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Microbiome, Probiotics and Autism: Where Do We Stand?

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Prebiotics and Probiotics".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 51131

Special Issue Editors

Department of Chemistry and Biology “A. Zambelli”, University of Salerno, Salerno, Italy
Interests: metabolomics; gut microbiome and nutrition; gut permeability
Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA 02114, USA
Interests: gut microbiome and nutrition; gut permeability; intestinal mucosal immunology; celiac disease and other gluten related disorders; autism, autoimmune diseases
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Special Issue Information

Dear Colleagues,

Autistic Spectrum Disorders (ASDs) are a major concern for healthcare systems, as they now affect 1 in 54 children worldwide (a 35-fold increase since 1960) and carry larger societal costs than cancer, heart disease, and stroke combined.

Since existing evidence indicates the involvement of the gut–immune–brain axis in ASDs, targeting the intestinal tract using immunomodulating medical food concepts could be of potential therapeutic value. Recent reports indicate that ASDs and accompanying gastrointestinal symptoms are characterized by a distinct and less diverse gut microbiome. The modulation of gut bacteria through short-term antibiotic treatment has been shown to lead to improvement in ASD-associated behavioral deficits. Specific beneficial bacteria (so-called probiotics, lactic acid producing bacteria, and bifidobacteria) influence the microbiome composition and intestinal barrier, alter the mucosal immune response, and possibly influence the brain. In addition, the underlying mechanism of non-digestible oligosaccharides (so-called prebiotic fibers) includes improvement of the microbiome via the induction beneficial bacteria growth and via direct actions to restore epithelial cells involved in intestinal immune homeostasis. Thus, treatment with specific beneficial bacteria in combination with non-digestible oligosaccharides to induce alterations in the microbiome, restore the intestinal epithelial barrier, and promote mucosal immune homeostasis could be a novel approach to ameliorate gastrointestinal problems and behavioral symptoms in ASD patients.

This Special Issue of Nutrients aims to present a collection of studies detailing the most recent advancements in the field of gut microbiota modification for the treatment of autism. Authors are invited to submit either original articles or comprehensive reviews that address a broad range of topics related to ASD and microbiota including, but not limited to diversity, compositional and functional differences in the gut microbiota and metabolome; functional food; probiotics; prebiotics; synbiotics; antibiotic use; and fecal transplantation. In particular, we aim to present advances in autism research that may have clinical applicability and basic/translational studies that mechanistically link microbiota composition/function and metabolomic profiles to the onset of ASDs with the overall goal of outlining pathways for clinical intervention to ameliorate or prevent ASDs.

Prof. Jacopo Troisi
Prof. Dr. Alessio Fasano
Guest Editors

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Keywords

  • Autistic Spectrum Disorders
  • microbiota
  • metabolomics
  • probiotics
  • prebiotics
  • synbiotics
  • fecal transplantation

Published Papers (8 papers)

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Research

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23 pages, 3153 KiB  
Article
Analysis of Faecal Microbiota and Small ncRNAs in Autism: Detection of miRNAs and piRNAs with Possible Implications in Host–Gut Microbiota Cross-Talk
by Federica Chiappori, Francesca Anna Cupaioli, Arianna Consiglio, Noemi Di Nanni, Ettore Mosca, Vito Flavio Licciulli and Alessandra Mezzelani
Nutrients 2022, 14(7), 1340; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14071340 - 23 Mar 2022
Cited by 7 | Viewed by 3895
Abstract
Intestinal microorganisms impact health by maintaining gut homeostasis and shaping the host immunity, while gut dysbiosis associates with many conditions, including autism, a complex neurodevelopmental disorder with multifactorial aetiology. In autism, gut dysbiosis correlates with symptom severity and is characterised by a reduced [...] Read more.
Intestinal microorganisms impact health by maintaining gut homeostasis and shaping the host immunity, while gut dysbiosis associates with many conditions, including autism, a complex neurodevelopmental disorder with multifactorial aetiology. In autism, gut dysbiosis correlates with symptom severity and is characterised by a reduced bacterial variability and a diminished beneficial commensal relationship. Microbiota can influence the expression of host microRNAs that, in turn, regulate the growth of intestinal bacteria by means of bidirectional host-gut microbiota cross-talk. We investigated possible interactions among intestinal microbes and between them and host transcriptional modulators in autism. To this purpose, we analysed, by “omics” technologies, faecal microbiome, mycobiome, and small non-coding-RNAs (particularly miRNAs and piRNAs) of children with autism and neurotypical development. Patients displayed gut dysbiosis related to a reduction of healthy gut micro- and mycobiota as well as up-regulated transcriptional modulators. The targets of dysregulated non-coding-RNAs are involved in intestinal permeability, inflammation, and autism. Furthermore, microbial families, underrepresented in patients, participate in the production of human essential metabolites negatively influencing the health condition. Here, we propose a novel approach to analyse faeces as a whole, and for the first time, we detected miRNAs and piRNAs in faecal samples of patients with autism. Full article
(This article belongs to the Special Issue Microbiome, Probiotics and Autism: Where Do We Stand?)
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20 pages, 4245 KiB  
Article
Different Alterations in Gut Microbiota between Bifidobacterium longum and Fecal Microbiota Transplantation Treatments in Propionic Acid Rat Model of Autism
by Turki S. Abujamel, Norah M. Al-Otaibi, Sameera Abuaish, Rahaf H. AlHarbi, Mushref B. Assas, Saleha Ahmad Alzahrani, Sohailah Masoud Alotaibi, Afaf El-Ansary and Kawther Aabed
Nutrients 2022, 14(3), 608; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14030608 - 30 Jan 2022
Cited by 13 | Viewed by 4208
Abstract
Autism spectrum disorders (ASD) consist of a range of neurodevelopmental conditions accompanied by dysbiosis of gut microbiota. Therefore, a number of microbiota manipulation strategies were developed to restore their balance. However, a comprehensive comparison of the various methods on gut microbiota is still [...] Read more.
Autism spectrum disorders (ASD) consist of a range of neurodevelopmental conditions accompanied by dysbiosis of gut microbiota. Therefore, a number of microbiota manipulation strategies were developed to restore their balance. However, a comprehensive comparison of the various methods on gut microbiota is still lacking. Here, we evaluated the effect of Bifidobacterium (BF) treatment and fecal microbiota transplantation (FT) on gut microbiota in a propionic acid (PPA) rat model of autism using 16S rRNA sequencing. Following PPA treatment, gut microbiota showed depletion of Bacteroidia and Akkermansia accompanied by a concomitant increase of Streptococcus, Lachnospiraceae, and Paraeggerthella. The dysbiosis was predicted to cause increased levels of porphyrin metabolism and impairments of acyl-CoA thioesterase and ubiquinone biosynthesis. On the contrary, BF and FT treatments resulted in a distinct increase of Clostridium, Bifidobacterium, Marvinbryantia, Butyricicoccus, and Dorea. The taxa in BF group positively correlated with vitamin B12 and flagella biosynthesis, while FT mainly enriched flagella biosynthesis. In contrast, BF and FT treatments negatively correlated with succinate biosynthesis, pyruvate metabolism, nitrogen metabolism, beta-Lactam resistance, and peptidoglycan biosynthesis. Therefore, the present study demonstrated that BF and FT treatments restored the PPA-induced dysbiosis in a treatment-specific manner. Full article
(This article belongs to the Special Issue Microbiome, Probiotics and Autism: Where Do We Stand?)
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15 pages, 2488 KiB  
Article
Altered Gut Microbiota in Korean Children with Autism Spectrum Disorders
by Sungji Ha, Donghun Oh, Sunghee Lee, Jaewan Park, Jaeun Ahn, Sungku Choi and Keun-Ah Cheon
Nutrients 2021, 13(10), 3300; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13103300 - 22 Sep 2021
Cited by 11 | Viewed by 4067
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and behavioral impairments. Recent studies have suggested that gut microbiota play a critical role in ASD pathogenesis. Herein, we investigated the fecal microflora of Korean ASD children to determine gut microbiota profiles [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and behavioral impairments. Recent studies have suggested that gut microbiota play a critical role in ASD pathogenesis. Herein, we investigated the fecal microflora of Korean ASD children to determine gut microbiota profiles associated with ASD. Specifically, fecal samples were obtained from 54 children with ASD and 38 age-matched children exhibiting typical development. Systematic bioinformatic analysis revealed that the composition of gut microbiota differed between ASD and typically developing children (TDC). Moreover, the total amounts of short-chain fatty acids, metabolites produced by bacteria, were increased in ASD children. At the phylum level, we found a significant decrease in the relative Bacteroidetes abundance of the ASD group, whereas Actinobacteria abundance was significantly increased. Furthermore, we found significantly lower Bacteroides levels and higher Bifidobacterium levels in the ASD group than in the TDC group at the genus level. Functional analysis of the microbiota in ASD children predicted that several pathways, including genetic information processing and amino acid metabolism, can be associated with ASD pathogenesis. Although more research is needed to determine whether the differences between ASD and TDC are actually related to ASD pathogenesis, these results provide further evidence of altered gut microbiota in children with ASD, possibly providing new perspectives on the diagnosis and therapeutic approaches for ASD patients. Full article
(This article belongs to the Special Issue Microbiome, Probiotics and Autism: Where Do We Stand?)
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Review

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20 pages, 500 KiB  
Review
Gastrointestinal Symptoms in Autism Spectrum Disorder: A Systematic Review
by Geraldine Leader, Cathal Abberton, Stephen Cunningham, Katie Gilmartin, Margo Grudzien, Emily Higgins, Lokesh Joshi, Sally Whelan and Arlene Mannion
Nutrients 2022, 14(7), 1471; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14071471 - 01 Apr 2022
Cited by 33 | Viewed by 6853
Abstract
This systematic review aims to offer an updated understanding of the relationship between gastrointestinal symptoms (GIS) and autism spectrum disorder (ASD) in children and adolescents. The databases PsycINFO, Medline, Cinahl, and ERIC were searched using keywords, and relevant literature was hand-searched. Papers ( [...] Read more.
This systematic review aims to offer an updated understanding of the relationship between gastrointestinal symptoms (GIS) and autism spectrum disorder (ASD) in children and adolescents. The databases PsycINFO, Medline, Cinahl, and ERIC were searched using keywords, and relevant literature was hand-searched. Papers (n = 3319) were systematically screened and deemed eligible if they were empirical studies published in English since 2014 and measured the GIS of individuals with ASD who were under 18 years old. Thirty studies were included in the final review. The study findings were synthesized under eight themes, including the prevalence and nature of GIS and their relationship with developmental regression, language and communication, ASD severity, challenging behavior, comorbid psychopathology, sleep problems, and sensory issues. The review found that GIS were common and that there was contradictory evidence concerning their relationship with co-occurring conditions. It also identified evidence of some causal relationships that support the existence of the gut–immune–brain pathways. Future research needs to use large prospective designs and objective and standardized GIS measurements to provide a nuanced understanding of GIS in the context of ASD. Full article
(This article belongs to the Special Issue Microbiome, Probiotics and Autism: Where Do We Stand?)
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23 pages, 1502 KiB  
Review
The Brain-Gut-Microbiome System: Pathways and Implications for Autism Spectrum Disorder
by Michelle A. Chernikova, Genesis D. Flores, Emily Kilroy, Jennifer S. Labus, Emeran A. Mayer and Lisa Aziz-Zadeh
Nutrients 2021, 13(12), 4497; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13124497 - 16 Dec 2021
Cited by 24 | Viewed by 16413
Abstract
Gastrointestinal dysfunction is one of the most prevalent physiological symptoms of autism spectrum disorder (ASD). A growing body of largely preclinical research suggests that dysbiotic gut microbiota may modulate brain function and social behavior, yet little is known about the mechanisms that underlie [...] Read more.
Gastrointestinal dysfunction is one of the most prevalent physiological symptoms of autism spectrum disorder (ASD). A growing body of largely preclinical research suggests that dysbiotic gut microbiota may modulate brain function and social behavior, yet little is known about the mechanisms that underlie these relationships and how they may influence the pathogenesis or severity of ASD. While various genetic and environmental risk factors have been implicated in ASD, this review aims to provide an overview of studies elucidating the mechanisms by which gut microbiota, associated metabolites, and the brain interact to influence behavior and ASD development, in at least a subgroup of individuals with gastrointestinal problems. Specifically, we review the brain-gut-microbiome system and discuss findings from current animal and human studies as they relate to social-behavioral and neurological impairments in ASD, microbiota-targeted therapies (i.e., probiotics, fecal microbiota transplantation) in ASD, and how microbiota may influence the brain at molecular, structural, and functional levels, with a particular interest in social and emotion-related brain networks. A deeper understanding of microbiome-brain-behavior interactions has the potential to inform new therapies aimed at modulating this system and alleviating both behavioral and physiological symptomatology in individuals with ASD. Full article
(This article belongs to the Special Issue Microbiome, Probiotics and Autism: Where Do We Stand?)
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15 pages, 894 KiB  
Review
Gut Reactions: How Far Are We from Understanding and Manipulating the Microbiota Complexity and the Interaction with Its Host? Lessons from Autism Spectrum Disorder Studies
by Martina Lombardi and Jacopo Troisi
Nutrients 2021, 13(10), 3492; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13103492 - 02 Oct 2021
Cited by 6 | Viewed by 4221
Abstract
Autism is a group of neurodevelopmental disorders, characterized by early onset difficulties in social communication and restricted, repetitive behaviors and interests. It is characterized by familial aggregation, suggesting that genetic factors play a role in disease development, in addition to developmentally early environmental [...] Read more.
Autism is a group of neurodevelopmental disorders, characterized by early onset difficulties in social communication and restricted, repetitive behaviors and interests. It is characterized by familial aggregation, suggesting that genetic factors play a role in disease development, in addition to developmentally early environmental factors. Here, we review the role of the gut microbiome in autism, as it has been characterized in case-control studies. We discuss how methodological differences may have led to inconclusive or contradictory results, even though a disproportion between harmful and beneficial bacteria is generally described in autism. Furthermore, we review the studies concerning the effects of gut microbial-based and dietary interventions on autism symptoms. Also, in this case, the results are not comparable due to the lack of standardized methods. Therefore, autism-specific microbiome signatures and, consequently, possible microbiome-oriented interventions are far from being recognized. We argue that a multi-omic longitudinal implementation may be useful to study metabolic changes connected to microbiome changes. Full article
(This article belongs to the Special Issue Microbiome, Probiotics and Autism: Where Do We Stand?)
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Other

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23 pages, 1045 KiB  
Systematic Review
Interventions on Microbiota: Where Do We Stand on a Gut–Brain Link in Autism? A Systematic Review
by Margherita Prosperi, Elisa Santocchi, Letizia Guiducci, Jacopo Frinzi, Maria Aurora Morales, Raffaella Tancredi, Filippo Muratori and Sara Calderoni
Nutrients 2022, 14(3), 462; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14030462 - 20 Jan 2022
Cited by 16 | Viewed by 3983
Abstract
The alteration of the microbiota–gut–brain axis has been recently recognized as a critical modulator of neuropsychiatric health and a possible factor in the etiopathogenesis of autism spectrum disorders (ASD). This systematic review offers practitioners an overview of the potential therapeutic options to modify [...] Read more.
The alteration of the microbiota–gut–brain axis has been recently recognized as a critical modulator of neuropsychiatric health and a possible factor in the etiopathogenesis of autism spectrum disorders (ASD). This systematic review offers practitioners an overview of the potential therapeutic options to modify dysbiosis, GI symptoms, and ASD severity by modulating the microbiota–gut–brain axis in ASD, taking into consideration limits and benefits from current findings. Comprehensive searches of PubMed, Scopus, the Web of Science Core Collection, and EMBASE were performed from 2000 to 2021, crossing terms referred to ASD and treatments acting on the microbiota–gut–brain axis. A total of 1769 publications were identified, of which 19 articles met the inclusion criteria. Data were extracted independently by two reviewers using a preconstructed form. Despite the encouraging findings, considering the variability of the treatments, the samples size, the duration of treatment, and the tools used to evaluate the outcome of the examined trials, these results are still partial. They do not allow to establish a conclusive beneficial effect of probiotics and other interventions on the symptoms of ASD. In particular, the optimal species, subspecies, and dosages have yet to be identified. Considering the heterogeneity of ASD, double-blind, randomized, controlled trials and treatment tailored to ASD characteristics and host-microbiota are recommended. Full article
(This article belongs to the Special Issue Microbiome, Probiotics and Autism: Where Do We Stand?)
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18 pages, 1226 KiB  
Hypothesis
Autonomic Nervous System Neuroanatomical Alterations Could Provoke and Maintain Gastrointestinal Dysbiosis in Autism Spectrum Disorder (ASD): A Novel Microbiome–Host Interaction Mechanistic Hypothesis
by Athanasios Beopoulos, Manuel Gea, Alessio Fasano and François Iris
Nutrients 2022, 14(1), 65; https://0-doi-org.brum.beds.ac.uk/10.3390/nu14010065 - 24 Dec 2021
Cited by 11 | Viewed by 5460
Abstract
Dysbiosis secondary to environmental factors, including dietary patterns, antibiotics use, pollution exposure, and other lifestyle factors, has been associated to many non-infective chronic inflammatory diseases. Autism spectrum disorder (ASD) is related to maternal inflammation, although there is no conclusive evidence that affected individuals [...] Read more.
Dysbiosis secondary to environmental factors, including dietary patterns, antibiotics use, pollution exposure, and other lifestyle factors, has been associated to many non-infective chronic inflammatory diseases. Autism spectrum disorder (ASD) is related to maternal inflammation, although there is no conclusive evidence that affected individuals suffer from systemic low-grade inflammation as in many psychological and psychiatric diseases. However, neuro-inflammation and neuro–immune abnormalities are observed within ASD-affected individuals. Rebalancing human gut microbiota to treat disease has been widely investigated with inconclusive and contradictory findings. These observations strongly suggest that the forms of dysbiosis encountered in ASD-affected individuals could also originate from autonomic nervous system (ANS) functioning abnormalities, a common neuro–anatomical alteration underlying ASD. According to this hypothesis, overactivation of the sympathetic branch of the ANS, due to the fact of an ASD-specific parasympathetic activity deficit, induces deregulation of the gut–brain axis, attenuating intestinal immune and osmotic homeostasis. This sets-up a dysbiotic state, that gives rise to immune and osmotic dysregulation, maintaining dysbiosis in a vicious cycle. Here, we explore the mechanisms whereby ANS imbalances could lead to alterations in intestinal microbiome–host interactions that may contribute to the severity of ASD by maintaining the brain–gut axis pathways in a dysregulated state. Full article
(This article belongs to the Special Issue Microbiome, Probiotics and Autism: Where Do We Stand?)
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