Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

Abstract

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a very high prevalence rate and a chronic disease course beginning in early childhood. Despite the tremendous burden of ASD, there are currently no disease-modifying treatments. Like many neuropsychiatric illnesses ASD has a complex pathophysiology driven by genetic and environmental factors. There is interest in identifying modifiable environmental factors as potential translational research strategies for development of therapeutics for ASD. A rapidly growing body of research demonstrates that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, have profound influence on brain and behavior. This gut-brain signaling pathway is highly relevant to ASD as the microbiome begins to form at birth, is heavily influenced by environmental factors throughout early life, and begins to stabilize at the same stage of development that symptoms of ASD begin to develop. To investigate potential gene x microbiome interactions in a model of ASD, we utilized mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3 KO ), which clinically manifests as Phelan-McDermid syndrome, as a model for genetic risk of ASD. Analysis of the gut microbiome of Shank3 KO mice demonstrated genotype effects on both microbiome composition and metabolite production. Behaviorally, Shank3 KO mice demonstrate decreased social interactions and have altered anxiety and compulsive-like behaviors. Disruption of the microbiome with broad spectrum antibiotics lead to an exacerbation of all behavioral phenotypes in Shank3 KO mice. Additionally, we found that Shank3 KO mice had markedly increased changes in gene expression in the prefrontal cortex following microbiome depletion. Taken together, our results suggest a gene x microbiome interaction in this mouse model for ASD and raise the possibility that targeting the microbiome may be a valid translational research strategy in developing therapeutics for ASD.

Fecal microbiota transplantation from individual with bipolar disorder and healthy control elicits distinct behaviors and metabolite profiles in mice

“…Interestingly, increased valeric acid and decreased acetic acid concentrations have been measured in fecal samples from children with autism [53], suggesting a connection between the regulation of these metabolites and neurodevelopmental disorders. Acetate supplementation has also rescued social deficits in an autistic mouse model, implicating decreased central acetic acid levels with impaired social interaction in BD mice [54].…”

Post-weaning A1/A2 β-casein milk intake modulates depressive-like behavior, brain μ-opioid receptors, and the metabolome of rats

“…The short-chain fatty acid acetate was also positively associated with formate, S -adenosylhomocysteine, and guanosine in the brain and negatively correlated with oxypurinol, phosphocholine, and acetylcholine. Gut-derived acetate can translocate to the brain and can affect histone acetylation and thus the epigenetic landscape of the brain, influencing behavior ( Mews et al., 2019 ; Osman et al., 2020 ). Decreased urinary excretion of acetate was noted in animals fed A1 β-casein compared to animals who received A2 β-casein milk.…”

Epigenetic Aberrations in Major Psychiatric Diseases Related to Diet and Gut Microbiome Alterations

“…Therefore, the use of microbiome-related metabolites such as acetate could be a reasonable approach to reverse social deficits in ASD via transcriptional changes in the frontal cortex. To this end, Kiraly et al examined the neuroprotective effects of acetate supplementation in mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3 KO ) [172]. In addition to social deficits, functional and compositional changes in the gut microbiome were seen in Shank3 KO mice.…”