Early Disruption of the Microbiome Leading to Decreased Antioxidant Capacity and Epigenetic Changes: Implications for the Rise in Autism

Abstract

Currently, 1 out of every 59 children in the United States is diagnosed with autism. While initial research to find the possible causes for autism were mostly focused on the genome, more recent studies indicate a significant role for epigenetic regulation of gene expression and the microbiome. In this review article, we examine the connections between early disruption of the developing microbiome and gastrointestinal tract function, with particular regard to susceptibility to autism. The biological mechanisms that accompany individuals with autism are reviewed in this manuscript including immune system dysregulation, inflammation, oxidative stress, metabolic and methylation abnormalities as well as gastrointestinal distress. We propose that these autism-associated biological mechanisms may be caused and/or sustained by dysbiosis, an alteration to the composition of resident commensal communities relative to the community found in healthy individuals and its redox and epigenetic consequences, changes that in part can be due to early use and over-use of antibiotics across generations. Further studies are warranted to clarify the contribution of oxidative stress and gut microbiome in the pathophysiology of autism. A better understanding of the microbiome and gastrointestinal tract in relation to autism will provide promising new opportunities to develop novel treatment modalities.

Keywords: autism; dysbiosis; epigenetics; gut microbiota; oxidative stress.

FIGURE 1

Intestinal microbial introduction by vaginal delivery vs. Cesarean delivery. In vaginal delivery, infants obtain Lactobacillus via the vaginal canal. This promotes normal intestinal microbial colonization and development of a competent gut immune system. In contrast, in Cesarean delivery, infants obtain skin microbes, including Staphylococcus. This abnormal gut microbe introduction leads to altered intestinal microbial colonization and increases the risk of immunologic disorders.

FIGURE 2

External factors affecting the intestinal microbiota of infants. Through infant developmental stages, multiple factors affect the constitution of intestinal microbiota. Beneficial modifications are highlighted in green and negative alterations are highlighted in red. At the prenatal stage, genetic factors or maternal microbes and intrauterine contamination can affect intestinal colonization. At birth, the delivery method is the main determining factor of gut microbiota. Type of feeding and probiotic/antibiotic treatments at weeks and months can contribute to alteration of intestinal microbes. Approximately at 1 year of age, infants accomplish adult-like gut microbe colonization.

FIGURE 3

Immune system mediated regulation of brain function. Proper immune system response plays a crucial role in protecting and maximizing brain function. Lack of T cell regulation leads to inappropriate activation of meningeal macrophage and microglia cells, causing impairment of brain function.

FIGURE 4

Gut–brain inflammation. (1) Stress, such as medications, neurotransmitters, enzymes, neuropeptides, intestinal flora, or immune dysregulation generates immunomodulatory and inflammatory fragments of dietary proteins. (2) These fragments can diffuse into endothelial cells lining the GI tract. (3) IL-1, which is one of the product of fragment of dietary proteins bind to IL-1 receptor on the lateral border of adjacent epithelial cell. (4) This IL-1/IL-1 receptor complex phosphorylates NF-kB. (5) Activated NF-kB further binds to DNA sequence in nucleus of endothelial cell, inducing transcription of MLCK (myosin-light chain kinase) mRNA. (6) MLCK mRNA travels to cytosol and is translated into MLCK proteins. (7) MLCK proteins bind to and open up the tight junction, where dietary fragment proteins are released into paracellular space. (8) These particles are further released into reticular tissue. (9) APC recognizes this dietary fragment and presents to T cells. (10) T cells generate killer T cell attacking epithelial cells that contain these inflammatory dietary fragments. (11) B cells are activated by T cells presenting the dietary fragment. In response, B cells generate antibodies against tight junction proteins, IgG and IgM antibodies against diet peptides. This leads to cross-reaction in various tissues and induction of autoimmune disorders in different organs. In addition, antigen-presenting cells (APC) such as dendritic cells (DCs) can produce proinflammatory cytokines that educate naive CD4+ T cells into inflammatory T cells that can help B cell maturation to produce antibodies.

FIGURE 5

Gut–brain axis and microbiota interplay. Brain, GI system, and microbiota interact with each other to produce physiological responses. In healthy individuals, CNS function enhances normal immune response, which promotes colonization of normal gut microbiota and maximizes GI function. In contrast, in diseased individuals, altered brain functions induce abnormal immune response and intestinal dysbiosis. This further contributes to abnormal gut physiology and function.

FIGURE 6

Blood–brain barrier. Blood capillaries are surrounded by astrocyte processes, which enhance transcapillary molecular transport. Small molecules such as gasses or lipid soluble substances in capillary lumen can travel into tissue fluid via diffusion. Larger molecules such as glucose, amino acid, or other hydrophilic proteins are released from brain capillary into tissue via protein carriers.