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In this study, the levels of concentration of carboxylic acids (benzoic acid, p-hydroxybenzoic acid, p-hydroxyphenylacetic acid, and hippuric acid) in the urine of autistic children were investigated and compared. The increased excretion of carboxylic acids is related to excessive bacterial activity in the gut, called bacterial overgrowth, which has been related to autism spectrum disorder (ASD) as an impairment in the gut-brain axis. The investigation was based on the analysis of urine samples obtained from 120 ASD children. To identify and quantify urinary carboxylic acids (UCAs), we applied gas chromatography coupled with mass spectrometry (GC-MS). Additionally, we checked the influence of probiotic supplementation, gender, body mass index (BMI) value and age of children on the level of different selected compounds. Most of the obtained results were found within reference ranges. In some cases, the levels of benzoic acid, p-hydroxybenzoic acid, and p-hydroxyphenylacetic acid were particularly elevated. Statistically significant differences were observed in supplementation with probiotics and the level of p-hydroxyphenylacetic acid (p=0.036). The obtained results may indicate disturbances in the intestinal flora in some autistic patients and suggest that supplements may have an influence on the levels of carboxylic acids in urine. Due to the small population of children taking the supplement, further study are needed.

Probiotics, live microorganisms with potential health benefits, have gained significant research interest for their impact on gut microbiota and neuroprotection. This paper highlights insights from two collaborative studies focusing on probiotics' multifaceted role in addressing autism spectrum disorder (ASD) and mitigating glutamate excitotoxicity. In the first study (Meguid et al., 2022), probiotic supplementation in children with ASD increased Bifidobacterium and Lactobacillus colony counts, reduced anxiety, and improved sleep, suggesting a therapeutic potential for ASD symptoms. The second study (El-Ansary et al., 2018) explored neuroprotective effects, revealing probiotics' ability to restore γ-aminobutyric acid (GABA) and magnesium (Mg2+) levels, mitigating glutamate excitotoxicity. Safety assessments indicated well-tolerated probiotic use in both studies. Future research should focus on personalized probiotic interventions and mechanistic studies to unlock probiotics' full potential in neurodevelopment and neuroprotection. [ABSTRACT FROM AUTHOR]

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. Image 1 • Glutathione (GSH) redox imbalance is a key factor in autism spectrum disorder (ASD). • GSH metabolism interferes with multiple mechanisms involved in ASD pathogenesis. • In ASD, plasma GSH and GSSG levels and their ratio is different from neurotypical controls. [ABSTRACT FROM AUTHOR]

• Children with autism spectrum disorder (ASD) frequently have gastrointestinal symptoms. • The intestinal microbiota may be different in ASD patients compared to controls. • In ASD, a connection may exist between the gut microbiome, GI symptoms, and behavior. • The gut-brain axis may affect brain development and behaviors. There is an emerging body of evidence associating children having autism spectrum disorder (ASD) with gastrointestinal (GI) symptoms, such as abdominal pain, chronic diarrhea, constipation, vomiting, gastroesophageal reflux, intestinal infections, and increased intestinal permeability. Moreover, in many studies, large differences in the composition of intestinal microbiota and metabolic products between ASD patients and controls were reported. Deepening the role and the biology of the gut microbiome may be fundamental to elucidate the onset of GI symptoms in ASD individuals and their etiopathogenetic causes. The gut-brain axis may affect brain development and behaviors through the neuroendocrine, neuroimmune, and autonomic nervous systems. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, verbal and non-verbal communication, and stereotypic behaviors. Many studies support a significant relationship between many different environmental factors in ASD etiology. These factors include increased daily exposure to various toxic metal-based environmental pollutants, which represent a cause for concern in public health. This article reviews the most relevant toxic metals, commonly found, environmental pollutants, i.e., lead (Pb), mercury (Hg), aluminum (Al), and the metalloid arsenic (As). Additionally, it discusses how pollutants can be a possible pathogenetic cause of ASD through various mechanisms including neuroinflammation in different regions of the brain, fundamentally occurring through elevation of the proinflammatory profile of cytokines and aberrant expression of nuclear factor kappa B (NF-κB). Due to the worldwide increase in toxic environmental pollution, studies on the role of pollutants in neurodevelopmental disorders, including direct effects on the developing brain and the subjects’ genetic susceptibility and polymorphism, are of utmost importance to achieve the best therapeutic approach and preventive strategies. [ABSTRACT FROM AUTHOR]

The association between the plasma levels of trace elements, such as copper (Cu), zinc (Zn) and selenium (Se), in people with autism spectrum disorder (ASD), has attracted the interest of many physicians in the very recent years, because the impaired homeostatic regulation of trace elements, including their levels in the bloodstream and their potential neurotoxicity, contribute to the onset and exacerbation of ASD. In this study, we investigated 23 pediatric subjects (≤ 18 yrs old, both sexes) with ASD, all residents in the city of Campo Grande in Brazil, by searching for their micronutrient levels in plasma in relation with metabolic and nutrition biomarkers. Aside for the few evidence reported, generally, the Brazilian cohort of ASD children here examined did not show a marked difference in micro-nutrient intake in relation with their resident geographical area and their dietary habit or metabolic state, although a slight difference in the levels of magnesium and phosphorus was retrieved due to sex difference. [ABSTRACT FROM AUTHOR]

Background Autism spectrum disorder ( ASD) is a frequent developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and nonverbal communication, and stereotyped patterns of interests and activities. It has been previously reported that there is vitamin D deficiency in autistic children; however, there is a lack of randomized controlled trials of vitamin D supplementation in ASD children. Methods This study is a double-blinded, randomized clinical trial ( RCT) that was conducted on 109 children with ASD (85 boys and 24 girls; aged 3-10 years). The aim of this study was to assess the effects of vitamin D supplementation on the core symptoms of autism in children. ASD patients were randomized to receive vitamin D3 or placebo for 4 months. The serum levels of 25-hydroxycholecalciferol (25 ( OH)D) were measured at the beginning and at the end of the study. The autism severity and social maturity of the children were assessed by the Childhood Autism Rating Scale ( CARS), Aberrant Behavior Checklist ( ABC), Social Responsiveness Scale ( SRS), and the Autism Treatment Evaluation Checklist ( ATEC). Trial registration number: UMIN- CTR Study Design : trial number : UMIN000020281. Results Supplementation of vitamin D was well tolerated by the ASD children. The daily doses used in the therapy group was 300 IU vitamin D3/kg/day, not to exceed 5,000 IU/day. The autism symptoms of the children improved significantly, following 4-month vitamin D3 supplementation, but not in the placebo group. This study demonstrates the efficacy and tolerability of high doses of vitamin D3 in children with ASD. Conclusions This study is the first double-blinded RCT proving the efficacy of vitamin D3 in ASD patients. Depending on the parameters measured in the study, oral vitamin D supplementation may safely improve signs and symptoms of ASD and could be recommended for children with ASD. At this stage, this study is a single RCT with a small number of patients, and a great deal of additional wide-scale studies are needed to critically validate the efficacy of vitamin D in ASD. [ABSTRACT FROM AUTHOR]

Objectives: Autism spectrum disorder (ASD) is a developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and non-verbal communication, and stereotyped patterns of interests and activities. Vitamin-D deficiency was previously reported in autistic children. However, the data on the relationship between vitamin D deficiency and the severity of autism are limited. Methods: We performed a case–controlled cross-sectional analysis conducted on 122 ASD children, to assess their vitamin D status compared to controls and the relationship between vitamin D deficiency and the severity of autism. We also conducted an open trial of vitamin D supplementation in ASD children. Results: Fifty-seven percent of the patients in the present study had vitamin D deficiency, and 30% had vitamin D insufficiency. The mean 25-OHD levels in patients with severe autism were significantly lower than those in patients with mild/moderate autism. Serum 25-OHD levels had significant negative correlations with Childhood Autism Rating Scale (CARS) scores. Of the ASD group, 106 patients with low-serum 25-OHD levels (<30 ng/ml) participated in the open label trial. They received vitamin D3 (300 IU/kg/day not to exceed 5000 IU/day) for 3 months. Eighty-three subjects completed 3 months of daily vitamin D treatment. Collectively, 80.72% (67/83) of subjects who received vitamin D3 treatment had significantly improved outcome, which was mainly in the sections of the CARS and aberrant behavior checklist subscales that measure behavior, stereotypy, eye contact, and attention span. Conclusion: Vitamin D is inexpensive, readily available and safe. It may have beneficial effects in ASD subjects, especially when the final serum level is more than 40 ng/ml. Trial registration number: UMIN-CTR Study Design: trial Number: R000016846. [ABSTRACT FROM AUTHOR]

The incidence of both obesity and autism spectrum disorders (ASD) has dramatically increased during the last decades. Moreover, the most recent studies have revealed increased risk of ASD in offspring of overweight and obese women. However, the mechanisms of association between ASD and maternal obesity are unknown. Taking into account the existing data indicating the association between mercury (Hg) exposure and development of obesity and ASD, we hypothesize that Hg may serve as an additional link between maternal obesity and ASD. In particular, it is supposed that obesity is associated with excessive accumulation of Hg in the maternal organism. After conception, the fetus is developing in the conditions of Hg overload within the body of obese women thus predisposing to the development of ASD. The proposed hypothesis may be confirmed by the existing data. In particular, previous studies demonstrated that overweight and obese persons are characterized by a significantly higher level of Hg in hair, blood and urine than the lean ones. Therefore, an obese organism is characterized by elevated Hg burden that may be transferred to the fetus during pregnancy. Moreover, multiple studies have demonstrated a tight association between maternal and children Hg status being indicative of placental transfer of metal from maternal organism to offspring. Finally, a growing body of data indicates the influence of Hg exposure and Hg status on the risk of ASD in children. However, additional experimental and clinical studies are required to prove the hypothesis and provide novel data on the role of Hg in maternal obesity-associated ASD development. In particular, the contribution of Hg to ASD development in children from obese mothers should be determined. If a significant role of Hg in maternal obesity ASD risk will be confirmed, this will open additional perspectives of risk modification. Taking into account the universal mechanisms of Hg toxicity, transport, and accumulation, further preventive actions may be undertaken to reduce the risk of Hg toxicity and Hg-associated ASD development. In particular, it is supposed that the use of Hg chelators (like N,N'bis-(2-mercaptoethyl)isophthalamide, NMBI), antioxidants, and anti-inflammatory compounds prior or during pregnancy may have a beneficial effect. However, the safety of such actions should repeatedly be tested to avoid adverse health effects in a developing fetus. [ABSTRACT FROM AUTHOR]

[Display omitted] • Awareness and knowledge among the health professionals in Egypt are not adequate. • Early screening and diagnosis are lacking in Egypt. • All Egyptian physicians should receive specialized ASD training. • The percentage of risk factors/associated-disorders in Egyptian ASD children differs from literature data. The aim of the present study was to determine the type and percentage of referral situations, risk factors, associated syndromes, and parental awareness of autism spectrum disorder (ASD) children who visited the Medical Research Centre of Excellence, National Research Centre in Cairo, specialized in ASD diagnosis and management. The study included 530 children who were diagnosed with ASD. For those, full medical history, clinical examination, severity evaluation, and testing the language and cognitive development were performed. The process of diagnosis and assessment of parents' awareness and knowledge about ASD was investigated using questionnaires. The clinic was mainly visited by self-referral. About half of the participants (51.4 %) had previously visited other doctors (1–5 physicians) who were mostly pediatricians. The parents' awareness was mostly limited to the term "autism", but not the nature of ASD. Caesarean section was the most common risk factor (57.4 %), followed by jaundice (30.1 %). The most common presenting symptoms were language (81.5 %) and social (60.4 %) deficits. ASD severity was found to be high in association with attention deficit hyperactivity disorder (ADHD) and electroencephalogram (EEG) changes (p = 0.001). The risk factors and associated syndromes in the Egyptian population studied were similar to those reported in previous studies performed in other populations, but their percentage was different. Perinatal problems were the most common risk factors, which may relate to the influence of gene-environmental interaction on the factors which could play a role in developing ASD or increasing its severity. The process of ASD diagnosis was commonly delayed among the participants. Increasing awareness and knowledge among health care professionals and parents is urgently needed to facilitate early diagnosis and intervention services, which will lead to improvement of the developmental outcomes for ASD children. The associated syndromes could be the driving force to seek medical advice and could influence the ASD severity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Imbalance of GSH redox system is an key factor in the pathophysiology of ASD. • Existing data support a protective role of the GSH system in ASD development. • External modulation of GSH levels may be used in the treatment of ASD. • Therapeutic approaches by targeting the GSH system are discussed. This paper reviews the potential role of glutathione (GSH) in autism spectrum disorder (ASD). GSH plays a key role in the detoxification of xenobiotics and maintenance of balance in intracellular redox pathways. Recent data showed that imbalances in the GSH redox system are an important factor in the pathophysiology of ASD. Furthermore, ASD is accompanied by decreased concentrations of reduced GSH in part caused by oxidation of GSH into glutathione disulfide (GSSG). GSSG can react with protein sulfhydryl (SH) groups, thereby causing proteotoxic stress and other abnormalities in SH-containing enzymes in the brain and blood. Moreover, alterations in the GSH metabolism via its effects on redox-independent mechanisms are other processes associated with the pathophysiology of ASD. GSH-related regulation of glutamate receptors such as the N-methyl-D-aspartate receptor can contribute to glutamate excitotoxicity. Synergistic and antagonistic interactions between glutamate and GSH can result in neuronal dysfunction. These interactions can involve transcription factors of the immune pathway, such as activator protein 1 and nuclear factor (NF)-κB, thereby interacting with neuroinflammatory mechanisms, ultimately leading to neuronal damage. Neuronal apoptosis and mitochondrial dysfunction are recently outlined as significant factors linking GSH impairments with the pathophysiology of ASD. Moreover, GSH regulates the methylation of DNA and modulates epigenetics. Existing data support a protective role of the GSH system in ASD development. Future research should focus on the effects of GSH redox signaling in ASD and should explore new therapeutic approaches by targeting the GSH system. [ABSTRACT FROM AUTHOR]

Mercury (Hg) is widely recognized as a neurotoxic metal, besides it can also act as a proinflammatory agent and immunostimulant, depending on individual exposure and susceptibility. Mercury exposure may arise from internal body pathways, such as via dental amalgams, preservatives in drugs and vaccines, and seafood consumption, or even from external pathways, i.e., occupational exposure, environmental pollution, and handling of metallic items and cosmetics containing Hg. In susceptible individuals, chronic low Hg exposure may trigger local and systemic inflammation, even exacerbating the already existing autoimmune response in patients with autoimmunity. Mercury exposure can trigger dysfunction of the autoimmune responses and aggravate immunotoxic effects associated with elevated serum autoantibodies titers. The purpose of the present review is to provide a critical overview of the many issues associated with Hg exposure and autoimmunity. In addition, the paper focuses on individual susceptibility and other health effects of Hg. • Mercury (Hg) is a proinflammatory agent and immunostimulant. • Exposure to Hg can trigger immunotoxic effects, inflammation, and autoimmune dysfunction. • In susceptible individuals, Hg may play a role in autoimmune diseases, including MS. • Characterization of epigenetic markers is needed to highlight individual predispositions to Hg-induced toxic outcomes. [ABSTRACT FROM AUTHOR]