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dc.contributor.advisorFriedman, Jacob E.
dc.contributor.authorSoderborg, Taylor Kristina
dc.date.accessioned2019-05-17T20:03:33Z
dc.date.available2020-05-16T19:43:49Z
dc.date.submitted2019
dc.identifierSoderborg_ucdenveramc_1639D_10642.pdf
dc.identifier.urihttps://hdl.handle.net/10968/3464
dc.descriptionIncludes bibliographical references.
dc.descriptionSpring
dc.description.abstractMaternal metabolism and obesity contribute significantly to the risk of obesity and non-alcoholic fatty liver disease (NAFLD) in the next generation, however the causal drivers of this relationship are currently unclear. Metabolic diseases in the pediatric population pose a unique challenge as the mechanisms driving their onset and progression are hypothesized to be the result of programming by early life exposures in addition to lifestyle factors. The earlier onset of obesity and NAFLD in the pediatric population is associated with a worse natural history and progression of these conditions compared to adults. At the time of diagnosis, half of pediatric patients have the more progressive, inflammatory version of NAFLD, non-alcoholic steatohepatitis (NASH), and those diagnosed in childhood have a worse prognosis that adults. Despite the alarming rate of pediatric NAFLD worldwide, particularly in obese youth, at present there are no interventions that have convincingly demonstrated efficacy to alter the progression of this disease. Importantly, given the involvement of inflammation in pediatric NASH, as demonstrated by a unique periportal inflammation, it is likely that the pathogenesis of NAFLD in children may have distinct features from that in adults. Evidence of leaky gut barriers in children with NASH in addition to histological evidence portal inflammation, suggests that the early gut microbiome may play a significant role in pediatric NAFLD. Early life dysbiosis has been found in offspring of obese and/or high fat diet fed mothers in both human, non-human primate and murine models. Research in humans also suggests that excessive gestational weight gain (EWG) and gestational diabetes mellitus (GDM) can also influence offspring microbiome composition. However, there are very limited prospective human data on the influence of commonly co-morbid metabolic conditions, such as EWG and obesity, or, GDM and obesity, on offspring gut colonization. Importantly, while there is correlative data associating early dysbiosis with worse metabolic outcomes in human offspring, causality has not yet been established. Throughout the following work we build upon the existing knowledge of how maternal phenotype influences human offspring microbiome composition and develop mechanistic connections between the altered gut microbiota and metabolic disease risk in a germ-free mice model. We demonstrate in a germ-free mouse model a causative role for this dysbiosis in predisposition to obesity and NAFLD upon exposure to a western style diet. Specifically, we discovered that dysbiosis results in a hypo-responsive bone marrow derived macrophage with dysfunction of both classical and alternative metabolism in a germ-free mouse model. Similar to the influence of maternal obesity on the human infant gut microbiome, we find that EWG and GDM independently and through their interaction with obesity, uniquely influence the composition of the human offspring microbiome at 2 weeks of life. Our findings suggest that maternal metabolic phenotype influences the colonization of the early human infant gut with lasting alterations of the innate immune system, as suggested by our germ-free mouse model. These results expand upon the current understanding of how maternal metabolic obesity, EWG and GDM in humans influences the human offspring gut microbiome and also provide insight to the mechanism by which maternal obesity could potentially cause NAFLD, as demonstrated in germ-free mice. This work supports targeting the early life microbiome in the development of effective preventative measures to impair the perpetuation of metabolic disease in the next generation.
dc.languageEnglish
dc.language.isoeng
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.subjectGerm-free mice
dc.subject.meshMacrophages
dc.subject.meshNon-alcoholic Fatty Liver Disease
dc.subject.meshPediatrics
dc.subject.meshMicrobiota
dc.subject.meshObesity
dc.titleHuman maternal obesity in the development of nonalcoholic fatty liver disease in a germ-free mouse model : identifying the role of the infant gut microbiome
dc.typeThesis
dc.rights.accessEmbargo Expires: 05/16/2020
dcterms.embargo.terms2020-05-16
dcterms.embargo.expires2020-05-16
dc.contributor.committeememberMacLean, Paul
dc.contributor.committeememberBarbour, Linda
dc.contributor.committeememberPietras, Eric
dc.contributor.committeememberWesolowski, Stephanie
dc.contributor.committeememberKuhn, Kristine
thesis.degree.nameDoctor of Philosophy (Ph.D.)
thesis.degree.levelDoctoral
thesis.degree.disciplineIntegrated Physiology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus


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