Dietary flavonoids modulate the gut microbiota: A new perspective on improving autism spectrum disorder through the gut-brain axis.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unknown etiology. It is associated with various factors and causes great inconvenience to the patient's life. The gut-brain axis (GBA), which serves as a bidirectional information channel for exchanging information between the gut microbiota and the brain, is vital in studying many neurodegenerative diseases. Dietary flavonoids provide anti-inflammatory and antioxidant benefits, as well as regulating the structure and function of the gut microbiota. The occurrence and development of ASD are associated with dysbiosis of the gut microbiota. Modulation of gut microbiota can effectively improve the severity of ASD. This paper reviews the links between gut microbiota, flavonoids, and ASD, focusing on the mechanism of dietary flavonoids in regulating ASD through the GBA.

The importance of nutritional management and education in the treatment of autism.

Autism spectrum disorders (ASDs) are an early-onset neurodevelopmental disorders. The key symptoms of ASD include social deficits, verbal and non-verbal communication deficits, and restricted, repetitive patterns of behaviour, interests, or activities. Dietary patterns have been evidenced to be related to maternal nutritional status that might lead to different metabolic conditions, and maternal metabolic dysfunction has been observed to be associated with ASD. Furthermore growing evidence suggests that the gut microbiota has a role in the pathophysiology of ASD. Differences in composition of the gastrointestinal (GI) microbiota in children with ASD compared to unaffected siblings and/or healthy unrelated controls have been reported in various studies. The above-mentioned ASD factors and symptoms can be regulated by proper nutrition. The importance of nutrition and its possible impact on ASD patients is key to integral therapy. According to numerous research studies, various nutritional approaches succeeded in reducing the severity of patients' core ASD symptoms. The numerous options for diet that is used in the ASD therapy, as described in the scientific literature, are related to the problem of choosing an appropriate nutritional treatment. Each nutrition programme needs to be personalised and tailored to an individual patient. The aim of the paper is to review the available literature on dietary interventions in children with ASD and provide up-to-date evidence.

Intergeneration transfer of diet patterns? Parental self-report of diet and their report of their young adult children with ASD.

Autism Spectrum Disorder (ASD) affects two percent of American children and often results in neophobia, hypersensitivity to foods, and firmly set food preferences, leading to higher proportions of individuals suffering from diet-related chronic diseases. Our objective was to conduct an explorative pilot study to examine parents' perception of food intake for themselves and their young adult children with ASD. We employed comparative analysis to discover potential pathways to improve diet quality and lower the risk for chronic disease in individuals with ASD. Data from an online survey in n = 493 parent-child dyads on parentally reported intake patterns, food group, and food consumption was analyzed using kappa statistics to determine the level of agreement between reported parental and child intake patterns, body weight status and activity level. Average age was 48 years for parents and 22 years for their children, respectively. Parent-child agreement for obesity was high. We found very strong agreement between the reported diet variety (kappa = 0.82) and changing daily intake (kappa = 0.63) and strong agreement for some vegetable intake patterns (kappa = 0.61 for orange, white, and starchy vegetables) but not in meat intake (no agreement). Results of this study indicate evidence for perceived intergenerational transfer of dietary intake patterns, which may offer effective approaches to change parental diet, to subsequently improve diet quality in young adults with ASD and prevent diet-related chronic diseases in individuals with ASD.

How the placenta-brain lipid axis impacts the nutritional origin of child neurodevelopmental disorders: Focus on attention deficit hyperactivity disorder and autism spectrum disorder.

Dietary fish is a rich source of omega-3 (n-3) fatty acids, and as such, is believed to have played an important role in the evolution of the human brain and its advanced cognitive function. The long chain polyunsaturated fatty acids, particularly the n-3 docosahexanoic acid (DHA), are critical for proper neurological development and function. Both low plasma DHA and obesity in pregnancy are associated with neurodevelopmental disorders such as attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in childhood, and n-3 supplementation has been shown to improve symptoms, as reviewed herein. The mechanisms underlying the connection between maternal obesity, n-3 fatty acid levels and offspring's neurological outcomes are poorly understood, but we review the evidence for a mediating role of the placenta in this relationship. Despite promising data that n-3 fatty acid supplementation mitigates the effect of maternal obesity on placental lipid metabolism, few clinical trials or animal studies have considered the neurological outcomes of offspring of mothers with obesity supplemented with n-3 FA in pregnancy.

Paving Plant-Food-Derived Bioactives as Effective Therapeutic Agents in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, where social and communication deficits and repetitive behaviors are present. Plant-derived bioactives have shown promising results in the treatment of autism. In this sense, this review is aimed at providing a careful view on the use of plant-derived bioactive molecules for the treatment of autism. Among the plethora of bioactives, curcumin, luteolin, and resveratrol have revealed excellent neuroprotective effects and can be effectively used in the treatment of neuropsychological disorders. However, the number of clinical trials is limited, and none of them have been approved for the treatment of autism or autism-related disorder. Further clinical studies are needed to effectively assess the real potential of such bioactive molecules.

Ketogenic Dietary Therapies in Patients with Autism Spectrum Disorder: Facts or Fads? A Scoping Review and a Proposal for a Shared Protocol.

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.

Lactobacillus plantarum PS128 and Other Probiotics in Children and Adolescents with Autism Spectrum Disorder: A Real-World Experience.

Autism Spectrum Disorder is a neurodevelopmental disorder. Recent data suggest that probiotics can reduce some symptoms of this disorder and Lactobacillus plantarum PS128 has been reported to be especially useful. We recruited a sample of 131 autistic children and adolescents (M:F = 122:19; age: 86.1 ± 41.1 months) and evaluated their changes after use of probiotics by mean of CGI. We found some significant improvements with very few side effects; these positive effects were more evident in younger children. Patients taking Lactobacillus plantarum PS128 had greater improvements and fewer side effects than those taking other probiotics. Our real-life data are consistent with existing literature showing a specific effect of Lactobacillus plantarum PS128 in Autism Spectrum Disorder.

Can probiotic supplements improve the symptoms of autism spectrum disorder in children?: A protocol for systematic review and meta analysis.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing incidence. The externalizing and internalizing problems among children with ASD often persistent and highly impair functioning of both the child and the family. Children with ASD often develop gut-related comorbidities and dysbiosis can have negative effects on not only the gastrointestinal (GI) tract, but also psychological symptoms. Dietary exclusions and probiotic supplements also have been investigated in the management of ASD symptoms. Especially, there is some anecdotal evidence that probiotics supplements are able to alleviate GI symptoms as well as improve behaviors in children with ASD. METHOD AND ANALYSIS: This review will report on overall studies that include randomized control trials, randomized cross-over studies and cluster-randomized trials designs that consider curative effect in children with ASD by probiotic supplements. We will search 6 databases: MEDLINE, Embase, Scopus, PubMed, The Cochrane Library, and Web of Science and we will perform a manual search the journal Autism and information of ongoing or unpublished studies. The Mixed Methods Appraisal Tool (MMAT) will be used to assess quality of articles and the Jadad scale will be used to assess for bias. Assessment of publication bias will be performed using funnel plots generated by Comprehensive Meta-Analysis (CMA) 3.0 software. Clarifying the evidence in this area will be important for future research directions when reformulating and promoting the therapeutic regime in the field. ETHICS AND DISSEMINATION: There are no human participants, data, or tissue being directly studied for the purposes of the review; therefore, ethics approval and consent to participate are not applicable. The results of this study will be presented at conferences and published in peer-reviewed journals. REGISTRATION AND STATUS: PROSPERO 2019 CRD42019132754.

Gluten and Autism Spectrum Disorder.

An expanding body of literature is examining connections between Autism Spectrum Disorder (ASD) and dietary interventions. While a number of specialist diets have been suggested as beneficial in ASD, gluten has received particularly close attention as a potentially exacerbating factor. Reports exist suggesting a beneficial effect of the gluten-free diet (GFD) in ameliorating behavioural and intellectual problems associated with ASD, while epidemiological research has also shown a comorbidity between ASD and coeliac disease. However, both caregivers and clinicians have expressed an uncertainty of the value of people with ASD going gluten-free, and as the GFD otherwise receives considerable public attention a discussion which focuses specifically on the interaction between ASD and gluten is warranted. In this review we discuss the historical context of ASD and gluten-related studies, and expand this to include an overview of epidemiological links, hypotheses of shared pathological mechanisms, and ultimately the evidence around the use and adoption of the GFD in people with ASD.

The Effect of a Combined Gluten- and Casein-Free Diet on Children and Adolescents with Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

There has been a growing interest in the gastrointestinal system and its significance for autism spectrum disorder (ASD), including the significance of adopting a gluten-free and casein-free (GFCF) diet. The objective was to investigate beneficial and safety of a GFCF diet among children with a diagnosis of ASD. We performed a systematic literature search in Medline, Embase, Cinahl, and the Cochrane Library up to January 2020 for existing systematic reviews and individual randomized controlled trials (RCTs). Studies were included if they investigated a GFCF diet compared to a regular diet in children aged 3 to 17 years diagnosed with ASD, with or without comorbidities. The quality of the identified existing reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR). The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool, and overall quality of evidence was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). We identified six relevant RCTs, which included 143 participants. The results from a random effect model showed no effect of a GFCF diet on clinician-reported autism core symptoms (standardized mean difference (SMD) -0.31 (95% Cl. -0.89, 0.27)), parent-reported functional level (mean difference (MD) 0.61 (95% Cl -5.92, 7.14)) or behavioral difficulties (MD 0.80 (95% Cl -6.56, 10.16)). On the contrary, a GFCF diet might trigger gastrointestinal adverse effects (relative risk (RR) 2.33 (95% Cl 0.69, 7.90)). The quality of evidence ranged from low to very low due to serious risk of bias, serious risk of inconsistency, and serious risk of imprecision. Clinical implications of the present findings may be careful consideration of introducing a GFCF diet to children with ASD. However, the limitations of the current literature hinder the possibility of drawing any solid conclusion, and more high-quality RCTs are needed. The protocol is registered at the Danish Health Authority website.

The Effect of the Low FODMAP Diet on Gastrointestinal Symptoms, Behavioral Problems and Nutrient Intake in Children with Autism Spectrum Disorder: A Randomized Controlled Pilot Trial.

Some research suggests that GI symptoms seen in children with ASD may relate to behavior problems. The objective of this pilot study was to assess the effect of the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet on GI and behavioral problems in children with ASD. At follow-up, the low FODMAP diet group had significant relief in some GI problems compared with both baseline in the group and control group. At baseline and at follow-up, there were no significant differences in behavioral problems between the low FODMAP diet group and the control group. Randomized controlled studies including larger sample sizes are needed to confirm the effects of low FODMAP diets in children with autism who have gastrointestinal problems.

The interplay between gut microbiota and autism spectrum disorders: A focus on immunological pathways.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impairments in social and cognitive activities, stereotypical and repetitive behaviors and restricted areas of interest. A remarkable proportion of ASD patients represent immune dysregulation as well as gastrointestinal complications. Hence, a novel concept has recently emerged, addressing the possible intercommunication between the brain, the immune system, the gut and its commensals. Here, we provide an overview of how gut microbes and their metabolites are associated with neurobehavioral features of ASD through various immunologic mechanisms. Moreover, we discuss the potential therapeutic options that could modify these features.

Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review.

Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named "non-neuronal cells." In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells-and therefore the control of neuroinflammation-depends on the local "on demand" synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide-either by decreasing its degradation or exogenous administration-is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.

Efficacy of gluten- and casein-free diets on autism spectrum disorders in children.

Food containing gluten and casein could play a role in autism spectrum disorders (ASD) symptoms. The present review aimed to update the evidence about the role of the gluten- and casein-free diet (GCFD) on the management of ASD. Web of Science, Science Direct, Google Scholar, and PubMed databases were used to search for randomized controlled trials (RCT) conducted between January 2000 and February 2020. In total, 9 RCT were included (521 participants) with age range between 2 to 18 years. Four of these studies did not show a significant improvement regarding the symptoms of ASD. The rest of these studies (n=5) showed improvement in communication, stereotyped movements, aggressiveness, language, hyperactivity, tantrums, and signs of attention deficit hyperactivity disorder compared to control group. Hence, the data remains insu cient to support the use of GCFD to improve the symptoms of ASD in children.

Difficulties and factors influencing purchase decision. The perspective of families with children with autism spectrum disorders on a gluten-free and casein-free diet. Preliminary study.

Background: Gluten-free and casein-free diet is frequently used in the support of therapy of children with autism spectrum disorders. In addition, many parents restrict the consumption of simple sugars for their children. Objective: The aim of this paper was to understand factors influencing purchase decision in case of family with children with autism spectrum disorders on gluten-free and/or casein-free and/or sugar-free diet and the difficulties associated with this type of nutrition. Material and methods: The study covered a group of 40 families with children with autism spectrum disorders (32 boys and 8 girls) aged 3 to 10 years. Data were collected with questionnaire included questions concerning overall characteristics of caregivers, availability of foods used in the special diet, factors affecting decision on the purchase of products, difficulties in maintaining the child nutrition method. Results: The factors having strongest impact on parents' decisions on the purchase of products were product composition, presence of a certificate confirming the absence of gluten and/or milk and taste values. Exclusion diet constituted a considerable obstruction for traveling, social gatherings and resulted in conflicts with family and the environment. The limited range of healthy gluten-free, casein-free and sugar-free foods, low taste quality and unsatisfactory quality impeded purchase and preparation of varied meals. Conclusions: The surveyed parents were aware consumers, paying attention primarily to product composition and safety. The respondents were looking for healthy, organic and nutritionally valuable products with low sugar content. Further development of the gluten/casein/ sugar free products market may considerably improve certain aspects of family's life with children with autism spectrum disorders.

[Is there place for nutrition in the treatment of children with autism spectrum disorder?]

Autism is a neurodevelopmental disorder associated with significant social and financial burden. In recent years there has been an increasing interest in the use of dietary interventions as a complementary therapeutic option for these patients. The aim of this systematic review is to provide literature data about the effect of specific dietary interventions on clinical aspects of children with autism. For this reason, a literature search was conducted using Pubmed as the medical database source. No year-of-publication restriction was placed. Prospective studies conducted in pediatric populations and evaluating changes in clinical aspects of autism were considered. Types of dietary interventions evaluated in these studies included amino acids, fatty acids, vitamins/minerals, as well as specific diets (free of gluten/casein, ketogenic). The underlying mechanism of action of nutritional interventions in this pediatric population mainly includes regulation of neurotransmitters levels, as well as modification of gut microbiota. More specifically, Ν-acetylcysteine was shown to exert a beneficial effect on symptoms of irritability. This beneficial effect could be attributed to its antiglutamergic and antioxidative properties. With regards to fatty acids, it is known that they are involved in dopamine and serotonin metabolism, while low values of fatty acids have been reported in serum of patients with various neuropsychiatric disorders. However, their administration in children with autism did not make any difference in terms of clinical aspects of the disease. On the other hand, available literature data about effect of D-cycloserine, dimethylglycine and vitamins/minerals was either few or controversial. In parallel, we were able to identify in literature clinical studies showing a beneficial effect of gluten/casein-free and ketogenic diet on clinical phenotype of autism. Finally, it should be highlighted that no moderate or serious adverse events were reported in any of the above nutritional interventions. In general, current literature data is encouraging. Nevertheless, more randomized clinical trials are needed to more clearly confirm the effect of specific dietary interventions on clinical aspects of autism.

The Promising Role of Probiotics in Managing the Altered Gut in Autism Spectrum Disorders.

Gastrointestinal symptoms (GIS) have been reported repeatedly in people with autism spectrum disorder (ASD) and studies have reported interesting correlations between severity of behavioral and gastrointestinal symptoms. Growing evidence indicates that the gut microbiota in ASD is altered with various shifts described at different taxonomic levels, pointing to the importance of considering the gut-brain axis in treatment of these disorders. Probiotics are live beneficial bacteria that are ingested as food or customized pills. These beneficial bacteria, when added in sufficient amounts, can correct the dysbiosis. Because probiotics have shown success in treating irritable bowel syndrome (IBS), it is plausible to investigate whether they can induce alleviation of behavioral symptoms as well. Probiotics show, in some clinical studies, their potential benefits (1) in improving gastrointestinal dysfunction, (2) in correcting dysbiosis, (3) in consequently reducing the severity of ASD symptoms. This review compiles data from selected studies that investigate these benefits and the mechanisms that mediate these effects, which include the production of metabolites, hormones, and neurotransmitters and the regulation of pro-inflammatory and regulatory cytokines. Future research based on more randomized, controlled studies with a larger population size and standardized use of strains, concentration of probiotics, duration of treatments, and methods of DNA extraction is still needed in this area, which may lead to more robust results.

Problemas gastrointestinales, nutricionales, endocrinológicos y de microbiota en el trastorno del espectro autista / Gastrointestinal, nutritional, endocrine, and microbiota conditions in autism spectrum disorder

Los problemas médicos gastrointestinales, nutricionales, metabólicos, endocrinológicos y de microbiota en los pacientes pediátricos con diagnóstico de trastorno del espectro autista (TEA) son parte de los problemas médicos concomitantes al diagnóstico. La prevalencia alcanza a más del 91 % en el caso de los problemas gastrointestinales, hasta el 89 % para los nutricionales y metabólicos, más del 50 % de disfunción tiroidea y hasta el 100 % para los relacionados con la microbiota.Es urgente actualizar la práctica médica para incluir la evaluación, testeo, diagnóstico y tratamiento de estos problemas médicos concomitantes al diagnóstico de TEA en la población pediátrica, adolescente y adulta. El tratamiento riguroso de dichos problemas genera cambios positivos en la calidad de vida y en la sintomatología bajo la cual el TEA se diagnostica en muchos casos. Debe basarse en evidencia científica de alta calidad, con control y cuidado médico adecuado

Gastrointestinal, nutritional, metabolic, endocrine, and microbiota medical problems in pediatric patients diagnosed with autism spectrum disorder (ASD) are some of the coexisting medical conditions in ASD diagnosis. Their prevalence reaches more than 91 % for gastrointestinal problems, up to 89 % for nutritional and metabolic disorders, more than 50 % for thyroid dysfunction, and up to 100 % for microbiota-related conditions.There is an urgency for medical practice to be updated and to include the assessment, testing, diagnosis, and treatment of these coexisting medical conditions in ASD diagnosis in the pediatric, adolescent, and adult population. A strict management of such conditions results in positive changes in the quality of life and symptoms based on which ASD is diagnosed many times. It should be based on high-quality scientific evidence with an adequate medical care and control

Aberrant Mitochondrial Morphology and Function in the BTBR Mouse Model of Autism Is Improved by Two Weeks of Ketogenic Diet.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that exhibits a common set of behavioral and cognitive impairments. Although the etiology of ASD remains unclear, mitochondrial dysfunction has recently emerged as a possible causative factor underlying ASD. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that augments mitochondrial function, and has been shown to reduce autistic behaviors in both humans and in rodent models of ASD. The aim of the current study was to examine mitochondrial bioenergetics in the BTBR mouse model of ASD and to determine whether the KD improves mitochondrial function. We also investigated changes in mitochondrial morphology, which can directly influence mitochondrial function. We found that BTBR mice had altered mitochondrial function and exhibited smaller more fragmented mitochondria compared to C57BL/6J controls, and that supplementation with the KD improved both mitochondrial function and morphology. We also identified activating phosphorylation of two fission proteins, pDRP1S616 and pMFFS146, in BTBR mice, consistent with the increased mitochondrial fragmentation that we observed. Intriguingly, we found that the KD decreased pDRP1S616 levels in BTBR mice, likely contributing to the restoration of mitochondrial morphology. Overall, these data suggest that impaired mitochondrial bioenergetics and mitochondrial fragmentation may contribute to the etiology of ASD and that these alterations can be reversed with KD treatment.

AUTISM SPECTRUM DISORDER: A SYSTEMATIC REVIEW ABOUT NUTRITIONAL INTERVENTIONS.

OBJECTIVE: To identify and analyze the scientific evidence of nutritional interventions performed in children and adolescents with Autism Spectrum Disorder. DATA SOURCES: A systematic review was conducted in the MEDLINE, Cochrane Library, Embase, LILACS, Google Scholar, PubMed, PsycINFO and Periódicos CAPES databases, using a search strategy to identify studies published between January 2003 and March 2018, in Portuguese, English and Spanish. Were included studies that described nutritional interventions in children and adolescents with autism spectrum disorders and assessed autistic behavior and/or gastrointestinal symptoms. We excluded other review articles and studies that did not include a control group in the research design. The studies were reviewed for descriptive information, and the quality of evidence was assessed through the GRADE system. DATA SYNTHESIS: 18 studies were included in the review, being 16 randomized clinical trials, 1 case-control study and 1 open-label trial. As a result, the implementation of a gluten-free and casein-free diet was the most used intervention among the studies. Of the total, 10 studies showed a positive association of intervention with the evaluated results, while 8 did not find of a significant association. CONCLUSIONS: Although some authors report progress in the symptoms associated with autism in individuals with Autistic Spectrum Disorder undergoing nutritional interventions, there is little scientific evidence to support the use of nutritional supplements or dietary therapies in children and adolescents with autism.