Personalized Anti-Inflammatory Fibres in Ulcerative Colitis

Not Applicable

Not yet recruiting

• Conditions: Ulcerative Colitis
• Interventions: Dietary Supplement: Microcrystalline Cellulose; Dietary Supplement: Acacia Gum; Dietary Supplement: Placebo

• Registration Number: NCT06515210
• Lead Sponsor: University of Alberta

Brief Summary

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.

Study Timeline

• Study First Submitted: 2024-07-10
• Study First Submitted QC: 2024-07-16
• Study First Posted: 2024-07-23
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-10
• Last Update Posted: 2024-12-12
• Study Start: 2025-03
• Primary Completion: 2026-09
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 69

Inclusion Criteria

• Known diagnosis of ulcerative colitis.
• Measured fecal calprotectin of >250 µg/g at screening.
• Mild disease: Partial Mayo Scoring Index Assessment for UC between 0-4 (adult patients).
• Mild disease: Pediatric UC Activity Index (PUCAI) between 0-34 (pediatric patients).
• Tanner stage 5 for pediatric patients.
• Weight >50kg.
• 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; the latter must be menstruating and using contraceptives.

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Exclusion Criteria

• Inability to provide informed consent.
• Presence of Crohn disease, IBD unclassified, non-IBD bowel conditions (e.g., celiac), or motility disorder.
• Use of systemic antibiotics for more than a week during two months prior to intervention, or any antibiotic use during the intervention.
• Use of probiotic, prebiotic, or fibre supplements in month prior to intervention 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 or stool softeners.
• History of abdominal surgery, including appendectomy.
• Pregnancy or intention of the patient to become pregnant during the study period.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Microcrystalline Cellulose	Microcrystalline Cellulose	Microcrystalline cellulose is a dietary fibre that is non-viscous and and non-fermentable. Female participants consume 12.5 grams each day for the first two days of the intervention, then consume 25 grams each day for the rest of the six-week intervention. Male participants consume 17.5 grams each day for the first two days of the intervention, then consume 35 grams each day for the rest of the six-week intervention. Those participants who voluntarily extend their treatment for an additional six weeks will continue with consuming the full dose daily.
Acacia Gum	Acacia Gum	Acacia gum is a dietary fibre with low-viscosity and is fermentable. Female participants consume 12.5 grams each day for the first two days of the intervention, then consume 25 grams each day for the rest of the six-week intervention. Male participants consume 17.5 grams each day for the first two days of the intervention, then consume 35 grams each day for the rest of the six-week intervention. Those participants who voluntarily extend their treatment for an additional six weeks will continue with consuming the full dose daily.
Maltodextrin	Placebo	Maltodextrin is a digestible carbohydrate. It is provided in isocaloric doses to the dietary fibres. Female participants consume 6.3 grams each day for the first two days of the intervention, then consume 12.5 grams each day for the rest of the six-week intervention. Male participants consume 8.8 grams each day for the first two days of the intervention, then consume 17.5 grams each day for the rest of the six-week intervention.

Primary Outcome Measures

Name	Time	Method
Changes in fecal calprotectin	Week 3 and Week 6 (and week 12, if applicable)	Calprotectin will be analyzed in fecal samples. Clinically-relevant reductions are defined as levels \<150 µg/g or reduced by at least 50% from baseline.

Secondary Outcome Measures

Name	Time	Method
Changes in disease activity	Week 3 and Week 6 (and week 12, if applicable)	Scores obtained from either the Partial Mayo Scoring Index Assessment for adult participants or the Pediatric Ulcerative Colitis Activity Index for pediatric participants.
Changes in fecal dry mass percentage	Week 3 and Week 6 (and week 12, if applicable)	Fecal moisture content, or percentage of dry mass, will be measured by drying fecal material overnight in an oven.
Changes in gut barrier function: plasma lipopolysaccharide binding protein	Week 3 and Week 6 (and week 12, if applicable)	Plasma from blood samples will be analyzed for changes in lipopolysaccharide binding protein (µg/mL).
Changes in fecal pH	Week 3 and Week 6 (and week 12, if applicable)	Fecal pH will be measured using a pH meter.
Changes in gastrointestinal symptoms	Week 3 and Week 6 (and week 12, if applicable)	Individual gastrointestinal symptoms will be measured by a gastrointestinal symptom questionnaire (scored on a scale of 0-5; higher scores indicating more symptoms).
Need for rescue therapy	Week 3 and Week 6 (and week 12, if applicable)	Changes to patient therapy regimes (e.g., steroids, dose escalation), inability to complete the study, and adverse events related to the intervention will be monitored and analyzed.
Changes in fecal bile acids	Week 3 and Week 6 (and week 12, if applicable)	Bile acid derivatives will be measured in fecal samples using ultrahigh performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (nmol/g).
Changes in routine clinical bloodwork	Week 3 and Week 6 (and week 12, if applicable)	Routine clinical bloodwork will be performed for patients (e.g., C-reactive protein, liver enzymes, albumin, etc.)
Changes in patient quality of life	Week 3 and Week 6 (and week 12, if applicable)	Patient quality of life will be evaluated using the EQ-5D-5L questionnaire.
Changes in fecal microbiome composition	Week 3 and Week 6 (and week 12, if applicable)	Fecal microbiome composition will be analyzed using whole metagenome sequencing to measure changes at different taxonomic levels (e.g. genus, species).
Changes in fecal short-chain fatty acids	Week 3 and Week 6 (and week 12, if applicable)	Short-chain fatty acids (acetate, propionate, butyrate, valerate) and branched-chain fatty acids (isovalerate, isobutyrate) will be measured in fecal samples using gas chromatography mass spectrometry (µmol/g).
Changes in the plasma inflammatory cytokines	Week 3 and Week 6 (and week 12, if applicable)	Several inflammatory cytokines (e.g., TNF-α, IL-6) will be analyzed in plasma samples using multiplex, electrochemiluminescence assays.
Changes in dietary intake	Week 3 and Week 6 (and week 12, if applicable)	Dietary intake will be measured by 24 hour dietary recalls (using ASA-24).
Changes in function of the fecal microbiome	Week 3 and Week 6 (and week 12, if applicable)	Fecal microbiome functions will be analyzed using whole metagenome sequencing to measure changes in enzymes and pathways encoded by gut microbiota.
Changes in gut barrier function: fecal zonulin	Week 3 and Week 6 (and week 12, if applicable)	Fecal samples will be analyzed for changes in zonulin (ng/mg).
Changes in the plasma metabolome	Week 3 and Week 6 (and week 12, if applicable)	Untargeted metabolomics will be applied to plasma samples via high performance chemical isotope labeling liquid chromatography mass spectrometry platform.
Changes in body weight	Week 3 and Week 6 (and week 12, if applicable)	Body weight will be measured in kilograms and will be used to calculate body mass index.