Chow, Janet (2011) A pathobiont of the mammalian microbiota balances intestinal inflammation and colonization. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:05022011-211415511
Humans and mammals are colonized by a multitude of microbial organisms that have co‐evolved with their hosts for millions of years. The majority of these microbes reside in the gastrointestinal (GI) tract as a complex and dynamic consortium. Though most associations with the host are symbiotic or commensal, some resident bacteria have the potential to cause disease under certain conditions. We refer to these bacteria as ‘pathobionts.’ Pathobionts are distinct from opportunistic pathogens, which are often acquired from the environment and cause acute infections. Bacterial type VI secretion systems (T6SSs) are one mechanism for mediating close host‐microbial interactions. Herein we report that the T6SS of H. hepaticus, a pathobiont of the murine intestinal microbiota, mediates critical protective functions during association with its mammalian host. In cell cultures, infection of intestinal epithelial cells (IECs) with H. hepaticus T6SS mutants results in increased bacterial association compared to wild‐type bacteria. In animals, T6SS mutants colonize the lower GI tract to a higher degree. Most importantly, H. hepaticus defective in type VI secretion is unable to restrain potent innate and adaptive immune responses in an animal model of experimental colitis. In addition, the H. hepaticus T6SS directs an anti‐inflammatory gene expression profile in IECs, and CD4+ T cells from mice colonized with T6SS mutants produce increased proinflammatory interleukin‐17 cytokine in response to IECs presenting H. hepaticus antigens. Thus, our findings reveal that H. hepaticus has evolved a T6SS as a mechanism to actively maintain a non‐pathogenic, symbiotic relationship in the GI tract by regulating bacterial colonization and host inflammation. Disturbances in the dynamic interaction between gut bacteria and the intestinal immune system may lead to exacerbated host inflammation. As intestinal bacteria profoundly influence host biology, our findings support an emerging hypothesis that alterations in the composition of the microbiota, known as dysbiosis, is a critical factor in various human disorders such as inflammatory bowel disease and colon cancer.
|Item Type:||Thesis (Dissertation (Ph.D.))|
|Subject Keywords:||Helicobacter hepaticus, pathobiont, inflammatory bowel disease|
|Degree Grantor:||California Institute of Technology|
|Thesis Availability:||Public (worldwide access)|
|Defense Date:||12 May 2011|
|Default Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Janet Chow|
|Deposited On:||31 May 2011 18:29|
|Last Modified:||22 Aug 2016 21:22|
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