Our long-term goal is to understand intestinal epithelial transport and barrier function. Substantial evidence suggests that these critical functions are altered in the setting of inflammatory bowel disease and other intestinal disorders. Moreover, we hypothesize that inflammatory bowel disease results when intestinal barrier function is inadequate to exclude luminal factors, thereby resulting in immune stimulation and a vicious cycle of inflammation and injury that further compromises transport and barrier homeostasis. We will also test the specific hypothesis that probiotic microorganisms exert protective effects on intestinal epithelial cells under both basal conditions and when they are compromised by pathogenic microorganisms or other injurious insults. We will test our hypotheses by addressing two specific aims. In the first, we will examine whether barrier and transport functions are altered in a mouse model of inflammatory bowel disease known to depend on an epithelial defect, and determine how such alterations contribute to the pathogenesis of inflammation and/or the generation of symptomatology. The interplay with luminal bacteria will also be sought. In the second aim, we will define mechanisms whereby probiotic microorganisms improve epithelial barrier and transport function under control conditions, when these functions are compromised in vitro, and in the model of inflammatory bowel disease described above. The approach will be to use the mdr1a -/- mouse which develops spontaneous colitis when conventionally housed, as well as human intestinal epithelial cell lines. We will also employ pathogenic bacteria and two representative probiotic strains. We will study transport and barrier functions in these models using electrophysiological approaches, and will apply molecular techniques to define protein targets of inflammation, or which underlie the beneficial effects of probiotics. The significance of this work lies in its potential to yield novel insights into the pathogenesis of inflammatory bowel disease. It may also provide a scientific rationale for continued exploration of probiotics, promising complementary/alternative therapies, in the treatment of inflammatory bowel disease and other intestinal disorders.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Pontzer, Carol H
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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McCole, Declan F; Barrett, Kim E (2007) Varied role of the gut epithelium in mucosal homeostasis. Curr Opin Gastroenterol 23:647-54
Resta-Lenert, Silvia; Barrett, Kim E (2006) Probiotics and commensals reverse TNF-alpha- and IFN-gamma-induced dysfunction in human intestinal epithelial cells. Gastroenterology 130:731-46
Barrett, Kim E (2005) A new twist on trefoils. Focus on ""TFF3 modulates NF-{kappa}B and a novel regulatory molecule of NF-{kappa}B in intestinal epithelial cells via a mechanism distinct from TNF-{alpha}"". Am J Physiol Cell Physiol 289:C1069-71
Resta-Lenert, Silvia; Smitham, Jane; Barrett, Kim E (2005) Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a-/- mice. Am J Physiol Gastrointest Liver Physiol 289:G153-62
Barrett, Kim E (2004) Mechanisms for amplified mediator release from colonic mast cells: implications for intestinal inflammatory diseases. World J Gastroenterol 10:617-9
Bertelsen, Lone S; Paesold, Gunther; Marcus, Sandra L et al. (2004) Modulation of chloride secretory responses and barrier function of intestinal epithelial cells by the Salmonella effector protein SigD. Am J Physiol Cell Physiol 287:C939-48