The Gut Microbiome in Health and in Disease
Inflammatory bowel diseases (IBD) are characterized by inappropriate inflammation in the gut resulting from a combination of environmental and genetic risk factors. Targets of the inflammatory response include the commensal microbiota, and IBD are associated with alterations in the gut microbiota, though it is not clear if microbial changes contribute to disease pathogenesis or develop as a result of local inflammation. Here, we highlight two recent publications describing the microbiome and host response measured in treatment-naïve pediatric patients with newly diagnosed IBD that provide early findings not confounded by anti-inflammatory therapies.
In the first report, 447 treatment-naïve pediatric Crohn's disease patients and 221 controls were included in a study in which the microbiome from multiple sites was characterized by 16S sequence analysis. Multivariate analysis identified microbial taxa significantly associated with disease phenotype in ileal and rectal samples but not from stool samples. The microbiome of Crohn's disease patients had a lower diversity, increased abundances of Enterobacteriaceae, Pasteurellaceae, Fusobacteriaceae, Neisseriaceae, Veillonellaceae, and Gemellaceae, and decreased abundances of Bifidobacteriaceae, Erysipelotrichaceae, Clostridiales, and Bacteroidales. Using these microbiome–disease associations, they formulated a microbial dysbiosis index that showed a strong positive correlation with clinical disease activity [pediatric Crohn's Disease activity index (PDCAI)] and a negative correlation with species richness (Table 1). In addition, microbiome comparison between Crohn's disease patients with and without antibiotic exposure revealed that antibiotic use amplifies the microbial dysbiosis associated with Crohn's disease. Of note, the authors demonstrate that many of their observations were only seen when analyzing hundreds of samples, emphasizing the importance of large-scale studies.
In the next report, host gene expression and the microbiome were characterized from the ileum of treatment-naïve pediatric patients with ileal Crohn's disease (iCD), colonic Crohn's disease (cCD), and ulcerative colitis as well as controls. A core iCD gene expression signature of 1281 genes was identified by comparing iCD and control groups. Upregulated genes included those induced by bacterial products and proinflammatory signals, and downregulated genes included nuclear receptors involved in metabolic pathways and anti-inflammatory signaling. Interestingly, the cCD group, including those without any microscopic inflammation, had a similar expression pattern in the ileum to the iCD group, and this pattern was different from control and ulcerative colitis groups, indicating a core Crohn's disease gene expression profile in the ileum independent of inflammation. Similarly, iCD and cCD groups had similar profiles of dysbiosis that was different from control and ulcerative colitis groups. Of note, an increase of antimicrobial dual oxidase expression was detected in association with an expansion of Proteobacteria in both ulcerative colitis and Crohn's disease, whereas expression of lipoprotein APOA1 gene was downregulated and associated with Crohn's disease-specific alterations in Firmicutes. Finally, multivariate analysis showed correlations between bacterial taxa, gene expression and clinical disease activity scores in Crohn's disease patients irrespective of the presence of ileal inflammation, and a prediction model based on gene expression, microbe abundance, and clinical factors outperformed clinical disease activity scores alone in predicting response to therapy.
These studies provide additional information toward understanding a potential role of the microbiota in the pathogenesis of IBD that has not been established to date. This stands in contrast to CDI in which microbiota alterations clearly increase the risk for disease and restoration of a diverse microbiota with FMT clearly prevents disease recurrence in most patients. Early efforts to utilize FMT for the treatment of IBD have been rather disappointing. It seems quite likely that the role of microbiota in IBD, and other multigenic traits, will prove to be more complex and depend on specific genetic susceptibilities and certain environmental factors. Therefore, it will be important to further characterize the microbiota population and its functions at various time points in IBD development in conjunction with assessments of host susceptibility, host response, and environmental exposures.
Inflammatory Bowel Disease
Inflammatory bowel diseases (IBD) are characterized by inappropriate inflammation in the gut resulting from a combination of environmental and genetic risk factors. Targets of the inflammatory response include the commensal microbiota, and IBD are associated with alterations in the gut microbiota, though it is not clear if microbial changes contribute to disease pathogenesis or develop as a result of local inflammation. Here, we highlight two recent publications describing the microbiome and host response measured in treatment-naïve pediatric patients with newly diagnosed IBD that provide early findings not confounded by anti-inflammatory therapies.
In the first report, 447 treatment-naïve pediatric Crohn's disease patients and 221 controls were included in a study in which the microbiome from multiple sites was characterized by 16S sequence analysis. Multivariate analysis identified microbial taxa significantly associated with disease phenotype in ileal and rectal samples but not from stool samples. The microbiome of Crohn's disease patients had a lower diversity, increased abundances of Enterobacteriaceae, Pasteurellaceae, Fusobacteriaceae, Neisseriaceae, Veillonellaceae, and Gemellaceae, and decreased abundances of Bifidobacteriaceae, Erysipelotrichaceae, Clostridiales, and Bacteroidales. Using these microbiome–disease associations, they formulated a microbial dysbiosis index that showed a strong positive correlation with clinical disease activity [pediatric Crohn's Disease activity index (PDCAI)] and a negative correlation with species richness (Table 1). In addition, microbiome comparison between Crohn's disease patients with and without antibiotic exposure revealed that antibiotic use amplifies the microbial dysbiosis associated with Crohn's disease. Of note, the authors demonstrate that many of their observations were only seen when analyzing hundreds of samples, emphasizing the importance of large-scale studies.
In the next report, host gene expression and the microbiome were characterized from the ileum of treatment-naïve pediatric patients with ileal Crohn's disease (iCD), colonic Crohn's disease (cCD), and ulcerative colitis as well as controls. A core iCD gene expression signature of 1281 genes was identified by comparing iCD and control groups. Upregulated genes included those induced by bacterial products and proinflammatory signals, and downregulated genes included nuclear receptors involved in metabolic pathways and anti-inflammatory signaling. Interestingly, the cCD group, including those without any microscopic inflammation, had a similar expression pattern in the ileum to the iCD group, and this pattern was different from control and ulcerative colitis groups, indicating a core Crohn's disease gene expression profile in the ileum independent of inflammation. Similarly, iCD and cCD groups had similar profiles of dysbiosis that was different from control and ulcerative colitis groups. Of note, an increase of antimicrobial dual oxidase expression was detected in association with an expansion of Proteobacteria in both ulcerative colitis and Crohn's disease, whereas expression of lipoprotein APOA1 gene was downregulated and associated with Crohn's disease-specific alterations in Firmicutes. Finally, multivariate analysis showed correlations between bacterial taxa, gene expression and clinical disease activity scores in Crohn's disease patients irrespective of the presence of ileal inflammation, and a prediction model based on gene expression, microbe abundance, and clinical factors outperformed clinical disease activity scores alone in predicting response to therapy.
These studies provide additional information toward understanding a potential role of the microbiota in the pathogenesis of IBD that has not been established to date. This stands in contrast to CDI in which microbiota alterations clearly increase the risk for disease and restoration of a diverse microbiota with FMT clearly prevents disease recurrence in most patients. Early efforts to utilize FMT for the treatment of IBD have been rather disappointing. It seems quite likely that the role of microbiota in IBD, and other multigenic traits, will prove to be more complex and depend on specific genetic susceptibilities and certain environmental factors. Therefore, it will be important to further characterize the microbiota population and its functions at various time points in IBD development in conjunction with assessments of host susceptibility, host response, and environmental exposures.
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