The multifaceted Paneth cell

Paneth cells (PCs) were described over a century ago as granulated cells located at the base of small intestinal crypts, the 'crypts of Lieberkühn.' Various histochemical staining procedures were developed that identified PCs based on their distinctive granule staining pattern. Early on, PCs were proposed to perform a specialized function other than absorption of digested nutrients, the predominant task of the small intestinal epithelium. Since then, many constituents of the PC granules have been biochemically characterized. The presence of various granule-associated antimicrobial substances and their release upon microbial challenge suggest that PCs function as specialized defense cells in the small intestine. Altered resistance to microbial infection in animal models with disrupted or augmented PC function provides further support for the host defense role of PCs. Other PC components suggest that PCs may also participate in the regulation of lumenal ionic composition, crypt development, digestion, and intestinal inflammation. Received 6 June 2001; received after revision 26 July 2001; accepted 27 July 2001     

Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin

Genetically encoded antibiotic peptides are evolutionarily ancient and widespread effector molecules of immune defence. Mammalian defensins, one subset of such peptides, have been implicated in the antimicrobial defence capacity of phagocytic leukocytes and various epithelial cells, but direct evidence of the magnitude of their in vivo effects have not been clearly demonstrated. Paneth cells, specialized epithelia of the small intestinal crypt, secrete abundant alpha-defensins and other antimicrobial polypeptides including human defensin 5 (HD-5; also known as DEFA5). Although antibiotic activity of HD-5 has been demonstrated in vitro, functional studies of HD-5 biology have been limited by the lack of in vivo models. To study the in vivo role of HD-5, we developed a transgenic mouse model using a 2.9-kilobase HD-5 minigene containing two HD-5 exons and 1.4 kilobases of 5'-flanking sequence. Here we show that HD-5 expression in these mice is specific to Paneth cells and reflects endogenous enteric defensin gene expression. The storage and processing of transgenic HD-5 also matches that observed in humans. HD-5 transgenic mice were markedly resistant to oral challenge with virulent Salmonella typhimurium. These findings provide support for a critical in vivo role of epithelial-derived defensins in mammalian host defence.     

The potter’s wheel: the host’s role in sculpting its microbiota

Animals, ranging from basal metazoans to primates, are host to complex microbial ecosystems; engaged in a symbiotic relationship that is essential for host physiology and homeostasis. Epithelial surfaces vary in the composition of colonizing microbiota as one compares anatomic sites, developmental stages and species origin. Alterations of microbial composition likely contribute to susceptibility to several distinct diseases. The forces that shape the colonizing microbial composition are the focus of much current investigation, and it is evident that there are pressures exerted both by the host and the external environment to mold these ecosystems. The focus of this review is to discuss recent studies that demonstrate the critical importance of host factors in selecting for its microbiome. Greater insight into host–microbiome interactions will be essential for understanding homeostasis at mucosal surfaces, and developing useful interventions when homeostasis is disrupted.