Creating and maintaining the gastrointestinal ecosystem: What we know and need to know from gnotobiology

Studying the cross talk between nonpathogenic organisms and their mammalian hosts represents an experimental challenge because these interactions ale typically subtle and the microbial societies that associate with mammalian hosts are very complex and dynamic. A large, functionally stable, climax co mmunity of microbes is maintained in the murine and human gastrointestinal tracts. This open ecosystem exhibits not only regional differences in the c omposition of its microbiota but also regional differences in the different iation programs of its epithelial cells and in the spatial distribution of its component immune cells. A key experimental strategy for determining whe ther "nonpathogenic" microorganisms actively create their own regional habi tats in this ecosystem is to define cellular function in germ-free animals and then evaluate the effects of adding single or several microbial species . This review focuses on how gnotobiotics-the study of germ-free animals-ha s been and needs to be used to examine how the gastrointestinal ecosystem i s created and maintained. Areas discussed include the generation of simplif ied ecosystems by using genetically manipulatable microbes and hosts to det ermine whether components of the microbiota actively regulate epithelial di fferentiation to create niches for themselves and for other organisms; the ways in which gnotobiology can help reveal collaborative interactions among the microbiota, epithelium, and mucosal immune system; and the ways in whi ch gnotobiology is and will be useful for identifying host and microbial fa ctors that define the continuum between nonpathogenic and pathogenic. A ser ies of tests of microbial contributions to several pathologic states, using germ-free and ex-germ-free mice, are proposed.