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7 
LACTOBACILLUS REUTERI SUPPRESSES PRO-INFLAMMATORY DRIVEN REACTIVE OXYGEN SPECIES IN VITRO IN HUMAN INTESTINAL EPITHELIAL CELLS AND IN VIVO IN A TNBS COLITIS MOUSE MODEL

molecules generated from microbial metabolism, knowledge of how inflammation alters the microbial metabolome and how epithelial cells react is important for a better understanding of how IBD develops and persists. Butyrate, a short chain fatty acid produced through fermentation of dietary polysaccharides, has long been known to inhibit histone deacetylases (HDACs), which represent one of the many types of enzymes responsible for the epigenetic control of gene expression through the post-translational modification of histone proteins. We and others have observed that colonic epithelial cells from germ-free mice have reduced levels of acetylation on histone H4, which appears to be distributed throughout the genome based on sequencing analysis. The decreased levels of H4 acetylation may stem from a lack of butyrate, and therefore uninhibited HDAC activity, in germ-free mice. However, since colonic epithelial cells utilize short chain fatty acids as an energy source, an alternative explanation is that the germ-free condition results in less oxidation of butyrate to acetyl-CoA, which is the donor substrate for histone acetylation reactions. Isotope tracing experiments, in which cultured cells were incubated with labeled butyrate, demonstrated that the acetyl groups of histones contained carbon derived from butyrate. We have also performed isotope tracing experiments in mice using labeled inulin, a plant polysaccharide that presumably undergoes fermentation into short chain fatty acids. In this more physiologically relevant model, we detected isotope incorporation into the acetylated histones of colonic epithelial cells at rates of 5–20%, which appears dependent on the microbiota since labeling is sensitive to antibiotic treatment. To identify the metabolic pathways that link inulin to histone acetylation, we are investigating which metabolites become isotopically labeled using untargeted metabolomics. We will apply the same approach to the DSS-induced model of colitis to investigate how inflammation modulates the gut metabolome as well as the metabolic connections between the microbiota and the host. Our studies may uncover metabolic pathways that become dysregulated during inflammation, which may contribute to the pathogenesis of diseases such as IBD.