A pilot randomized controlled trial investigating the effects of an anti-inflammatory dietary pattern on disease activity, symptoms and microbiota profile in adults with inflammatory bowel disease

The study addresses the uncertainty in dietary prescriptions for inflammatory bowel disease (IBD) due to heterogeneous prior research and limited well-designed randomized controlled trials. Incidence of IBD has paralleled adoption of ultra-processed Western dietary patterns. The traditional Mediterranean diet (TMD) is associated with anti-inflammatory effects and beneficial gut microbiota profiles, whereas ultra-processed diets, characterized by additives such as artificial sweeteners, emulsifiers, and carrageenan, are linked to inflammation and oxidative stress. Evidence from in vitro and animal models suggests common food additives can damage the gut mucous layer and perturb the microbiota, but translation to IBD patients is unclear. The research question tests whether an IBD-modified anti-inflammatory diet (IBD-MAID) designed to minimize exposure to specific food additives improves disease activity, inflammatory markers, symptoms, quality of life, and microbiota compared with standard general healthy eating in adults with IBD over eight weeks.

Background literature highlights: (1) the role of diet in IBD pathogenesis and the rise of IBD alongside Westernized, ultra-processed dietary patterns; (2) the Mediterranean diet’s anti-inflammatory properties and association with improved gut microbiota; (3) ultra-processed diets’ association with elevated inflammatory cytokines and oxidative stress; (4) mechanistic evidence that additives (non-nutritive sweeteners, emulsifiers, carrageenan, maltodextrin, nitrates/nitrites) can impair the gut barrier and disturb microbiota. The discussion references Lewis et al. (2021), a randomized trial comparing specific carbohydrate diet versus Mediterranean diet in Crohn’s disease, which found no between-group differences but within-group improvements, suggesting benefits may stem from fresh, minimally processed foods possibly via reduced additive exposure. Prior studies on UC-specific diet effects are lacking. Overall, the literature supports testing a low-additive, Mediterranean-style dietary pattern in IBD.

Design: Pilot randomized controlled trial adhering to CONSORT guidelines, conducted September 2019–January 2022 at a tertiary hospital in Queensland, Australia. Registered ACTRN12619001500145. Ethics approvals obtained; informed consent was obtained. Participants: Adults aged 18–60 with established ulcerative colitis (UC) or Crohn’s disease (CD), reporting deteriorating symptoms, with faecal calprotectin (FC) > 50 µg/g. Exclusions included inability to consent/English limitations, smoking (current or quit within 12 months), pregnancy/lactation, food allergies/intolerances limiting adherence, ostomy, stricturing/penetrating CD likely needing surgery within six months, and unstable IBD medications (specified wash-in periods for thiopurines, methotrexate, JAK inhibitors, anti-TNFs, vedolizumab/other biologics, and corticosteroid dose changes). Stable medical therapy at consent required. Residence within 20 km of hospital required for meal delivery. Randomization and groups: 1:1 allocation stratified by disease subtype (UC/CD) and gender to Intervention (IBD-MAID meals) or Comparator (general healthy eating, GHE). Intervention: two meals/day (lunch, dinner) for 8 weeks prepared/delivered by a catering company from study dietitian recipes, education on IBD-MAID principles, and breakfast/snack recipes; ad libitum intake with approved extra snacks for higher needs. Comparator: watched a GHE educational video and received Australian government ‘Eat for Health’ materials and recipes. From weeks 8–16, Comparator participants crossed over to IBD-MAID via education and provision of key ingredients (extra virgin olive oil, unsalted nuts/almonds, probiotic yoghurt) to assess real-life feasibility (IBD-MAID education). Dietary prescription: IBD-MAID is a modified anti-inflammatory, Mediterranean-style pattern designed to be low in specific additives (artificial sweeteners, emulsifiers including P80/CMC, carrageenan gum, maltodextrin, nitrites/nitrates). High-fiber, whole-food emphasis. Outcomes and timepoints: Assessed at baseline, week 8 (primary comparison), and week 16. Primary outcome: change in disease activity at week 8 (SCCAI for UC, range 0–19; CDAI for CD, range 0–600). Secondary outcomes: quality of life (SIBDQ), symptom severity (PRO2), intestinal inflammation (FC, log-transformed), systemic inflammation (CRP; response defined as CRP <5 mg/L at week 8 or ≥50% reduction from baseline). Diet adherence assessment: 3-day food diaries every 4 weeks (app or paper) plus daily checklist. Mediterranean Diet Adherence Screener (MEDAS; adherence defined as ≥9) and a study-developed food additives score (five subgroups: non-nutritive sweeteners, nitrites/nitrates, maltodextrin, P80/CMC/carrageenan, other emulsifiers). For each subgroup over 3 days: 0 for 0–1 instance, 1 for 2–4, 2 for >4; total 0–10. Compliance defined as <3. Microbiome: Stool collected for 16S rRNA sequencing and metagenomics by Australian Centre for Ecogenomics. DNA extracted via bead-beating, quantified (Nanodrop), stored at −80°C. Processing/assignment via cutadapt and DADA2 in QIIME2. Beta diversity via PCoA; supervised (RDA) and unsupervised (ADONIS) multivariate analyses; linear mixed-effects models for taxon differences; multiple testing correction (FDR or Bonferroni). Analyses by overall IBD and by subtype (UC/CD). Statistical analysis: Modified intention-to-treat using Stata 18; plots in R (v4.1.0). Participants withdrawing before week 8 excluded from final analysis due to missing data. Per-protocol excluded medication changes during intervention or non-adherence (MEDAS <9 or additives score ≥3 at end). Descriptive statistics reported as mean±SD or median (IQR), categorical as n (%). Primary analysis: independent-samples t-test for change (week 8 − baseline) between groups; ANCOVA with baseline as covariate for potential imbalance. Within-group changes via paired t-test. Additional comparisons for IBD-MAID meals (baseline to week 8) vs IBD-MAID education (Comparator baseline to week 16) using t-tests/ANCOVA. Spearman correlations assessed relationships between change in diet adherence (MEDAS and additives scores) and changes in outcomes. Power: targeted 50 participants (25/arm) for pilot with main trial planning; anticipated 25% attrition led to recruitment target 67.

- Enrollment/randomization: 280 screened; 58 randomized (29 Intervention: IBD-MAID meals; 29 Comparator: GHE). Withdrawals before week 8: Intervention 3; Comparator 3 (plus 2 lost to follow-up). Modified ITT at week 8: Intervention n=26; Comparator n=24. - Baseline: 75% UC, 25% CD; demographics largely balanced. Baseline mean food additives score: Comparator 3.4±1.4, Intervention 3.3±1.6; baseline MEDAS higher in Intervention (7.14±1.5 vs 6.2±1.6). Microbiome differed by UC vs CD (MANOVA P<0.02) but not by treatment group at baseline (P=0.78). - Primary outcome (change in disease activity at week 8): • UC (SCCAI): Comparator −0.3±3.3 (n=18, p=0.72 within-group); Intervention −0.7±2.5 (n=19, p=0.21). Between-group mean difference in change −0.5 (95% CI −2.4 to 1.5), p=0.63. • CD (CDAI): Comparator −22.6±46.3 (n=5, p=0.34); Intervention −46.0±43.1 (n=7, p=0.030). Between-group mean difference in change −23.4 (95% CI −81.3 to 34.5), p=0.39. - Secondary outcomes (week 0 to 8): • Symptoms (PRO2): Comparator −1.6±6.2 (n=24, p=0.20); Intervention −4.3±5.8 (n=25, p=0.001). Between-group difference −2.6 (95% CI −6.1 to 0.8), p=0.13. • Quality of life (SIBDQ): Comparator +0.3±0.7 (n=24, p=0.019); Intervention +0.5±0.8 (n=25, p=0.004). Between-group difference 0.2 (95% CI −0.3 to 0.6), p=0.45. • Faecal calprotectin (FC, geometric mean fold change): Comparator 0.64 (95% CI 0.29–1.40, n=23, p=0.25); Intervention 0.28 (95% CI 0.13–0.59, n=25, p=0.002). Between-group ratio 0.43 (95% CI 0.15–1.26), p=0.12. • CRP response achieved: 73% (16/22) Intervention vs 65% (13/20) Comparator; OR 1.4 (95% CI 0.4–5.3), p=0.59. - Adherence: • Intervention (week 0→8): MEDAS increased 7.1±1.5 to 10.5±1.2 (p<0.001); 92% met MEDAS ≥9. Food additives score decreased 3.4±1.4 to 0.2±0.5 (p<0.001); all achieved <3. Overall adherence at week 8: 92%. • Comparator: After 8 weeks GHE, MEDAS 6.2±1.6 to 6.4±1.7 (p=0.55) and additives 3.3±1.6 to 3.2±1.5 (p=0.84). After subsequent 8 weeks IBD-MAID education (week 16): MEDAS 9.4±1.7 (p<0.001); additives 2.6±1.6 (p=0.036); ~70% met each adherence criterion; overall adherence ~60%. - Correlations (baseline→week 8): • Higher MEDAS increase correlated with greater FC reduction (r=−0.33, adj p=0.039); not significant for PRO2 or SIBDQ after adjustment. • Greater decrease in food additives score associated with greater improvements: FC (r=−0.35, adj p=0.039), PRO2 (r=−0.33, adj p=0.039), SIBDQ (r=−0.37, adj p=0.039). UC-only analyses confirmed associations after multiple comparison correction for SIBDQ (r=−0.69, p=0.03), FC (r=−0.37, p<0.05), PRO2 (r=−0.41, p=0.04). - Microbiome: No significant between-group differences at week 8 (MANOVA P=0.37). No significant changes in diversity/richness from baseline to week 8 (ANCOVA P=0.22); age influenced diversity (P=0.02). No significant differences in change in diversity/richness between groups (mixed-effects P=0.25). - Safety: IBD-MAID well tolerated; one hospitalization for flare during meals phase deemed unrelated to intervention.

The absence of statistically significant between-group differences at 8 weeks likely reflects similarities in both dietary prescriptions emphasizing improved diet quality (more fruits, vegetables, whole grains; reduced processed foods), mild baseline disease limiting detectable change, and the pilot sample size. Nevertheless, within-group improvements were more pronounced with IBD-MAID, including significant reductions in symptoms, FC, and improved quality of life, and a significant reduction in CDAI among CD participants, suggesting a potential treatment effect. A key and novel observation is the association between reduced food additive exposure and improvements in inflammatory markers (FC), symptoms (PRO2), and quality of life (SIBDQ). Alignment with anti-inflammatory diet principles (MEDAS) correlated with FC reduction but was less consistently associated with symptoms or QOL after adjustment, underscoring the potential specific role of additives. Despite these clinical associations, no significant microbiome compositional or diversity changes were detected, possibly due to limited power, short duration, and the heterogeneity of including both UC and CD. The findings align with prior RCTs (e.g., Lewis et al., 2021) showing within-group improvements with whole-foods-based diets without between-group differences. Practical challenges exist in educating patients to reduce additive exposure due to limited labeling transparency; meal provision facilitated better adherence (larger reductions in additives and higher MEDAS scores) than education alone, although education with key ingredients was feasible and reasonably effective. Concerns that high-FODMAP or higher-fiber content might exacerbate symptoms were not supported; increases in symptoms occurred at similar rates across groups and were more likely linked to disease activity. Overall, results support recommending a low–food additive Mediterranean-style pattern for IBD, while highlighting the need for better methods to quantify additive intake and for trials powered to detect modest effects and assess endoscopic healing.

IBD-MAID, a modified anti-inflammatory Mediterranean-style diet designed to minimize specific food additives, was feasible, well tolerated, and achieved high adherence. At 8 weeks, there were no statistically significant between-group differences versus general healthy eating; however, within the IBD-MAID group, significant improvements were seen in symptoms, quality of life, faecal calprotectin, and Crohn’s disease activity, while the comparator showed improvement mainly in quality of life. The most novel contribution is the observed correlation between reduced food additive intake and improvements in inflammation, symptoms, and quality of life. Future research should include adequately powered RCTs, longer follow-up, endoscopic endpoints, UC-focused analyses, validated methods to quantify additive intake, tools to help identify additives in foods, and consideration of regulatory changes to improve additive transparency.

- Pilot design with limited sample size powered only for large effects; recruitment shortfall (COVID-19 constraints) and underpowered CD subgroup. - Mild baseline disease activity (many in remission or mild disease), reducing capacity to detect improvements, particularly in UC. - Short intervention duration (8 weeks) may be insufficient for detecting changes in some outcomes, including mucosal healing. - No endoscopic assessment; mucosal healing not evaluated. - Potential dilution of intervention effect due to improvements in the comparator group from general healthy eating. - Microbiome analyses may have been underpowered to detect compositional changes; inclusion of both UC and CD increased heterogeneity. - Measurement challenges in accurately quantifying food additive exposure using available dietary assessment and labeling practices.