Abstract
When identifying the key immunologic-microbial interactions leading to either mucosal homeostasis in normal hosts or intestinal inflammatory responses in genetically susceptible individuals, it is important to not only identify microbial community correlations but to also define the functional pathways involved. Gnotobiotic rodents are a very effective tool for this purpose as they provide a highly controlled environment in which to identify the function of complex intestinal microbiota, their individual components, and metabolic products. Herein we review specific strategies using gnotobiotic mice to functionally evaluate the role of various intestinal microbiota in host responses. These studies include basic comparisons between host responses in germ-free (GF), specific-pathogen-free or conventionally raised wild-type mice or those with underlying genetic susceptibilities to intestinal inflammation. We also discuss what can be learned from studies in which GF mice are colonized with single wild-type or genetically-modified microbial isolates to examine the functions of individual bacteria and their targeted bacterial genes, or colonized by multiple defined isolates to determine interactions between members of defined consortia. Additionally, we discuss studies to identify functions of complex microbial communities from healthy or diseased human or murine hosts via fecal transplant into GF mice. Finally, we conclude by suggesting ways to improve studies of immune-microbial interactions using gnotobiotic mice.
Highlights
Gnotobiotic rodents are extremely helpful to dissect functional complexity of host/microbial interactions in mucosal immunology and immune-mediated inflammation. This complexity exists at several levels: [1] the incredibly diverse intestinal microbiota that are composed of myriad bacteria, viruses, fungi, and archaea with longitudinal anatomical diversity from the mouth to the distal colon; [2] the interacting innate and adaptive immune responses in the various intestinal compartments that include bone marrow-derived cells, epithelial and mesenchymal cells; lymphoid cells that are “educated” centrally in the thymus (T cells), bone marrow (B cells) spleen
Using cells from specific pathogen-free (SPF) toll-like receptor (TLR), MyD88 and phosphatidylinositol 3-kinase (PI3K) knockout (KO) mice, TLR agonists and pharmacologic antagonists, we demonstrated that induction of IL-10 in GF B cells involves TLR2 signaling through MyD88 and the PI3K subunit p110δ [23]
They first demonstrated that resident microbiota activate colonic Tregs by showing that SPF BALB/c, IQI and C57BL/6 mice had substantially higher percentages of lamina propria (LP) FoxP3+ CD4+ cells than did GF mice, but no such differences were observed in the small intestine
Summary
Gnotobiotic rodents are extremely helpful to dissect functional complexity of host/microbial interactions in mucosal immunology and immune-mediated inflammation. This complexity exists at several levels: [1] the incredibly diverse intestinal microbiota that are composed of myriad bacteria, viruses, fungi, and archaea with longitudinal anatomical diversity from the mouth to the distal colon; [2] the interacting innate and adaptive immune responses in the various intestinal compartments that include bone marrow-derived cells, epithelial and mesenchymal cells; lymphoid cells that are “educated” centrally in the thymus (T cells), bone marrow (B cells) spleen
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