Single-cell delineation of the microbiota-gut-brain axis: Probiotic intervention in Chd8 haploinsufficient mice

Abstract

Emerging research underscores the gut microbiome's impact on the nervous system via the microbiota-gut-brain axis, yet comprehensive insights remain limited. Using a CHD8-haploinsufficient model for autism spectrum disorder (ASD), we explored host-gut microbiota interactions by constructing a single-cell transcriptome atlas of brain and intestinal tissues in wild-type and mutant mice across three developmental stages. CHD8 haploinsufficiency caused delayed development of radial glial precursors and excitatory neural progenitors in the E14.5 brain, inflammation in the adult brain, immunodeficiency, and abnormal intestinal development. Selective CHD8 knockdown in intestinal epithelial cells generated Chd8^ΔIEC mice, which exhibited normal sociability but impaired social novelty recognition. Probiotic intervention with Lactobacillus murinus selectively rescued social deficits in Chd8^ΔIEC mice, with single-cell transcriptome analysis revealing underlying mechanisms. This study provides a detailed single-cell transcriptomic dataset of ASD-related neural and intestinal changes, advancing our understanding of the gut-brain axis and offering potential therapeutic strategies for ASD.

Keywords: ASD; CHD8; Lactobacillus murinus; autism spectrum disorder; microbiota-gut-brain axis; probiotic; single-cell transcriptome sequencing; social deficits.