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Background: Mounting evidence indicates that aberrant immune responses to commensal intestinal microbes contribute to the development of inflammatory bowel diseases (IBDs). However, little is known about the effects of inflammation on gut microbial function. We previously reported that colitis induces commensal luminal Escherichia coli to upregulate stress-response genes in monoassociated Il-10-/(KO) mice, but colitis-associated microbial transcription in complex luminal bacterial communities has not been explored. Understanding how inflammation affects gut microbes in a manner that perpetuates colitis could identify novelmicrobial pathways that can be targeted for therapeutic purposes. Hypothesis:Mixtures of commensal bacterial isolates induce colitis in KO mice and respond to inflammation by upregulating genes that promote microbial survival. Methods: Germ-free wild-type (WT) and KO 129 SvEv mice were colonized for up to 10 weeks with 8 commensal, predominantly human-derived bacterial isolates (Table) representing each major phylum of the gut microbiome. Intestinal inflammation was quantified by blinded histological scores and spontaneous secretion of Il-12/23p40 by colon explant cultures. Fecal bacterial composition at 5 wks was measured by real-time PCR. Cecal microbial metatranscriptomes at 10 wks were characterized using Illumina-based microbial RNA-Seq and Gene Set Enrichment Analysis of conserved domains. Results: At 5 and 10 weeks, KO mice had increased histological inflammation and Il-12/23p40 secretion by colon explant cultures compared to WT mice. At 5 weeks, fecal bacterial composition in WT and KOmice was similar and was dominated by Bacteroides thetaiotaomicron and Ruminococcus gnavus. Gut microbial metatranscriptomes in KO and WT mice were significantly different at 10 weeks. While relatively few E. faecalis mRNA's were detected in cecal contents, they comprise the majority of differentially expressed microbial genes (Table). Overall, 76 conserved domains were significantly enriched with genes that are upregulated in bacteria from KO mice including tRNA synthetase (false discovery rate/ FDR=0.001), translation factors (FDR=0.002), cell wall biosynthesis (FDR=0.011), nucleotide salvage pathways (FDR=0.013), bacterial sugar transferase (FDR=0.015), and DNA repair (FDR=0.039). 7 conserved domains were enriched with genes that are downregulated in bacteria from KO mice including thioredoxin (FDR=0.052) and cation transporting ATPase (FDR=0.155). Conclusions: A representative mixture of predominantly human commensal bacterial isolates induces colitis in gnotobiotic Il-10-/mice and responds to inflammation by upregulating genes in metabolic, synthetic and DNA repair pathways. Mechanistic studies of differentially expressed bacterial genes may reveal novel pathways that initiate and/or perpetuate IBDs.

P003 Selective inhibition of eIF2alpha dephosphorylation prevents colitis and shows therapeutic potential in a new model of ulcerative colitis X. Treton1 *, E. Pedruzzi1, C. Guichard2, M. Vallee1, S. Sedghi1, Y. Ladeiro1, N. Montcuquet3, J.N. Freund4, I. Van Seuningen5, F. Barreau1, J.P. Hugot1, D. Cazals-Hatem6, F. Daniel1, E. OgierDenis1, Y. Bouhnik7. 1Paris 7 University, Inserm U773, Paris, 2Univ. Paris-Diderot Sorbonne Paris-Cite, INSERM U674, 3Univ. Paris-Diderot Sorbonne Paris-Cite, INSERM U989, 4Inserm U 682, Strasbourg, 5INSERM UMR837, Lille, 6Hopital Beaujon, APHP, Pathology, Clichy, 7Hopital Beaujon, APHP, Gastroenterology, Clichy, France