Enteric Ecosystem Disruption in Autism Spectrum Disorder: Can the Microbiota and Macrobiota be Restored?

Slattery, John C.; MacFabe, Derrick F.; Kahler, Stephen G.; Frye, Richard E.

doi:10.2174/1381612822666160905123953

Cited by 18 publications

(27 citation statements)

References 208 publications

(255 reference statements)

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“…The enteric microbiome, a diverse ecosystem of bacteria, fungi, viruses and their collective genomes, resides in the GI tract and aids in vitamin synthesis, immune regulation and host metabolism [12]. Folate is synthesized by enteric bacterial species, particularly Bifidobacteria, Prevotella and certain Lactobacilli species [13][14][15][16][17].…”

Section: The Importance Of the Microbiome And Folate Transporters In Fomentioning

confidence: 99%

“…The notion that disruption of folate metabolism during gestation could contribute to ASD is supported by two epidemiological studies which demonstrated that folate supplementation during the preconception period as well as pregnancy was protective of offspring from developing ASD or NTD [51,52]. It has also been suggested that maternal microbiome disruption during pregnancy could also contribute to abnormal folate metabolism during pregnancy and be associated with ASD development [12]. The connection between FRAAs during pregnancy and ASD is supported by a recent rodent model developed in the Quadros laboratory.…”

Section: Effect Of Fraas In Pregnancymentioning

confidence: 99%

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Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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Autism spectrum disorder (ASD) has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD. Autism spectrum disorder: an emerging disorder with unclear etiology Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 2% of children in the USA [1]. Although it is defined through observation of the presence of abnormal behavior and absence of typical developmental milestones, ASD is associated with a wide range of medical abnormalities such as sleep, immune and gastrointestinal disorders and epilepsy. In addition to medical comorbidities, many children with ASD have disruptions in body physiology such as abnormalities in folate, cobalamin, tetrahydrobiopterin (BH 4 ), neurotransmitter, carnitine, redox and mitochondrial metabolism [2]. The connection between underlying physiological abnormalities and behavior is an area of active research. In this review, we will provide evidence that abnormalities of one-carbon folate metabolism are particularly important in ASD.Although the etiology of ASD is not known, genetics has been the focus of ASD research for many decades [3]. A notion of a pure genetic etiology is tempered by the fact that single gene and chromosomal defects are found in a minority of ASD cases, accounting for only 15.8% of cases when both chromosomal microarray and whole exome sequencing were used in one recent large study [4]. ASD has also been associated with exposures to numerous environmental agents during the prenatal and postnatal period [5]. Studies that have examined the contribution of the environmental and genetic components highlight that ASD arises as a consequence of complicated interactions between genetic predisposition and environmental factors [6,7]. As we will outline in this review, abnormalities in folate metabolism provide an excellent model of how environment factors can interact with genetic predisposition to cause ASD.At this time, the standard of care for ASD treatment is applied behavioral analysis and other equivalent behavioral interventions along with educational, developmental, occupational and speech therapy. Optimal application of behavioral therapy requires full-time one-on-one therapist for many years; however, even when this optimal therapy is applied, suboptimal outcomes are common. In addition, controlled studies examining the efficacy of variou...

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Section: The Importance Of the Microbiome And Folate Transporters In Fomentioning

confidence: 99%

Section: Effect Of Fraas In Pregnancymentioning

confidence: 99%

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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“…The groups of MacFabe and Frye have published extensively on the potential importance of propionic acid including its use as a food preservative . There is evidence that increased propionate could result from changes in the microbiome which in turn relates to gastrointestinal disorders and mitochondrial function . At least four reviews of the relevance of the microbiome to autism appeared in 2016 , and the potential for interaction with brain carnitine deficiency could be substantial.…”

Section: Mitochondrial Abnormalities Generally In Autismmentioning

confidence: 99%

Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis

Beaudet

2017

BioEssays

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Could 10–20% of autism be prevented? We hypothesize that nonsyndromic or “essential” autism involves extreme male bias in infants who are genetically normal, but they develop deficiency of carnitine and perhaps other nutrients in the brain causing autism that may be amenable to early reversal and prevention. That brain carnitine deficiency might cause autism is suggested by reports of severe carnitine deficiency in autism and by evidence that TMLHE deficiency – a defect in carnitine biosynthesis – is a risk factor for autism. A gene on the X chromosome (SLC6A14) likely escapes random X-inactivation (a mixed epigenetic and genetic regulation) and could limit carnitine transport across the blood-brain barrier in boys compared to girls. A mixed, common gene variant-environment hypothesis is proposed with diet, minor illnesses, microbiome, and drugs as possible risk modifiers. The hypothesis can be tested using animal models and by a trial of carnitine supplementation in siblings of probands. Perhaps the lack of any Recommended Dietary Allowance for carnitine in infants should be reviewed.

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“…Therefore, most of such conditions represent the consequence of interaction between individual's genetic profile and the environment that he/she is exposed to (Blatt, ). Emerging research has shown microbiota and their metabolites dynamically affect host metabolic, immune, behavioural processes and gut‐brain communications throughout the lifecycle (Bilbo, Block, Bolton, Hanamsagar, & Tran, ; Kim, Yun, Oh, & Choi, ; MacFabe, ; Sharon et al, ; Shenderov & Midtvedt, ; Slattery, MacFabe, Kahler, & Frye, ;). The relationship between gastrointestinal symptoms and many neurological states, such as anxiety, depression, stress and ASD is shown in numerous studies (Foster, Rinaman, & Cryan, ; Fung, Olson, & Hsiao, ; Ishii et al, ).…”

Section: Introductionmentioning

confidence: 99%

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

Lobzhanidze

Japaridze²,

Lordkipanidze

et al. 2020

Intl J of Devlp Neuroscience

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Short chain fatty acids, produced as gut microbiome metabolites but also present in the diet, exert broad effects in host physiology. Propionic acid (PPA), along with butyrate and acetate, plays a growing role in health, but also in neurological conditions. Increased PPA exposure in humans, animal models and cell lines elicit diverse behavioural and biochemical changes consistent with organic acidurias, mitochondrial disorders and autism spectrum disorders (ASD). ASD is considered a disorder of synaptic dysfunction and cell signalling, but also neuroinflammatory and neurometabolic components. We examined behaviour (Morris water and radial arm mazes) and the ultrastructure of the hippocampus and medial prefrontal cortex (electron microscopy) following a single intraperitoneal (i.p.) injection of PPA (175 mg/kg) in male adolescent rats. PPA treatment showed altered social and locomotor behaviour without changes in learning and memory. Both transient and enduring ultrastructural alterations in synapses, astro‐ and microglia were detected in the CA1 hippocampal area. Electron microscopic analysis showed the PPA treatment significantly decreased the total number of synaptic vesicles, presynaptic mitochondria and synapses with a symmetric active zone. Thus, brief systemic administration of this dietary and enteric short chain fatty acid produced behavioural and dynamic brain ultrastructural changes, providing further validation of the PPA model of ASD.

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Enteric Ecosystem Disruption in Autism Spectrum Disorder: Can the Microbiota and Macrobiota be Restored?

Abstract: If these theoretical models prove to be valid, they may lead to the development of practical interventions which could decrease ASD prevalence and/or morbidity.

Cited by 18 publications

References 208 publications

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

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