We propose to investigate the hypothesis that consistent changes in the human gut microbiome are associated with Crohn's disease, a form of inflammatory bowel disease, and that altered microbiota contributes to pathogenesis. Analysis of this problem is greatly complicated by the fact that multiple factors influence the composition of the gut microbiota, including diet, host genotype, and disease state. For example, data from others and us document a drastic impact of diet on the composition of the gut microbiome. No amount of sequencing will yield a useful picture of the role of the microbiota in disease if samples are confounded with uncontrolled variables. Our proposed project will take advantage of our experience with deep sequencing to characterize the composition of the gut microbiome, but also control diet, host genotype, and disease state. Diet will be controlled by analyzing children treated for Crohn's disease by placing them on a standardized elemental diet, and by testing effects of different diets on the gut microbiome composition in adult volunteers. Genotype will be analyzed by large scale SNP genotyping, which is already underway and separately funded team member Hokan Hakonarson is currently genotyping 50 children a week at ~half a million loci each and investigating connections with inflammatory bowel disease. Clinical status will be ascertained in the very large IBD practice in the UPenn/CHOP hospital system. Effects of diet, host genotype, and disease state on the gut microbiome will be summarized in a multivariate model, allowing connections between microbiome and disease to be assessed free of confounding factors.
The bacteria present in the intestinal tract, known as the gut microbiome, probably play a role in the pathogenesis of Crohn's disease, but the mechanism remains unclear. In this study, we propose to determine the composition of the gut microbiome associated with Crohn's disease while controlling for confounding factors known to alter the gut microbiome, such as host genetics and diet. These studies will provide a clearer vision of the types of bacteria associated with Crohn's disease and provide new insights into pathogenic mechanisms and potential therapy.
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| Ni, Josephine; Shen, Ting-Chin David; Chen, Eric Z et al. (2017) A role for bacterial urease in gut dysbiosis and Crohn's disease. Sci Transl Med 9: |
| Wu, Gary D; Compher, Charlene; Chen, Eric Z et al. (2016) Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut 65:63-72 |
| Shen, Ting-Chin David; Albenberg, Lindsey; Bittinger, Kyle et al. (2015) Engineering the gut microbiota to treat hyperammonemia. J Clin Invest 125:2841-50 |
| Lee, Dale; Albenberg, Lindsey; Compher, Charlene et al. (2015) Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology 148:1087-106 |
| Chehoud, Christel; Albenberg, Lindsey G; Judge, Colleen et al. (2015) Fungal Signature in the Gut Microbiota of Pediatric Patients With Inflammatory Bowel Disease. Inflamm Bowel Dis 21:1948-56 |
| Bryson, Alexandra L; Hwang, Young; Sherrill-Mix, Scott et al. (2015) Covalent Modification of Bacteriophage T4 DNA Inhibits CRISPR-Cas9. MBio 6:e00648 |
| Lewis, James D; Chen, Eric Z; Baldassano, Robert N et al. (2015) Inflammation, Antibiotics, and Diet as Environmental Stressors of the Gut Microbiome in Pediatric Crohn's Disease. Cell Host Microbe 18:489-500 |
| Albenberg, Lindsey; Esipova, Tatiana V; Judge, Colleen P et al. (2014) Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology 147:1055-63.e8 |
| Albenberg, Lindsey G; Wu, Gary D (2014) Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology 146:1564-72 |
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