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.

The contribution of age-related changes in the gut-brain axis to neurological disorders.

Trillions of microbes live symbiotically in the host, specifically in mucosal tissues such as the gut. Recent advances in metagenomics and metabolomics have revealed that the gut microbiota plays a critical role in the regulation of host immunity and metabolism, communicating through bidirectional interactions in the microbiota-gut-brain axis (MGBA). The gut microbiota regulates both gut and systemic immunity and contributes to the neurodevelopment and behaviors of the host. With aging, the composition of the microbiota changes, and emerging studies have linked these shifts in microbial populations to age-related neurological diseases (NDs). Preclinical studies have demonstrated that gut microbiota-targeted therapies can improve behavioral outcomes in the host by modulating microbial, metabolomic, and immunological profiles. In this review, we discuss the pathways of brain-to-gut or gut-to-brain signaling and summarize the role of gut microbiota and microbial metabolites across the lifespan and in disease. We highlight recent studies investigating 1) microbial changes with aging; 2) how aging of the maternal microbiome can affect offspring health; and 3) the contribution of the microbiome to both chronic age-related diseases (e.g., Parkinson's disease, Alzheimer's disease and cerebral amyloidosis), and acute brain injury, including ischemic stroke and traumatic brain injury.

Monospecies probiotic preparation and administration with downstream analysis of sex-specific effects on gut microbiome composition in mice.

Dysbiosis of the gut microbiome is implicated in the growing burden of non-communicable chronic diseases, including neurodevelopmental disorders, and both preclinical and clinical studies highlight the potential for precision probiotic therapies in their prevention and treatment. Here, we present an optimized protocol for the preparation and administration of Limosilactobacillus reuteri MM4-1A (ATCC-PTA-6475) to adolescent mice. We also describe steps for performing downstream analysis of metataxonomic sequencing data with careful assessment of sex-specific effects on microbiome composition and structure. For complete details on the use and execution of this protocol, please refer to Di Gesù et al.1.

Maternal gut microbiota mediate intergenerational effects of high-fat diet on descendant social behavior.

Dysbiosis of the maternal gut microbiome during pregnancy is associated with adverse neurodevelopmental outcomes. We previously showed that maternal high-fat diet (MHFD) in mice induces gut dysbiosis, social dysfunction, and underlying synaptic plasticity deficits in male offspring (F1). Here, we reason that, if HFD-mediated changes in maternal gut microbiota drive offspring social deficits, then MHFD-induced dysbiosis in F1 female MHFD offspring would likewise impair F2 social behavior. Metataxonomic sequencing reveals reduced microbial richness among female F1 MHFD offspring. Despite recovery of microbial richness among MHFD-descendant F2 mice, they display social dysfunction. Post-weaning Limosilactobacillus reuteri treatment increases the abundance of short-chain fatty acid-producing taxa and rescues MHFD-descendant F2 social deficits. L. reuteri exerts a sexually dimorphic impact on gut microbiota configuration, increasing discriminant taxa between female cohorts. Collectively, these results show multigenerational impacts of HFD-induced dysbiosis in the maternal lineage and highlight the potential of maternal microbiome-targeted interventions for neurodevelopmental disorders.

Diet-induced dysbiosis of the maternal gut microbiome in early life programming of neurodevelopmental disorders.

The maternal gut microbiome plays a critical role in fetal and early postnatal development, shaping fundamental processes including immune maturation and brain development, among others. Consequently, it also contributes to fetal programming of health and disease. Over the last decade, epidemiological studies and work in preclinical animal models have begun to uncover a link between dysbiosis of the maternal gut microbiome and neurodevelopmental disorders in offspring. Neurodevelopmental disorders are caused by both genetic and environmental factors, and their interactions; however, clinical heterogeneity, phenotypic variability, and comorbidities make identification of underlying mechanisms difficult. Among environmental factors, exposure to maternal obesity in utero confers a significant increase in risk for neurodevelopmental disorders. Obesogenic diets in humans, non-human primates, and rodents induce functional modifications in maternal gut microbiome composition, which animal studies suggest are causally related to adverse mental health outcomes in offspring. Here, we review evidence linking maternal diet-induced gut dysbiosis to neurodevelopmental disorders and discuss how it could affect pre- and early postnatal brain development. We are hopeful that this burgeoning field of research will revolutionize antenatal care by leading to accessible prophylactic strategies, such as prenatal probiotics, to improve mental health outcomes in children affected by maternal diet-induced obesity.