Division of Gastroenterology and Hepatology
7309A Medical Biomedical Research Building, CB #7032
Our long term goals are to better define mechanisms of chronic intestinal inflammation and to identify areas for therapeutic intervention. Research in our laboratories is in the following four general areas.
Induction and perpetuation of chronic intestinal and extraintestinal inflammation by resident intestinal bacteria and their cell wall polymers.
We are exploring the hypothesis that normal luminal bacteria can induce immune-mediated chronic inflammation in the genetically susceptible host. We demonstrated that germ free (sterile) HLA-B27 transgenic rats, IL-10 knock out and IL-2 knock out mice fail to develop colitis, and that colitis develops within one week of colonization with specific pathogen free bacteria in these genetically engineered hosts. Moreover, all bacteria do not have equal capacities to induce inflammation, since Bacteroids vulgatus induces aggressive colitis in HLA-B27 transgenic rats, E. coli do not cause any inflammation and Lactobacilli is protective.
Mechanisms of genetically determined host susceptibility to bacterial products.
We demonstrated differential host genetic susceptibility to chronic inflammation in inbred rat strains using these experimental models of inflammation and are now exploring mechanisms of differential immunoregulation in these rat strains, concentrating on cytokine profiles and the kallikrein-kinin pathway.
Regulation of immunosuppressive molecules in intestinal epithelial cells.
We are investigating the in vivo regulation of intracellular IL-1 receptor antagonist (ic IL-1 RA) and the IkB/NFkB complex regulation of these molecules in epithelial cell lines. We have demonstrated altered IkBa degradation in intestinal epithelial cells and are exploring mechanisms of this delayed, incomplete degradation. Biologic importance of these inhibitors are examined by selective pharmacologic and molecular blockade and over expression of these molecules (i.e. dominant negative constructs and antisense oligonucleotides).
Performing clinical trials of novel therapeutic agents in inflammatory bowel disease patients.
We are investigating selective inhibitors such as rh IL-10 and anti-TNFa mAB in Crohn's disease patients and antibiotics and probiotic cocktails in ulcerative colitis patients.
Liu B, Tonkonogy SL, Sartor RB (2011). Antigen-presenting cell production of IL-10 inhibits T-helper 1 and 17 cell responses and suppresses colitis in mice. Gastroenterology. 141(2):653-662.e4.
Sartor RB (2010). Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis. Gastroenterology. 139(6):1816-9.
Sartor RB (2009). Microbial-host interactions in inflammatory bowel diseases and experimental colitis. Nestle Nutr Workshop Ser Pediatr Program. 64:121-32.
Moran JP, Walter J, Tannock GW, Tonkonogy SL, Sartor RB (2009). Bifidobacterium animalis causes extensive duodenitis and mild colonic inflammation in monoassociated interleukin-10-deficient mice.
Inflamm Bowel Dis. 15(7):1022-31.
Walton KL, Holt L, Sartor RB (2009). Lipopolysaccharide activates innate immune responses in murine intestinal myofibroblasts through multiple signaling pathways. Am J Physiol Gastrointest Liver Physiol. 296(3):G601-11.
Hansen JJ, Holt L, Sartor RB (2009). Gene expression patterns in experimental colitis in IL-10-deficient mice. Inflamm Bowel Dis. 15(6):890-9.
Qian BF, Tonkonogy SL, Sartor RB (2008). Aberrant innate immune responses in TLR-ligand activated HLA-B27 transgenic rat cells. Inflamm Bowel Dis. 14(10):1358-65.
Shaheen NJ, Sartor RB (2008). Our new president--Robert S. Sandler, MD, MPH. Gastroenterology. 134(5):1596-600.
Qian BF, Tonkonogy SL, Sartor RB (2008). Reduced responsiveness of HLA-B27 transgenic rat cells to TGF-beta and IL-10-mediated regulation of IFN-gamma production. Inflamm Bowel Dis. 14(7):921-30.
Kim SC, Tonkonogy SL, Karrasch T, Jobin C, Sartor RB (2007). Dual-association of gnotobiotic IL-10-/- mice with 2 nonpathogenic commensal bacteria induces aggressive pancolitis. Inflamm Bowel Dis. 13(12):1457-66.
Hoentjen F, Tonkonogy SL, Qian BF, Liu B, Dieleman LA, Sartor RB (2007). CD4(+) T lymphocytes mediate colitis in HLA-B27 transgenic rats monoassociated with nonpathogenic Bacteroides vulgatus. Inflamm Bowel Dis. 13(3):317-24.
Sartor RB (2005). Are we losing control? Medical costs can no longer be ignored. Gastroenterology. 129(4):1149.
Qian BF, Tonkonogy SL, Hoentjen F, Dieleman LA, Sartor RB (2005). Dysregulated luminal bacterial antigen-specific T-cell responses and antigen-presenting cell function in HLA-B27 transgenic rats with chronic colitis. Immunology. 116(1):112-21.
Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri M, De Simone C, Sartor RB (2005). VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol. 100(7):1539-46.
Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ, Braun J, Huycke MM, Sartor RB (2005). Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 128(4):891-906.