Background: Current evidence indicates that inflammatory bowel diseases (IBD) may be caused in part by aberrant immune responses to commensal intestinal microbes including Bacteroides thetaiotaomicron (B. theta). Healthy, germ-free HLA-B27 transgenic (Tg) rats develop chronic colitis when colonized with complex gut commensal bacteria or Bacteroides vulgatus whereas non-transgenic (nTg) rats remain disease-free. However, the role of B. theta, a well-characterized anaerobic commensal bacterium, in causing disease in Tg rats is unknown. Moreover, while host immune responses to the gut microbiota have been extensively studied, relatively little is known about how microbes respond to host inflammation. Hypothesis: B. theta monoassociated Tg rats develop chronic, immune-mediated colitis that is associated with transcriptional responses in the bacteria that initiate and perpetuate disease. Methods: Four Tg and five nTg rats were monoassociated with a human isolate of B. theta (VPI-5482) for six weeks. Colonic inflammation was quantified by blinded histological scoring and real-time RT-PCR assays of pro-inflammatory cytokines. Cecal bacterial concentrations were measured by quantitative plating on BHI agar. Whole genome transcriptional profiling of B. theta recovered from the cecum was performed using custom GeneChips and data analyzed using DChip, Significance Analysis of Microarrays, and Gene Set Enrichment Analysis (GSEA) software. Results: B. theta monoassociated Tg rats had significantly more colonic inflammation and increased colonic levels of pro-inflammatory cytokine mRNAs than nTg controls (Table). Transcriptional profiles of cecal B. theta were significantly different in Tg vs. nTg rats (329 transcripts representing 44 KEGG canonical pathways). GSEA revealed that the GO molecular function of receptor activity, which is comprised mainly of genes that encode nutrient binding proteins, was significantly enriched with genes upregulated in B. theta from Tg rats [GSEA false discovery rate (FDR)=0.148]. KEGG canonical pathways of ribosome (FDR=0.048), oxidative phosphorylation (FDR=0.098), pyrimidine metabolism (FDR=0.081), purine metabolism (FDR=0.197), peptidoglycan biosynthesis (FDR=0.184), and metabolism (FDR=0.191) were significantly enriched with genes downregulated in B. theta from Tg rats. Numbers of viable bacteria/gram cecal contents in Tg vs. nTg rats were not significantly different. Conclusions: A well-characterized human isolate of B. theta induces mild colitis in HLA-B27 Tg rats and colitis is associated with changes in the expression of microbial metabolic and nutrient binding pathways, but no difference in concentrations of viable cecal bacteria. Mechanistic studies of differentially expressed B. theta genes may reveal novel pathways that initiate and/or perpetuate IBD.