Pathophysiology of autism spectrum disorders: Revisiting gastrointestinal involvement and immune imbalance

Abstract

Autism spectrum disorders (ASD) comprise a group of neurodevelopmental abnormalities that begin in early childhood and are characterized by impairment of social communication and behavioral problems including restricted interests and repetitive behaviors. Several genes have been implicated in the pathogenesis of ASD, most of them are involved in neuronal synaptogenesis. A number of environmental factors and associated conditions such as gastrointestinal (GI) abnormalities and immune imbalance have been linked to the pathophysiology of ASD. According to the March 2012 report released by United States Centers for Disease Control and Prevention, the prevalence of ASD has sharply increased during the recent years and one out of 88 children suffers now from ASD symptoms. Although there is a strong genetic base for the disease, several associated factors could have a direct link to the pathogenesis of ASD or act as modifiers of the genes thus aggravating the initial problem. Many children suffering from ASD have GI problems such as abdominal pain, chronic diarrhea, constipation, vomiting, gastroesophageal reflux, and intestinal infections. A number of studies focusing on the intestinal mucosa, its permeability, abnormal gut development, leaky gut, and other GI problem raised many questions but studies were somehow inconclusive and an expert panel of American Academy of Pediatrics has strongly recommended further investigation in these areas. GI tract has a direct connection with the immune system and an imbalanced immune response is usually seen in ASD children. Maternal infection or autoimmune diseases have been suspected. Activation of the immune system during early development may have deleterious effect on various organs including the nervous system. In this review we revisited briefly the GI and immune system abnormalities and neuropeptide imbalance and their role in the pathophysiology of ASD and discussed some future research directions.

Fatal case of acute gastroenteritis with multiple viral coinfections

“…AGE occurring at extreme ages (>85 and <2 years of age) and in immunocompromised hosts are associated with more severe outcomes [16]. Our patient was affected by ASD and many studies support the possibility that this disease can be associated with immune dysregulation [17,18]. However, little is known about the increased risk of these patients for severe gastrointestinal diseases.…”

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

“…The intestinal barrier is the largest mucosal surface that separates diverse stressors (trillions of microbes, toxins, and food antigens) on one side from the largest immune system on the other. A compromised gut barrier allows microbes and unwanted antigens to cross the epithelium and generate inflammation (systemic endotoxemia), which may contribute to a variety of diseases, ranging from metabolic syndrome and chronic organ dysfunctions to neurodegenerative diseases and cancers (Yacyshyn et al, 1996;Barbara, 2006;Camilleri & Gorman, 2007;Sandek et al, 2007Sandek et al, , 2008Sandek et al, , 2012Alam et al, 2014;Bischoff et al, 2014;Nouri et al, 2014;Samsam et al, 2014;van De Sande et al, 2014;Clairembault et al, 2015;Lee et al, 2015;Buscarinu et al, 2016;Xue et al, 2016;Ghosh, 2017). Evidence also shows that aging-related genes, that is, the sirtuins (SIRTs1, 3, 6), are critical for the integrity of the gut barrier and for controlling inflammation in the gut (Akimova et al, 2014;Akbulut et al, 2015;Liu et al, 2017b;Zhang et al, 2018).…”

Pediatric Traumatic Brain Injury and Autism: Elucidating Shared Mechanisms

“…The underlying cause of microflora demise is partly mediated by the release of high mobility group box 1 protein from necrotic tissue in the intestines [66]. The release triggers a cytokine storm, which causes an inflammatory cascade [67]. The inflammatory cascade leads to increased permeability in the intestine, which further exacerbates the microbiome disruption [68].…”