AN INULIN-TYPE FRUCTAN ENRICHED EXCLUSIVE ENTERAL NUTRITION FORMULA SUPPRESSES COLITIS THROUGH GUT MICROBIOME MODULATION AND PROMOTING EXPANSION OF ANTI-INFLAMMATORY T CELL SUBSETS

Background & Aims Exclusive enteral nutrition (EEN) is used to treat pediatric Crohn’s disease (CD), but therapeutic benefits are not long lasting. Due to reported lower efficacy EEN is not routinely used to treat pediatric ulcerative colitis (UC). Inulin-type fructans (IN) beneficially modulate the gut microbiome and promote expansion of anti-inflammatory immune cells. We hypothesized that enriching EEN with IN (EENIN) would enhance treatment efficacy. To test this, we examined the effects of EEN-IN on colitis development, the gut microbiome and CD4+ T cells using an adoptive T cell transfer model of colitis. Methods TCR-ß deficient mice were randomized to one of four groups: 1) Control, 2) Chow, 3) EEN and 4) EEN-IN, and naïve CD4+ T cells were adoptively transferred into groups 2-4, after which mice were monitored for 5-weeks prior to experimental endpoint. Results Mice fed EEN-IN showed greater colitis protection, with colonic shortening, goblet cell and crypt density loss reduced over that of EEN fed mice and reduced disease activity and immune cell infiltration compared to chow fed mice, and less crypt hyperplasia and higher survival compared to both groups. EENIN mice maintained colonic mucus layer thickness and had increased levels of Foxp3+IL-10+ and Rorγt+IL- 22+ and reduced levels of Tbet+IFNγ+ and Tbet+TNF+ CD4+ T cells. EEN-IN also lead to higher butyrate, Bifidobacterium spp. and Bacteroides spp. concentrations. Conclusion The EEN-IN group showed reduced colitis development as compared to the chow and EEN groups. This highlights the potential benefits of EEN-IN as a novel induction therapy for pediatric CD and UC patients. Synopsis We demonstrated that inulin-type fructan enriched exclusive enteral nutrition formula reduced colitis development likely due to butyrate-dependent pathways that helped preserve the mucus layer and promote an anti-inflammatory intestinal environment via expansion of regulatory T cells. ### Competing Interest Statement The authors have declared no competing interest. * BCFA : branch-chain fatty acids CD : Crohn’s disease DAS : disease activity score ddPCR : droplet digital PCR EEN : exclusive enteral nutrition EEN-IN : inulin-type fructan enriched exclusive enteral nutrition GI : gastrointestinal tract GPR : G-protein coupled receptor HDAC : histone deacetylase IBD : inflammatory bowel disease IN : inulin-type fructan IP : intraperitoneal MLN : mesenteric lymph nodes NF-κB : nuclear-factor-kappa B PAS : periodic acid-Schiff PBS : phosphate buffered saline PPARy : proliferator-activated receptor gamma SCFA : short-chain fatty acid Tregs : regulatory T cells.