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The Gut Microbiota and the Liver: Collaborators in Host Immunity and Metabolism

Corbitt, Natasha (2011) The Gut Microbiota and the Liver: Collaborators in Host Immunity and Metabolism. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    The gut microbiota consists of over one hundred trillion commensal bacteria required for proper gut immunity development. Commensals also augment the host’s ability to extract energy from the diet. Although restricted to the gut lumen by intestinal barrier epithelia, commensals shed microbial associated molecule patterns (MAMPs) into the circulation where they augment aspects of systemic immunity. Commensals also release fermentation byproducts into the portal blood stream. Since the liver receives 80% of its blood via the portal vein and contains a unique repertoire of immune cells particularly enriched in Kupffer Cells (KC) and Natural Killer T cells, we proposed that gut-derived MAMPs contribute to the development of residential hepatic leukocyte subsets. Because of the contributions of gut bacteria to digestion, we suspected that gut bacteria add an additional level of regulation to host metabolism and would generate a specific hepatic metabolic gene profile. Results showed that a cocktail of MAMPs translocate into the portal circulation of normal conventional (CL) mice stimulating KC expansion. ICAM1 expression, thought to be constitutive on sinusoidal endothelium, was significantly reduced without gut bacteria and was required for KC accumulation. The finding that constitutive ICAM1 expression by LSEC was dependent on gut bacteria lead us to investigate if the frequency of intra-hepatic lymphocytes known to bind ICAM1 were affected by gut bacteria. Results showed that intra-hepatic T lymphocyte populations including NKT (TCRβ+NK1.1+) cells and T helper (CD4+TCRβ+) cells were significantly reduced in GF mice and AVMN mice. In addition to the significant cellular composition changes of the liver related to gut bacteria density, notable changes in murine weight and metabolic gene profiles were observed. The average body mass of CL, GF, and AVMN mice was 37.8g, 33.4g, and 34.1g respectively. Our whole-liver gene array analysis included 217 probe sets mapped to 163 differentially expressed genes between groups, of which forty-eight have roles in lipid metabolism. In conclusion, gut bacteria affect both the hepatic metabolic gene profile and the inflammatory potential of the liver. These finding have implications for many hepatic pathologies including obesity, NAFLD, and autoimmune disease like PBC and AIH mediated by liver leukocytes.


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    Item Type: University of Pittsburgh ETD
    Creators/Authors:
    CreatorsEmailORCID
    Corbitt, Natashanatashacorbitt@hotmail.com
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairStolz, Donnadstolz@pitt.edu
    Committee MemberBilliar, Timothybilliartr@upmc.edu
    Committee MemberHackam, Daviddavid.hackam@chp.edu
    Committee MemberMorelli, Adrianmorelli@imap.pitt.edu
    Committee MemberOury, Timtdoury@pitt.edu
    Thesis AdvisorDemetris, Anthony J.demetrisaj@umpc.edu
    Title: The Gut Microbiota and the Liver: Collaborators in Host Immunity and Metabolism
    Status: Published
    Abstract: The gut microbiota consists of over one hundred trillion commensal bacteria required for proper gut immunity development. Commensals also augment the host’s ability to extract energy from the diet. Although restricted to the gut lumen by intestinal barrier epithelia, commensals shed microbial associated molecule patterns (MAMPs) into the circulation where they augment aspects of systemic immunity. Commensals also release fermentation byproducts into the portal blood stream. Since the liver receives 80% of its blood via the portal vein and contains a unique repertoire of immune cells particularly enriched in Kupffer Cells (KC) and Natural Killer T cells, we proposed that gut-derived MAMPs contribute to the development of residential hepatic leukocyte subsets. Because of the contributions of gut bacteria to digestion, we suspected that gut bacteria add an additional level of regulation to host metabolism and would generate a specific hepatic metabolic gene profile. Results showed that a cocktail of MAMPs translocate into the portal circulation of normal conventional (CL) mice stimulating KC expansion. ICAM1 expression, thought to be constitutive on sinusoidal endothelium, was significantly reduced without gut bacteria and was required for KC accumulation. The finding that constitutive ICAM1 expression by LSEC was dependent on gut bacteria lead us to investigate if the frequency of intra-hepatic lymphocytes known to bind ICAM1 were affected by gut bacteria. Results showed that intra-hepatic T lymphocyte populations including NKT (TCRβ+NK1.1+) cells and T helper (CD4+TCRβ+) cells were significantly reduced in GF mice and AVMN mice. In addition to the significant cellular composition changes of the liver related to gut bacteria density, notable changes in murine weight and metabolic gene profiles were observed. The average body mass of CL, GF, and AVMN mice was 37.8g, 33.4g, and 34.1g respectively. Our whole-liver gene array analysis included 217 probe sets mapped to 163 differentially expressed genes between groups, of which forty-eight have roles in lipid metabolism. In conclusion, gut bacteria affect both the hepatic metabolic gene profile and the inflammatory potential of the liver. These finding have implications for many hepatic pathologies including obesity, NAFLD, and autoimmune disease like PBC and AIH mediated by liver leukocytes.
    Date: 16 December 2011
    Date Type: Publication
    Defense Date: 28 November 2011
    Approval Date: 16 December 2011
    Submission Date: 10 December 2011
    Release Date: 16 December 2011
    Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
    Patent pending: No
    Number of Pages: 150
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    Uncontrolled Keywords: Kupffer Cells, Liver Immunity, Natural Killer T Cells, Gut Bacteria
    Schools and Programs: School of Medicine > Cellular and Molecular Pathology
    Date Deposited: 16 Dec 2011 07:36
    Last Modified: 16 Jul 2014 17:03

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