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Establishing causal relationships between pathobionts, the gut microbiota and intestinal inflammation: Lessons from gnotobiotic mice
Numerous reports describe a population expansion of members of the phylum Proteobacteria in Inflammatory Bowel Disease (IBD) patients. However, whether this association has a causal role in disease is yet to be determined. Certain bacterial species within the phylum Proteobacteria, commonly called pathobionts, are implicated as contributors to the development of chronic intestinal inflammation. However, this bacterial phylum is phylogenetically diverse, containing species capable of inducing a variety of immunological phenotypes that are just beginning to be investigated. Unfortunately, assessing the specific role of any given bacterial species in a complex ecosystem is a difficult task. To overcome this limitation, the use of defined microbial communities in gnotobiotic mice allow one to ask both immunological and ecological mechanistic questions regarding the role of single bacterial species in health or disease. We have developed a new molecular quantitative method for use with such a defined microbiota, the Altered Schaedler Flora (ASF), that allowed for accurately assessing their abundance in the gut ecosystem. We have also demonstrated that Helicobacter bilis, a natural mouse pathobiont from the phylum epsilon-Proteobacteria, synergizes with the ASF microbiota to increase the severity of intestinal inflammation in mice. This synergistic relationship between the gut pathobiont and other symbionts triggered a T helper 17 immune phenotype in the absence of microbial dysbiosis. The pathobiont induced a pathogenic CD4+ T cell response targeting other gut symbionts rather than itself, and the absence of the adaptive immune system limited pathology, demonstrating its importance in disease. However, the removal of those targeted symbionts did not alter the disease outcome, suggesting a potential shift of the immune response towards other gut symbionts. Collectively, these experimental findings indicate that a pathobiont may cause inflammation by an immune-mediated mechanism in the absence of a predictive ecological signature. If applicable to IBD, these results suggest that the analysis of dysbiotic patterns across gut microbial communities in healthy versus diseased individuals as a means of identifying specific, disease-causing organisms, should be interpreted cautiously.
Gomes Neto, Joao Carlos, "Establishing causal relationships between pathobionts, the gut microbiota and intestinal inflammation: Lessons from gnotobiotic mice" (2016). ETD collection for University of Nebraska-Lincoln. AAI10247161.