Basic Science Review Paneth Cell Defensins and Innate Immunity of the Small Bowel *Andre J. Ouellette and †Charles L. Bevins *Departments of Pathology and Microbiology & Molecular Genetics, College of Medicine, University of California, Irvine, California; and †The Departments of Immunology, Gastroenterology, and Colorectal Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A. Evidence from many lines of investigation supports the hypothesis that the release of gene-encoded antimi- crobial peptides by epithelial cells contributes to innate mucosal immunity. In the small intestine, Paneth cells at the base of the crypts of Lieberkühn secrete defensins and other antimicrobial proteins in response to bacteria. It is likely that the Paneth cell products released into the narrow lumen of the crypt help to protect the epithelial stem cells from noxious microbes. The stem cells, which reside at the neck of the crypt, are responsible for con- tinual renewal of epithelial cells, which line both the small intestinal villi and crypts. In addition to this pro- tective function, Paneth cell secretions also may interact with bacteria that exist in the intestinal lumen and affect the composition of the enteric microbial flora. Mouse matrilysin, a metalloproteinase produced by Paneth cells, proteolytically processes prodefensin precursors to ma- ture defensins. Disruption of the matrilysin gene in trans- genic mice eliminates production of mature defensins and results in defective clearing of orally administered Escherichia coli and increased susceptibility to virulent Salmonella typhimurium. Further defining the mecha- nisms that regulate Paneth cell function should improve our understanding of the role of these cells, and their products, in sustaining normal small bowel function. The investigation of possible defects in Paneth cell biol- ogy in the pathophysiology of Crohn’s disease and ul- cerative colitis may prove to be a valuable area for future studies. HOST DEFENSE AT THE MUCOSA OF THE SMALL INTESTINE The epithelium of the small bowel is the largest sur- face at which an organism interacts directly with the external environment, serving as a barrier between the luminal contents and portal circulation. This monolayer of epithelial cells must absorb vital nutrients while in- hibiting invasive challenges by luminal microbes. Throughout the lifetime of mammals, this epithelium is replaced continually by a process involving stem cell proliferation, cellular differentiation, migration, apopto- sis, and exfoliation. Stem cells that reside in the neck of the intestinal crypts replicate at a rate appropriate for maintaining a constant supply of new epithelial cells, which are crucial for the repopulation of crypts and villi (1). The interruption of this stem cell replication, or le- sions introduced in the epithelium by various insults, including infection or inflammation, could generate por- tals of entry for luminal bacteria. Therefore, mechanisms that protect crypts against bacterial overgrowth and in- fection are vital to maintain epithelial monolayer integ- rity by preserving stem cell viability. Remarkably, the bacterial load in the small intestine lumen is approximately 10 4 to 10 6 -fold fewer microbes per gram of tissue than in the adjacent colon, but the responsible factors are not completely understood (2). Activities associated with digestion and the normal physiology of the gastrointestinal tract, including gastric acidity, digestive enzymes, bile salts, peristalsis, mucus, the resident commensal flora, and exfoliation of entero- cytes during epithelial renewal are likely to help to con- trol the small intestinal bacterial population (3). In addi- tion to their protecting the crypt from microbial chal- lenge, the secretion of gene-encoded antimicrobial peptides and proteins may also help reduce the numbers of bacteria in the small intestinal lumen (4,5). Received and accepted December 5, 2000. Address correspondence and reprint requests to Dr. A. J. Ouellette, Department of Pathology, D-440, Med Sci I, College of Medicine, University of California, Irvine, CA 92697-4800, U.S.A. E-mail: aouellet@uci.edu or to Dr. C. L. Bevins, Lerner Research Institute/ NB30, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, U.S.A. E-mail: bevinsc@ccf.org Inflammatory Bowel Diseases 7(1):43–50 © 2001 Crohn’s & Colitis Foundation of America, Inc. 43 Downloaded from https://academic.oup.com/ibdjournal/article/7/1/43/4719393 by guest on 25 January 2023