Sa1742 Microbiome and Host Factors Communicate Protection Against Acute Murine Colitis Following Omega-6 Fatty Acid Induced Transient Pediatric Obesity

Abstract

Background: Dietary influences may affect microbiota composition and host immune responses at the intestinal surface. These nutritionally induced biologic component changes may modulate propensity towards inflammatory bowel diseases (IBD), including Crohn disease (CD) and ulcerative colitis (UC). IBD present most commonly in young adults, indicating childhood as a potentially vulnerable developmental period for disease pathogenesis. Dietary omega-6 fatty acids (ω-6) have been associated with UC in prospective human epidemiologic studies. However, the critical developmental period, when ω-6 consumption may induce UC is not known. We examined the prolonged effects of transient high ω-6 diet during pediatric development in a murine colitis model. Methods: C57Bl/6J mice received high (40% caloric content [cc]), or control (12% cc) ω-6 diet from postnatal day 30 (P30) to P80, then reversed to control diet for 40 days (P120). Body composition was examined by qMRI. Colitis was induced by dextran sulfate sodium (DSS). The severity of colitis was assessed by weight loss and histological scoring. Selective microbiome effects on DSS colitis were studied following fecal transplantation into germ-free mice. The mucosal microbiome was interrogated by next-generation pyrosequencing of the bacterial 16S rRNA gene. Microarrays to study DNA methylation and gene expression from colonic mucosa were utilized. T cell populations in mesenteric lymph nodes (MLNs) and spleen were analyzed by flow cytometry. Plasma of 12 treatment Naive (TN) UC, 11 TN CD and 10 controls were used for quantification of circulating CXCL13 levels by ELISA. Results: Mice transiently became obese on high ω-6 diet. Surprisingly, those were protected against DSS colitis. Protection against colitis was fat type and dietary reversal dependent. Germ-free mice receiving cecal content from the transiently obese mice were protected against colitis. No significant colonic mucosal DNA methylation or gene expression changes were detected. In the meantime, the number of CD4+ cells was decreased in both the spleens and MLNs of the high ω-6 reversed mice. MLN Cxcr5+/CD4+ cells, specifically, were decreased following transient obesity. AntiCxcl13 (the ligand of Cxcr5) antibody treatment decreased DSS induced histological colitis severity. Elevated CXCL13 concentrations (CD: 1.8-fold, p=0.0077; UC: 1.9-fold, p=0.056) were found in the serum of human pediatric IBD patients. Summary: Loss of ω-6 diet induced pediatric obesity protected against acute colitis inmice. This phenotype was communicated by prolongedmicrobiome changes and associatedwith immune organ compositionmodification. The Cxcr5-Cxcl13 pathway was indicated to be an important host factor in modulating DSS colitis severity following the dietary reversal. Our human serologic observations supported the translational relevance of our findings.