Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome

Abstract

Autism spectrum disorder (ASD) affects a significant number of individuals worldwide with the prevalence continuing to grow. It is becoming clear that a large subgroup of individuals with ASD demonstrate abnormalities in mitochondrial function as well as gastrointestinal (GI) symptoms. Interestingly, GI disturbances are common in individuals with mitochondrial disorders and have been reported to be highly prevalent in individuals with co-occurring ASD and mitochondrial disease. The majority of individuals with ASD and mitochondrial disorders do not manifest a primary genetic mutation, raising the possibility that their mitochondrial disorder is acquired or, at least, results from a combination of genetic susceptibility interacting with a wide range of environmental triggers. Mitochondria are very sensitive to both endogenous and exogenous environmental stressors such as toxicants, iatrogenic medications, immune activation, and metabolic disturbances. Many of these same environmental stressors have been associated with ASD, suggesting that the mitochondria could be the biological link between environmental stressors and neurometabolic abnormalities associated with ASD. This paper reviews the possible links between GI abnormalities, mitochondria, and ASD. First, we review the link between GI symptoms and abnormalities in mitochondrial function. Second, we review the evidence supporting the notion that environmental stressors linked to ASD can also adversely affect both mitochondria and GI function. Third, we review the evidence that enteric bacteria that are overrepresented in children with ASD, particularly Clostridia spp., produce short-chain fatty acid metabolites that are potentially toxic to the mitochondria. We provide an example of this gut–brain connection by highlighting the propionic acid rodent model of ASD and the clinical evidence that supports this animal model. Lastly, we discuss the potential therapeutic approaches that could be helpful for GI symptoms in ASD and mitochondrial disorders. To this end, this review aims to help better understand the underlying pathophysiology associated with ASD that may be related to concurrent mitochondrial and GI dysfunction.

Autism in patients with propionic acidemia

“…This has been also suggested in several publications evaluating the possible correlation between gastrointestinal propionic acid production and autism [18]. Abnormal branch chained amino acid ratios have also been correlated with poor neuropsychologic outcome [8].…”

“…Furthermore, amino acid levels in autistic patients have been reported as significantly different from non-autistic control groups [3,5,14]. Inborn errors of metabolism such as propionic acidemia have been suggested to increase the risk for autism in a few cases [4,18]. Interestingly in another case report partial biotinidase deficiency, leading among others to decreased activity of propionyl-CoA carboxylase, the defective enzyme in PA, could also cause ASD [13].…”

Mitochondria, Microbiome and Their Potential Psychiatric Modulation

“…Interestingly, many individuals who have ASD also exhibit mitochondrial dysfunctionality and gastrointestinal (GI) symptoms [14,15]. Individuals that have ASD and also mitochondrial disorders often do not exhibit primary genetic mutations.…”

A Current Approach to Microbiota: Autism and Microbiota

“…Örne-ğin; intestinal mikrobiyotanın bir yıkım ürünü olan propiyonatın mitokondri metabolizmasını etkileyerek nörotoksisiteye neden olabilen bir mitokondriyal toksin olmasından dolayı mitokondriyal bozukluklar oluşturarak gastrointestinal semptomları tetiklediği düşünülmektedir. 30 Ayrıca, otizmli çocuklarda beraberinde eşlik eden gastrointestinal semptomlar; heksoz (sodyuma bağımlı glukoz taşıyıcıları) ve glukoz taşıyı-cılarının, karbonhidratların sindirimini yapan Bununla birlikte bireyin beslenme düzeni, intestinal mikrobiyota içeriğini değiştirerek barsakbeyin ekseni üzerinde etkili olmaktadır. Otizmli çocukların problemli yeme davranışları; gastrointestinal semptomları, besin allerjilerini veya metabolik anomalilikleri de beraberinde getirmektedir.…”