phenotypes can be transferred via microbiome transplantation into germ-free mice (Nagao-Kitamoto et al., 2016; Birtton et al., 2019), suggesting a causal role of the gut microbiome in IBD. Fibre-based treatments for UC have been proposed and tested for UC but results are mixed, quite modest in many cases, and many gaps remain in defining the most appropriate clinical approach (Di Rosa et al., 2022; Limketkai et al, 2020).

Dietary fibre has great potential as a safe, complementary, microbiome-targeted treatment strategy to reduce inflammation in UC. Food supplementation with fermentable fibres alters microbiome composition (So et al., 2018) and increases microbial production of bioactive metabolites like short-chain fatty acids (SCFAs) that can attenuate inflammation (Parada Venegas et al., 2019; Levine et al., 2018). Provision of growth substrates in the form of fibre also enhances gut barrier function by decreasing mucus degradation, thus reducing bacterial encroachment and immune activation that may drive inflammation (Desai et al., 2016; Earle et al., 2015). However, specific fibre structures elicit distinct health effects due to differences in physicochemical properties (Gill et al., 2020). Therefore, important open questions remain, such as which fibres and physicochemical properties are most beneficial in the context of UC, and are their effects microbiome-dependent?

Hypothesis: Acacia gum (AG; soluble and fermentable fibre) and microcrystalline cellulose (MCC; insoluble and non-fermentable fibre) will decrease gut inflammation in patients with UC, but through different mechanisms given their differences in fermentability.

The overall goal of this study is to determine the clinical effects of AG and MCC in patients with UC, using normalization of FCP as the primary outcome.

Voluntary trial extension: Participants in whom the primary outcome has been achieved at week 6 will be invited to participate in an optional (completely voluntary) extension of the trial and continue their assigned treatment for an additional six weeks. This will allow for exploratory assessment of longer-term efficacy of the fibres (primary and secondary outcomes assessed again at week 12). Apart from the planned study, if a clinical decision is made by the patient and physician to perform sigmoidoscopy or colonoscopy (which is justified in many cases), bio samples and data from these procedures will be collected if patients agree. The procedure will not be a research procedure, but the patients will be approached and consented for bio sample collection. The optional extension will advantageously provide further biological insights into the effects of the fibres and can inform future intervention studies.

Interventions

• Dietary supplement Acacia Gum
  Participants (n=23) incorporate the fibre supplement into their usual diet daily.
• Dietary supplement Microcrystalline Cellulose
  Participants (n=23) incorporate the fibre supplement into their usual diet daily.
• Dietary supplement Placebo
  Participants (n=23) incorporate the placebo into their usual diet daily.

Primary outcome measures

• Changes in fecal calprotectin [Time frame: Week 3 and Week 6 (and week 12, if applicable)]

Secondary outcome measures (12)

• Changes in disease activity [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in fecal microbiome composition [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in function of the fecal microbiome [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in gut barrier function: fecal zonulin [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in gut barrier function: plasma lipopolysaccharide binding protein [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in fecal short-chain fatty acids [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in fecal bile acids [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in fecal pH [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in fecal dry mass percentage [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in the plasma metabolome [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in the plasma inflammatory cytokines [Time frame: Week 3 and Week 6 (and week 12, if applicable)]
• Changes in routine clinical bloodwork [Time frame: Week 3 and Week 6 (and week 12, if applicable)]

Eligibility criteria

Inclusion criteria

• Known diagnosis of ulcerative colitis.
• Evidence of active disease, defined as either 1) measured FCP >100 µg/g at screening, OR 2) Partial Mayo Scoring Index Assessment for UC ≥2 (adult patients) OR Pediatric UC Activity Index (PUCAI) ≥10 (pediatric patients). Patients who are in clinical remission (Partial Mayo <2 or PUCAI <10) that have active inflammation (elevated FCP >100 µg/g) would also be eligible, as will patients with active symptoms, regardless of availability of FCP.
• Tanner stage ≥4 for pediatric patients.
• Weight >40kg.
• No changes to IBD-related medications in three months prior to study onset (stable therapy, including use of 5-aminosalicylic acid, biologics, and immunosuppressive medications; some minor adjustments allowed, such as increasing dose for weight change, or change to a compatible/generic treatment).
• Men and women that use adequate contraceptive methods.
• Able to maintain current lifestyle (diet, exercise, supplements/medications, and sleep) throughout study.

Exclusion criteria

• Inability to provide informed consent.
• Presence of Crohn disease, IBD unclassified, non-IBD bowel conditions (e.g., celiac), or motility disorder.
• Presence of abnormal constrictions of the gastrointestinal tract, diseases of the esophagus and/or the superior opening of the stomach (cardia), potential or existing intestinal blockage, paralysis of the intestine, megacolon, fecal impaction, inflamed bowel or appendicitis, or have failed to defecate after taking another laxative.
• History of significant chronic disorders such as severe cardiac disease, malignancy requiring systemic chemotherapy or radiation therapy, significant renal failure, severe pulmonary disease, kidney disorders, diabetes, arthritis, multiple sclerosis, or other immune-mediated conditions requiring systemic therapy.
• Presence of serious infection (e.g., infectious colitis).
• Presence of severe anemia, defined as hemoglobin <100 g/L or considered clinically significant based on physician discretion.
• Presence of disease or condition that negatively impacts ability to swallow, which may interfere with intake of supplement.
• Use of systemic antibiotics for more than a week during two months prior to intervention, or any antibiotic use during the intervention.
• Use of medications that inhibit peristaltic movement (e.g. opioids, loperamide)
• Consistent use of topical therapies (e.g., rectal suppositories, enemas) for at least a week, with a resulting improvement in symptoms (defined based on physician discretion).
• Use of probiotic, prebiotic, or fibre supplements in month prior to intervention or during the course of the trial that are known to affect the gut microbiome (if these are present in foods, such as yogurt or fermented foods, this will be allowed).
• Chronic use of laxatives, stool softeners, or anti-diarrheal medications.
• Chronic use of illicit drugs and/or excessive alcohol (e.g., average of >7 drinks/week).
• Current smoker (cigarettes).
• History of abdominal surgery, including appendectomy.
• Pregnancy or intention of the patient to become pregnant during the study period.
• Breastfeeding.
• Allergy to any ingredients of investigational products or placebo (i.e., acacia gum, microcrystalline cellulose, or maltodextrin).
• Unable to maintain high fiber intake through supplementation during intervention.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Canada · 1 center

• University of Alberta Hospital — Edmonton

Publications

• Crohn's and Colitis Canada. Impact of inflammatory bowel disease in Canada. Available from: https://crohnsandcolitisca/About-Us/Resources-Publications/Impact-of-IBD-Report2023.
• Kayal M, Shah S. Ulcerative Colitis: Current and Emerging Treatment Strategies. J Clin Med. 2019 Dec 30;9(1):94. doi: 10.3390/jcm9010094. PMID 31905945
• Michail S, Durbin M, Turner D, Griffiths AM, Mack DR, Hyams J, Leleiko N, Kenche H, Stolfi A, Wine E. Alterations in the gut microbiome of children with severe ulcerative colitis. Inflamm Bowel Dis. 2012 Oct;18(10):1799-808. doi: 10.1002/ibd.22860. Epub 2011 Dec 14. PMID 22170749
• Nagao-Kitamoto H, Shreiner AB, Gillilland MG 3rd, Kitamoto S, Ishii C, Hirayama A, Kuffa P, El-Zaatari M, Grasberger H, Seekatz AM, Higgins PD, Young VB, Fukuda S, Kao JY, Kamada N. Functional Characterization of Inflammatory Bowel Disease-Associated Gut Dysbiosis in Gnotobiotic Mice. Cell Mol Gastroenterol Hepatol. 2016 Mar 3;2(4):468-481. doi: 10.1016/j.jcmgh.2016.02.003. eCollection 2016 Jul. PMID 27795980
• Britton GJ, Contijoch EJ, Mogno I, Vennaro OH, Llewellyn SR, Ng R, Li Z, Mortha A, Merad M, Das A, Gevers D, McGovern DPB, Singh N, Braun J, Jacobs JP, Clemente JC, Grinspan A, Sands BE, Colombel JF, Dubinsky MC, Faith JJ. Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORgammat+ Regulatory T Cells and Exacerbate Colitis in Mice. Immunity. 2019 Jan 15;50( PMID 30650377
• Di Rosa C, Altomare A, Imperia E, Spiezia C, Khazrai YM, Guarino MPL. The Role of Dietary Fibers in the Management of IBD Symptoms. Nutrients. 2022 Nov 11;14(22):4775. doi: 10.3390/nu14224775. PMID 36432460
• Limketkai BN, Gordon M, Mutlu EA, De Silva PS, Lewis JD. Diet Therapy for Inflammatory Bowel Diseases: A Call to the Dining Table. Inflamm Bowel Dis. 2020 Mar 4;26(4):510-514. doi: 10.1093/ibd/izz297. PMID 31819987
• So D, Whelan K, Rossi M, Morrison M, Holtmann G, Kelly JT, Shanahan ER, Staudacher HM, Campbell KL. Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis. Am J Clin Nutr. 2018 Jun 1;107(6):965-983. doi: 10.1093/ajcn/nqy041. PMID 29757343

Identifiers

NCT: NCT06515210 · Pro00137948

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗