The interplay between inflammation and microbial activities in colorectal cancer Public Deposited

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  • March 19, 2019
Creator
  • Tomkovich, Sarah
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The microbiota affects host immune health by influencing immune system development and promoting tolerogenic immune responses, effects that have the potential to influence vaccine and cancer immunotherapy efficacy. Disruption of the delicate homeostatic balance between the host and microbiota can lead to intestinal diseases such as inflammatory bowel diseases (IBD) and colorectal cancer (CRC) and also extra-intestinal pathologies such as metabolic syndrome and autoimmune diseases. This dissertation focuses on the impact of the microbiota on host intestinal immune responses in relation to inflammation and carcinogenesis. The aim of the first project was to evaluate the role of the microbiota in modulating systemic neutrophil numbers and function in the developing zebrafish. Using a gnotobiotic approach we demonstrated colonization of germ-free (GF) zebrafish with a conventional microbiota increased neutrophil numbers and myeloperoixidase expression, altered neutrophil localization and migratory behavior and improved neutrophil recruitment to extra-intestinal injury. We showed that neutrophil migratory behavior was mediated through the acute phase response protein serum amyloid A (SAA), which was also induced by the microbiota. In vitro experiments revealed SAA exposure activated nuclear factor (NF)-κB in zebrafish cells, and NF-κB was also required within neutrophils for SAA-dependent migration. The goal of the second project was to evaluate the ability of CRC-associated microbes to induce inflammation and CRC in genetically susceptible gnotobiotic mice. Fusobacterium nucleatum and Escherichia coli that contain the genotoxic island, polyketide synthase (pks) are part of the altered microbiota that is associated with human CRC. We mono-associated ApcMin/+;Il10-/- mice with either F. nucleatum or E. coli and found only pks+ E. coli had the capacity to induce inflammation and tumorigenesis. Next, we examined the functional role of human biofilm associated microbes in CRC development using ApcMin/+;Il10-/- mice. We found that biofilm forming microbes promoted tumorigenesis, suggesting bacterial organization also plays a role in CRC pathogenesis. Taken together these studies stress the importance of balance in host-microbiota interactions. Elucidating host and microbial factors that contribute to disease states has the potential to transform how diseases are prevented and treated.
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Rights statement
  • In Copyright
Advisor
  • Tamayo, Rita
  • Hansen, Jonathan
  • Jobin, Christian
  • Rawls, John
  • Richardson, Anthony
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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