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The present study investigated that maternal type 1 diabetes may contribute to autism pathogenesis in offspring, and that insulin therapy during pregnancy may prevent the onset of autism. As evidenced, selected brain biomarkers representing the accepted etiological mechanism of autism in newborn rats from diabetic mothers and diabetic mothers receiving insulin therapy compared to the propionic acid (PPA) rodent model of autism were screened. Female Wistar rats with a controlled fertility cycle were randomly divided into three groups: a control group, a group treated with a single dose of 65 mg/kg streptozotocin (STZ) to induce type 1 diabetes (T1D), and a group treated with a single dose of STZ to induce T1D along with insulin therapy. Neonatal rats from these groups were divided into four experimental groups of six animals each: the control group, oral buffered PPA-treated group administered a neurotoxic dose of 250 mg/kg PPA for 3 days to induce autism, neonatal rats from mothers with T1D, and neonatal rats from mothers with T1D receiving insulin therapy. Biochemical parameters of oxidative stress, neuroinflammation, and glutamate excitotoxicity were examined in brain homogenates from all neonatal rats. The development of pathogenic bacteria was monitored in stool samples from all rat groups. Descriptive analyses of changes in fecal microbiota and overgrowth of Clostridium species were performed in diabetic mothers, diabetic mothers treated with insulin therapy, and their offspring. Clostridium species may induce autism-relevant behaviors in offspring from mothers with T1D. Maternal T1D without insulin therapy increased lipid peroxidation levels, reduced GST activity, and lower offspring’ vitamin C and GSH levels. Increased IL-6 levels and reduced GABA levels were detected in brain homogenates from neonatal rats whose mothers had T1D. Interestingly, insulin therapy reduced MDA and IL-6 levels and increased GST, GSH, and vitamin C levels in brain homogenates of neonatal rats from mothers with T1D receiving insulin therapy compared to the PPA-treated group. Based on our results, the PPA-treated group and neonatal rats from mothers with T1D exhibited similar results. These findings suggest that neonatal rats from mothers with T1D may develop autism-relevant biochemical autistic features and that insulin therapy may ameliorate oxidative stress, poor detoxification, inflammation, and excitotoxicity as ascertained mechanisms involved in the etiology of autism.

Autism spectrum disorders (ASD) express as impaired social interactions and stereotypes. The gut microbiome which is remarkably different in ASD compared with controls may contribute to the sex bias of this disorder, with females being less vulnerable to clinically present autism. This review aims to understand the role of gut microbiota and female sex hormone in the sex bias of autism. Recent evidence proved that transplanted gut microbiota from autistic donors but not healthy controls into germ-free mice were effective in inducing autistic features. Moreover selective probiotic known to be more abundant in females than males was effective as a treatment strategy. The higher autistic phenotypes in males compared with females could be attributed to the protective effect of estrogen, the higher diversity and predominance of probiotics in females, the lower liability of females to develop leaky gut, neuroinflammation, and excitotoxicity as etiological mechanisms.

The marked heterogeneity of autism spectrum disorders is a challenge for research into biomarkers of these disorders. The present study aimed to assess the association of the thioredoxin (TRX) system and vasopressin with autism in children. Thirty-five autistic children were recruited with thirty-one healthy controls children matched for age and gender. Total antioxidant capacity (TAC), vasopressin, peroxiredoxin (PRDX1, PRDX3), phox domain-containing protein kinase-like protein, and TRX1 levels were measured in plasma and mercury and lead levels were measured in red blood cells. Children with autism had significantly lower levels of PRDX1 and TRX1 and significantly higher levels of lead and mercury compared with controls. Significantly higher levels of vasopressin were also observed in more severe cases of autism. Receiver operating characteristics analysis demonstrated satisfactory specificity and sensitivity of TAC, PRDX1, PRDX3, and TRX1 for the diagnosis of autism. The optimal cut-off value for plasma TRX1 levels, as an indicator of autism, was 10.6 ng/mL. Significant positive correlations existed between TRX system components, lead, and mercury. A negative correlation was found between vasopressin and TRX1, but positive correlations were found between vasopressin and mercury and lead. In conclusion, TAC, PRDX1, PRDX3, and TRX1 may be useful biomarkers for the diagnosis of autism in Saudi populations. Vasopressin-resistance in autistic patients may be due to an increased oxidative burden.

It is proposed that gluten- and casein-rich diets (GRD and CRD) can synergistically exacerbate dysbiosis as comorbidity in autism by worsening leaky gut that affects the brain through the gut–brain axis. In this study, 35 young male rats were divided into 7 groups, Group 1 serves as control; Group 2, clindamycin (CL)-treated; and Group 3, propionic acid (PPA)-induced rodent model of autism. These three groups were fed standard diet until the end of the experiment. Groups 4–7 are rats treated similarly with CL and PPA, then fed on CRD or GRD until the end of the experiment. Serum zonulin, glutathione (GSH), lipid peroxides, and gut microbial composition were measured in the seven studied groups. Data demonstrate the significant increase in serum zonulin as marker of leaky gut in the CL-treated groups fed on CRD or GRD. Lipid peroxides were significantly higher in the serum of GRD-fed rats compared to CRD-fed or normal diet-fed rats. GSH was much lower in CL-treated groups fed on CRD or GRD compared to PPA-treated rats fed on both diets. Both diets differentially affected the diversity of the gut microbiota. This study demonstrates that CRD and GRD exacerbates leaky gut, according to serum zonulin, which was used as marker for increased gut permeability.

Background Innovative research highlighted the probable connection between autism spectrum disorder (ASD) and gut microbiota as many autistic individuals have gastrointestinal problems as co-morbidities. This review emphasizes the role of altered gut microbiota observed frequently in autistic patients, and the mechanisms through which such alterations may trigger leaky gut. Main body Different bacterial metabolite levels in the blood and urine of autistic children, such as short-chain fatty acids, lipopolysaccharides, beta-cresol, and bacterial toxins, were reviewed. Moreover, the importance of selected proteins, among which are calprotectin, zonulin, and lysozyme, were discussed as biomarkers for the early detection of leaky gut as an etiological mechanism of ASD through the less integrative gut–blood–brain barriers. Disrupted gut–blood–brain barriers can explain the leakage of bacterial metabolites in these patients. Conclusion Although the cause-to-effect relationship between ASD and altered gut microbiota is not yet well understood, this review shows that with the consumption of specific diets, definite probiotics may represent a noninvasive tool to reestablish healthy gut microbiota and stimulate gut health. The diagnostic and therapeutic value of intestinal proteins and bacterial-derived compounds as new possible biomarkers, as well as potential therapeutic targets, are discussed.

Autism is associated with gastrointestinal dysfunction and gut microbiota dysbiosis, including an overall increase in Clostridium. Modulation of the gut microbiota is suggested to improve autistic symptoms. In this study, we explored the implementation of two different interventions that target the microbiota in a rodent model of autism and their effects on social behavior: the levels of different fecal Clostridium spp., and hippocampal transcript levels. Autism was induced in young Sprague Dawley male rats using oral gavage of propionic acid (PPA) for three days, while controls received saline. PPA-treated animals were divided to receive either saline, fecal transplant from healthy donor rats, or Bifidobacterium for 22 days, while controls continued to receive saline. We found that PPA attenuated social interaction in animals, which was rescued by the two interventions. PPA-treated animals had a significantly increased abundance of fecal C. perfringens with a concomitant decrease in Clostridium cluster IV, and exhibited high hippocampal Bdnf expression compared to controls. Fecal microbiota transplantation or Bifidobacterium treatment restored the balance of fecal Clostridium spp. and normalized the level of Bdnf expression. These findings highlight the involvement of the gut–brain axis in the etiology of autism and propose possible interventions in a preclinical model of autism.

A high extracellular concentration of glutamate has the potential to induce autism. Presently no appropriate treatment is available to modulate glutamate-mediated injury; however, increased levels of glutamate transporters, which aid in glutamate clearance, may potentially limit and prevent glutamate excitotoxicity, and β-lactam antibiotics have been found to activate the expression of a glutamate transporter. To identify the beneficial role of β-lactam in autism, we used an animal model of autism by administrating propionic acid (PPA) to juvenile rats and then treated these animals with this antibiotic. Animals were divided into three groups: (1) an untreated control group, (2) a PPA-intoxicated group and (3) a PPA-intoxicated group treated with β-lactam. Selected parameters related to glutamate signaling were measured in brain homogenates of all groups. The obtained data demonstrated neurotoxicity of PPA through glutamate (GLU) excitotoxicity. Moreover, the rats treated with β-lactam exhibited higher glutamate transporter 1 (Glt-1) levels than the control group (p = 0.044). Furthermore, compared to the expression in the control group and the untreated autism model group, Glt-1 gene expression was much higher in brain samples from β-lactam-treated autism model rats (p < 0.056). Receiver operating characteristic (ROC) analyses revealed that measured parameters such as GLU and GLU/γ-aminobutyric acid, Glt-1, and GLU/Glt-1 were found to be predictive markers of the protective effect of β-lactam against GLU excitotoxicity. Immediate upregulation of Glt-1 may reduce extracellular GLU levels and thereby prevent damage to neurons. Therefore, increasing Glt-1 expression could be a potential approach to prevent excitotoxicity in the brain.

Autism, a neurodevelopmental disorder, is characterized by a high level of social interaction insufficiency, impairment in language, and repetitive behavior. The gut–brain axis (GBA) is considered a bidirectional communication pathway between the gut and the brain. Growing evidence shows that the GBA contributes to the etiology of autism. The phenotypic behaviors of autism and the gastrointestinal problems that are comorbidity in autism are associated with modified gut microbiota. Understanding the role of the gut microbiota in oxidative stress, heavy metal toxicity, glutamate excitotoxicity, impaired lipid metabolism, and neuroinflammation as pathological mechanisms of autism might support the use of nutritional and dietary interventions through the supplementation of probiotics for the amelioration of unhealthy perinatal and postnatal gut microbiota. This could lead to strategies to prevent, or at least control, autism through the correction of these pathological mechanisms. The aim of this chapter is to understand how autism is responsive to the composition of the gut microbiota, which can be targeted to treat this disorder.

The role of glutathione in autism spectrum disorder (ASD) is emerging as a major topic, due to its role in the maintenance of the intracellular redox balance. Several studies have implicated glutathione redox imbalance as a leading factor in ASD, and both ASD and many other neurodevelopmental disorders involve low levels of reduced glutathione (GSH), high levels of oxidized glutathione (GSSG), and abnormalities in the expressions of glutathione-related enzymes in the blood or brain. Glutathione metabolism, through its impact on redox environment or redox-independent mechanisms, interferes with multiple mechanisms involved in ASD pathogenesis. Glutathione-mediated regulation of glutamate receptors [e.g., N-methyl- d -aspartate (NMDA) receptor], as well as the role of glutamate as a substrate for glutathione synthesis, may be involved in the regulation of glutamate excitotoxicity. However, the interaction between glutathione and glutamate in the pathogenesis of brain diseases may vary from synergism to antagonism. Modulation of glutathione is also associated with regulation of redox-sensitive transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) and downstream signaling (proinflammatory cytokines and inducible enzymes), thus providing a significant impact on neuroinflammation. Mitochondrial dysfunction, as well as neuronal apoptosis, may also provide a significant link between glutathione metabolism and ASD. Furthermore, it has been recently highlighted that glutathione can affect and modulate DNA methylation and epigenetics. Review analysis including research studies meeting the required criteria for analysis showed statistically significant differences between the plasma GSH and GSSG levels as well as GSH:GSSG ratio in autistic patients compared with healthy individuals (P = 0.0145, P = 0.0150 and P = 0.0202, respectively). Therefore, the existing data provide a strong background on the role of the glutathione system in ASD pathogenesis. Future research is necessary to investigate the role of glutathione redox signaling in ASD, which could potentially also lead to promising therapeutics.

Metabolites of proper fatty acids modulate the inflammatory response and are essential for normal brain development; equally, abnormal fatty acid metabolism plays a critical role in the pathology of autism. Currently, dietary supplements are often used to improve the core symptoms of Autism spectrum disorder (ASD). The present study analyzed the effects of orally supplemented omega-3 (ω-3) and vitamin B12 on ameliorating oxidative stress and impaired lipid metabolism in a propionic acid (PPA)-induced rodent model of autism, together with their effect on the gut microbial composition, where great fluctuations in the bacterial number and strains were observed; interestingly, polyunsaturated fatty acids such as omega-3 induced higher growth of the gram-positive bacterium Staphylococcus aureus and decreased the survival rates of Clostridia sp. as well as other enteric bacterial strains. Thirty-five young male western albino rats were divided into five equal groups. The first group served as the control; the second group was given an oral neurotoxic dose of PPA (250 mg/kg body weight/day) for 3 days. The third group received an oral dose of ω-3 (200 mg/kg body weight/day) for 30 days after the 3-day PPA treatment. Group four was given an oral dose of vitamin B12 (16.7 mg/kg/day) for 30 days after PPA treatment. Finally, group five was given a combination of both ω-3 and vitamin B12 at the same dose for the same duration after PPA treatment. Biochemical parameters related to oxidative stress and impaired fatty acid metabolism were investigated in the brain homogenates of each group. The effects of the dietary supplements on the gut microbiota were also observed. The PPA-treated autistic model expressed significantly higher levels of lipid peroxides and 5-lipoxygenase (5-LOX) and significantly less glutathione (GSH), glutathione S-transferase (GST), and cyclooxygenase 2 (COX2) than the control group. However, a remarkable amelioration of most of the impaired markers was observed with oral supplementation with ω-3 and vitamin B12, either alone or in combination. Our results concluded that impairment at various steps of the lipid metabolic pathways may contribute to the development of autism; however, supplementation with ω-3 and vitamin B12 can result in a positive therapeutic effect.

Autism spectrum disorder (ASD) is a multifactorial disorder caused by an interaction between environmental risk factors and a genetic background. It is characterized by impairment in communication, social interaction, repetitive behavior, and sensory processing. The etiology of ASD is still not fully understood, and the role of neuroinflammation in autism behaviors needs to be further investigated. The aim of the present study was to test the possible association between prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), prostaglandin PGE2 EP2 receptors and nuclear kappa B (NF-κB) and the severity of cognitive disorders, social impairment, and sensory dysfunction. PGE2, COX-2, mPGES-1, PGE2-EP2 receptors and NF-κB as biochemical parameters related to neuroinflammation were determined in the plasma of 47 Saudi male patients with ASD, categorized as mild to moderate and severe as indicated by the Childhood Autism Rating Scale (CARS) or the Social Responsiveness Scale (SRS) or the Short Sensory Profile (SSP) and compared to 46 neurotypical controls. The data indicated that ASD patients have remarkably higher levels of the measured parameters compared to neurotypical controls, except for EP2 receptors that showed an opposite trend. While the measured parameter did not correlate with the severity of social and cognitive dysfunction, PGE2, COX-2, and mPGES-1 were remarkably associated with the dysfunction in sensory processing. NF-κB was significantly increased in relation to age. Based on the discussed data, the positive correlation between PGE2, COX-2, and mPGES-1 confirm the role of PGE2 pathway and neuroinflammation in the etiology of ASD, and the possibility of using PGE2, COX-2 and mPGES-1 as biomarkers of autism severity. NF-κB as inflammatory inducer showed an elevated level in plasma of ASD individuals. Receiver operating characteristic analysis together with predictiveness diagrams proved that the measured parameters could be used as predictive biomarkers of biochemical correlates to ASD.

Aim Autism is a heterogeneous neurological disorder that is characterized by impairments in communication and social interactions, repetitive behaviors, and sensory abnormalities. The etiology of autism remains unclear. Animal, genetic, and post-mortem studies suggest that an imbalance exists in the neuronal excitation and inhibition system in autism. The aim of this study was to determine whether alterations of the measured parameters in children with autism are significantly associated with the risk of a sensory dysfunction. Methods The glutamine synthetase (GS), kidney-type glutaminase (GLS1), and glutamic acid decarboxylase autoantibody levels were analyzed in 38 autistic children and 33 age- and sex-matched controls using enzyme-linked immunosorbent assays. Results The obtained data demonstrated significant alterations in glutamate and glutamine cycle enzymes, as represented by GS and GLS1, respectively. While the glutamic acid decarboxylase autoantibodies levels were remarkably increased, no significant difference was observed compared to the healthy control participants. Conclusion The obtained data indicate that GS and GLS1 are promising indicators of a neuronal excitation and inhibition system imbalance and that combined measured parameters are good predictive biomarkers of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental pathology characterized by an impairment in social interaction, communication difficulties, and repetitive behaviors. Glutamate signaling abnormalities are thought to be considered as major etiological mechanisms leading to ASD. The search for amino-acidic catabolytes related to glutamate in patients with different levels of ASD might help current research to clarify the mechanisms underlying glutamate signaling and its disorders, particularly in relation to ASD. In the present study, plasma levels of the amino acids and their derivatives glutamate, glutamine, and γ-aminobutyric acid (GABA), associated with their relative ratios, were evaluated using an enzyme-linked immunosorbent assay (ELISA) technique in 40 male children with ASD and in 38 age- and gender-matched neurotypical health controls. The Social Responsiveness Scale (SRS) was used to evaluate social cognition, and the Childhood Autism Rating Scale (CARS) was used to assess subjects' behaviors. Children with ASD exhibited a significant elevation of plasma GABA and glutamate/glutamine ratio, as well as significantly lower levels of plasma glutamine and glutamate/GABA ratios compared to controls. No significant correlation was found between glutamate levels and the severity of autism, measured by CARS and SRS. In receiver operating characteristic (ROC) curve analysis, the area under the curve for GABA compared to other parameters was close to one, indicating its potential use as a biomarker. Glutamine appeared as the best predictive prognostic markers in the present study. The results of the present study indicate a disturbed balance between GABAergic and glutamatergic neurotransmission in ASD. The study also indicates that an increased plasma level of GABA can be potentially used as an early diagnostic biomarker for ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is behaviorally defined by social and communication impairments and restricted interests and repetitive behaviors. There is currently no biomarkers that can help in the diagnosis. Several studies suggest that mitochondrial dysfunction is commonly involved in ASD pathophysiology, but standard mitochondrial biomarkers are thought to be very variable. In the present study we examine a wide variety of plasma biomarkers of mitochondrial metabolism and the related abnormalities of oxidative stress and apoptosis in 41 ASD patients assessed for ASD severity using the Childhood Autism Rating Scales and 41 non-related age and sex matched healthy controls. Our findings confirm previous studies indicating abnormal mitochondrial and related biomarkers in children with ASD including pyruvate, creatine kinase, Complex 1, Glutathione S-Transferase, glutathione and Caspase 7. As a novel finding, we report that lactate dehydrogenase is abnormal in children with ASD. We also identified that only the most severe children demonstrated abnormalities in Complex 1 activity and Glutathione S-Transferase. Additionally, we find that several biomarkers could be candidates for differentiating children with ASD and typically developing children, including Caspase 7, gluthatione and Glutathione S-Transferase by themselves and lactate dehydrogenase and Complex I when added to other biomarkers in combination. Caspase 7 was the most discriminating biomarker between ASD patients and healthy controls suggesting its potential use as diagnostic marker for the early recognition of ASD pathophysiology. This study confirms that several mitochondrial biomarkers are abnormal in children with ASD and suggest that certain mitochondrial biomarkers can differentiate between ASD and typically developing children, making them possibly useful as a tool to diagnosis ASD and identify ASD subgroups.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can cause significant social, communication and behavioral challenges. Environmental contribution to ASD is due in large part to the sensitivity of the developing brain to external exposures such as lead (Pb), and mercury (Hg) as toxic heavy metals or due to a poor detoxification ability as the phenotype of this disorder. Selenium (Se) as an antioxidant element that counteracts the neurotoxicity of Hg, and Pb, presumably through the formation of nontoxic complexes. In the present study, Pb, Hg, and Se were measured in red blood cells (RBCs) of 35 children with ASD and 30 age- and gender-matched healthy control children using atomic absorption spectrometry. Receiver Operating Characteristics (ROC) analysis of the obtained data was performed to measure the predictive value of their absolute and relative concentrations. The obtained data demonstrates a significant elevation of Hg and Pb together with a significant decrease in the Se levels in RBCs of patients with ASD when compared to the healthy controls. The ratios of Se to both Pb and Hg were remarkably altered, being indicative of heavy metal neurotoxicity in patients with ASD. In conclusion, the present study indicates the importance of Se for prevention and/or therapy of heavy metal neurotoxicity.

BackgroundNeuroinflammation plays a major role in the pathogenesis of autism because the cytokine levels are typically disturbed in the brain in autistic patients. Prebiotics-rich diet maintains the healthy gut microbiota and hence can regulate the neuroinflammation indirectly. The study aimed to investigate the role of bee pollen and propolis in ameliorating neuroinflammation, including cytokine levels, in an animal model of autism.MethodsHamsters were classified as four groups: Group I, control; Group II, autistic model/animals treated with 250 mg propionic acid (PPA)/kg body weight (BW)/day for 3 days; Group III, animals treated with bee pollen at a dose of 250 mg/kg BW/day for 4 weeks; and Group IV, animals treated with propolis at a dose of 250 mg/kg BW/day for 4 weeks. Neuroinflammatory responses were evaluated using the levels of interferon γ (IFN-γ), interleukin 1 alpha (IL-1α), IL-6, IL-10, IL-12 (p70), vascular endothelial growth factor (VEGF), and tumor necrosis factor α (TNFα).ResultsSignificant decrease of IL-10 (PPPPPPPPConclusionsOur findings indicate that both bee pollen and propolis protect against neuroinflammation in the rodent model of autism. However, further studies are needed to investigate the clinical benefits of prebiotics-rich diet in neurodevelopmental disorders, such as autism.

Background Autism spectrum disorder (ASD) is a complex group of heterogeneous neurodevelopmental disorders the prevalence of which has been in the rise in the past decade. In an attempt to better target the basic causes of ASD for diagnosis and treatment, efforts to identify reliable biomarkers related to the body’s metabolism are increasing. Despite an increase in identifying biomarkers in ASD, there are none so far with enough evidence to be used in routine clinical examination, unless medical illness is suspected. Promising biomarkers include those of mitochondrial dysfunction, oxidative stress, energy metabolism, and apoptosis. Methods and participants Sodium (Na+), Potassium (K+), glutathione (GSH), glutathione-s-transferase (GST), Creatine kinase (CK), lactate dehydrogenase (LDH), Coenzyme Q10, and melatonin (MLTN) were evaluated in 13 participants with ASD and 24 age-matched healthy controls. Additionally, five ratios, which include Na+/K+, GSH:GST, CK:Cas7, CoQ10: Cas 7, and Cas7:MLTN, were tested to measure their predictive values in discriminating between autistic individuals and controls. These markers, either in absolute values, as five ratios, or combined (9 markers + 5 ratios) were subjected to a principal component analysis and multidimensional scaling (MDS), and hierarchical clustering, which are helpful statistical tools in the field of biomarkers. Results Our data demonstrated that both PCA and MDS analysis were effective in separating autistic from control subjects completely. This was also confirmed through the use of hierarchical clustering, which showed complete separation of the autistic and control groups based on nine biomarkers, five biomarker ratios, or a combined profile. Excellent predictive value of the measured profile was obtained using the receiver operating characteristics analysis, which showed an area under the curve of 1. Conclusion The availability of an improved predictive profile, represented by nine biomarkers plus the five ratios, inter-related different etiological mechanisms in ASD and would be valuable in providing greater recognition of the altered biological pathways in ASD. Our predictive profile could be used for the diagnosis and intervention of ASD.

Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder characterized by reduced social communication as well as repetitive behaviors. Many studies have proved that defective synapses in ASD influence how neurons in the brain connect and communicate with each other. Synaptopathies arise from alterations that affecting the integrity and/or functionality of synapses and can contribute to synaptic pathologies. This study investigated the GABA levels in plasma being an inhibitory neurotransmitter, caspase 3 and 9 as pro-apoptotic proteins in 20 ASD children and 20 neurotypical controls using the ELISA technique. Analysis of receiver-operating characteristic (ROC) of the data that was obtained to evaluate the diagnostic value of the aforementioned evaluated biomarkers. Pearson's correlations and multiple regressions between the measured variables were also done. While GABA level was reduced in ASD patients, levels of caspases 3 and 9 were significantly higher when compared to neurotypical control participants. ROC and predictiveness curves showed that caspases 3, caspases 9, and GABA might be utilized as predictive markers in autism diagnosis. The present study indicates that the presence of GABAergic dysfunction promotes apoptosis in Egyptian ASD children. The obtained GABA synaptopathies and their connection with apoptosis can both relate to neuronal excitation, and imbalance of the inhibition system, which can be used as reliable predictive biomarkers for ASD.

Neurotrophic factors, including the glial cell line–derived neurotrophic factor (GDNF), are of importance for synaptic plasticity regulation, intended as the synapses’ ability to strengthen or weaken their responses to differences in neuronal activity. Such plasticity is essential for sensory processing, which has been shown to be impaired in autism spectrum disorder (ASD). This study is the first to investigate the impact of auditory integration therapy (AIT) of sensory processing abnormalities in autism on plasma GDNF levels. Fifteen ASD children, aged between 5 and 12 years, were enrolled and underwent the present research study. AIT was performed throughout 10 days with a 30-min session twice a day. Before and after AIT, Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Short Sensory Profile (SSP) scores were calculated, and plasma GDNF levels were assayed by an EIA test. A substantial decline in autistic behavior was observed after AIT in the scaling parameters used. Median plasma GDNF level was 52.142 pg/ml before AIT. This level greatly increased immediately after AIT to 242.05 pg/ml (P

To identify neuroinflammatory biomarkers in patients with various severity of autism spectrum disorder (ASD) increases the insight about the pathogenesis and pathophysiology of this neurodevelopmental disorder. The aim of the present study was to analyze the levels in plasma of TGFβ2, Heat shock protein 70 (HSP70), and hematopoietic prostaglandin D2 synthase (H-PGDS) in Saudi ASD children and healthy age-matched neurotypical controls. Also, it was in the present study examined the correlation among these neuroinflammatory biomarkers and the sensory deficit exhibited by the ASD children. Blood samples from 38 Saudi children with ASD and 32 age-matched neurotypical controls were withdrawn after an overnight fast. For the blood taking 3 mL EDTA containing blood collection tubes was used. The samples were centrifuged for 20 min (4 °C; 3000×g) directly after the blood sampling. The harvested plasma was used for in vitro quantification of TGF-β2, HSP70, and H-PGDS by using the sandwich enzyme immunoassay. Receiver operating characteristic (ROC) analysis and predictiveness curves showed that each of TGF-β2, HSP70 or H-PGDS alone could not be used as a predictive neuroinflammatory biomarker for ASD. However, when TGF-β2 and HSP70 were combined in one ROC curve, the AUC was increased to an appreciable value that makes them together robust predictors of variation between the ASD and neurotypical control groups. Overall, it was in the present study found significant differences for TGF-β2 and HSP70 when the ASD and neurotypical control groups were compared, independently of the sensory deficit level. In conclusion, the present study highlights the usefulness of TGF-β2, HSP70, and H-PGDS as diagnostic tools to differentiate between ASD and neurotypical control children, but not among subgroups of ASD children exhibiting different severity levels of sensory dysfunction. The presented data also suggest the effectiveness of ROC as a powerful statistical tool, which precisely can measure a combined effect of neuroinflammatory biomarkers intended for diagnostic purposes.

Background Abnormal phospholipid metabolism is a major component of many neurodevelopmental disorders including autism. Oral administration of propionic acid (PPA) can produce behavioral abnormalities and biochemical features in rodents similar to those observed in autism and can thus be used as a model to understand impaired brain fatty acid metabolism in autism. Methods The present study was designed to understand alterations in phospholipid metabolism in the brain of a rodent model of autism and to explore omega-3 and vitamin B12 as remedies. Five groups of rats were selected: Group 1 was the control. Group 2 was the rodent model of autism treated with a neurotoxic dose of PPA. Group 3 was given vitamin B12 cobalamin (16.7 mg/kg/day) for 30 days after PPA treatment. Group 4 was given pharmaceutical grade Omega-3 (200 mg cholesterol free-DHA/kg body weight/day), a product of Madre lab, Germany, for 30 days after PPA treatment for 3 days. Group 5 was given a combined dose of ω-3 + Vitamin B12 for the same duration post-PPA treatment. Phospholipid levels and Phospholipase A2 were measured in the brain homogenates of all the groups. ELISA and western blotting were used to detect the cPLA2 protein level. Results A significant decrease in phospholipid levels and a significant increase in cPLA2 were found in brain tissue of PPA-treated rats; however, both ω-3 and vitamin B12 were efficient in ameliorating the neurotoxic effect of PPA. Conclusion Both ω-3 and vitamin B12 may play a role in ameliorating impaired phospholipid metabolism in autism; however, proper clinical trials are needed.

The gut microbiota is a complex ecosystem that makes a great contribution toward the health of its host. One of the recent findings is the importance of the gut–brain axis as a bidirectional pathway through which the microbiota in the gut has potential influence on behavior and mental states. Gastrointestinal disorders are commonly reported in autistic patients, which may be due to altered composition of the gut microbiota, promoting the overgrowth of pathogenic bacteria. This can support the role of dysbiosis in the development of persistent autistic features. It is well known that diet plays an important role in the etiology of autism. Understanding the mechanism of diet–microbiota interaction may help to avoid the increasing prevalence of this disorder. Strategies to decrease the overgrowth of pathogenic bacteria and thus improve the composition of gut microbiota of autistic patients through dietary intervention may help to ameliorate gastrointestinal disorders commonly seen in autistic patients.

Autism spectrum disorder (ASD) is a neuro-behavioral syndrome with a broad spectrum of different mechanisms and etiologies that are caused by abnormal brain development. To date, no highly reliable and effective diagnostic biomarker to assess ASD is available so far. The present study investigated the predictivity potential of some suggested markers in ASD diagnosis focusing onto the relative ratios of several plasma biomarkers of electron transport chain function, and mitochondrial metabolism in 41 patients with ASD evaluated for behavior deficits measured using Childhood Autism Rating Scales (CARS). The control matched for further 41 healthy subjects. The relation of these relative ratios to ASD severity was also examined, as well as their ability to distinguish ASD children from neurotypical children. All predictive ratios were found to be markedly altered and correlated in ASD patients. However, no ratio was connected with autism severity. Interestingly, MRCC-I/caspase-7, GSH/GST, and MRCC-I/COQ10 were the most distinctive relative ratios between neurotypical controls and ASD patients and may thereby be useful biomarkers for early diagnosis of ASD. Overall, this investigation proves that relative ratios of numerous mitochondrial biomarkers might be predictive and efficient to differentiate between neurotypical children and ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder afflicting about one in every 68 children. It is behaviorally diagnosed based on a triad of symptoms, including impairment in communication, impairment in sociability and abnormal and stereotypic behavior. The subjectivity of behavioral diagnosis urges the need for clinical biomarker tests to improve and complement ASD diagnosis and treatment. Over the past two decades, researchers garnered a broad range of biomarkers associated with ASD and often correlating with the severity of ASD, which includes metabolic and genetic biomarkers or neuroimaging abnormalities. Metabolic biomarkers are either involved in key pathways such as a trans-sulfuration pathway or produced due to the derangement of these pathways in the case of oxidative stress. Recent studies reported several genetic abnormalities related to ASD, encompassing various mechanisms, from copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) to chromosomal anomalies. However, it is still premature to consider these genetic variants as true biomarkers for ASD, due to their low reproducibility and regional-specific nature. Herein, we comprehensively review state of the art about major biomarkers reported in ASD and the association of some biomarkers with ASD symptoms and severity. It is important to establish those biomarkers to be able to help in the diagnosis and to optimize the treatment of ASD.

Autism spectrum disorders are complex developmental disorders with increasing incidence and poorly understood etiology. Imbalance of amino acids profoundly influences brain function, and is thought to be one of the key players in the pathophysiology of autism. This study aimed to measure the plasma amino acid profiles of 20 Egyptian and 20 Saudi autistic patients in comparison to matching healthy controls to clarify the role of impaired amino acid concentrations in the etiology of autism. Plasma amino acids profiles were measured using high performance liquid chromatography. While plasma levels of glutamic, aspartic, and glycine recorded the most significant percentage elevated amino acids, glutamine, asparagine, arginine, tyrosine and isoleucine recorded the most remarkable percentage decrease in autistic patients from both populations compared to controls. Among the calculated relative values, only acidic/basic, and glutamate/glutamine ratios were significantly higher in autistics compared to controls. Non-essential/essential and glucogenic/ketogenic ratios were unaltered in autistics compared to controls. Increased plasma glutamate/glutamine ratio, together with increased glycine, arginine, aspartate, aspargine levels, and acidic/basic amino acid ratio can serve as a predictive tools for the early detection of autism. These findings suggest that glu- tamatergic abnormalities in the brain may be associated with the pathobiology of autism.

Autism spectrum disorder (ASD) affects about 1% of the world’s population. Vitamin D is thought to be essential for normal brain development and modulation of the immune system. Worldwide about 1 billion people are affected by vitamin D deficiency. High-sensitivity C-reactive protein (hs-CRP), cytochrome P450 2E1 (CYP2E1) and 8-hydroxy-2′-deoxyguanosine (8-OH-dG) are biomarkers related to inflammation and oxidative stress. In the present study, these biomarkers were together with serum 25-hydroxyvitamin D (25(OH)D3) analyzed in 28 (mean age seven years) Saudi male patients with ASD. The study was conducted to determine if there is any relationship between vitamin D levels, the tested biomarkers and the presence and severity of ASD. The hope was to identify if these biomarkers may be useful for early ASD diagnosis. The Childhood Autism Rating Scale (CARS) and the Social Responsiveness Scale (SRS) were used to measure autism severity. The results of the ASD children were compared with 27 age and gender-matched neurotypical controls. The data indicated that Saudi patients with ASD have significantly lower plasma levels of 25(OH)D3 than neurotypical controls (38 ng/ml compared to 56 ng/ml, respectively; [P = 0.001]). Surprisingly, the levels of CYP2E1 were lower in the children with ASD than the neurotypical controls (0.48 ± 0.08 vs. 69 ± 0.07 ng/ml, respectively; P = 0.001). The ASD children also had significantly higher levels of hs-CRP (0.79 ± 0.09 vs. 0.59 ± 0.09 ng/ml, respectively; P = 0.001) and 8-OH-dG (8.17 ± 1.04 vs. 4.13 ± 1.01 ng/ml, respectively; P = 0.001, compared to neurotypical age and gender-matched controls. The values for hs-CRP and 8-OH-dG did not correlate [P

Autism spectrum disorder (ASD) as a neurodevelopmental disorder is characterized by impairments in social interaction, communication, and restricted, repetitive behavior. Several and reproducible studies have suggested that oxidative stress may represent one of the primary etiological mechanism of ASD that can be targeted for therapeutic intervention. In the present study, multiple regression and combined receiver operating characteristic (ROC) analysis were used to search for a relationship between impaired energy and oxidative metabolic pathways in the etiology of ASD and to find the linear combination that maximizes the partial area under a ROC curve for a pre-identified set of markers related to energy metabolism and oxidative stress. Thirty children with ASD and 30 age and gender matched controls were enrolled in the study. Using either spectrophotometric or ELISA-colorimetric assay, levels of lipid peroxides, vitamin E, vitamin C, glutathione (GSH)/glutathione disulfide (GSSG) together with the enzymatic activity of catalase, plasma glutathione peroxidase (GPx), and blood superoxide dismutase (SOD), were measured in peripheral blood samples, as biomarkers related to oxidative stress. Creatine kinase, ectonucleotidases (ADPase and ATPase) Na+/K+ (ATPase), lactate, inorganic phosphate, and levels of adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP) together with adenylate energy charge, were also measured as markers of impaired energy metabolism. Statistical analysis using ROC curves, multiple and logistic regression were performed. A remarkable increase in the area under the curve for most of the combined markers, representing both energy impaired metabolism or oxidative stress, was observed by using combined ROC analyses. Moreover, higher specificity and sensitivity of the combined markers were also reported. The present study indicated that the measurement of the predictive value of selected biomarkers related to energy metabolism and oxidative stress in children with ASD using ROC analysis should lead to the better identification of the etiological mechanism of ASD associated with metabolism and diet. Agents with activity against the impaired metabolic pathway associated with ASD including the metabolic defects and involved enzymes hold a promise as a novel therapy for ASD.

Background Autism is neurodevelopmental disorder that is characterized by developmental, behavioral, social and sensory abnormalities. Researchers have focused in last years in immunological alteration and inflammation as a hot subject in autism field. This work aims to study the alteration in phospholipids (PE, PS, and PC) together with the change in cPLA2 concentration as the main phospholipid hydrolytic enzyme in autistic patients compared to control. It was also extended to find a correlation between these biomarkers and severity of autism measured as childhood autism rating scale (CARS), Social responsiveness scale (SRS), and Short sensory profile (SSP). Methods Phospholipids (PE, PS, PC) and cPLA2 as biochemical parameters were determined in the plasma of 48 Saudi autistic male patients, categorized as mild-moderate and severe as indicated by their Childhood Autism Rating Scale (CARS), social responsiveness scale (SRS) and short sensory profile (SSP) and compared to 40 age- and gender-matched control samples. Results The reported data demonstrate significantly lower levels of PE, PS, and PC together with a significant increase in cPLA2. While association between severity of autism and impaired phospholipid concentration was completely lacked, an association between cPLA2 and impaired sensory processing was observed. Conclusions The impaired phospholipid level and remarkable increased in cPLA2 concentration asserted their roles in the etiology of autism. Receiver operating characteristic analysis together with predictiveness diagrams proved that the measured parameters could be used as predictive biomarkers of clinical symptoms and provide significant guidance for future therapeutic strategy to re-establish physiological homeostasis.

Background Autism is a neurodevelopmental disorder that displays significant heterogeneity. Comparison of subgroups within autism, and analyses of selected biomarkers as measure of the variation of the severity of autistic features such as cognitive dysfunction, social interaction impairment, and sensory abnormalities might help in understanding the pathophysiology of autism. Methods and Participants In this study, two sets of biomarkers were selected. The first included 7, while the second included 6 biomarkers. For set 1, data were collected from 35 autistic and 38 healthy control participants, while for set 2, data were collected from 29 out of the same 35 autistic and 16 additional healthy subjects. These markers were subjected to a principal components analysis using either covariance or correlation matrices. Moreover, libraries composed of participants categorized into units were constructed. The biomarkers used include, PE (phosphatidyl ethanolamine), PS (phosphatidyl serine), PC (phosphatidyl choline), MAP2K1 (Dual specificity mitogen-activated protein kinase kinase 1), IL-10 (interleukin-10), IL-12, NFκB (nuclear factor-κappa B); PGE2 (prostaglandin E2), PGE2-EP2, mPGES-1 (microsomal prostaglandin synthase E-1), cPLA2 (cytosolic phospholipase A2), 8-isoprostane, and COX-2 (cyclo-oxygenase-2). Results While none of the studied markers correlated with CARS and SRS as measure of cognitive and social impairments, six markers significantly correlated with sensory profiles of autistic patients. Multiple regression analysis identifies a combination of PGES, mPGES-1, and PE as best predictors of the degree of sensory profile impairment. Library identification resulted in 100% correct assignments of both autistic and control participants based on either set 1 or 2 biomarkers together with a satisfactory rate of assignments in case of sensory profile impairment using different sets of biomarkers. Conclusion The two selected sets of biomarkers were effective to separate autistic from healthy control subjects, demonstarting the possibility to accurately predict the severity of autism using the selected biomarkers. The effectiveness of the identified libraries lied in the fact that they were helpful in correctly assigning the study population as control or autistic patients and in classifying autistic patients with different degree of sensory profile impairment.

Objectives Energy metabolism is usually manipulated in many neurodegenerative diseases. Autism is considered a definable systemic disorder resulting in a number of diverse factors that may affect the brain development and functions both pre and post natal. The increased prevalence of autism will have enormous future public implications and has stimulated intense research into potential etiologic factors. This study aims to establish a connection between autism and the deterioration accompanied it, especially in the brain cognitive areas through a postulation of energy manipulation. Materials and methods The biochemical changes in activities of enzymes and pathways that participate in the production of ATP as the most important high-energy compound needed by the human brain were measured in Saudi autistic children. Na + /K + ATPase, ectonucleotidases (NTPDases) (ADPase and ATPase) and creatine kinase (CK), were assessed in plasma of 30 Saudi autistic patients and compared to 30 age-matching control samples. In addition, adenosine mono, di and trinucleotides (ATP, ADP, and AMP) were measured calorimetrically in the red blood cells of both groups and the adenylate energy charge (AEC) was calculated. Moreover, lactate concentration in plasma of both groups was monitored. Results The obtained data recorded 148.77% and 72.35% higher activities of Na + /K + ATPase and CK respectively in autistic patients which prove the impairment of energy metabolism in these children compared to age and sex matching healthy controls. While ADPase was significantly higher in autistic patients, ATPase were non-significantly elevated compared to control. In spite of the significant increase of Na + /K + ATPase activity in autistic patients, there was no significant difference in the levels of ATP, ADP, and AMP in both groups and the calculated AEC values were 0.814 ± 0.094 and 0.806 ± 0.081 for autistic and control groups respectively. The unchanged AEC value in autistic patients was easily correlated with the induced activity of CK and ADPase as two enzymes playing a critical role in the stabilization of AEC. Lactate as an important energy metabolite for the brain was significantly higher in autistic patients compared to control showing about 40% increase. Conclusion The present study confirmed the impairment of energy metabolism in Saudi autistic patients which could be correlated to the oxidative stress previously recorded in the same investigated samples. The identification of biochemical markers related to autism would be advantageous for earlier clinical diagnosis and intervention.

Background It is now well documented that postnatal exposure to certain chemicals has been reported to increase the risk of autism spectrum disorder. Propionic acid (PA), as a metabolic product of gut microbiotaandas a commonly used food additive, has been reported to mediate the effects of autism. Results from animal studies may help to identify environmental neurotoxic agents and drugs that can ameliorate neurotoxicity and may thereby aid in the treatment of autism. The present study investigated the ameliorative effects of natural bee pollen against acute and sub-acute brain intoxication induced by (PA) in rats. Methods Twenty-four young male Western Albino ratswere enrolled in the present study. They were classified into four equal groups, eachwith6 rats. The control group received only phosphate buffered saline; the oral buffered PA-treated groups (II and III) received a neurotoxic dose of 750 mg/kg body weight divided in 3 dose of 250 mg/kg body weight/day serving asthe acute group and 750 mg/kg body weight divided in 10 equal dose of 75 mg/kg body weight/day as the sub-acute group. The fourth group received 50 mg bee pollen for 30 days after PA-acute intoxication. Results The obtained data showed that the PA-treated groups demonstrated multiple signs of brain toxicity, as indicated by a depletion of serotonin (5HT), dopamine and nor-adrenaline, together withan increase in IFN-γ and caspase 3. Bee pollen was effective in ameliorating the neurotoxic effect of PA. All measured parameters demonstrated minimal alteration in comparison with thecontrol animal than did those of acute and sub-acute PA-treated animals. Conclusions In conclusion, bee pollen demonstrates anti-inflammatory and anti-apoptotic effects while ameliorating the impaired neurochemistry of PA-intoxicated rats.

Hypothesis A healthy gut with normal intestinal microflora is completely disrupted by oral antibiotics. The byproducts of harmful gut bacteria can interfere with brain development and may contribute to autism. Strategies to improve the gut microflora profile through dietary modification may help to alleviate gut disorders in autistic patients. Method Sixty young male western albino rats were divided into six equal groups. The first group served as the control; the second group was given an oral neurotoxic dose of propionic (PPA) (250 mg/kg body weight/day) for three days. The third group received an orogastric dose of ampicillin (50 mg/kg for three weeks) with a standard diet. Groups 4, 5 and 6 were given an orogastric dose of ampicillin and fed high-carbohydrate, high-protein and high-lipid diets, respectively, for 10 weeks. Biochemical parameters related to oxidative stress were investigated in brain homogenates from each group. Result The microbiology results revealed descriptive changes in the fecal microbiota of rats treated with ampicillin either alone or with the three dietary regimens. The results of PPA acid and ampicillin treatment showed significant increases in lipid peroxidation and catalase with decreases in glutathione and potassium compared with levels in the control group. A protein-rich diet was effective at restoring the glutathione level, while the carbohydrate-rich diet recovered lipid peroxidation and catalase activity. In addition, the three dietary regimens significantly increase the potassium level in the brain tissue of the test animals. Lactate dehydrogenase was remarkably elevated in all groups relative to the control. No outstanding effects were observed in glutathione S-transferase and creatine kinase. Conclusion The changes observed in the measured parameters reflect the neurotoxic effects of PPA and ampicillin. Lipid peroxide and catalase activity and the levels of glutathione and potassium are satisfactory biomarkers of PPA and ampicillin neurotoxicity. Based on the effects of the three dietary regimens, a balanced diet can protect against PPA or ampicillin-induced neurotoxicity that might induce autistic traits. These outcomes will help efforts directed at controlling the prevalence of autism, a disorder that has recently been associated with PPA neurotoxicity.

Background Autism spectrum disorder (ASD) is characterized by three core behavioral domains: social deficits, impaired communication, and repetitive behaviors. Glutamatergic/GABAergic imbalance has been found in various preclinical models of ASD. Additionally, autoimmunity immune dysfunction, and neuroinflammation are also considered as etiological mechanisms of this disorder. This study aimed to elucidate the relationship between glutamatergic/ GABAergic imbalance and neuroinflammation as two recently-discovered autism-related etiological mechanisms. Methods Twenty autistic patients aged 3 to 15 years and 19 age- and gender-matched healthy controls were included in this study. The plasma levels of glutamate, GABA and glutamate/GABA ratio as markers of excitotoxicity together with TNF-α, IL-6, IFN-γ and IFI16 as markers of neuroinflammation were determined in both groups. Results Autistic patients exhibited glutamate excitotoxicity based on a much higher glutamate concentration in the autistic patients than in the control subjects. Unexpectedly higher GABA and lower glutamate/GABA levels were recorded in autistic patients compared to control subjects. TNF-α and IL-6 were significantly lower, whereas IFN-γ and IFI16 were remarkably higher in the autistic patients than in the control subjects. Conclusion Multiple regression analysis revealed associations between reduced GABA level, neuroinflammation and glutamate excitotoxicity. This study indicates that autism is a developmental synaptic disorder showing imbalance in GABAergic and glutamatergic synapses as a consequence of neuroinflammation.

Background Reducing exposure to toxic environmental agents is a critical area of intervention. Prenatal or postnatal exposure to certain chemicals has been documented to increase the risk of autism spectrum disorder. Propionic acid (PA) found in some foods and formed as a metabolic product of gut microbiota has been reported to mediate the effects of autism. Results from animal studies may help to identify environmental contaminants and drugs that produce or prevent neurotoxicity, and may thereby aid in the treatment of neurodevelopmental disorders such as autism. The present study investigated the protective and/or therapeutic effects of vitamin D against brain intoxication induced by propionic acid (PPA) in rats. Methods Twenty-eight young male Western Albino rats were enrolled in the present study. They were grouped into four equal groups of 7. The control group received only phosphate buffered saline; the oral buffered PPA-treated group received a neurotoxic dose of 250 mg/kg body weight/day for 3 days; and the Vitamin D-protected group received 1000 IU/kg/day of alpha, 25-dihydroxyvitamin D (3) (1, 25-VD) for two weeks, after which the rats were injected with PPA 250 mg/Kg body weight/day for 3 days. The fourth group received PPA 250 mg/Kg body weight/day for 3 days followed by alpha, 25-dihydroxyvitamin D (3) (1, 25-VD) for two weeks (Vitamin D therapeutic effect). Vitamin D and calcium were measured in the plasma of the four studied groups. Serotonin, interferon gamma (IFN-γ), glutathione-s-transferase activity and DNA double helix breaks were assayed in the brain tissue of the rats for all groups. Results The obtained data showed that the PPA-treated group demonstrated higher plasma vitamin D levels compared to the control rats, together with multiple signs of brain toxicity, as indicated by a depletion of serotonin (5HT), an increase in IFN-γ and inhibition of glutathione-s-transferase activity as three biomarkers of brain dysfunction. Additionally, Comet DNA assays showed remarkably higher tail length, tail DNA % damage and tail moment as a neurotoxic effect of PPA. Conclusions Vitamin D showed a greater protective than therapeutic effect on PPA-induced neurotoxicity in rats, as there was a remarkable amelioration of the impaired biochemically measured parameters representing neurochemical, inflammation, and detoxification processes.

Background Fatty acids are essential dietary nutrients, and one of their important roles is providing polyunsaturated fatty acids (PUFAs) for the growth and function of nervous tissue. Short chain fatty acids (SCFAs) are a group of compounds derived from the host microbiome that were recently linked to effects on the gut, the brain, and behavior. They are therefore linked to neurodevelopmental disorders such as autism. Reduced levels of PUFAs are associated with impairments in cognitive and behavioral performance, which are particularly important during brain development. Recent studies suggest that omega -3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are involved in neurogenesis, neurotransmission, and protection from oxidative stress. Omega-3 PUFAs mediate some of these effects by antagonizing Omega-6 PUFA (arachidonic acid, AA)-induced proinflammatory prostaglandin E2; (PGE2) formation. Methods In this work, the absolute and relative concentrations of propionic (PPA), butyric and acetic acids, as well as PUFAs and their precursors (α-Linolenic and linoleic), were measured in the brain tissue of PPA-neurointoxicated rat pups (receiving 250 mg PPA/Kg body weight for 3 consecutive days) as a rodent model with persistent autistic features compared with healthy controls. Results The data revealed remarkably lower levels of omega6/omega3, α-Linolenic/Linoleic, α-Linolenic/EPA, α-Linolenic/DHA, EPA/DHA, and AA/Linoleic acid ratios in PPA-intoxicated rats. The role of these impaired ratios is discussed in relation to the activity of desaturases and elongases, which are the two enzymatic groups involved in the synthesis of PUFAs from their precursors. The relationship between the abnormal relative concentrations of the studied fatty acids and oxidative stress, neurotransmission, and neuroinflammation is also discussed in detail. Conclusions This study demonstrates that fatty acid ratios are useful for understanding the mechanism of PPA neurotoxicity in a rodent model of autism. Therefore, it is possible to use these ratios for predictions in patients with this disorder.

Background Autism Spectrum Disorders (ASD) is a syndrome with a number of etiologies and different mechanisms that lead to abnormal development. The identification of autism biomarkers in patients with different degrees of clinical presentation (i.e., mild, moderate and severe) will give greater insight into the pathogenesis of this disease and will enable effective early diagnostic strategies and treatments for this disorder. Methods In this study, the concentration of two toxic heavy metals, lead (Pb) and mercury (Hg), were measured in red blood cells, while glutathione-s-transferase (GST) and vitamin E, as enzymatic and non-enzymatic antioxidants, respectively, were measured in the plasma of subgroups of autistic patients with different Social Responsiveness Scale (SRS) and Childhood Autism Rating Scale (CARS) scores. The results were compared to age- and gender-matched healthy controls. Results The obtained data showed that the patients with autism spectrum disorder had significantly higher Pb and Hg levels and lower GST activity and vitamin E concentrations compared with the controls. The levels of heavy metals (Hg and Pb), GST and vitamin E were correlated with the severity of the social and cognitive impairment measures (SRS and CARS). Receiver Operating Characteristics (ROC) analysis and predictiveness curves indicated that the four parameters show satisfactory sensitivity, very high specificity and excellent predictiveness. Multiple regression analyses confirmed that higher levels of Hg and Pb, together with lower levels of GST and vitamin E, can be used to predict social and cognitive impairment in patients with autism spectrum disorders. Conclusion This study confirms earlier studies that implicate toxic metal accumulation as a consequence of impaired detoxification in autism and provides insight into the etiological mechanism of autism.