Front. Psychiatry Frontiers in Psychiatry Front. Psychiatry 1664-0640 Frontiers Media S.A. 10.3389/fpsyt.2023.1119142 Psychiatry Mini Review The importance of comprehensive support based on the three pillars of exercise, nutrition, and sleep for improving core symptoms of autism spectrum disorders Yano Nozomu1* Hosokawa Kenji2 1Graduate School of Health Sciences, Doctoral Course, Kagoshima University Graduate School, Kagoshima, Japan 2Department of Child Care and Education, Odawara Junior College, Nagoya, Japan

Edited by: Leonardo Zoccante, Integrated University Hospital Verona, Italy

Reviewed by: Gianfranco Di Gennaro, University of Calabria, Italy

 *Correspondence: Nozomu Yano, k8047973@kadai.jp

This article was submitted to Autism, a section of the journal Frontiers in Psychiatry

 16 05 2023 2023 14 1119142 08 12 2022 15 03 2023 Copyright © 2023 Yano and Hosokawa. 2023 Yano and Hosokawa

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder. The Diagnostic and Statistical Manual of Mental Disorders (DSM)-V, which first described ASD, lists persistent deficits in social communication and interrelationships, as well as limited and recurrent modes of behavior, interests, and activities as diagnostic items. Until recently, understanding the pathophysiology of ASD has been mostly from a neurophysiological perspective, and interventions have been mostly behavioral and psychological. In recent years, however, it has become clear that ASD also affects many bodily systems, including the immune system, the sensorimotor system, and the gut-brain axis, and that these factors simultaneously influence it. In light of this background, a new “connectivome theory” has been proposed as a hypothesis for understanding ASD. “Exercise,” “nutrition,” and “sleep,” which are discussed in this mini-review, have a particularly strong relationship with the immune, musculoskeletal, and gut systems among the pathologies mentioned in the “connectivome theory,” furthermore, many reports suggest improvements in stereo-responsive behavior and social and communication skills, which are the core symptoms of ASD. In addition, these interventions are characterized by being less subject to location and cost limitations and excel in the continuity of therapeutic intervention, and the three interventions may have a reciprocal positive impact and may function as three pillars to support ASD.

 autism neurodevelopmental disorder exercise nutrition sleep Introduction

Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder (NDD) in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-V and International Statistical Classification of Diseases and Related Health Problems (ICD)-11. The DSM-V, which first described ASD, lists persistent deficits in social interaction and communication (Social communication: SC), as well as limited and repetitive patterns of behavior, interests, and activities (Stereotypic behavior: SB) as diagnostic items.

Many hypotheses have been proposed to interpret ASD based on the research findings of each era. For example, the “theory of mind disorder hypothesis” (1), the “synaptic abnormality hypothesis,” which seeks causes in abnormal synaptic connections such as Neuroligin (NLGN) and Neurexin (NRXN), which have been discovered as synaptic adhesion molecules (2), and the “serotonin hypothesis,” which theorizes the pathogenic mechanism of ASDs based on abnormalities in serotonin metabolism found in the brains of ASDs (3).

Although most studies have focused on the neurofunctional aspect of ASDs it has recently become clear that ASDs affect many bodily systems, including the immune system, the sensorimotor system, and the gut-brain axis, and that ASDs are affected by these factors simultaneously. In light of this background, Zoccante et al. (4) proposed a new “connectivome theory” as a hypothesis for understanding ASD.

This mini-review focuses on the topics of “exercise,” “nutrition,” and “sleep” as interventions for the conditions mentioned in the “connectivome theory” that are mainly related to the immune, musculoskeletal, and gut systems and are not limited by location or cost. Exercise, nutrition, and sleep are the three pillars for improving core symptoms of ASD (SB, SC), and the importance of each pillar and their interactions will be briefly introduced.

Exercise

Autism spectrum disorder also has a high 60–80% rate of motor impairment (5, 6). This is a significant social participation barrier and affects SC and SB (7). Exercise interventions are currently attracting attention due to their cost-effectiveness and multiplicity of effects. Here, we discuss previous studies of exercise interventions targeting SC and SB and present the mechanisms of the efficacy of exercise interventions and recommended parameters for such interventions.

Effects of exercise interventions

Various exercise interventions have been conducted to date, including aerobic exercises such as jogging and bicycling, martial arts such as karate and judo, ball-handling exercises such as basketball, swimming, and other physical activities such as dance, yoga, and games. These exercise interventions have commonly shown positive effects on physical and cognitive aspects as well as psychosocial aspects, such as improvements in SC and SB (8, 9).

For example, sports such as badminton are more effective for motivation and increasing exercise persistence than simple exercises such as treadmill running (10). In addition, team sports such as mini-basketball and compound exercises that combine several different exercises have been reported to be highly effective in improving psychosocial functioning because they stimulate more brain regions (11).

Furthermore, the effectiveness of interventions combining exercise with other therapies is now being demonstrated (12). Exercise, in particular, is a fundamental component of health and development, along with nutrition and sleep, and comprehensive support of these components is considered essential in the underlying treatment of ASD symptoms.

 Mechanisms of improvement with exercise intervention

Various hypotheses have been proposed regarding the mechanisms by which exercise improves core symptoms of ASD, but one primary mechanism is the regulation of metabolism. This involves the transport of trophic factors and neurotransmitters (13–15) and may contribute to improving core symptoms of ASD by temporarily normalizing brain activity.

In addition, metabolic modulation may progressively lead to structural and functional changes in the cranial nervous system. In this regard, a Chinese research team has used brain imaging techniques to find changes in white matter fiber connectivity with exercise intervention (16) and changes in functional brain connectivity such as the default mode network (DNM) and executive control network (ECN) during resting state (17, 18).

Furthermore, Wang et al. (19) reported improved executive function and SC after an exercise intervention similar to that of Yang et al. (18). In addition, a meta-analysis of these previous studies organized the neurological effects of exercise intervention into three categories: (1) stabilization of cortical arousal, (2) normalization of resting-state social brain connections, and (3) efficiency of executive processes (20).

 Time, frequency, and duration of recommended interventions

The time, frequency, and duration of intervention are essential variables that determine the magnitude and persistence of intervention effects (21). A meta-analysis of the effects of exercise interventions in RCTs reported that the range of time, frequency, and duration of interventions was 30–90 min *2–13 times per week *4–24 week. They further stated that long-term interventions of 45–75 min *1–2 times per week *12 weeks or longer were necessary to increase motor skills (20). similarly stated that long-term interventions are more effective than short-term interventions, recommending interventions of at least 50 min *1–2 times per week *10 weeks or more to produce neurological changes and improved psychosocial functioning.

Nekar et al. (22) stated that “the major limitation of cognitive and social training in children with autism remains the engagement and motivation of the children to participate in the intervention program,” and it is essential to optimize exercise events, content, and teaching methods to increase exercise persistence.

 Recommended exercise intensity

Exercise intensity is essential for the operation of metabolic and associated neurological mechanisms. Exercise intensity is usually measured by heart rate, and Lang et al. (9) suggest that more intense exercise produces more pronounced effects than gentle exercise. The World Health Organization (WHO) recommends 60–69% of maximal heart rate (MHR = 220 – participant’s age) as moderate to vigorous physical activity (MVPA) (23). In contrast, Tse et al. (24) stated that for children with ASD, more than 50% of MHR should be considered MVPA given their low physical activity levels.

Considering that longer-term interventions can have more significant effects, continuity of exercise should be a priority, and it would be advisable to approach MVPA in stages, with the assessment of rating of perceived exertion (RPE), as physical fitness levels vary from individual to individual.

 Recommended methods of teaching movement

In addition to core symptoms, children with ASD have low motor function and difficulty with confidence and competence. In light of this, most researchers conducting exercise interventions mention step-by-step instructional methods (small-step instructional methods) and errorless learning based on behavioral findings (11, 19, 22). This is important in avoiding psychological anxiety, frustration, and helplessness in children and enhancing exercise continuity.

Finally, while physical activity has been restricted in recent years by the new coronavirus, online meeting tools have spread rapidly. Taking advantage of this, several researchers have proposed telehealth physical activity support (25–28). This method, in which professional support personnel provides exercise coaching and feedback on results, could be an effective means of increasing home-based exercise practices during the coronavirus.

 Nutrition

Autism spectrum disorders are frequently associated with eating disorders (29, 30). They are characterized by a preference for foods high in calories and low in nutrients and an aversion to fruits, vegetables, and grains (31–34). Due to this, they are deficient in micronutrients such as iron, calcium, iodine, magnesium, selenium, vitamins D, E, B 12, folic acid, and biotin, and the need for nutritional management is undisputed. In addition, adequate intake of nutrients requires the presence of a healthy digestive system for uptake by the body (35).

Here we present interventions for micronutrient deficiencies that may contribute to reducing SB and improving SC, as well as interventions from a brain-gut-microbiota axis perspective.

Interventions for micronutrient deficiencies

Vitamin supplementation has been suggested by many studies to be effective in improving metabolic and nutritional status in ASD, including mitigation of glutathione, methylation, sulfation, oxidative stress, NADH, ATP, and NADPH (36). Antioxidant vitamin C supplementation improves SB and decreases autism severity (37), and Vitamin D supplementation, which helps functional protein function, improves autism severity, SC, and SB (38). Some have reported improved SC and SB with a combined supplementation of vitamin B6, which acts as a coenzyme, and magnesium (39). Among these, folic acid has attracted attention due to its important function in metabolism and its importance in ASD. The effects of folic acid supplementation on ASD have been reported to improve SC, SB, and verbal communication disorders (40, 41).

 Interventions from the brain-gut-microbiota axis perspective

There is bidirectional communication between the gut-brain axis, which can regulate gastrointestinal tract and central nervous system functions, and the gut microbiota is believed to play an important role in regulating this bidirectional signaling (42).

The ketogenic diet (KD) involves a high-fat, adequate-protein, low-carbohydrate diet (43–45). KD may improve core symptoms of ASD by normalizing GABA, improving mitochondrial function, improving inflammatory activity and oxidative stress in the brain, inhibiting the mTOR signaling pathway, and modulating the gut microbiota (46).

A gluten- and casein-free diet (GFCF) removes casein from milk and dairy products and gluten from wheat (47). In a meta-analysis reported by Keller et al. (48), providing the GFCF diet to children and adolescents with ASD is no benefit for clinician-reported core symptoms of autism or parent-reported functioning levels and behavioral difficulties. On the contrary, the GFCF diet may cause adverse gastrointestinal effects (48). On the other hand, a meta-analysis reported in 2022 by Quan et al. (49) showed that the GFCF diet could reduce SB, improve perceptions of ASDs, and is safe (49). More extensive studies are needed to conclude the effectiveness and safety of the GFCF diet.

In the intervention comparing KD and GFCF diets, both KD and GFCF diets showed significant improvement in ASD severity compared to the control group. On the other hand, KD showed better results in cognition and SC compared to the GFCF diet, and the GFCF diet showed better results in SB improvement than KD (both p > 0.05) (50).

Gastrointestinal symptoms with ASDs are associated with behavioral disorders, sleep disturbances, and attention problems (51, 52).

Autism spectrum disorders have been shown to have large amounts of harmful bacteria and fewer beneficial bacteria in their intestines compared to typically developing children (53).

As defined by the International Scientific Association for Probiotics and Prebiotics (ISAPP), probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host” New interventions are expected to include prob. and their growth factors, prebiotics (54).

These effects have been reported to include decreased ASD severity, increased attention level, decreased SB, improved SC, and improved gastrointestinal disturbances (55–58).

On the other hand, the results of the meta-analysis showed no significant improvement in ASD severity, gastrointestinal problems, or psychopathology comorbid with ASD. However, they cite the small number of background studies and methodological uncertainty as concerns and conclude that further research on standardized intervention programs is needed (59). And a research protocol for a large-scale randomized controlled trial of probiotics and prebiotics is currently being drafted (60).

We hope that the study will proceed successfully and that it will yield better results. Although we have presented the effectiveness of single nutritional interventions, nutritional interventions need to be comprehensive, observing the individual’s condition.

In a comprehensive nutrition intervention by Adamas et al. that sequentially deployed vitamin and mineral supplementation, essential fatty acid supplementation, Epsom salt baths, carnitine supplementation, digestive enzyme supplementation, GFCF, and healthy eating, the result was a significant improvement in ASD severity, communication, social skills, sensory deficits, and developmental age. It should be noted, however, that in some cases, there were detrimental effects in the process (61).

As we can learn from this excellent study, we will need to pay attention to the eating disorders of ASDs and comprehensive nutritional interventions.

 Sleep

Sleep disorders are often a problem in ASDs, with prevalence rates ranging from 64 to 93% (62). The most common sleep problems are insomnia, increased bedtime resistance, sleep-disordered breathing, early morning awakenings, and daytime sleepiness (63). And it has been reported that ASD sleep disturbances are associated with SB and ASD severity (64–66). Here we present a report of a sleep disorder intervention that led to a reduction in SB and an improvement in SC.

The American Academy of Neurology published guidelines on sleep disturbances in ASD in 2020, which stated that melatonin, and cognitive behavioral therapy (CBT), alone or in combination, are highly effective in resistance to sleep, falling asleep, and staying asleep (67).

As noted above, there are many reports that provide evidence that sleep disturbances exacerbate ASD symptoms (68). On the other hand, not many reports examine whether sleep interventions changed SB and SC in ASDs. However, reports suggest that persistent melatonin improves self-aggressive internalizing behaviors such as withdrawal, anxiety, and depression (69), and interesting reports have emerged from telephone-based sleep consultant interventions for parents with children with coexisting ASD and ADHD, which have shown improvement in sleep problems and improvements in, SB, and SC (70).

 Interrelationships among the three pillars of “exercise,” “nutrition,” and “sleep”

From the above, it seems as if “exercise,” “nutrition,” and “sleep” each have an independent influence on ASD. However, I will briefly introduce the connection between the three elements, including the author’s thoughts.

Adequate nutrition is the foundation of exercise (physical activity), but the view may be broadened when “depression and stress” are intervened. Adequate nutrition and improvement of the intestinal environment have been shown to contribute to the improvement of depression and stress and may well be expected to increase social participation and physical activity. Increased physical activity has been suggested to regulate hunger for ASDs as well as for typically developing children (71), and it is expected to positively impact improving the eating habits of ASD. Moreover, this is not only true in the nutrition-to-exercise direction; depression and stress negatively affect exercise (physical activity), nutrition (appetite), and sleep. And given that exercise, nutrition, and sleep have each been shown to have a positive effect on depression and stress, and it can be assumed that each intervention interacts with the other. The effects of aerobic exercise have been reported to improve sleep efficiency, shorten sleep onset latency, and delay waking time after falling asleep (72, 73). Furthermore, there are reports that a combination of regular exercise and high protein intake (nutrition) contributes to good sleep quality (74). In addition, taking into account that gut microbiota and related metabolites have been suggested to be altered in ASDs sleep disorders, it is clear that the elements of “exercise,” “nutrition,” and “sleep” are inextricably linked (75).

 Conclusion

Until now, behavioral and psychological interventions have dominated most interventions for ASDs, but their impact has been limited. The exercise, nutrition, and sleep interventions presented in this review have been effective in improving social communication, and stereotypic behavior in ASDs in many cases and have the advantage of being less constrained by location and cost and can be started at any time. We hope that the interventions for ASDs will be more comprehensive and help people to have a richer social life.

 Author contributions

NY and KH: conception and design of the study, data collection, data analysis and interpretation, writing the manuscript, revising it critically for important intellectual content, final approval of the version to be submitted. All authors contributed to the article and approved the submitted version.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

The authors would like to thank the Official Journal of the Japanese Society of Child Neurology and all the researchers who have contributed to treating ASD.

 References Baron-Cohen AM Leslie UF. Does the autistic child have a theory of mind? Cognition. (1985) 21:37–46. doi: 10.1016/0010-0277(85)90022-8 Carroll L Braeutigam S Dawes JM Krsnik Z Kostovic I Coutinho E . Autism Spectrum disorders: multiple routes to, and multiple consequences of, abnormal synaptic function and connectivity. Neuroscientist. (2021) 27:10–29. doi: 10.1177/1073858420921378, PMID: 32441222 Harrington RA Lee L-C Crum RM Zimmerman AW Hertz-Picciotto I. Serotonin hypothesis of autism: implications for selective serotonin reuptake inhibitor use during pregnancy. Autism Res. (2013) 6:149–68. doi: 10.1002/aur.1288, PMID: 23495208 Zoccante L Ciceri ML Gozzi LA Gennaro GD Zerman N. The connectivome theory: a new model to understand autism spectrum disorders. Front Psych. (2022) 12:794516. doi: 10.3389/fpsyt.2021.794516, PMID: 35250650 Green D Charman T Pickles A Chandler S Loucas T Simonoff E . Impairment in movement skills of children with autistic spectrum disorders. Dev Med Child Neurol. (2009) 51:311–6. doi: 10.1111/j.1469-8749.2008.03242.x, PMID: 19207298 Sokhadze EM Tasman A Sokhadze GE El-Baz AS Casanova MF. Behavioral, cognitive, and motor preparation deficits in a visual cued spatial attention task in autism spectrum disorder. Appl Psychophysiol Biofeedback. (2016) 41:81–92. doi: 10.1007/s10484-015-9313-x, PMID: 26377686 Pan CY Frey GC. Physical activity patterns in youth with autism spectrum disorders. J Autism Dev Disord. (2006) 36:597–606. doi: 10.1007/s10803-006-0101-6, PMID: 16652237 Zhao M Chen S. The effects of structured physical activity program on social interaction and communication for children with autism. Biomed Res Int. (2018) 2018:1–13. doi: 10.1155/2018/1825046 Lang R Koegel LK Ashbaugh K Regester A Ence W Smith W. Physical exercise and individuals with autism spectrum disorders: a systematic review. Res Autism Spectr Disord. (2010) 4:565–76. doi: 10.1016/j.rasd.2010.01.006 Chen CJ Ryuh YJ Donald M Rayner M. The impact of badminton lessons on health and wellness of young adults with intellectual disabilities: a pilot study. Int J Dev Disabil. (2021) 68:703–11. doi: 10.1080/20473869.2021.1882716, PMID: 36210894 Haghighi AH Broughani S Askari R Shahrabadi H Souza D Gentil P. Combined physical training strategies improve physical fitness, behavior, and social skills of autistic children. J Autism Dev Disord. (2022). doi: 10.1007/s10803-022-05731-8, PMID: 36083392 Mahmoodifar E Sotoodeh MS. Combined transcranial direct current stimulation and selective motor training enhances balance in children with autism spectrum disorder. Percept Mot Skills. (2020) 127:113–25. doi: 10.1177/0031512519888072, PMID: 31744385 Bamidis PD Vivas AB Styliadis C Frantzidis C Klados M Schlee W . A review of physical and cognitive interventions in aging. Neurosci Biobehav Rev. (2014) 44:206–20. doi: 10.1016/j.neubiorev.2014.03.019, PMID: 24705268 Fissler P Küster O Schlee W Kolassa IT. Novelty interventions to enhance broad cognitive abilities and prevent dementia: synergistic approaches for the facilitation of positive plastic change. Prog Brain Res. (2013) 207:403–34. doi: 10.1016/B978-0-444-63327-9.00017-5, PMID: 24309264 Herold F Hamacher D Schega L Müller NG. Thinking while moving or moving while thinking - concepts of motor-cognitive training for cognitive performance enhancement. Front Aging Neurosci. (2018) 10:228. doi: 10.3389/fnagi.2018.00228, PMID: 30127732 Cai K Yu Q Herold F Liu Z Wang J Zhu L . Mini-basketball training program improves social communication and white matter integrity in children with autism. Brain Sci. (2020) 10:803. doi: 10.3390/brainsci10110803, PMID: 33142694 Yu H Qu H Chen A Du Y Liu Z Wang W. Alteration of effective connectivity in the default mode network of autism after an intervention. Front Neurosci. (2021) 15:796437. doi: 10.3389/fnins.2021.796437, PMID: 35002608 Yang S Liu Z Xiong X Cai K Zhu L Dong X . Effects of mini-basketball training program on social communication impairment and executive control network in preschool children with autism Spectrum disorder. Int J Environ Res Public Health. (2021) 18:5132. doi: 10.3390/ijerph18105132, PMID: 34066139 Wang JG Cai KL Liu ZM Herold F Zou L Zhu LN . Effects of mini-basketball training program on executive functions and Core symptoms among preschool children with autism Spectrum disorders. Brain Sci. (2020) 10:263. doi: 10.3390/brainsci10050263, PMID: 32365853 Su WC Amonkar N Cleffi C Srinivasan S Bhat A. Neural effects of physical activity and movement interventions in individuals with developmental disabilities-a systematic review. Front Psych. (2022) 13:794652. doi: 10.3389/fpsyt.2022.794652, PMID: 35242063 Huang J Du C Liu J Tan G. Meta-analysis on intervention effects of physical activities on children and adolescents with autism. Int J Environ Res Public Health. (2020) 17:1950. doi: 10.3390/ijerph17061950, PMID: 32192008 Nekar DM Kang H Alao H Yu J. Feasibility of using multiplayer game-based dual-task training with augmented reality and personal health record on social skills and cognitive function in children with autism. Children (Basel). (2022) 9:1398. doi: 10.3390/children9091398, PMID: 36138707 Bull FC Al-Ansari SS Biddle S Borodulin K Buman MP Cardon G . World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br J Sports Med. (2020) 54:1451–62. doi: 10.1136/bjsports-2020-102955, PMID: 33239350 Tse ACY Lee PH Zhang J Lai EWH. Study protocol for a randomised controlled trial examining the association between physical activity and sleep quality in children with autism spectrum disorder based on the melatonin-mediated mechanism model. BMJ Open. (2018) 8:e020944. doi: 10.1136/bmjopen-2017-020944, PMID: 29654045 Bhat A Su WC Cleffi C Srinivasan S. A hybrid clinical trial delivery model in the COVID-19 era. Phys Ther. (2021) 101:pzab116. doi: 10.1093/ptj/pzab116, PMID: 33909902 Cleffi C Su WC Srinivasan S Bhat A. Using telehealth to conduct family-centered, movement intervention research in children with autism Spectrum disorder during the COVID-19 pandemic. Pediatr Phys Ther. (2022) 34:246–51. doi: 10.1097/PEP.0000000000000872, PMID: 35184077 Srinivasan SM Su WC Cleffi C Bhat AN. From social distancing to social connections: insights from the delivery of a clinician-caregiver co-mediated telehealth-based intervention in young children with autism Spectrum disorder. Front Psych. (2021) 12:700247. doi: 10.3389/fpsyt.2021.700247, PMID: 34276452 Su WC Srinivasan S Cleffi C Bhat A. Short report on research trends during the COVID-19 pandemic and use of telehealth interventions and remote brain research in children with autism spectrum disorder. Autism. (2021) 25:1816–22. doi: 10.1177/13623613211004795, PMID: 33836625 Ledford JR Gast DL. Feeding problems in children with autism spectrum disorders: a review. Focus Autism Other Dev Disabil. (2006) 21:153–66. doi: 10.1177/10883576060210030401 Cermak SA Curtin C Bandini LG. Food selectivity and sensory sensitivity in children with autism spectrum disorders. J Am Diet Assoc. (2010) 110:238–46. doi: 10.1016/j.jada.2009.10.032 Green G. An assessment of food acceptance in children with autism or pervasive developmental disorder—not otherwise specified. J Autism Dev Disord. (2001) 31:505–11. doi: 10.1023/A:1012221026124 Schreck KA Williams K Smith AF. A comparison of eating behavior between children with and without autism. J Autism Dev Disord. (2004) 34:433–8. doi: 10.1023/B:JADD.0000037419.78531.86 Williams KE Gibbons BG Schreck KA. Comparing selective eaters with and without developmental disabilities. J Dev Phys Disabil. (2005) 17:299–309. doi: 10.1007/s10882-005-4387-7 Sharp WG Berry RC McCracken C Nuhu NN Marvel E Saulnier CA . Feeding problems and nutrient intake in children with autism Spectrum disorders: a meta-analysis and comprehensive review of the literature. J Autism Dev Disord. (2013) 43:2159–73. doi: 10.1007/s10803-013-1771-5, PMID: 23371510 Ranjan S Nasser JA. Nutritional status of individuals with autism spectrum disorders: do we know enough? Adv Nutr. (2015) 6:397–407. doi: 10.3945/an.114.007914, PMID: 26178024 Bjørklund G Waly MI Al-Farsi Y Saad K Dadar M Rahman Md. M . The role of vitamins in autism Spectrum disorder: what do we know? J Mol Neurosci. (2019) 67:373–87. doi: 10.1007/s12031-018-1237-5, PMID: 30607900 Dolske MC Spollen J McKay S Lancashire E Tolbert L. A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog Neuro-Psychopharmacol Biol Psychiatry. (1993) 17:765–74. doi: 10.1016/0278-5846(93)90058-Z, PMID: 8255984 Saad K Abdel-Rahman AA Elserogy YM Al-Atram AA Cannell JJ Bjørklund G . Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children. Nutr Neurosci. (2016) 19:346–51. doi: 10.1179/1476830515Y.0000000019, PMID: 25876214 Mousain-Bosc M Roche M Polge A Pradal-Prat D Rapin J Bali JP. Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. II Pervasive developmental disorder-autism. Mag Res. (2006) 19:53–62. Frye R Slattery J Delhey L Furgerson B Strickland T Tippett M . Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. (2018) 23:247–56. doi: 10.1038/mp.2016.168, PMID: 27752075 Sun C Zou M Zhao D Xia W Wu L. Efficacy of folic acid supplementation in autistic children participating in structured teaching: an open-label trial. Nutrients. (2016) 8:337. doi: 10.3390/nu8060337, PMID: 27338456 Van De Sande M Van Buul V Brouns F. Autism and nutrition: the role of the gut–brain axis. Nutr Res Rev. (2014) 27:199–214. doi: 10.1017/S0954422414000110 Newell CB Bomhof MR Reimer RA Hittel DS Rho JM Shearer J. Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder. Mol Autism. (2016) 7:37. doi: 10.1186/s13229-016-0099-3, PMID: 27594980 Evangeliou A Vlachonikolis I Mihailidou H Spilioti M Skarpalezou A Makaronas N . Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. (2003) 18:113–8. doi: 10.1177/08830738030180020501, PMID: 12693778 Frye RE Sreenivasula S Adams JB. Traditional and non-traditional treatments for autism spectrum disorder with seizures: an on-line survey. BMC Pediatr. (2011) 11:37. doi: 10.1186/1471-2431-11-37, PMID: 21592359 Qinrui L Jingjing L Na F Ying H Jiong Q. A ketogenic diet and the treatment of autism spectrum disorder. Front Pediatr. (2021) 9. doi: 10.3389/fped.2021.650624 Elder JH Kreider CM Schaefer NM de Laosa MB. A review of gluten- and casein-free diets for treatment of autism: 2005-2015. Nutr Diet Suppl. (2015) 7:87–101. doi: 10.2147/NDS.S74718, PMID: 28111520 Keller A Rimestad ML Friis Rohde J Holm Petersen B Bruun Korfitsen C Tarp S . The effect of a combined gluten- and casein-free diet on children and adolescents with autism Spectrum disorders: a systematic review and meta-analysis. Nutrients. (2021) 13:470. doi: 10.3390/nu13020470, PMID: 33573238 Quan L Xu X Cui Y Han H Hendren RL Zhao L . A systematic review and meta-analysis of the benefits of a gluten-free diet and/or casein-free diet for children with autism spectrum disorder. Nutr Rev. (2022) 80:1237–46. doi: 10.1093/nutrit/nuab073, PMID: 34617108 El-Rashidy O El-Baz F El-Gendy Y Khalaf R Reda D Saad K. Ketogenic diet versus gluten free casein free diet in autistic children: a case-control study. Metab Brain Dis. (2017) 32:1935–41. doi: 10.1007/s11011-017-0088-z, PMID: 28808808 Restrepo B Angkustsiri K Taylor SL Rogers SJ Cabral J Heath B . Developmental-behavioral profiles in children with autism spectrum disorder and co-occurring gastrointestinal symptoms. Autism Res. (2020) 13:1778–89. doi: 10.1002/aur.2354, PMID: 32767543 McCue LM Flick LH Twyman KA Xian H. Gastrointestinal dysfunctions as a risk factor for sleep disorders in children with idiopathic autism spectrum disorder: a retrospective cohort study. Autism. (2017) 21:1010–20. doi: 10.1177/1362361316667061 Iglesias-Vázquez L Van Ginkel Riba G Arija V Canals J. Composition of gut microbiota in children with autism Spectrum disorder: a systematic review and meta-analysis. Nutrients. (2020) 12:792. doi: 10.3390/nu12030792, PMID: 32192218 Hill C Guarner F Reid G Gibson GR Merenstein DJ Pot B . Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. (2014) 11:506–14. doi: 10.1038/nrgastro.2014.66, PMID: 24912386 Grimaldi R Gibson GR Vulevic J Giallourou N Castro-Mejía JL Hansen LH . A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome. (2018) 6:133. doi: 10.1186/s40168-018-0523-3, PMID: 30071894 Shaaban SY El Gendy YG Mehanna NS El-Senousy WM El-Feki HSA Saad K . The role of probiotics in children with autism spectrum disorder: a prospective, open-label study. Nutr Neurosci. (2018) 21:676–81. doi: 10.1080/1028415X.2017.1347746, PMID: 28686541 Mensi MM Rogantini C Marchesi M Borgatti R Chiappedi M. Lactobacillus plantarum PS128 and other probiotics in children and adolescents with autism Spectrum disorder: a real-world experience. Nutrients. (2021) 13:2036. doi: 10.3390/nu13062036, PMID: 34198499 Elisa S Letizia G Margherita P Sara C Melania G Fabio A . Effects of probiotic supplementation on gastrointestinal, sensory and Core symptoms in autism Spectrum disorders: a randomized controlled trial. Front Psych. (2020) 11. doi: 10.3389/fpsyt.2020.550593, PMID: 33101079 Song W Zhang M Teng L Wang Y Zhu L. Prebiotics and probiotics for autism spectrum disorder: a systematic review and meta-analysis of controlled clinical trials. J Med Microbiol. (2022) 71. doi: 10.1099/jmm.0.001510, PMID: 35438624 Zhang L Xu Y Li H Li B Duan G Zhu C. The role of probiotics in children with autism spectrum disorders: a study protocol for a randomised controlled trial. PLoS One. (2022) 17:e0263109. doi: 10.1371/journal.pone.0263109, PMID: 35202432 Adams JB Audhya T Geis E Gehn E Fimbres V Pollard EL . Comprehensive nutritional and dietary intervention for autism spectrum disorder-a randomized, controlled 12-month trial. Nutrients. (2018) 10:369. doi: 10.3390/nu10030369, PMID: 29562612 Claudia C Laura P Danila C Isabella M Lino N Antonio V . Systematic review of sleep disturbances and circadian sleep desynchronization in autism spectrum disorder: toward an integrative model of a self-reinforcing loop. Front Psych. (2019) 10:366. doi: 10.3389/fpsyt.2019.00366 Kose S Yilmaz H Ocakoglu FT Ozbaran NB. Sleep problems in children with autism spectrum disorder and intellectual disability without autism spectrum disorder. Sleep Med. (2017) 40:69–77. doi: 10.1016/j.sleep.2017.09.021, PMID: 29221782 Yang XL Liang S Zou MY Sun CH Han PP Jiang XT . Are gastrointestinal and sleep problems associated with behavioral symptoms of autism spectrum disorder? Psychiatry Res. (2018) 259:229–35. doi: 10.1016/j.psychres.2017.10.040 Johnson CR Smith T DeMand A Lecavalier L Evans V Gurka M . Exploring sleep quality of young children with autism spectrum disorder and disruptive behaviors. Sleep Med. (2018) 44:61–6. doi: 10.1016/j.sleep.2018.01.008 Souders MC Zavodny S Eriksen W Sinko R Connell J Kerns C . Sleep in children with autism spectrum disorder. Curr Psychiatry Rep. (2017) 19:34. doi: 10.1007/s11920-017-0782-x Buckley AW Hirtz D Oskoui M Armstrong MJ Batra A Bridgemohan C . Practice guideline: treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder. Report of the guideline development, dissemination, and implementation Subcommittee of the American Academy of Neurology. Neurology. (2020) 94:392–404. doi: 10.1212/WNL.0000000000009033, PMID: 32051244 Cohen S Conduit R Lockley SW Rajaratnam SMW Cornish KM. The relationship between sleep and behavior in autism spectrum disorder (ASD): a review. J Neurodevelop Disord. (2014) 6:44. doi: 10.1186/1866-1955-6-44, PMID: 25530819 Schroder CM Malow BA Maras A Melmed RD Findling RL Breddy J . Pediatric prolonged-release melatonin for sleep in children with autism Spectrum disorder: impact on child behavior and Caregiver’s quality of life. J Autism Dev Disord. (2019) 49:3218–30. doi: 10.1007/s10803-019-04046-5, PMID: 31079275 Papadopoulos N Sciberras E Hiscock H Mulraney M McGillivray J Rinehart N. The efficacy of a brief behavioral sleep intervention in school-aged children with ADHD and comorbid autism spectrum disorder. J Atten Disord. (2019) 23:341–50. doi: 10.1177/1087054714568565, PMID: 25646022 Jones RA Downing K Rinehart NJ Barnett LM May T McGillivray JA . Physical activity, sedentary behavior and their correlates in children with autism spectrum disorder: a systematic review. PLoS One. (2017) 12:e0172482. doi: 10.1371/journal.pone.0172482, PMID: 28245224 Brand S Jossen S Holsboer-Trachsler E Pühse U Gerber M. Impact of aerobic exercise on sleep and motor skills in children with autism spectrum disorders - a pilot study. Neuropsychiatr Dis Treat. (2015) 11:1911–20. doi: 10.2147/NDT.S85650, PMID: 26346856 Oriel KN Kanupka JW DeLong KS Noel K. The impact of aquatic exercise on sleep behaviors in children with autism Spectrum disorder: a pilot study. Focus Autism Other Dev Disabil. (2016) 31:254–61. doi: 10.1177/1088357614559212 Suzuki F Morita E Miyagi S Tsujiguchi H Hara A Nguyen TTT . Protein intake in inhabitants with regular exercise is associated with sleep quality: results of the Shika study. PLoS One. (2021) 16:e0247926. doi: 10.1371/journal.pone.0247926, PMID: 33635905 Xueying H Jiang Z Ting Y Min G Qiu L Jie C . The gut microbiota and associated metabolites are altered in sleep disorder of children with autism spectrum disorders. Front Psych. (2020) 11:855. doi: 10.3389/fpsyt.2020.00855, PMID: 32982808