Using Breath Tests to Study Gut Sulfur Changes During Dietary Therapy

Purpose To determine whether a short-term elemental diet followed by a reduced sulfur diet is a safe, tolerable, and effective non-pharmacologic strategy to improve clinical outcomes, reduce inflammation, and beneficially modulate the gut microbiome in adults with mild-to-moderate ulcerative colitis. A secondary purpose is to validate breath-based biomarkers as non-invasive tools to monitor sulfur metabolism and disease activity. Breath biomarkers include volatile organic compounds (VOCs) and exhaled breath condensate (EBC) to assess sulfur-related metabolites.

Hypothesis A 2-week elemental diet followed by a 10-week reduced sulfur diet will reduce intestinal inflammation and improve clinical outcomes by shifting the gut microbiome away from pro-inflammatory, sulfur-metabolizing bacteria, resulting in reduced sulfur metabolite production detectable through exhaled volatile organic compounds and exhaled breath condensate.

Justification Despite advances in biologic therapies, many UC patients fail to achieve sustained remission, and current treatments do not address upstream drivers such as diet-microbiome interactions. Elemental diets have demonstrated efficacy in Crohn's disease but remain understudied in UC. Emerging evidence links dietary sulfur, microbial sulfur metabolism, and toxic metabolites to UC pathogenesis. This study addresses critical gaps by testing a feasible dietary intervention and validating non-invasive breath biomarkers for real-time disease monitoring and precision nutrition.

Objectives

• Evaluate the clinical efficacy, safety, and feasibility of an elemental diet followed by an reduced sulfur diet.
• Characterize changes in gut microbiome composition, inflammatory markers, and sulfur-related metabolic outputs.
• Validate breath-based volatile organic compounds and exhaled breath condensate as biomarkers of sulfur metabolism and treatment response.
• Identify microbial and metabolic signatures predictive of dietary response.

Research Design A prospective, randomized, controlled trial in adults with mild-to-moderate UC. All participants complete a 2-week elemental diet, followed by randomization (2:1) to either a reduced sulfur diet group (intervention group) or return to habitual diet group (control group) for 10 weeks. Clinical indices, inflammatory biomarkers, stool microbiome profiles and breath samples are collected longitudinally. The initial 2-week elemental diet is applied uniformly to standardize baseline microbial and metabolic conditions prior to randomization and does not replace or delay clinical care decisions.

Statistical Analysis Primary outcomes will be assessed using within- and between-group comparisons of clinical and biochemical response at week 12. Microbiome and metabolomic data will be analyzed using multivariate and differential abundance methods. Correlations between breath biomarkers, microbiome features, and clinical outcomes will assess sensitivity and specificity.

Inclusion criteria

• Age 19-70 years.

=Diagnosis of mild-to-moderate ulcerative colitis, defined by a partial Mayo score (pMayo) of 2-7.

• Evidence of active inflammation at enrollment, defined as:
• C-reactive protein (CRP) > 5 mg/L; or
• Fecal calprotectin (FCP) > 200 µg/g.
• Receiving stable medical therapy for ulcerative colitis for at least 8 weeks prior to enrollment.
• No corticosteroid use at the time of recruitment.
• Under consideration by the treating physician for treatment escalation or biologic switch due to inadequate response to current therapy.

Exclusion criteria

• Partial Mayo score (pMayo) > 7.
• Pregnant or breastfeeding.
• Body mass index (BMI) < 18 kg/m².
• History of an eating disorder.
• Severe psychiatric disorder.
• Severe medical conditions, including:
• Active cancer;
• Significant cardiovascular disease;
• Diabetes mellitus; or
• Severe food allergies.
• Known allergy or intolerance to corn, dextrose, or maltodextrin.
• Antibiotic use within 3 months prior to enrollment.
• Probiotic use within 3 months prior to enrollment.
• Use of herbal anti-inflammatory supplements during the study period, including but not limited to:
• Serrapeptidase;
• Curcumin;
• Boswellia; or
• Bromelain.
• History of major gastrointestinal surgery, including:
• Ostomy;
• Total colectomy; or
• Short bowel syndrome.
• Inability or unwillingness to comply with study procedures, including anticipated travel or other commitments that may interfere with participation.