Abstract Background The gut microbiota in ulcerative colitis (UC) is characterised by a disrupted ecology, such as a reduction in abundance of certain Firmicutes and Bifidobacterium species 1. Prebiotics could positively modulate the gut microbiota and reduce inflammation in UC. Human milk oligosaccharides (HMOs) are promising prebiotic candidates with both in vitro and clinical evidence in UC 2,3,4. Methods PRInCE-UC (NCT06050811) was an adequately powered randomised double-blind placebo-controlled crossover design clinical trial assessing the effect of supplementation of 5g per day of the HMO 2’-fucosyllactose (2’-FL) in UC. 38 patients with mild to moderate symptoms and active disease defined by at least one of faecal calprotectin (FCP) ≥150 µg/g, serum C-reactive protein (CRP) 5mg/L or active disease at endoscopy were enrolled and randomised to consume either 5g per day of 2’-FL or 5g per day of maltodextrin (MDX) placebo for 28 days table 1. After 28 days, participants underwent a 21 day washout period, before consuming 28 days of the other product, followed by a final 21 day washout period. Validated patient-reported outcome measures (Simple Clinical Colitis Activity Index, SCCAI, and IBD-Control-8), faeces, serum and urine were collected at weeks 0, 4, 7, 11, and 14. The primary endpoint was clinical response (SCCAI reduction by ≥ 2 points), with secondary outcomes of clinical remission, IBD related quality of life, FCP, and microbiota changes. Results 33 patients completed the trial (intention to treat, ITT), of whom 27 of these completed the trial per protocol (PP). Adherence to both products was high, with no difference in dropout rates nor adverse effects with 2’-FL vs MDX. PERMANOVA analysis validated the effectiveness of the crossover design with adequate washout periods (R² ≈ 0.006–0.024, p = 1.000). No significant difference was seen in the primary outcome of clinical response (2’-FL vs MDX, 18.5% vs 37%, p = 0.22). 2’-FL significantly increased total bacterial count (post vs pre, 9.64 vs 9.53 log10 cells mL-1, p = 0.032), and significantly increased Bifidobacterium relative abundance vs MDX (4.73% vs 0.65% delta change, p = 0.0063). 2’-FL reduced FCP vs MDX, albeit not significantly (-46.1 vs + 10.9, p = 0.35) figure 1. Age predicted response to 2’-FL with an area under the receiver operating characteristic (ROC) curve of 0.773 at an optimal cut-off of 50 years old, with a response-associated microbiota signature. Conclusion This is the largest crossover trial of prebiotics in IBD to date, and the world’s first randomised controlled trial of an HMO in IBD. 2’-FL positively modulated the gut microbiota with a trend towards reduction in FCP, positioning HMOs as potential dietary adjuncts to current UC therapy. References: 1. Kennedy JM, De Silva A, Walton GE, Gibson GR. A review on the use of prebiotics in ulcerative colitis. Trends Microbiol. 2024;32(5):507-515. 2. Kennedy JM, De Silva A, Walton GE, Poveda C, Gibson GR. Comparison of prebiotic candidates in ulcerative colitis using an in vitro fermentation model. J Appl Microbiol. 2024;135(2):lxae034. doi:10.1093/jambio/lxae034 3. Ryan JJ, Monteagudo-Mera A, Contractor N, Gibson GR. Impact of 2’-Fucosyllactose on gut microbiota composition in adults with chronic gastrointestinal conditions: batch culture fermentation model and pilot clinical trial findings. Nutrients. 2021;13(3):938. doi:10.3390/nu13030938 4. Fanous N, Talley NJ, Chaemsupaphan T, et al. Microbiota-targeted strategies in IBD: therapeutic promise of 2’-fucosyllactose and beyond. Therap Adv Gastroenterol. 2025;18:17562848251386319. doi:10.1177/17562848251386319 Conflict of interest: Dr. Kennedy, James: No conflict of interest Sanz Morales, Patricia: None. Poveda Turrado, Carlos G: No conflict of interest Walton, Gemma: No conflict of interest De Silva, Aminda: No conflicts Gibson, Glenn: No conflict of interest
Kennedy et al. (Thu,) studied this question.