Dataset Information

Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice

ABSTRACT: Autism spectrum disorder (ASD) manifests as alterations in complex human behaviors including social communication and stereotypies. In addition to genetic risks, the gut microbiome differs between typically-developing (TD) and ASD individuals, though it remains unclear whether the microbiome contributes to symptoms. We transplanted gut microbiota from human donors with ASD and TD controls into germ-free mice, and reveal that colonization with ASD microbiota was sufficient to induce hallmark autistic behaviors. The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes. Microbiome and metabolome profiles of mice harboring human microbiota predict that specific bacterial taxa and their metabolites modulate ASD behaviors. Indeed, treatment of an ASD mouse model with candidate microbial metabolites improves behavioral abnormalities and affects neuronal excitability in the brain. We propose that the gut microbiome modulates behaviors in mice via production of neuroactive metabolites, suggesting that gut-brain connections contribute to the pathophysiology of ASD.

OTHER RELATED OMICS DATASETS IN: GSE109827

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR) -, Gas Chromatography MS - positive

SUBMITTER: Tom Metz

PROVIDER: MTBLS726 | MetaboLights | 2019-07-04

REPOSITORIES: MetaboLights

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Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice.

Sharon Gil G Cruz Nikki Jamie NJ Kang Dae-Wook DW Gandal Michael J MJ Wang Bo B Kim Young-Mo YM Zink Erika M EM Casey Cameron P CP Taylor Bryn C BC Lane Christianne J CJ Bramer Lisa M LM Isern Nancy G NG Hoyt David W DW Noecker Cecilia C Sweredoski Michael J MJ Moradian Annie A Borenstein Elhanan E Jansson Janet K JK Knight Rob R Metz Thomas O TO Lois Carlos C Geschwind Daniel H DH Krajmalnik-Brown Rosa R Mazmanian Sarkis K SK

Cell 20190501 6

Autism spectrum disorder (ASD) manifests as alterations in complex human behaviors including social communication and stereotypies. In addition to genetic risks, the gut microbiome differs between typically developing (TD) and ASD individuals, though it remains unclear whether the microbiome contributes to symptoms. We transplanted gut microbiota from human donors with ASD or TD controls into germ-free mice and reveal that colonization with ASD microbiota is sufficient to induce hallmark autisti ...[more]

PMID: 31150625

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Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development is poorly understood. Here we investigate how depletion, and selective reconstitution, of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

			Action	DRS
	MTBLS726	Other
	FILES	Other
	a_MTBLS726_Fecal_GCMS.txt	Txt
	a_MTBLS726_NMR.txt	Txt
	a_MTBLS726_Serum_GCMS.txt	Txt