COMMON FOOD ADDITIVES ACCELERATE ONSET OF INFLAMMATORY BOWEL DISEASE IN MICE BY ALTERING MICROBIOME COMPOSITION AND HOST-MICROBE INTERACTION

Abstract

Multiple factors contribute to inflammatory bowel disease (IBD) pathogenesis, including diet. Although correlations exist between the introduction of processed foods and a rise in IBD prevalence, it is not understood what components of processed foods drive disease pathogenesis or how. Despite a FDA classification of Generally Regarded As Safe (GRAS), food additives significantly impact microbe communities and phenotypes. We hypothesized that common food additives, such as maltodextrin (MDX) and carboxymethyl cellulose (CMC), alter intestinal microbes and increase the onset and progression of IBD. We tested this hypothesis using the interleukin-10 deficient (IL10KO) mouse model of spontaneous colitis. To standardize disease onset, IL10KO mice were pre-conditioned with fecal material from nucleotide-binding oligomerization domain 2 deficient mice (NOD2KO) to promote intestinal inflammation. Pre-conditioned IL10KO mice were randomized to chow diets containing either 1% MDX, 1% CMC, or a control diet. MDX and CMC accelerated the onset of colitis compared to the control diet. This was accompanied by elevated fecal lipocalin-2 (p<0.05) and serum amyloid A (p<0.01), intestinal infiltration of CD3+ cells, and intestinal pathology consistent with chronic inflammation (p<0.05). Although both dietary additives promote disease in this model, the molecular mechanisms involved appear to be distinct. Intestinal mucus modulates interactions of the microbiome and the host. Strikingly, goblet cells in MDX fed mice had reduced mucin granule content (∼50% of control diet) as assessed by Muc2 and Periodic Acid Schiff staining. This mucin depletion did not correlate with degree of disease activity, suggesting this deficiency is not a result of inflammation in MDX fed mice and was not observed in CMC fed mice or control diet mice. Food additives also altered the intestinal microbiome, with MDX fed mice demonstrating a significant decrease in microbiome alpha diversity (p<0.05, ANOVA), and both food additives resulting in a significant shift in beta diversity (R2=0.40, p=0.002, PERMANOVA) as compared to the control diet. Flagella expression by microbes was slightly elevated in CMC-fed mice, but not in MDX-fed mice, suggesting that these food additives have distinct actions on microbes. Magnitude of genus-level changes in microbial abundance correlated with disease severity as assessed by serum amyloid A levels. This data indicates that common food additives are not biologically inert substances, and may drive the progression of inflammatory bowel disease through additive-specific alterations of the microbiome and host-microbe interactions.