Disruption of Complex Enteric Commensal Microbial Communities and Their Mutualistic Functions with the Host Contributes to the Severity of Common Intestinal Disorders and Serves as a Promising Therapeutic Target Public Deposited

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  • March 22, 2019
Creator
  • Packey, Christopher Dennis
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Many people were surprised when the Human Genome Project revealed that the human genome contains only about 20,000 protein-coding genes, comparable to the number in the fruit fly genome. The complexities of human health and disease may lie in the human microbiota, the constellation of microbes living inside and on the body that harbors at least 3.3 million non-redundant genes. The human gut is the natural environment for a diverse and dynamic microbial ecosystem. A better understanding of the human intestinal microbiota and how to manipulate it safely may lead to better ways to prevent harm and promote health. An overall goal of this work was to generate data that guides the design and implementation of diagnostic and therapeutic strategies that intentionally manipulate the human microbiota to optimize its performance in the context of an individual's physiology. We utilized novel, high-throughput technologies with next-generation gene sequencing and powerful bioinformatics analysis tools integrated with metagenomics, gnotobiology and microbiota transplantation to provide deep insights into the composition, structure and activities of the gut microbiota over time in rodents and humans with injury and inflammation in the small intestine and colon. We characterized significant shifts in the composition of the microbiota in several forms of intestinal disease, including irritable bowel syndrome, spontaneous, chronic, immune-mediated colitis, and radiation enteropathy. We identified interventions that alter dysbiosis and the course of intestinal disease, including antibiotics, probiotics and fecal microbiota transplantation. Host innate immune molecules including antimicrobial peptides produced by cells in the small intestinal mucosa contribute to phenotypes. Our studies have improved the knowledge of how the host and bacteria interact during intestinal inflammation and injury and how the microbiota responds and is regulated. Given the abrupt rise in incidence of intestinal disorders that appears to have coincided with socioeconomic development and dietary changes, expeditious progress in this area of research is crucial in order to impede the dramatic acceleration of the prevalence of these diseases. These data may yield valuable clinical tools in restoring a healthy microbiota to prevent or treat intestinal disorders without administering broad, immunosuppressive medications that are accompanied by severe side effects.
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  • In Copyright
Advisor
  • Sartor, Ryan
Degree
  • Doctor of Philosophy
Graduation year
  • 2014
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