Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

Kari Neier, Tianna E. Grant, Rebecca L. Palmer, Demario Chappell, Sophia M. Hakam, Kendra M. Yasui, Matt Rolston, Matthew L. Settles, Samuel S. Hunter, Abdullah Madany, Paul Ashwood, Blythe Durbin-Johnson, Janine M. LaSalle, Dag H. Yasui

Research output: Contribution to journalArticlepeer-review

Abstract

Rett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.

Original languageEnglish (US)
Article number1408
JournalCommunications Biology
Volume4
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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