Dynamic and Systemic Perspective in Autism Spectrum Disorders: A Change of Gaze in Research Opens to A New Landscape of Needs and Solutions

Abstract

The first step for a harmonious bio-psycho-social framework in approaching autism spectrum disorders (ASD) is overcoming the conflict between the biological and the psychosocial perspective. Biological research can provide clues for a correct approach to clinical practice, assuming that it would lead to the conceptualization of a pathogenetic paradigm able to account for epidemiologic and clinical findings. The upward trajectory in ASD prevalence and the systemic involvement of other organs besides the brain suggest that the epigenetic paradigm is the most plausible one. The embryo-fetal period is the crucial window of opportunity for keeping neurodevelopment on the right tracks, suggesting that women's health in pregnancy should be a priority. Maladaptive molecular pathways beginning in utero, in particular, a vicious circle between the immune response, oxidative stress/mitochondrial dysfunction, and dysbiosis-impact neurodevelopment and brain functioning across the lifespan and are the basis for progressive multisystemic disorders that account for the substantial health loss and the increased mortality in ASD. Therefore, the biological complexity of ASD and its implications for health requires the enhancement of clinical skills on these topics, to achieve an effective multi-disciplinary healthcare model. Well-balanced training courses could be a promising starting point to make a change.

Keywords: autism; comorbidities; epigenetics; healthcare; microbiota; mitochondrial impairment; multi-disciplinarity; neuroinflammation; oxidative stress; prevention.

Figure 1

The recent upward trajectory in prevalence and the multifaceted phenotype in ASD suggest that autism is in most cases the result of an early perturbation of ontogenetic pathways, with different age-related outcomes, in line with the DOHaD Theory [34,37,38]. The early start of a vicious circle between inflammation, dysbiosis, and oxidative stress/mitochondrial impairment (the “bad trio”) launches a multi-step frailty trajectory, and inserts the major comorbidities in ASD within the pathogenetic framework. From the womb to adulthood, the nervous system might be progressively involved, from inflammatory to degenerative processes. The circle of the “bad trio” is in relationship with the environment, in the broad sense of the “exposome” (the colored dots), that is the sum of all the factors our body is exposed to. Both risks and opportunities for human health come from the exposome, and major impact occurs through the action of the bad trio. The substantial loss of health across the lifespan and the increased mortality in ASD encourage best efforts aimed at “improving the soil around the tree”.

Figure 2

Risk factors for neurodevelopment and suggestions for clinical practice [14,50,60,83,275,276,277,278,279,280,281,282,283,284]. The picture shows some of the most relevant risk factors for ASD. We mention only maternal risk factors, however also some paternal characteristic (in particular, age > 40) are a risk factor for ASD. During pregnancy, a broad array of interconnecting pathways link each factor to the others and in a more or less direct way could contribute to the vicious circle of the “Bad Trio”. In some cases, the link is more evident: antibiotic use favors dysbiosis; infections in pregnancy cause immune activation. Mechanisms involving other risk factors might be not so straightforward—e.g., mother’s health status may or may not affect low-grade inflammation in numerous metabolic disorders, such as obesity and diabetes. Nutrient deficiencies may be prevented or corrected through specific supplementation, provided they are diagnosed in time. The relevance of gut permeability and microbial balance within the immuno-neuro-endocrine system underscores the usefulness of some laboratory assays, such as the evaluation of maternal serum zonulin and the microbiota analysis. As far as the role of the microbial balance, evidence concerning the relationship between maternal oral dysbiosis and the risk of ASD in offspring underscores that the gut microbiota is not the only one to pay attention to. A further important investigation extensively discussed in the text concerns the titration of anti-FR α autoantibodies. Intra-uterine growth retardation (IUGR) and pre-term birth are the most frequent outcomes of the abovementioned multi-etiological placental insufficiency. They are the result of a previous frailty trajectory and themselves are the premise of further risks, involving, once again, the “bad trio”. In fact, there is a correlation between IUGR, pre-term birth, increased oxidative stress, susceptibility to infections, and consequent early antibiotic use. The careful monitoring of the neurodevelopmental trajectory of high-risk children should go hand-in-hand with the monitoring of biological abnormalities and gastrointestinal symptoms. Persistent crying (discussed in the text) should be considered a red flag, indicating early ANS abnormalities, that suggest investigating through the study of microbiota and of erythrocyte lipidomic analysis. Perspective studies are required to ascertain if the early and tailored restoration of the biological balance has positive impact on neurodevelopment of high-risk infants. Similar considerations concern the biological abnormalities in children and adults with ASD, that are represented to the right of the red dashed-line. Personalized supplementation and nutritional adjustments suggested in the green box might tune the metabolic, immunologic, and microbiologic imbalances and favorably impact both neurodevelopment and comorbidities.