P916 Small bowel permeability improvement is associated with microbial changes seen in mild to moderate active paediatric Crohn’s disease patients on nutritional therapy

Background Barrier disruption leading to impaired intestinal permeability in Crohn’s Disease (CD) has been associated with various processes, including (pro-inflammatory) cytokine production, impaired mucus production and altered tight junction protein expression. A recent study showed that healthy first-degree relatives of CD patients had abnormal intestinal permeability which was associated with altered gut microbiome composition. We have previously reported that intestinal permeability improves with nutritional therapy (by either Crohn’s disease exclusion diet (CDED) or exclusive enteral nutrition (EEN)). We hypothesized this improvement in permeability might be associated with changes in the gut microbiome caused by nutritional therapy. Methods Paediatric participants with mild-to-moderate CD from a prospective clinical trial evaluating nutritional therapy (with CDED+PEN or EEN) for induction of remission were included (NCT01728870). A lactulose/mannitol (L/M) test for intestinal permeability was performed at weeks 0 and 3 by administering a sugar solution containing lactulose (5 g) and mannitol (1 g) followed by urine collection for LC-MS/MS analysis. A cut-off L/M ratio 0.025 was used (Leibovitzh, Gastroenterology 2022). We compared 16S rRNA (V4V5) changes of dietary responders between weeks 0 and 6 to identify microbial changes associated with improved intestinal permeability. Results Paired L/M ratios were available for 53 patients (26 CDED+PEN and 27 EEN). Normal L/M ratios were seen in 15/26 (58%) of CDED+PEN patients and 15/27 (56%) of EEN patients at baseline, which improved to 19/26 (73%) in CDED+PEN and 17/27 (63%) in EEN (generalized linear model, p=0.574) at week 3. Notably, 7/11 (63%) CDED+PEN patients with abnormal intestinal permeability at baseline normalised, compared to 5/12 (41%) patients in the EEN group (NS). Dietary response has been shown to be associated with significant increases in Clostridia and decrease in Gammaproteobacteria (Gastroenterology 2019). Of dietary responders, intestinal permeability “non-improvers” showed no significant changes in microbial composition, whereas “improvers” showed significant increases in different genera of Eubacteriales (Clostridia), accompanied by increase in Alphaproteobacteria (all p2) at week 6. Conclusion A subset of patients with paediatric CD have impaired intestinal barrier function and disrupted intestinal permeability. Achieving clinical remission and improvement in intestinal permeability share features of microbiome correction. Further study to characterise the effect of the microbiome and metabolome (including whole metagenome analysis) on intestinal permeability, particularly within a dysbiotic state such as CD, is warranted.