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      SEX-DEPENDENT GUT MICROBIOME DIFFERENCES IN A TRANSGENIC MOUSE MODEL OF AUTISM

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      OBYRNE-THESIS-2021.pdf (9.106Mb)
      Date
      2021-04-21
      Author
      O'Byrne, George-Paul C
      ORCID
      0000-0001-6456-4022
      Type
      Thesis
      Degree Level
      Masters
      Metadata
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      Abstract
      A number of studies provide compelling evidence of a relationship between the overexpression of sAPPα, the non-amyloidogenic cleavage product of Amyloid Precursor Peptide (APP), and the abnormal neurological development observed in individuals with Autism Spectrum Disorder (ASD). Changes in the diversity of the gut flora, and co-occurring gastrointestinal pathologies, have been consistently noted in studies of individuals with ASD. A number of mechanisms exist through which sAPPα overexpression may exert an influence on the initial development of the gut microbi-ome, or contribute to proinflammatory conditions within the gastrointestinal tract. In or-der to examine whether a relationship exists between sAPPα expression and gut microbiome composition, we performed cpn60 amplicon sequencing on fecal samples taken from transgenic mice expressing human sAPPα(NtgsAPPα = 10; Nwt = 18). We found no evidence of a strong effect on alpha or beta diversity, but did find significant reductions in the proportional abundance of Akkermansia muciniphila within sAPPα-overexpressing mice; suggesting that the sAPPα fragment may mediate differences in the growth medium provided by the intestinal mucosa. Though male and female controls differed in terms of the abundance of Akkermansia muciniphila detected at baseline, TgsAPPα males and females did not, suggesting that sex may influence the nature and extent of an sAPPα-mediated effect. With these observations in mind, we argue for a link between overexpression of the sAPPα fragment and reduced abundance of Akkermansia muciniphila, before discussing the potential relevance of this finding to the intestinal pathology commonly seen in ASD. Finally, we discuss a number of variables which, based on the results of this study, may be of interest in further research.
      Degree
      Master of Science (M.Sc.)
      Department
      Physiology
      Program
      Physiology
      Supervisor
      Mousseau, Darrell; Hill, Janet
      Committee
      Howland, John; Widenmaier, Scott; Korber, Darren
      Copyright Date
      May 2021
      URI
      https://hdl.handle.net/10388/13347
      Subject
      gut microbiome
      dysbiosis
      autism spectrum disorder
      gut-brain axis
      Akkermansia muciniphila
      sAPPα
      soluble amyloid precursor protein alpha
      cpn60 amplicon
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