DOI: 10.7910/dvn/vavi4l
title: Environmental and genetic factors in autism spectrum disorders

description: Autistic spectrum disorder (ASD) or spectrum of autism disorders (SAD) is a developmental, multifactorial disorder characterized by symptoms that develop with age and have a negative impact on the development of the child. Over the past years, research has shown a dramatic increase in incidence of ASD. Although the direct cause of an increase in the prevalence of autism is unknown, the increase may be partly explained by increased awareness and improved diagnosis. Ethology and ASD's pathogenesis are not yet fully understood. Studies show that the heredity in ASD is an important factor, while a lesser emphasis is placed on defining the importance of various environmental factors. Autism can be derived from the interaction between genetic, environmental, behavioral and immunological factors, with oxidative stress as a mechanism that connects these risk factors. An increasing number of studies are studying the involvement of intestinal microbiota in ASD, especially in recent years with the methods of microbiomics. In different studies the reduced diversity of the entire microbiota and the changed proportions of some important microbial groups in ASD is described. One of the possible mechanisms contributing to inflammatory changes typical for ASD is increased intestinal permeability and consequent bacterial translocation or translocation of bacterial components, such as lipopolysaccharides (LPS) of cell walls of Gram negative bacteria, into systemic circulation. It is not yet well known whether children with ASD and GI symptoms are a unique phenotype within the ASD or if it is a co-morbidity that is not related to neurological development. We want to investigate whether microbiota and peripheral immune response in children with ASD symptoms will be altered and whether there are biological markers of immune dysfunction. For the assessment of the condition, we will determine the proinflammatory cytokines IL-1a, IL-1b, IL-6, IL-12 (p40 and p70) and the tumor necrosis factor (TNF) α. To evaluate the response of the T cells, we will analyze IFNDA (TH1), IL-4 and IL-13 (TH2), and to assess the immune regulation of IL-10 and the transforming growth factor (TGF) b1. In addition, also the levels of cytokines IL-5, IL-15 and IL-17 will be determined. Calprotectin is a calcium binding protein and is found in the cytoplasm of neutrophil granulocytes and macrophages. Objective of the proposed research with particular emphasis on the originality of the proposed research and its potential impact for the development of new research directions, 1. Intestinal microbiome dysbiosis is characteristic and plays an important role in the development or presentation of ASD symptoms, which will be demonstrated by molecular microbiological analyzes involving amplicon deep sequencing of 16S rRNA genes and "shotgun" metagenomic sequencing of the microbial DNA isolated from the samples of the selected patients 2. In children with ASD, we expect increased concentrations of inflammatory factors 3. In children with ASD, we expect increased isopropanol concentrations and the changed ratios of the short-chain fatty acids and bile acids in faeces, which will be in correlation with the changes in the microbiome, as a consequence of the increased / decreased number of genes involved in the metabolism of these substances 4. In children with ASD, a change in the ratio of quinurenine / tryptophan to urine is expected 5. In children with ASD, higher concentrations of calprotectin in faeces are expected 6. On the basis of the analysis of exome sequences of the selected subgroup of the study participants, using the machine learning methodology, we will try to disclose the connections between the genomic data and the data retrieved from the analysis of the microbiome, immune status and metabolic markers.