The neural crest-derived enteric nervous system (ENS) provides the intrinsic innervation of the gut with diverse neuronal subtypes and glial cells. The ENS regulates all essential gut functions, such as motility, nutrient uptake, immune response, and microbiota colonization. Deficits in ENS neuron numbers and composition cause debilitating gut dysfunction. Yet, few studies have identified genes that control neuronal differentiation and the generation of the diverse neuronal subtypes in the ENS.

Utilizing existing CRISPR/Cas9 genome editing technology in zebrafish, we have developed a rapid and scalable screening approach for identifying genes that regulate ENS neurogenesis.

As a proof-of-concept, F0 guide RNA-injected larvae (F0 crispants) targeting the known ENS regulator genes sox10, ret, or phox2bb phenocopied known ENS phenotypes with high efficiency. We evaluated 10 transcription factor candidate genes as regulators of ENS neurogenesis and function. F0 crispants for five of the tested genes have fewer ENS neurons. Secondary assays in F0 crispants for a subset of the genes that had fewer neurons reveal no effect on enteric progenitor cell migration but differential changes in gut motility.

Our multistep, yet straightforward CRISPR screening approach in zebrafish tests the genetic basis of ENS developmental and disease gene functions that will facilitate the high-throughput evaluation of candidate genes from transcriptomic, genome-wide association, or other ENS-omics studies. Such in vivo ENS F0 crispant screens will contribute to a better understanding of ENS neuronal development regulation in vertebrates and what goes awry in ENS disorders.

Objective: To explore recent findings on how nutritional, gastrointestinal, social, and epigenetic factors interact in autism spectrum disorder, highlighting their implications for clinical management and intervention strategies that could improve development and quality of life of affected children. Sources: Studies published from 2000 to 2024 in the PubMed, Web of Science, Scopus, Scielo, Lilacs, and Google Scholar databases were collected. The process for the review adhered to the Search, Appraisal, Synthesis, and Analysis framework. Summary of the findings: Children with autism spectrum disorder have restrictive eating habits and often exhibit food selectivity with either hyper- or hypo-sensory characteristics. This review provides an overview of the literature on diagnosis and intervention strategies for selectivity in autism spectrum disorder, including the involvement of family members in meals, sharing a healthy diet and positive relationship with food, and the importance of exploring visual, olfactory, and tactile experiences of food and introducing new foods through play activities to expand the food repertoire. Modifications in the microbiota and gastrointestinal disorders may also be present in autism spectrum disorder and are presented due to their frequent nutritional repercussions. The medium and long-term implications of food preferences and behavior issues for nutritional status are also discussed, given the tendency for children with autism spectrum disorder to consume low-quality and energy-dense foods, leading to nutritional problems. Conclusions: Children with autism spectrum disorder have feeding difficulties, especially selectivity, gastrointestinal problems, changes in the microbiota and can evolve with micronutrient deficiencies, malnutrition and obesity. This review describes the evidence for possible targets for interventions aiming to improve nutritional health for children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by challenges in social communication, restricted interests, and repetitive behaviors. It is also associated with a high prevalence of eating disorders, gastrointestinal (GI) symptoms, and alterations in gut microbiota composition. One of the most pressing concerns is food selectivity. Various eating disorders, such as food neophobia, avoidant/restrictive food intake disorder (ARFID), specific dietary patterns, and poor-quality diets, are commonly observed in this population, often leading to nutrient deficiencies. Additionally, gastrointestinal problems in children with ASD are linked to imbalances in gut microbiota and immune system dysregulation. The aim of this narrative review is to identify previous associations between the gut-brain axis and gastrointestinal problems in ASD. We discuss the impact of the "microbiome-gut-brain axis", a bidirectional connection between gut microbiota and brain function, on the development and symptoms of ASD. In gastrointestinal problems associated with ASD, a 'vicious cycle' may play a significant role: ASD symptoms contribute to the prevalence of ARFID, which in turn leads to microbiota degradation, ultimately worsening ASD symptoms. Current data suggest a link between gastrointestinal problems in ASD and the microbiota, but the amount of evidence is limited. Further research is needed, targeting the correlation of a patient's microbiota status, dietary habits, and disease course.

Autism spectrum disorder (ASD) presents unique challenges related to feeding and nutritional management. Children with ASD often experience feeding difficulties, including food selectivity, refusal, and gastrointestinal issues. Various interventions have been explored to address these challenges, including dietary modifications, vitamin supplementation, feeding therapy, and behavioral interventions.

To provide a comprehensive overview of the current evidence on nutritional management in ASD. We examine the effectiveness of dietary interventions, vitamin supplements, feeding therapy, behavioral interventions, and mealtime practices in addressing the feeding challenges and nutritional needs of children with ASD.

We systematically searched relevant literature up to June 2024, using databases such as PubMed, PsycINFO, and Scopus. Studies were included if they investigated dietary interventions, nutritional supplements, or behavioral strategies to improve feeding behaviors in children with ASD. We assessed the quality of the studies and synthesized findings on the impact of various interventions on feeding difficulties and nutritional outcomes. Data extraction focused on intervention types, study designs, participant characteristics, outcomes measured, and intervention effectiveness.

The review identified 316 studies that met the inclusion criteria. The evidence indicates that while dietary interventions and nutritional supplements may offer benefits in managing specific symptoms or deficiencies, the effectiveness of these approaches varies. Feeding therapy and behavioral interventions, including gradual exposure and positive reinforcement, promise to improve food acceptance and mealtime behaviors. The findings also highlight the importance of creating supportive mealtime environments tailored to the sensory and behavioral needs of children with ASD.

Nutritional management for children with ASD requires a multifaceted approach that includes dietary modifications, supplementation, feeding therapy, and behavioral strategies. The review underscores the need for personalized interventions and further research to refine treatment protocols and improve outcomes. Collaborative efforts among healthcare providers, educators, and families are essential to optimize this population's nutritional health and feeding practices. Enhancing our understanding of intervention sustainability and long-term outcomes is essential for optimizing care and improving the quality of life for children with ASD and their families.

Many studies have demonstrated the impact of intestinal microbiota on normal brain development. Moreover, the gut microbiota (GM) is impacted by multiple endogenous and environmental factors that may promote gut dysbiosis (GD). An increasing number of studies are investigating the possible role of the GD in the development of neurological and behavioral disorders. For autism spectrum disorders (ASD), specific intestinal bacterial signatures have been identified, knowing that gastrointestinal symptoms are frequently found in ASD. In this review, the peri and post-natal factors modulating the GM are described and the specific gut bacterial signature of ASD children is detailed. Through bidirectional communication between the GM and the brain, several mechanisms are involved in the development of ASD, such as cytokine-mediated neuroinflammation and decreased production of neuroprotective factors such as short-chain fatty acids by the GM. Imbalance of certain neurotransmitters such as serotonin or gamma-aminobutyric acid could also play a role in these gut-brain interactions. Some studies show that this GD in ASD is partly reversible by treatment with pre- and probiotics, or fecal microbiota transplantation with promising results. However, certain limitations have been raised, in particular concerning the short duration of treatment, the small sample sizes and the diversity of protocols. The development of standardized therapeutics acting on GD in large cohort could rescue the gastrointestinal symptoms and behavioral impairments, as well as patient management.

Autism spectrum disorders (ASDs) are a pool of neurodevelopment disorders in which social impairment is the main symptom. Presently, there are no definitive medications to cure the symptoms but the therapeutic strategies that are taken ameliorate them. The purpose of this study was to investigate the effects of melatonin (MLT) in treating ASDs using an autistic mouse model BTBR T+Itpr3tf/J (BTBR). We evaluated the hepatic cytoarchitecture and some markers of autophagy, ferritinophagy/ferroptosis, in BTBR mice treated and not-treated with MLT. The hepatic morphology and the autophagy and ferritinophagy/ferroptosis pathways were analyzed by histological, immunohistochemical, and Western blotting techniques. We studied p62 and microtubule-associated protein 1 light chain 3 B (LC3B) for evaluating the autophagy; nuclear receptor co-activator 4 (NCOA4) and long-chain-coenzyme synthase (ACSL4) for monitoring ferritinophagy/ferroptosis. The liver of BTBR mice revealed that the hepatocytes showed many cytoplasmic inclusions recognized as Mallory-Denk bodies (MDBs); the expression and levels of p62 and LC3B were downregulated, whereas ACSL4 and NCOA4 were upregulated, as compared to control animals. MLT administration to BTBR mice ameliorated liver damage and reduced the impairment of autophagy and ferritinophagy/ferroptosis. In conclusion, we observed that MLT alleviates liver damage in BTBR mice by improving the degradation of intracellular MDBs, promoting autophagy, and suppressing ferritinophagy/ferroptosis.

Autism spectrum disorder (ASD) is associated with differences in social communication, and these differences are related to trait emotional intelligence (TEI), alexithymia, and empathy. Autism is known to present differently in males and females, but research on sex differences in TEI, alexithymia, and empathy is largely relegated to non-autistic people. Therefore, the current research sought to explore individual relationships between autistic characteristics and TEI, alexithymia, and empathy, as well as the possible influence of sex in these relationships. In the current study, autistic and non-autistic adults reported on their autistic characteristics, TEI, alexithymia, and empathy. Based on previous research, it was hypothesized that more autistic characteristics would be associated with less TEI, more alexithymia, and less empathy, and that these relationships would be more prominent amongst males. More autistic characteristics were associated with greater challenges across the three areas of interest. However, only the relationship between TEI and autistic characteristics was moderated by sex, such that males demonstrated higher support needs related to TEI than females. Results from this analysis indicate that adults with more autistic characteristics, regardless of diagnostic status, demonstrate differences in TEI, alexithymia, and empathy. The current analysis may offer additional context to the evolving understanding of empathy and autism by suggesting that TEI and alexithymia could account for differences in empathy. Moreover, sex seems to play a role in the relationship between autistic characteristics and TEI such that differences are especially prominent for males.

Autism Spectrum Disorder (ASD) is a multifactorial disorder involving genetic and environmental factors leading to pathophysiologic symptoms and comorbidities including neurodevelopmental disorders, anxiety, immune dysregulation, and gastrointestinal (GI) abnormalities. Abnormal intestinal permeability has been reported among ASD patients and it is well established that disturbances in eating patterns may cause gut microbiome imbalance (i.e., dysbiosis). Therefore, studies focusing on the potential relationship between gut microbiota and ASD are emerging. We compared the intestinal bacteriome and mycobiome of a cohort of ASD subjects with their non-ASD siblings. Differences between ASD and non-ASD subjects include a significant decrease at the phylum level in Cyanobacteria (0.015% vs. 0.074%, p < 0.0003), and a significant decrease at the genus level in Bacteroides (28.3% vs. 36.8%, p < 0.03). Species-level analysis showed a significant decrease in Faecalibacterium prausnitzii, Prevotella copri, Bacteroides fragilis, and Akkermansia municiphila. Mycobiome analysis showed an increase in the fungal Ascomycota phylum (98.3% vs. 94%, p < 0.047) and an increase in Candida albicans (27.1% vs. 13.2%, p < 0.055). Multivariate analysis showed that organisms from the genus Delftia were predictive of an increased odds ratio of ASD, whereas decreases at the phylum level in Cyanobacteria and at the genus level in Azospirillum were associated with an increased odds ratio of ASD. We screened 24 probiotic organisms to identify strains that could alter the growth patterns of organisms identified as elevated within ASD subject samples. In a preliminary in vivo preclinical test, we challenged wild-type Balb/c mice with Delftia acidovorans (increased in ASD subjects) by oral gavage and compared changes in behavioral patterns to sham-treated controls. An in vitro biofilm assay was used to determine the ability of potentially beneficial microorganisms to alter the biofilm-forming patterns of Delftia acidovorans, as well as their ability to break down fiber. Downregulation of cyanobacteria (generally beneficial for inflammation and wound healing) combined with an increase in biofilm-forming species such as D. acidovorans suggests that ASD-related GI symptoms may result from decreases in beneficial organisms with a concomitant increase in potential pathogens, and that beneficial probiotics can be identified that counteract these changes.

Autism spectrum disorder (ASD) is a developmental disorder characterized by social deficits and repetitive behavior. Gastrointestinal (GI) problems, such as constipation, diarrhea, and inflammatory bowel disease, commonly occur in patients with ASD. Previously, GI problems of ASD patients were attributed to intestinal inflammation and vertical mother-to-infant microbiome transmission.

To explore whether GI problems in ASD are related to maternal intestinal inflammation and gut microbiota abnormalities.

An ASD rat model was developed using valproic acid (VPA). Enzyme-linked immunosorbent assay and fecal 16S rRNA sequencing were used to test GI changes.

VPA exposure during pregnancy led to pathological maternal intestinal changes, resulting in alterations in maternal gut microbiota. Additionally, the levels of inflammatory factors also increased. Moreover, prenatal exposure to VPA resulted in impaired duodenal motility in the offspring as well as increased levels of inflammatory factors.

GI problems in ASD may be associated with maternal intestinal inflammation and microbiota abnormality. Future research is required to find more evidence on the etiology and treatment of GI problems in ASD.

The prevalence of autism has been increasing at an alarming rate. Even accounting for the expansion of autism spectrum disorder diagnostic (ASD) criteria throughout the 1990's, there has been an over 300% increase in ASD prevalence since the year 2000. The often debilitating personal, familial, and societal sequelae of autism are generally believed to be lifelong. However, there have been several encouraging case reports demonstrating the reversal of autism diagnoses, with a therapeutic focus on addressing the environmental and modifiable lifestyle factors believed to be largely underlying the condition. This case report describes the reversal of autism symptoms among dizygotic, female twin toddlers and provides a review of related literature describing associations between modifiable lifestyle factors, environmental exposures, and various clinical approaches to treating autism. The twins were diagnosed with Level 3 severity ASD "requiring very substantial support" at approximately 20 months of age following concerns of limited verbal and non-verbal communication, repetitive behaviors, rigidity around transitions, and extensive gastrointestinal symptoms, among other common symptoms. A parent-driven, multidisciplinary, therapeutic intervention involving a variety of licensed clinicians focusing primarily on addressing environmental and modifiable lifestyle factors was personalized to each of the twin's symptoms, labs, and other outcome measures. Dramatic improvements were noted within several months in most domains of the twins' symptoms, which manifested in reductions of Autism Treatment Evaluation Checklist (ATEC) scores from 76 to 32 in one of the twins and from 43 to 4 in the other twin. The improvement in symptoms and ATEC scores has remained relatively stable for six months at last assessment. While prospective studies are required, this case offers further encouraging evidence of ASD reversal through a personalized, multidisciplinary approach focusing predominantly on addressing modifiable environmental and lifestyle risk factors.

Neurodevelopmental disorders, such as autism spectrum disorder (ASD), have been increasingly associated with eosinophilic gastrointestinal disorders (EGID). However, the relationship between these diseases remains unclear. We performed a systematic review with meta-analysis to address this issue.

The search was performed according to the PRISMA guidelines using descriptors for ASD and EGIDs from the MEDLINE, Embase, PsycInfo, LILACS, and Web of Science databases. Observational studies with the prevalence of ASD in any EGID were included. The study protocol was registered on the PROSPERO platform under the number CRD42023455177.

The total dataset comprised 766,082 participants. The result of the single-arm meta-analysis showed an overall prevalence of ASD in the population with EGID of 21.59% (95% CI: 10.73-38.67). There was an association between EGID and ASD (OR: 3.44; 95% CI: 1.25-2.21), also significant when restricted only to EoE (OR: 3.70; 95% CI: 2.71-5.70).

Recent studies have implicated the influence of an inadequate epithelial barrier integrity in the pathogenesis of several diseases. The role of this mechanism can be extended to situations beyond allergic reactions, including other conditions with underlying immunological mechanisms. Several diseases are potentially related to the systemic effect of bacterial translocation in tissues with defective epithelial barriers.

Our meta-analysis provides evidence that supports the consideration of EGID in patients with ASD and ASD in patients with EGID. Despite its limitations, the results should also be validated by future studies, preferably using multicenter prospective designs in populations with low referral bias.

Adolescents with autism spectrum disorder (ASD) are at an increased risk of overweight/obesity and adverse childhood experiences (ACEs).

This study examined whether ACEs increased the odds of overweight/obesity in adolescents with ASD.

This cross-sectional study used National Survey of Children's Health (NSCH) 2018-2019 data (N = 31,533 children ages 10-17 years, including n = 480 children with mild ASD and n = 423 children with moderate/severe ASD with normal or overweight/obese BMI). Parent-reported body mass index (BMI) was coded as overweight/obesity vs. normal weight. The independent variable was the count of nine ACEs. Binary logistic regression was conducted, controlling for social ecological factors.

The odds of overweight/obesity in adolescents with ASD with 1-2 ACEs (OR 1.3, CI 1.1-1.4) and 3+ ACEs (OR 1.6, CI 1.3-2.0) were higher than those with 0 ACEs; odds increased with higher counts of ACEs. Household income level was the most significant sociodemographic influence on odds of obesity in adolescents with ASD (0-99 % Federal Poverty Level: OR 1.9, CI 1.6-2.3). Adolescents with moderate/severe ASD (OR 1.7, CI 1.2-2.5) and mild ASD (OR 1.6, CI 1.0-2.4) had higher odds of overweight/obesity after accounting for ACEs, race/ethnicity, sex, household income, and physical activity.

Findings indicated ACEs are associated with ASD, which calls for integration of ACEs information within trauma-informed care practices for obesity prevention and intervention for adolescents with ASD. Persistent disparities of overweight/obesity exist by race/ethnicity, sex, and household income within this population, which indicates the need for tailoring trauma-informed approaches to the unique needs of this population.

Eating behavior, which includes eating habits and preferences, frequency of eating, and other features related to diet, is a major characteristic not only of a person's nutritional status, but also of health in general. In recent years, the prevalence of eating disorders in children has tended to increase; they also require cross-system approaches in diagnosis by a variety of specialists and correction requires appropriate selection of optimal methods. Maladaptive eating attitudes formed at an early age can contribute to the formation of eating disorders, which can lead to or worsen various neuropsychiatric diseases, digestive diseases, and other related conditions. In children with autism spectrum disorder (ASD), eating disorders often appear earlier than other major symptoms of the condition. However, the clinical manifestations of eating disorders in children with ASD are varied and differ in severity and duration, whereas these disorders in neurotypical children might present as short-lived and may not lead to serious consequences. Nevertheless, cases of progressive eating disorders accompanied by a child presenting as under- or overweight and/or with macronutrient and micronutrient deficiencies cannot be excluded. Given the high prevalence of eating disorders in children, many researchers have highlighted the lack of a valid and universally accepted instruments to assess atypical eating behaviors in this population. Therefore, in this review, we wanted to highlight the problems and causes of eating disorders in children, and also to analyze the existing approaches to the validation of these problems, taking into account the existing behavioral features in children with ASD.

Dietary and gastrointestinal (GI) problems have been frequently reported in autism spectrum disorder (ASD). However, the relative contributions of autism-linked traits to dietary and GI problems in children with ASD are poorly understood. This study firstly compared the dietary intake and GI symptoms between children with ASD and typically developing children (TDC), and then quantified the relative contributions of autism-linked traits to dietary intake, and relative contributions of autism-linked traits and dietary intake to GI symptoms within the ASD group.

A sample of 121 children with ASD and 121 age-matched TDC were eligible for this study. The dietary intake indicators included food groups intakes, food variety, and diet quality. The autism-linked traits included ASD symptom severity, restricted repetitive behaviors (RRBs), sensory profiles, mealtime behaviors, and their subtypes. Linear mixed-effects models and mixed-effects logistic regression models were used to estimate the relative contributions.

Children with ASD had poorer diets with fewer vegetables/fruits, less variety of food, a higher degree of inadequate/unbalanced dietary intake, and more severe constipation/total GI symptoms than age-matched TDC. Within the ASD group, compulsive behavior (a subtype of RRBs) and taste/smell sensitivity were the only traits associated with lower vegetables and fruit consumption, respectively. Self-injurious behavior (a subtype of RRBs) was the only contributing trait to less variety of food. Limited variety (a subtype of mealtime behavior problems) and ASD symptom severity were the primary and secondary contributors to inadequate dietary intake, respectively. ASD symptom severity and limited variety were the primary and secondary contributors to unbalanced dietary intake, respectively. Notably, unbalanced dietary intake was a significant independent factor associated with constipation/total GI symptoms, and autism-linked traits manifested no contributions.

ASD symptom severity and unbalanced diets were the most important contributors to unbalanced dietary intake and GI symptoms, respectively. Our findings highlight that ASD symptom severity and unbalanced diets could provide the largest benefits for the dietary and GI problems of ASD if they were targeted for early detection and optimal treatment.

Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut-brain-microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother's obesity as potentially environmental factors of ASD. The purpose of this review is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder. Major interplays between the gastrointestinal (GI) tract and the central nervous system (CNS) seem to be driven by gut microbiota (GM). Herein, we provide a GM functional characterization, based on GM metabolomics, mapping of bacterial biochemical pathways, and anamnestic, clinical, and nutritional patient metadata.

Fecal samples collected from children with ASD and neurotypical children were analyzed by gas-chromatography mass spectrometry coupled with solid phase microextraction (GC-MS/SPME) to determine volatile organic compounds (VOCs) associated with the metataxonomic approach by 16S rRNA gene sequencing. Multivariate and univariate statistical analyses assessed differential VOC profiles and relationships with ASD anamnestic and clinical features for biomarker discovery. Multiple web-based and machine learning (ML) models identified metabolic predictors of disease and network analyses correlated GM ecological and metabolic patterns.

The GM core volatilome for all ASD patients was characterized by a high concentration of 1-pentanol, 1-butanol, phenyl ethyl alcohol; benzeneacetaldehyde, octadecanal, tetradecanal; methyl isobutyl ketone, 2-hexanone, acetone; acetic, propanoic, 3-methyl-butanoic and 2-methyl-propanoic acids; indole and skatole; and o-cymene. Patients were stratified based on age, GI symptoms, and ASD severity symptoms. Disease risk prediction allowed us to associate butanoic acid with subjects older than 5 years, indole with the absence of GI symptoms and low disease severity, propanoic acid with the ASD risk group, and p-cymene with ASD symptoms, all based on the predictive CBCL-EXT scale. The HistGradientBoostingClassifier model classified ASD patients vs. CTRLs by an accuracy of 89%, based on methyl isobutyl ketone, benzeneacetaldehyde, phenyl ethyl alcohol, ethanol, butanoic acid, octadecane, acetic acid, skatole, and tetradecanal features. LogisticRegression models corroborated methyl isobutyl ketone, benzeneacetaldehyde, phenyl ethyl alcohol, skatole, and acetic acid as ASD predictors.

Our results will aid the development of advanced clinical decision support systems (CDSSs), assisted by ML models, for advanced ASD-personalized medicine, based on omics data integrated into electronic health/medical records. Furthermore, new ASD screening strategies based on GM-related predictors could be used to improve ASD risk assessment by uncovering novel ASD onset and risk predictors.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder evolving over the lifetime of individuals. The oral and gut microbial ecosystems are closely connected to each other and the brain and are potentially involved in neurodevelopmental diseases. This narrative review aims to identify all the available evidence emerging from observational studies focused on the role of the oral microbiome in ASD. A literature search was conducted using PubMed and the Cochrane Library for relevant studies published over the last ten years. Overall, in autistic children, the oral microbiota is marked by the abundance of several microbial species belonging to the Proteobacteria phylum and by the depletion of species belonging to the Bacteroidetes phylum. In mouse models, the oral microbiota is marked by the abundance of the Bacteroidetes phylum. Oral dysbiosis in ASD induces changes in the human metabolome, with the overexpression of metabolites closely related to the pathogenesis of ASD, such as acetate, propionate, and indoles, together with the underexpression of butyrate, confirming the central role of tryptophan metabolism. The analysis of the literature evidences the close relationship between oral dysbiosis and autistic core symptoms; the rebuilding of the oral and gut ecosystems by probiotics may significantly contribute to mitigating the severity of ASD symptoms.

Our previous work revealed that unbalanced dietary intake was an important independent factor associated with constipation and gastrointestinal (GI) symptoms in children with autism spectrum disorder (ASD). Growing evidence has shown the alterations in the gut microbiota and gut microbiota-derived metabolites in ASD. However, how the altered microbiota might affect the associations between unbalanced diets and GI symptoms in ASD remains unknown. We analyzed microbiome and metabolomics data in 90 ASD and 90 typically developing (TD) children based on 16S rRNA and untargeted metabolomics, together with dietary intake and GI symptoms assessment. We found that there existed 11 altered gut microbiota (FDR-corrected P-value <0.05) and 397 altered metabolites (P-value <0.05) in children with ASD compared with TD children. Among the 11 altered microbiota, the Turicibacter, Coprococcus 1, and Lachnospiraceae FCS020 group were positively correlated with constipation (FDR-corrected P-value <0.25). The Eggerthellaceae was positively correlated with total GI symptoms (FDR-corrected P-value <0.25). More importantly, three increased microbiota including Turicibacter, Coprococcus 1, and Eggerthellaceae positively modulated the associations of unbalanced dietary intake with constipation and total GI symptoms, and the decreased Clostridium sp. BR31 negatively modulated their associations in ASD children (P-value <0.05). Together, the altered microbiota strengthens the relationship between unbalanced dietary intake and GI symptoms. Among the altered metabolites, ten metabolites derived from microbiota (Turicibacter, Coprococcus 1, Eggerthellaceae, and Clostridium sp. BR31) were screened out, enriched in eight metabolic pathways, and were identified to correlate with constipation and total GI symptoms in ASD children (FDR-corrected P-value <0.25). These metabolomics findings further support the modulating role of gut microbiota on the associations of unbalanced dietary intake with GI symptoms. Collectively, our research provides insights into the relationship between diet, the gut microbiota, and GI symptoms in children with ASD.

The gut-brain axis involves several bidirectional pathway communications including microbiome, bacterial metabolites, neurotransmitters as well as immune system and is perturbed both in brain and in gastrointestinal disorders. Consistently, microbiota-gut-brain axis has been found altered in autism spectrum disorder (ASD). We reasoned that such alterations occurring in ASD may impact both on methylation signatures of human host fecal DNA (HFD) and possibly on the types of human cells shed in the stools from intestinal tract giving origin to HFD. To test this hypothesis, we have performed whole genome methylation analysis of HFD from an age-restricted cohort of young children with ASD (N = 8) and healthy controls (N = 7). In the same cohort we have previously investigated the fecal microbiota composition and here we refined such analysis and searched for eventual associations with data derived from HFD methylome analysis. Our results showed that specific epigenetic signatures in human fecal DNA, especially at genes related to inflammation, associated with the disease. By applying methylation-based deconvolution algorithm, we found that the HFD derived mainly from immune cells and the relative abundance of those differed between patients and controls. Consistently, most of differentially methylated regions fitted with genes involved in inflammatory response. Interestingly, using Horvath epigenetic clock, we found that ASD affected children showed both epigenetic and microbiota age accelerated. We believe that the present unprecedented approach may be useful for the identification of the ASD associated HFD epigenetic signatures and may be potentially extended to other brain disorders and intestinal inflammatory diseases.

This study presents the results of the effectiveness of 13 therapeutic diets for autism spectrum disorder from 818 participants of a national survey, including benefits, adverse effects, and symptom improvements. The average Overall Benefit of diets was 2.36 (0 = no benefit, 4 = great benefit), which was substantially higher than for nutraceuticals (1.59/4.0) and psychiatric/seizure medications (1.39/4.0), p < 0.001. The average Overall Adverse Effects of diets was significantly lower than psychiatric/seizure medications (0.10 vs. 0.93, p < 0.001) and similar to nutraceuticals (0.16). Autism severity decreased slightly over time in participants who used diet vs. increasing slightly in those that did not (p < 0.001). Healthy and Feingold diets were the two top-rated diets by Overall Benefit; the ketogenic diet was the highest for nine symptoms (though had fewer respondents); and the gluten-free/casein-free diet was among the top for overall symptom improvements. Different diets were reported to affect different symptoms, suggesting that an individual's symptoms could be used to guide which diet(s) may be the most effective. The results suggest that therapeutic diets can be safe and effective interventions for improving some ASD-related symptoms with few adverse effects. We recommend therapeutic diets that include healthy foods and exclude problematic foods. Therapeutic diets are inexpensive treatments that we recommend for consideration by most people with ASD.

Children with autism spectrum disorders (ASD) or autism are more prone to gastrointestinal (GI) disorders than the general population. These disorders can significantly affect their health, learning, and development due to various factors such as genetics, environment, and behavior. The causes of GI disorders in children with ASD can include gut dysbiosis, immune dysfunction, food sensitivities, digestive enzyme deficiencies, and sensory processing differences. Many studies suggest that numerous children with ASD experience GI problems, and effective management is crucial. Diagnosing autism is typically done through genetic, neurological, functional, and behavioral assessments and observations, while GI tests are not consistently reliable. Some GI tests may increase the risk of developing ASD or exacerbating symptoms. Addressing GI issues in individuals with ASD can improve their overall well-being, leading to better behavior, cognitive function, and educational abilities. Proper management can improve digestion, nutrient absorption, and appetite by relieving physical discomfort and pain. Alleviating GI symptoms can improve sleep patterns, increase energy levels, and contribute to a general sense of well-being, ultimately leading to a better quality of life for the individual and improved family dynamics. The primary goal of GI interventions is to improve nutritional status, reduce symptom severity, promote a balanced mood, and increase patient independence.

Autism spectrum disorder (ASD) encompasses a group of disorders characterized by difficulties with social interaction and repetitive behavior. The condition is supposed to originate from early shifts in brain development, while the underlying processes are unknown. Moreover, a considerable number of patients with ASD experience digestive difficulties. Metalloproteases (ADAMs) are a class of enzymes capable of cleaving membrane-bound proteins. Members of this family, ADAM17 and ADAM22, have the ability to cleave proteins like the pro-inflammatory cytokine TNF-ά and glutamate synaptic molecules, which are both engaged in neuro-inflammation and glutamate excitotoxicity as crucial etiological mechanisms in ASD. ADAM17 and ADAM22 may also have a role in ASD microbiota-gut-brain axis connections by regulating immunological and inflammatory responses in the intestinal tract.

Using ELISA kits, the plasma levels of ADAM17 and ADAM22 were compared in 40 children with ASD and 40 typically developing children. All of the autistic participants' childhood autism rating scores (CARS), social responsiveness scales (SRS), and short sensory profiles (SSP) were evaluated as indicators of ASD severity.

Our results showed that plasma levels of ADAM17 were significantly lower in ASD children than in control children, while ADAM22 demonstrated non-significantly lower levels. Our data also indicate that while ADAM17 correlates significantly with age, ADAM22 correlates significantly with CARS as a marker of ASD severity.

Our interpreted data showed that alteration in ADAM17 and ADAM22 might be associated with glutamate excitotoxicity, neuroinflammation, and altered gut microbiota as etiological mechanisms of ASD and could be an indicator of the severity of the disorder.

Since there is no known cure for autism spectrum disorder (ASD), its incidence rate is on the rise. Common comorbidities like gastrointestinal problems are observed as common signs of ASD and play a major role in controlling social and behavioral symptoms. Although there is a lot of interest in dietary treatments, no harmony exists with regard to the ideal nutritional therapy. To better direct prevention and intervention measures for ASD, the identification of risk and protective factors is required. Through the use of a rat model, our study aims to assess the possible danger of exposure to neurotoxic doses of propionic acid (PPA) and the nutritional protective effects of prebiotics and probiotics. Here, we conducted a biochemical assessment of the effects of dietary supplement therapy in the PPA model of autism. We used 36 male Sprague Dawley albino rat pups divided into six groups. Standard food and drink were given to the control group. The PPA-induced ASD model was the second group; it was fed a conventional diet for 27 days before receiving 250 mg/kg of PPA orally for three days. The four other groups were given 3 mL/kg of yoghurt daily, 400 mg/Kg of artichokes daily, 50 mg/kg of luteolin daily and Lacticaseibacillus rhamnosus GG at 0.2 mL daily for 27 days before being given PPA (250 mg/kg BW) for three days along with their normal diet. All groups had their brain homogenates tested for biochemical markers, which included gamma-aminobutyric acid (GABA), glutathione peroxidase 1 (GPX1), glutathione (GSH), interleukin 6 (IL-6), interleukin 10 (IL-10) and tumor necrosis factor-alpha (TNF). When compared with the control group, the PPA-induced model presented increased oxidative stress and neuroinflammation but groups treated with all four dietary therapies presented improvements in biochemical characteristics for oxidative stress and neuroinflammation. As all of the therapies show sufficient anti-inflammatory and antioxidant effects, they can be used as a useful dietary component to help prevent ASD.

Children with autism spectrum disorder (ASD) and food selectivity are at increased risk for nutritional deficiencies which could affect bone health.

We report on four male patients with ASD and avoidant restrictive food intake disorder (ARFID) with significant bone conditions including rickets, vertebral compression fractures, osteopenia, and slipped capital femoral epiphyses.

Each patient was at risk for at least one nutritional deficiency. Two out of four patients had deficiencies in Vitamins A, B12, E, and zinc. Calcium and Vitamin D deficiency were noted in all four. Two out of four patients with Vitamin D deficiency developed rickets.

Provisional evidence suggests that children with ASD and ARFID are at elevated risk for serious adverse bone health outcomes.

The hamartomatous polyposis syndromes are a set of clinically distinct disorders characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumor syndrome. Although each of the syndromes has distinct phenotypes, the hamartomatous polyps can be challenging to differentiate histologically. Additionally, each of these syndromes is associated with increased lifetime risks of gene-specific and organ-specific cancers, including those outside of the gastrointestinal tract. Germline pathogenic variants can be identified in a subset of individuals with these syndromes, which facilitates molecular diagnosis and subsequent gene-enabled management in the setting of genetic counseling. Although the malignant potential of hamartomatous polyps remains elusive, timely recognition of these syndromes is important and enables presymptomatic cancer surveillance and management before symptom exacerbation. Presently, there are no standard agents to prevent the development of polyps and cancers in the hamartomatous polyposis syndromes.

Stigma maydis polysaccharide (SMPS) is a plant polysaccharide that participates in immune regulation and gastrointestinal motility. Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders, and ASD patients often present intestinal microflora imbalance problems; however, there is no effective treatment method. This study explores the effect of SMPS intervention on the gut microbiota in autism model rats as well as the potential action pathways. Female Wistar rats were intraperitoneally injected with sodium valproic acid (VPA) or normal saline at embryonic day 12.5 to establish an autism model or normal control in their offspring. The offspring prenatally exposed to VPA were randomly assigned to the VPA and the SMPS groups. The SMPS group was administered SMPS from E0.5 to postnatal day (PND) 21. We performed 16S rRNA and transcriptomics analyses to reveal the gut microbiota (GM) and differentially expressed genes in the autism model rats in response to SMPS intervention. SMPS intervention significantly improved the diversity and structure of the GM in autism model rats compared with the VPA rats. Moreover, the relative abundance of Prevotellaceae and Lachnospiraceae_NK4A136_group was increased after SMPS intervention. Transcriptome sequencing showed that 496 differentially expressed genes (DEGs) were identified after SMPS administration compared with the VPA group. Meanwhile, gene ontology (GO) enrichment analysis of DEGs was showed that the SMPS group had significant 653 GO terms. SMPS intervention had a major influence on oxidative phosphorylation, retrograde endocannabinoid signaling, thermogenesis, ribosome, protein digestion and absorption, renin-angiotensin system, calcium signaling pathway, glycosphingolipid biosynthesis-ganglio series, and propanoate metabolism pathways. Overall, this study suggests that SMPS interventions in early life may have an impact on gut microbiota, and then affect the transcriptomics levels of the hippocampal tissue in the VPA-induced autism model rats. It provides scientific evidence for the role of the microbe-gut-brain axis in ASD research.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, which affects 1 in 44 children and may cause severe disabilities. Besides socio-communicational difficulties and repetitive behaviors, ASD also presents as atypical sensorimotor function and pain reactivity. While chronic pain is a frequent co-morbidity in autism, pain management in this population is often insufficient because of difficulties in pain evaluation, worsening their prognosis and perhaps driving higher mortality rates. Previous observations have tended to oversimplify the experience of pain in autism as being insensitive to painful stimuli. Various findings in the past 15 years have challenged and complicated this dogma. However, a relatively small number of studies investigates the physiological correlates of pain reactivity in ASD. We explore the possibility that atypical pain perception in people with ASD is mediated by alterations in pain perception, transmission, expression and modulation, and through interactions between these processes. These complex interactions may account for the great variability and sometimes contradictory findings from the studies. A growing body of evidence is challenging the idea of alterations in pain processing in ASD due to a single factor, and calls for an integrative view. We propose a model of the pain cycle that includes the interplay between the molecular and neurophysiological pathways of pain processing and it conscious appraisal that may interfere with pain reactivity and coping in autism. The role of social factors in pain-induced response is also discussed. Pain assessment in clinical care is mostly based on subjective rather than objective measures. This review clarifies the strong need for a consistent methodology, and describes innovative tools to cope with the heterogeneity of pain expression in ASD, enabling individualized assessment. Multiple measures, including self-reporting, informant reporting, clinician-assessed, and purely physiological metrics may provide more consistent results. An integrative view on the regulation of the pain cycle offers a more robust framework to characterize the experience of pain in autism.

Several metabolomics-based studies have provided evidence that autistic subjects might share metabolic abnormalities with gut microbiota dysbiosis and alterations in gut mucosal permeability. Our aims were to explore the most relevant metabolic perturbations in a group of autistic children, compared with their healthy siblings, and to investigate whether the increased intestinal permeability may be mirrored by specific metabolic perturbations. We enrolled 13 autistic children and 14 unaffected siblings aged 2-12 years; the evaluation of the intestinal permeability was estimated by the lactulose:mannitol test. The urine metabolome was investigated by proton nuclear magnetic resonance (1H-NMR) spectroscopy. The lactulose:mannitol test unveiled two autistic children with altered intestinal permeability. Nine metabolites significantly discriminated the urine metabolome of autistic children from that of their unaffected siblings; however, in the autistic children with increased permeability, four additional metabolites-namely, fucose, phenylacetylglycine, nicotinurate, and 1-methyl-nicotinamide, strongly discriminated their urine metabolome from that of the remaining autistic children. Our preliminary data suggest the presence of a specific urine metabolic profile associated with the increase in intestinal permeability.

In research on autism spectrum disorder (ASD), cognitive, speech- and anxiety-related impairments have been the focus of the majority of studies. One consistently reported ASD symptom that has rarely attracted attention is disordered appetite. The goal of this paper is to assess whether ASD-related dysregulation of food intake impacts consumption of palatable foods, including sugar.

Aberrant neural processing at the reward system level is at least partially responsible for excessive intake of palatable tastants, including sugar. Impaired oxytocin (OT) signaling likely contributes to the magnitude of this overconsumption. Since intake for reward is generally elevated in individuals with ASD, one strategy to curb sugar overconsumption might utilize presentation of alternative palatable food choices that are more nutritionally adequate than sucrose. Furthermore, OT, which is clinically tested to alleviate other ASD symptoms, might be an effective tool to curb overconsumption of sugar, as well as - likely - of other excessively ingested palatable foods, especially those that have sweet taste.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing incidence. An expanding body of literature is examining connections between ASD and dietary interventions. Existing reports suggest a beneficial effect of ketogenic dietary therapies (KDTs) in improving behavioral symptoms in ASD. In this context, the purpose of this scoping review was to identify and map available evidence in the literature about the feasibility and potential efficacy of KDTs in pediatric patients with ASD and to inform clinical practice in the field. Moreover, based on the resulting data from the literature review, we aimed to provide a shared protocol to develop a personalized KDT intervention in patients with ASD. A comprehensive and structured web-based literature search was performed using PubMed and Scopus and it yielded 203 records. Seven papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study designs and dietary aspects emerged among selected studies. Results supported the effectiveness of KDTs in promoting behavioral improvements. Clinical recommendations on which patients may benefit most from KDTs implementation and difficulties in dietary adherence were discussed.

Children with autism commonly suffer from comorbid functional gastrointestinal disorders (FGID) and anxiety. The raised prevalence of both conditions in autism suggests complex reciprocal relationships, which are seldom explored in non-treatment-seeking FGID. The relationships between subtypes of FGID and anxiety are also unclear. This study recruited boys with autism and age-matched typically developing (TD) boys, aged 4-11 years, who were not actively seeking help for gastrointestinal problems. Their parents completed the Rome IV Diagnostic Questionnaires for Pediatric FGID. Four groups of children with and without autism/FGID were identified and compared on their anxiety level using the Spence children's anxiety scale. In 69 boys with autism and 69 age-matched TD boys, FGID were identified in 22 and 16 boys, respectively. ANCOVA demonstrated a significant interaction effect of autism and FGID on anxiety (F[1, 129] = 5.43, p = 0.021), while conditional logistic regression identified an interaction effect of autism and anxiety on the odds of FGID (OR 1.038, 95% CI 1.002-1.075, p = 0.038). Explorative post hoc analysis showed higher anxiety in functional nausea and vomiting disorder (p = 0.033) and functional abdominal pain disorder (p = 0.029) among boys with autism than TD boys with the same respective subtypes of FGID. In summary, among prepubertal boys with autism, the presence of FGID that are non-treatment-seeking in nature, has a significantly stronger association with higher levels of anxiety than TD boys. The strength of association may be more prominent in subtypes of FGID. Possible pathomechanisms including the underlying microbiota spectra and inflammatory paths should be explored in future studies. LAY SUMMARY: Anxiety and gastrointestinal problems are common symptoms in autism. Given that gut health could be linked to emotions, their association in young boys with autism was studied. The presence of nausea vomiting, or abdominal pain were associated with raised anxiety among boys with autism, yet this was not observed in typically developing boys. This suggests that anxiety among autistic children could be partly explained by the presence of FGID.