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

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.