The early life exposome and autism risk: a role for the maternal microbiome?

Autism spectrum disorders (ASD) are highly heritable, heterogeneous neurodevelopmental disorders characterized by clinical presentation of atypical social, communicative, and repetitive behaviors. Over the past 25 years, hundreds of ASD risk genes have been identified. Many converge on key molecular pathways, from translational control to those regulating synaptic structure and function. Despite these advances, therapeutic approaches remain elusive. Emerging data unearthing the relationship between genetics, microbes, and immunity in ASD suggest an integrative physiology approach could be paramount to delivering therapeutic breakthroughs. Indeed, the advent of large-scale multi-OMIC data acquisition, analysis, and interpretation is yielding an increasingly mechanistic understanding of ASD and underlying risk factors, revealing how genetic susceptibility interacts with microbial genetics, metabolism, epigenetic (re)programming, and immunity to influence neurodevelopment and behavioral outcomes. It is now possible to foresee exciting advancements in the treatment of some forms of ASD that could markedly improve quality of life and productivity for autistic individuals. Here, we highlight recent work revealing how gene X maternal exposome interactions influence risk for ASD, with emphasis on the intrauterine environment and fetal neurodevelopment, host-microbe interactions, and the evolving therapeutic landscape for ASD.

Microbial determinants of dementia risk in subjects of Mexican descent with type 2 diabetes living in South Texas.

Type 2 diabetes (T2D) is a common forerunner of neurodegeneration and dementia, including Alzheimer's Disease (AD), yet the underlying mechanisms remain unresolved. Individuals of Mexican descent living in South Texas have increased prevalence of comorbid T2D and early onset AD, despite low incidence of the predisposing APOE-e4 variant and an absence of the phenotype among relatives residing in Mexico - suggesting a role for environmental factors in coincident T2D and AD susceptibility. Here, in a small clinical trial, we show dysbiosis of the human gut microbiome could contribute to neuroinflammation and risk for AD in this population. Divergent Gastrointestinal Symptom Rating Scale (GSRS) responses, despite no differences in expressed dietary preferences, provided the first evidence for altered gut microbial ecology among T2D subjects (sT2D) versus population-matched healthy controls (HC). Metataxonomic 16S rRNA sequencing of participant stool revealed a decrease in alpha diversity of sT2D versus HC gut communities and identified BMI as a driver of gut community structure. Linear discriminant analysis effect size (LEfSe) identified a significant decrease in the relative abundance of the short-chain fatty acid-producing taxa Lachnospiraceae, Faecalibacterium, and Alistipes and an increase in pathobionts Escherichia-Shigella, Enterobacter, and Clostridia innocuum among sT2D gut microbiota, as well as differentially abundant gene and metabolic pathways. These results suggest characterization of the gut microbiome of individuals with T2D could identify key actors among "disease state" microbiota which may increase risk for or accelerate the onset of neurodegeneration. Furthermore, they identify candidate microbiome-targeted approaches for prevention and treatment of neuroinflammation in AD.

Persistent ∆FosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice.

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ∆FosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ∆JunD to interfere with ∆FosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ∆FosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.