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1 June 2023

Interconnection between Microbiota–Gut–Brain Axis and Autism Spectrum Disorder Comparing Therapeutic Options: A Scoping Review

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1
Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy
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Implant Dentistry College of Medicine and Dentistry Birmingham, University of Birmingham, Birmingham B4 6BN, UK
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Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Microorganisms2023, 11(6), 1477;https://doi.org/10.3390/microorganisms11061477
This article belongs to the Special Issue Host-Associated Microbiome and the Diet-Gut-Brain Axis
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Abstract

Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental illnesses characterized by difficulty in social communication, social interaction, and repetitive behaviors. These clinical diagnostic criteria can be seen in children as early as one year old and are commonly associated with long-term difficulties. ASD is connected with a higher frequency of various medical diseases such as gastrointestinal complaints, seizures, anxiety, interrupted sleep, and immunological dysfunction, in addition to the range of developmental abnormalities listed. Methods: From 1 January 2013 to 28 February 2023, we searched PubMed, Scopus and Web of Science for English-language papers that matched our topic. The following Boolean keywords were utilized in the search approach: “autism” AND “microbiota”. After deleting duplicates, a total of 2370 publications were found from the databases, yielding 1222 articles. (1148). Nine hundred and eighty-eight items were excluded after their titles and abstracts were scrutinized. The method resulted in the removal of 174 items for being off-topic. The final 18 articles for qualitative analysis are included in the evaluation. Conclusion: The findings of this extensive study revealed that probiotics, prebiotics, their combination as synbiotics, fecal microbiota transplantation, and microbiota transfer therapy may benefit ASD patients suffering from both gastrointestinal and central nervous system symptoms.

1. Introduction

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by a variety of deficits in behavioral areas such as social communication, social interaction, and repetitive activities [1]. These clinical diagnostic criteria can be seen in children as early as one year old and are often associated with lifetime difficulties [2]. ASD is associated with a higher prevalence of other medical conditions, such as gastrointestinal (GI) symptoms, seizures, anxiety, disordered sleep, and immune dysfunction, in addition to the spectrum of developmental impairments described; these conditions may have an impact on individual and family quality of life, as well as increase the cost and complexity of medical care [3,4,5]. GI problems, in particular diarrhea, constipation, and abdominal discomfort, are commonly reported in children with ASD, and growing data suggest that GI comorbidity may have downstream consequences on problematic behaviors in ASD [6]. A relationship between the gut and the brain has long been suspected, but research in recent years has begun to investigate the gut–brain interaction in ASD, leading to the identification of links between the gut microbiota (GM) and the pathophysiology of ASD [7]. Microorganisms (mostly bacteria, but also fungi, viruses, archaea, bacteriophages, and protozoa) that live in the lower GI tract, particularly the small intestine and colon, are referred to as the gut microbiome [7,8]. Individuals with ASD have altered gut bacteria profiles when compared to neurotypical controls, suggesting a potential role for GM in ASD [9,10,11]. The influence of GM on the GI system has been widely established, with GI motility, intestinal epithelial permeability, and mucus production all being influenced [12]. The severity of GI symptoms in ASD patients has been linked to derangements in the GM, such as during antibiotic administration. It was also discovered that if the antibiotics were withdrawn, the GI and behavioral problems resolved [13,14]. This offers new study opportunities for the function of GM-altering medicines such as probiotics as a possible treatment alternative. Recent research suggests that probiotics can help with a variety of psychological symptoms, including depression and anxiety [15,16]. The microbiota–gut–brain axis (MGBA) is thought to be a complex interaction between the brain and the GI tract [17]. The gut bacteria play a crucial role in controlling this gut–brain axis, and dysbiosis can have a deleterious impact not only on the GI tract but also on psychiatric symptoms [18,19]. Food restrictions and supplements have been studied in the therapy of ASD symptoms [20]. Apart from probiotics, the effect of prebiotics on the gut flora should not be overlooked. Nondigestible carbohydrates are one example. Exclusion diets and prebiotics were recently studied in children with ASD, with results showing substantial changes in GM composition and metabolism, as well as improvement in GI and behavioral symptoms [21,22]. A recent study found that transplanting gut microbial communities from ASD patients to wild-type germ-free mice induced classic autistic symptoms (increased repetitive behavior, decreased locomotion, and decreased communication compared to mice colonized with samples from typically developing controls) [23]. Treatment with microbial metabolites reduced (i.e., 5-aminovaleric acid) in the ASD microbiome; on the other hand, it regulated neuronal excitability in the prefrontal cortex (a regulator of social cognition), hence enhancing repetitive and social behaviors [23,24,25]. These findings provide additional evidence for a link between the GM and the area of the central nervous system (CNS) that underpins the pathology of ASD, providing a possible foundation for modulating the microbiota–gut–brain axis with microbial-based therapies to address ASD behavioral symptoms. Probiotics and prebiotics have received a lot of interest as possible therapy for ASD [26,27]. When a probiotic and a prebiotic are combined to provide health advantages, the combo is referred to as a complementary synbiotic (each component operates independently) or a synergistic synbiotic (prebiotic is selectively utilized by the co-administered live microorganisms) [28]. Fecal microbiota transplantation (FMT) is another treatment option being researched in ASD [29,30,31]. FMT may rebuild the recipient’s microbiota in a considerable and long-lasting way by injecting a solution of fecal matter from a healthy donor into the recipient’s digestive tract [32]. In 2019, the FDA awarded fast track status to an FMT therapy for the children with ASD [33]. In reference to this, one must also consider that microbiota transfer treatment (MTT), a treatment that includes antibiotics, an intestinal cleanse, a stomach acid suppressor, and FMT therapy, was developed. These therapies may influence ASD symptoms or progression via multiple GM-mediated immune, endocrine, and direct neural pathways (Figure 1) [7].
Figure 1. Manipulation of microbiota–gut–brain signals in autism spectrum disorder (ASD) using probiotics or fecal microbiota transplantation (FMT). The red arrows represent processes related with gut dysfunction and gut microbiota disturbances, whereas the blue arrows represent probiotic/prebiotic/FMT processes and effects. The vagus nerve (yellow) connects to enteric neurons and acts as a communication link between the gut and the brain.
Locally, these actions may change the microbial ecology toward helpful bacteria and away from harmful bacteria [34]. Beneficial bacteria may boost the synthesis of microbial metabolites (for example, short-chain fatty acids (SCFAs)) and anti-inflammatory cytokines, which may improve intestinal barrier integrity and reduce intestinal and systemic inflammation [35]. Moreover, neuroactive metabolites such as SCFAs may have an influence on the CNS by modulating neuroplasticity, epigenetics, and gene expression [36]. The vagus nerve is a primary communication channel between the stomach and the brain that is activated in response to particular microorganisms. The stimulation of the vagus nerve, as carried out using L. reuteri therapy, may enhance oxytocin levels in the brain, positively altering behavioral elements of brain function [37]. Moreover, neurotransmitters and their precursors, such as gamma-aminobutyric acid (GABA), serotonin (5-hydroxytryptamine), tryptophan, glutamate, and dopamine, are produced by the microbiota [38,39]. Probiotics that stimulate inhibitory neurotransmission (e.g., greater GABA concentrations) may assist in restoring excitatory/inhibitory balance and hence correct the decreased social interaction associated with ASD [40,41]. Because there are few evidence-based therapy options for ASD, it is critical to investigate potential novel therapeutic targets for the social and behavioral symptoms. Preclinical studies on the GM offer intriguing new paths for behavior modification, and the rationale for testing gut microbial-based therapy for ASD grows stronger [42,43]. The goal of this scoping review is to provide an overview of the available data on the efficacy and safety of probiotic, prebiotic, synbiotic, and FMT therapies and MTT for the treatment of core and co-occurring behavioral symptoms in persons with autism spectrum disorder. The effect of these therapies on GI symptoms was also investigated. Several clinical trials have been filed with the goal of developing viable microbial-based therapeutics for ASD; this review provides an overview assessment of these trials as well as clarification of recent exploratory achievements.

2. Materials and Methods

2.1. Protocol and Registration

This review was conducted using the standards of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Extension for Scoping Reviews (PRISMA-ScR) [44].

2.2. Search Processing

We searched PubMed, Scopus and Web of Science with a constraint on English-language papers from 1 January 2013 through 28 February 2023 that matched our topic. The following Boolean keywords were utilized in the search strategy: “autism” AND “microbiota”. These terms were chosen because they best described the goal of our inquiry, which was to learn more about the interconnectedness between microbiota dysbiosis in patients with autism spectrum and whether the gut–diet–brain axis undergoing treatment through the use of prebiotics and/or probiotics, FMT, and MTT has positive neurological and gastrointestinal outcomes. The search indicators are listed below in Table 1.
Table 1. Database search indicators.

2.3. Eligibility Criteria and Study Selection

We chose studies that looked at the effects of prebiotics, probiotics, synbiotics, FMT, and MTT on ASD. The selection method was divided into two stages: (1) title and abstract evaluation and (2) full text examination. Any article that met the following criteria was considered: (a) human intervention studies (clinical trials); (b) supplementation with probiotics, prebiotics, synbiotic combinations, FMT, or MTT; (c) studies assessing ASD; (d) treatment was compared to a placebo, no intervention, or other interventions; (e) English language full text; and (f) behavioral assessments were performed before and after the interventions using validated measures. Publications that did not include original data (e.g., meta-analyses, research procedures, conference abstracts, in vitro or animal studies) were excluded. The preliminary search’s titles and abstracts were retrieved and assessed for relevancy. For additional evaluation, full publications from relevant research were obtained. Two separate reviewers (F.P. and F.I.) evaluated the retrieved studies for inclusion using the criteria specified above, and disagreements were addressed by consensus.

2.4. Data Processing

Author differences over the article selection were discussed and resolved.

2.5. Data Extraction

A standardized form was used to capture data on research design and locations, population characteristics (e.g., sex, age, presence of comorbidities), type of intervention and comparison, baseline measurements, and reported results. Each study was also evaluated for its handling of missing data and effect measurements. For extraction accuracy, two reviewers (F.P. and F.I.) worked separately; divergences were resolved by consensus. Because of the substantial variability in the treatments and outcomes reported, meta-analysis was not possible; consequently, papers were synthesized qualitatively.

2.6. Data Analysis

For homogeneous research, the fixed effect model was used, while for heterogeneous studies, the random effect model was used. In all analyses, the effect size was calculated using the standardized difference of means.

2.7. PICOS Criteria

Table 2 depicts the PICOS (population, intervention, comparison, outcome, study design) criteria components, which include population, intervention, comparison, outcomes, and research design, as well as their use in this evaluation.
Table 2. PICOS criteria.

2.8. Study Evaluation

The article data were independently evaluated by the reviewers using a special electronic form designed according to the following categories: number of subjects, dose and type of intervention, study duration, type of study, age average of subjects, year of study, and main results.

3. Results

A total of 2370 publications were identified from the following databases: PubMed (720), Scopus (973), and Web of Science (677), which led to 1222 articles after removing duplicates (1148). Analysis of the title and abstract resulted in the exclusion of 988 articles. The writers successfully sought the remaining 234 papers for retrieval and evaluated their eligibility. The approach resulted in the exclusion of 174 articles for being off-topic. The evaluation includes the final 18 papers for qualitative analysis (Figure 2). The characteristics of the included studies are described in Table 3.
Figure 2. PRISMA flowchart diagram of the inclusion process.
Table 3. Characteristics of the included studies.

4. Discussion

We surveyed the original literature on therapeutic options targeting the GM for ASD in this scoping review, offering a resource to guide therapy based on evidence. There is mounting evidence that the GM may impact the onset and course of ASD. However, the lack of consistent knowledge implicit in the novelty of these considerations, as well as the ongoing lack of understanding of the complex microbial and metabolome distinctive signature in ASD patients, frequently translates into difficulties in microbiota-based therapy planning, which is typically performed on a basis of trial and error. This scoping review looked at 18 clinical studies that looked at the use of probiotics, prebiotics, probiotic/prebiotic compounds, FMT, or MTT in the treatment of core symptoms in juvenile ASD patients. The administration of these therapies had an effect on ASD symptoms in the fifteen RCTs. Moreover, the three non-RCT studies, on the other hand, imply that probiotics and prebiotics may modify behavior and GI symptoms in children with ASD. Prebiotics and the studied synbiotic formulations appear to be effective in selected ASD behaviors, although the extent of benefit is unknown, and there is less research that utilizes these techniques. Although clinical trial findings are limited, they urge additional investigation into FMT in ASD. This scoping review found that probiotic, prebiotic, synbiotic, FMT, or MTT supplementation improved different domains of ATEC score, including sociability, sensory or cognitive awareness, speech/communication/language, and health/physical/behavior, and there were improvements in behavioral symptoms in other studies that used different questionnaires (not ATEC) [29,45,46,47,48,50,52,54,55,57,58]. Concerning GI symptoms, all of the included trials found that probiotic, prebiotic, or symbiotic treatment improved the frequency of bowel movement-associated pain, diarrhea, constipation, and stool frequency [45]. It is difficult to determine which product is better for ASD symptoms among prebiotics, probiotics, or synbiotics because each study uses mostly one of these products, and even studies that use the same product differ in terms of dosage, treatment duration, or even the checklists they use to evaluate the results.

4.1. Probiotics/Prebiotics

Probiotics have the ability to mitigate gut dysbiosis, in some cases increasing the Bacteroidetes/Firmicutes ratio to that of healthy individuals; decreasing the growth of Candida, Desulfovibrio, and Clostridia species; and increasing beneficial bacteria such as Lactobacilli and Enterococci [61,62,63,64]. Lactobacilli species were also increased by prebiotic administration with galactooligosaccharide B-GOS® [21,65]. MTT, on the other hand, appears to enhance Desulfovibrio species [29,56,60,61,66,67]. Probiotic investigation found a reduction in short-chain fatty acids (SCFAs), which are fermentation products of dietary carbohydrates generated by Clostridium, Ruminococcaceae, Lachnospiraceae, and Desulfovibrio, among others [50,60,68,69]. SCFA levels have been reported to be elevated in ASD [70,71,72,73]. However, with ketogenic diet (KD) adoption in ASD youngsters, which boosted SCFA-producing species, autistic core symptoms significantly improved but their significance in the etiopathogenesis of ASD remains unknown [74,75,76,77]. L. reuteri, for example, is an indigenous bacteria of the human GI tract that has been extensively researched, with accumulating evidence indicating its advantages as a probiotic [78]. In numerous mice models of ASD, L. reuteri was repeatedly demonstrated to produce OXT-dependent behavioral improvement [11,37,79,80,81]. It appears to have therapeutic promise in enhancing social and behavioral functioning in people with ASD. Nevertheless, only one experiment has been completed but not yet published that looked into the effectiveness of L. reuteri in ASD patients [50,82]. The bulk of probiotics utilized in research are from a small number of species, including Lactobacillus spp., Limosilactobacillus spp., and Bifidobacterium spp., and Eubacterium coprostanoligenes are not isolated from human GI tracts [58,83]. Bifidobacteria levels appear to be inversely associated via feedback interactions with Desulfovibrio and Clostridium, two of the most likely bacteria strains involved in ASD etiopathogenesis [84]. In this vein, our analysis suggests that when baseline counts are aberrant, enhancing Bifidobacterial populations (MTT, B-GOS® supplementation) or reducing Desulfovibrio and Clostridium growth rates might be viable targets in microbiota-based ASD therapy [46,47,48,49,50,51,52]. It is critical to understand which gut commensals are associated with better symptoms in order to generate next-generation probiotics (also known as live biotherapeutic products) that evolve the features required to complete within the GI tract of ASD patients [85].

4.2. Alternative Medicines

It should be mentioned that alternative medicines such as Ayurveda, used in Dinesh’s study, also have positive implications on rebalancing the microbiota in ASD patients. A polyherbal formulation increased bifidobacterial abundance in the test group compared to the control group [53].

4.3. Synbiotics

Existing data on the effectiveness of probiotic, prebiotic, or synbiotic combinations in ASD is inconclusive and complicated by the fact that treatment regimens across studies are very varied, with varying formulations, doses, treatment periods, and administration procedures [86]. Increased efforts are recommended to focus on the effects of prebiotics in future clinical studies, since they may be safer, less expensive, affect a wide range of microorganisms, and be more widely accepted by all demographic groups [87]. Creating a synbiotic is more difficult. In an ideal world, a synbiotic would provide a health benefit greater than the sum of its individual components [88]. One published trial examining probiotic/prebiotic combinations in people with ASD did not systematically evaluate whether the combined products increase the ecological features and/or health effects of certain probiotic strains when compared to the probiotic alone [54,89]. Future research should look at other combinations and dosages, as well as comparing the ecological and functional aspects of each rationally chosen synbiotic to the substrate alone, the living microbes alone, and a control. At least one well-designed trial demonstrating a health advantage (complementary synbiotic) or both selective utilization of the substrate and a health benefit (synergistic synbiotic) in the target host has been carried out [28,54].

4.4. Dietary Supplements

Detailed dietary data should be included to assist in elucidating variables such as the influence of nondigestible carbohydrate consumption. In fact, the study by Bent et al. [55] discussed the beneficial effects of sulforaphane, which is a chemical produced when cruciferous vegetables such as broccoli, cauliflower, and broccoli sprouts are chewed. A component in these veggies called glucoraphanin interacts with a human enzyme called myrosinase to make sulforaphane. Through the intake of this product, it could be seen that urine metabolite changes were connected to oxidative stress, amino acid metabolism/gut microbiome metabolites, neurotransmitters, stress, and other hormones, while behavioral benefits have been associated with seven different chemical forms of sphingomyelin [55].

4.5. FMT and MTT

Fecal microbiota transplantation is an untargeted therapeutic for GM. Kang and colleagues created a modified FMT procedure called MTT for autistic youngsters [29]. This therapy alleviated ASD behavioral symptoms to some extent, with excellent tolerance indicated and improvements lasting 2 years after treatment ceased. The therapeutic relevance of these increases in behavioral assessment scores and improvement of GI disorders are confirmed in subsequent studies by Kang [57,60]: one of this two studies demonstrated that only p-cresol sulfate altered considerably following MTT. Significant associations have been made between p-cresol sulfate and Desulfovibrio, indicating that Desulfovibrio may have a role in p-cresol sulfate metabolism and the genesis of autism [60]. In a study by Turriziani et al., variation in p-cresol absorption appeared to contribute minimally, if at all, to behavioral alterations; in fact, a lowering of p-cresol was noted subsequent to PEG ingestion [45]. There are several other studies that support the beneficial effects of FMT and MTT, such as the Nirmalkar study, which found that the abundance of Prevotella and Bifidobacterium decreased over time (2 years), implying that a longer MTT treatment period or a booster after a certain amount of time may be required to retain these bacteria. MTT, in a similar manner, resulted in the normalization of numerous bacterial gene levels. Fascinatingly, microbial metabolic genes for folate biosynthesis, oxidative stress defense, and sulfur metabolism were dissimilar from those found in normally developing (TD) patients at ASD baseline but mirrored those found in TD and/or donors following MTT [56]. The positive effects of FMT can also be seen in a study by Li et al. [58]. In a meta-analysis of FMT in recurrent Clostridium difficile infection, Tariq et al. [90] discovered that the therapy was linked with decreased cure rates in randomized trials (67.7%) compared to open-label studies (82.7%; p = 0.001). To further study the causation between the GM and ASD symptoms, larger, randomized, double-blind trials comprising a matched control group of children with ASD who undergo an autologous transplant should be carried out. The FMT experiment discovered no difference in effectiveness between oral and rectal delivery [59]. Repeated FMT injections may be necessary to accomplish therapy goals. Depending on the mode of delivery, there are procedural hazards. For stool delivery, colonoscopy and oral routes have been demonstrated to be more successful than nasoduodenal tubes and enema [91]. It is also critical to anticipate potential issues with children with ASD’s willingness to receive FMT. However, FMT candidates should be examined in order to determine the most safe and effective FMT delivery mechanism in the setting of ASD. Continuing research into the mechanisms of action, the impact on the host’s immune response, and the refinement of the microbial inoculum may lead to a wider use of the treatment in the future. Furthermore, the safety profile of FMT in ASD is unknown, while the reported long-term experience of FMT for ASD patients in Kang and colleagues’ studies is reassuring. In the near future, further safety data will be provided by planned FMT studies that will conduct long-term monitoring and assessments. The reported FMT study subjects exhibited a variety of GI disorders, including diarrhea, constipation, and alternating diarrhea/constipation [29]. Current trials with bigger sample numbers involve more homogenous cohorts and may identify patients who are most likely to react [92]. In these research, adjunct therapies such as antibiotic pretreatment and colon cleansing were employed to reduce bacterial load and allow engraftment of potentially beneficial microbial taxa in the host [93]. Future research should focus on differences between patients within the same cohort as well as differences between study cohorts. Individuals’ illness presentations and levels of impairment might vary greatly. Individual disparities in responsiveness to intervention have been observed in previous studies into ASD treatments; treatment results may be impacted by biological characteristics such as age, linguistic ability, and autistic severity, as well as environmental factors (e.g., mother age and education) [94]. None of the included research investigated the possible impacts of traditional ASD medication therapies, such as proton pump inhibitors, as a confounding factor that might create a unique microbial profile [95].
Moreover, animal evidence shows that the microbiota’s modulatory CNS effects are sex-specific [96]; more female patients should be included in trials examining microbial-based therapy. Age is a crucial factor to consider in future ASD therapy research and should be adequately recorded in every intervention trial. Liu et al. [52] discovered that younger children who were treated with PS128 benefited more than older children. Previous research has found that a younger child’s age at the commencement of intervention is connected with favorable treatment results [94]. Probiotic, prebiotic, synbiotic interventions, FMT or MTT in early life with the goal of enhancing development in children at risk of ASD could become treatments of common use in the near future, as the GM shapes in infancy and any interventions in later years must be sustained for a long time, if not forever, to sustain the conferred benefit. Maintaining a healthy gut in infancy, which would most likely support healthy brain development throughout important developmental windows, may be more cost-effective and practicable than taking the supplements for extended periods of time later in life.
Based on the research presented in this review, it is theoretically possible to use multiple-strain combinations to investigate the attenuating effects of probiotics, prebiotics, synbiotics, FMT, and MTT on gut microbiota with the goal of reducing neurogastrointestinal symptoms in people with ASD. Similar research examining the effect of different strains on the GM can be conducted in order to create novel anti-ASD foods. Such analyses may reveal fresh and revolutionary pharmacological and food product pipelines with vast industrial uses. Some recent studies on the issue can serve as a good theoretical foundation for future study into GM regulation by assessing the impacts of these items. Future studies may need investigations into the manipulation of these pathogenic microbes for microbiota therapy reasons. In the near future, fresh starting cultures with more in vivo trials may emerge to support the hypothesis that microbiota therapies have more direct impacts on the inhibition of pathways and processes inside the human GM that predispose persons to ASD. This area of study is expected to significantly reduce the present ethical, cultural, and religious constraints inhibiting microbiota biotechnology research and the marketing of functional food components.

5. Conclusions

Several investigations in recent years have indicated qualitative and quantitative changes in the gut flora in a variety of neuropsychiatric illnesses, supporting the role of GM in the maintenance of physiological condition in the CNS. Within neurobehavioral disorders, it appears that at least a portion of ASD instances are linked to, and maybe reliant on, the health and wellbeing of the GM. The rising prevalence of ASD in recent years, combined with indications of a strong relationship between ASD and GI disorders, has sparked a specific interest in studying the reciprocal impacts between GM, brain, and microbiota under the so-called MGBA. The findings of this comprehensive analysis indicated that supplementation with probiotics, prebiotics, or their combination as synbiotics might be useful in alleviating both GI and CNS symptoms in ASD patients. It may also be argued that additional homogeneous trials using the same dosages and certain well-known probiotic or prebiotic products are required to apply the findings of these studies with more confidence. The research describes changes in GM composition in children with ASD that mostly consist of lower amounts of Bifidobacterium and higher levels of Clostridium spp. and Desulfovibrio. However, the current data do not allow for the definition of a distinct ASD profile. If dysbiosis is proven to be a precipitating factor in ASD, a variety of possible therapeutic options ranging from probiotics and prebiotics to FMT, MTT, and other nutritional techniques may be beneficial adjuvant therapy in these individuals. Furthermore, because dysbiosis contributes to a major proportion of ASD, identifying particular ASD endophenotypes would enable patient classification and targeted therapies. Addressing microbial processes might be the goal of the next ASD pharmaceutical therapy, which could assist in relieving the burden of this condition for the millions of individuals worldwide.

Author Contributions

Conceptualization, A.M.I., F.P., A.M., A.D.I. and G.D.; methodology, G.P., F.I., F.P., G.M. and A.P. (Assunta Patano); software, A.D.I., A.P. (Andrea Palermo), G.D., A.M.I. and F.I.; validation, F.P., F.I., G.M., A.P. (Assunta Patano) and G.P.; formal analysis, G.P., A.M.I., A.D.I., F.P. and A.M.; investigation, A.P. (Andrea Palermo), F.I., G.M., G.D. and A.P. (Assunta Patano); resources, A.P. (Andrea Palermo), A.M., F.P., F.I. and G.M.; data curation, A.M.I., G.P., A.P. (Andrea Palermo), F.I. and G.P.; writing—original draft preparation, G.M., F.P., A.P. (Assunta Patano), A.M. and F.I.; writing—review and editing, A.M.I., A.D.I., G.D., A.P. (Andrea Palermo) and A.M.I.; visualization, A.P. (Assunta Patano), F.P., G.P., A.D.I. and G.D.; supervision, G.D., A.M.I., F.I., A.D.I. and A.P. (Assunta Patano); project administration, G.P., A.P. (Assunta Patano), G.D., A.D.I. and A.P. (Andrea Palermo); funding acquisition, G.M., A.M.I., F.P., F.I. and A.P. (Assunta Patano). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ABCAberrant Behavior Checklist;
ABC-2Aberrant Behavior Checklist second edition;
AFUActive Fluorescent Units;
ASDautism spectrum disorders;
ATECAutismTreatment Evaluation Checklist;
CARSChildhood Autism Rating Scale;
CFUcolony-forming units;
CNScentral nervous system;
CGIClinical Global Impression;
CPRS-RConners’ Parent Rating Scale—Revised;
FDAFood and Drug Administration;
FMTfecal microbiota transplantation;
GABAgamma-aminobutyric acid;
GIgastrointestinal;
GMgut microbiota;
GOSgalactooligosaccharides;
GRglucoraphanin;
ISAPPInternational Scientific Association for Probiotics and Prebiotics;
IUinternational unit;
KDketogenic diet;
LPSlipopolysaccharide;
MGBAmicrobiota–gut–brain axis;
MTTmicrobiota transfer therapy;
OXToxytocin;
PEGpolyethylene glycol;
PICOSpopulation, intervention, comparison, outcome, study design;
PRISMAPreferred Reporting Items for Systematic Reviews and Meta-Analyses;
PRIMSA-ScrPRISMA Extension for Scoping Reviews;
PROSPEROInternational Prospective Register of Systematic Reviews;
RBS-RRepetitive Behavior Scale—Revised;
SCFAshort-chain fatty acids;
SHGMStandardized Human Gut Microbiota;
SpCOcarboxyhemoglobin;
SRSSocial Responsiveness Scale;
TDtypically developing.

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