Hypothesis for a systems connectivity model of autism spectrum disorder pathogenesis: Links to gut bacteria, oxidative stress, and intestinal permeability
Introduction
Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders that include Autism, Asperger’s Syndrome, and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). It has implications in cognitive impairments, sociability impairments, impairments in language and communication skills, restricted interests, and stereotyped behaviors [1]. Currently, observations of these behaviors are the best and only way to diagnose ASDs. A diagnosis is usually made before a child reaches age 3, and diagnoses have dramatically increased in the past several years. Current estimates state that 1 in 88 (11.4 in 1000) children in the US in 2008 had some form of autism, up from 9 in 1000 in 2006 and 6.4 in 1000 in 2002. Incidence of autism could possibly be more now. ASDs are about four times more prevalent in males than females, for reasons that are still unclear.
Gastrointestinal problems have been implicated in people with ASDs by some, but there is much discrepancy on this topic: some studies seem to confirm this correlation as significant when compared to healthy, age-matched controls [2], [3], [4], and yet others state that the differences in gastrointestinal problems in ASD patients are not statistically significant [5], [6], [7]. Despite these discrepancies, when ASD patients are put on gluten and casein exclusion diets there is usually a partial alleviation of symptoms soon afterwards [2]. Gluten allergies are pervasive in Celiac Disease and type 1 diabetes [8], [9], [10]. It is an autoimmune condition, thought to be aggravated by a weakening of the small or large intestine’s epithelial barrier function, intended to limit trafficking of cells and molecules between the gut and blood circulation. This suggests that there is a link between the gut and autism pathogenesis. Gastrointestinal problems (such as diarrhea, constipation, ulcerative colitis) might not be present in all people with ASDs, but there does seem to be a link between gastrointestinal symptom severity and autism severity, which gives more evidence for the gut-to-brain link [2].
Section snippets
Proposed pathogenesis
Fig. 1, depicted below, represents a summary of our proposed systems connectivity model for autism spectrum disorder pathogenesis. A review of the recent literature is necessary to understand the full implications and reasoning behind the model and will be addressed after the introduction of the model. The model is quite complex, involving both linear and cyclic relationships. The model can be broken down into three main sections or pathogenesis routes: oxidative stress and subsequent sulfur
Abnormal gut bacteria
Given the gut-to-brain link in ASDs, there have been numerous studies on intestinal bacteria composition in relation to ASDs. Anaerobic bacteria naturally reside in the human large intestine (and similar mammals) acting as another collective “organ” of the human body [14], [15], [16], [8]. They ferment polysaccharides from the diet that are indigestible by human enzymes and produce short chain fatty acids (SCFAs), mainly acetate, propionate, and butyrate. The main bacterial genera responsible
Conflict of interest
There are to the best knowledge of the authors no conflicts of interests associated with this manuscript.
Acknowledgement
None.
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