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Takyi E, Nirmalkar K, Adams J, Krajmalnik-Brown R. Interventions targeting the gut microbiota and their possible effect on gastrointestinal and neurobehavioral symptoms in autism spectrum disorder. Gut Microbes 2025; 17:2499580. [PMID: 40376856 PMCID: PMC12087657 DOI: 10.1080/19490976.2025.2499580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 04/22/2025] [Accepted: 04/24/2025] [Indexed: 05/18/2025] Open
Abstract
Autism spectrum disorder (ASD) is a developmental disorder that is characterized by deficits in social communication and restricted, repetitive, and stereotyped behaviors. In addition to neurobehavioral symptoms, children with ASD often have gastrointestinal symptoms (e.g. constipation, diarrhea, gas, abdominal pain, reflux). Several studies have proposed the role of gut microbiota and metabolic disorders in gastrointestinal symptoms and neurodevelopmental dysfunction in ASD patients; these results offer promising avenues for novel treatments of this disorder. Interventions targeting the gut microbiota - such as fecal microbiota transplant (FMT), microbiota transplant therapy (MTT), probiotics, prebiotics, synbiotics, antibiotics, antifungals, and diet - promise to improve gut health and can potentially improve neurological symptoms. The modulation of the gut microbiota using MTT in ASD has shown beneficial and long-term effects on GI symptoms and core symptoms of autism. Also, the modulation of the gut microbiota to resemble that of typically developing individuals seems to be the most promising intervention. As most of the studies carried out with MTT are open-label studies, more extensive double-blinded randomized control trials are needed to confirm the efficacy of MTT as a therapeutic option for ASD. This review examines the current clinical research evidence for the use of interventions that target the microbiome - such as antibiotics, antifungals, probiotics/prebiotics, synbiotics, and MTT - and their effectiveness in changing the gut microbiota and improving gastrointestinal and neurobehavioral symptoms in ASD.
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Affiliation(s)
- Evelyn Takyi
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ, USA
| | - Khemlal Nirmalkar
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ, USA
| | - James Adams
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ, USA
- School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, USA
| | - Rosa Krajmalnik-Brown
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ, USA
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ, USA
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Farhat EK, Banjari I, Džidić-Krivić A, Ejubović M, Sher EK. Gut microbiota mediated regulation of vitamin B homeostasis in autism spectrum disorders. Brain Res 2025; 1860:149661. [PMID: 40324672 DOI: 10.1016/j.brainres.2025.149661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/21/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025]
Abstract
The exact cause of autism spectrum disorder (ASD) is yet unknown, although possible causes include early childhood, foetal development, gestation, delivery mode, genetics, and environmental variables. Approximately 1% of children worldwide have ASD, and this percentage is rising. The immunological, endocrine, gut microbiota and brain-gut axis quality influence the intensity of ASD symptoms. Deficits in the composition and diversity of gut microbiota are common in children with ASD, accounting for 9-90% of these illnesses, including elevated inflammatory cytokines, inflammation, leaky gut syndrome, and pathological microflora growth. Dysbiosis can be made worse by eating issues that are prevalent in ASD. B vitamins, such as cobalamin and folate, which are essential methyl donors for DNA epigenetic changes, are usually produced by a healthy gut microbiota. 50% of people with ASD have a vitamin B deficit. This work summarises research on the impact of gut microbiota on DNA methylation and B vitamin synthesis in ASD, as well as etiological variables connected to dysbiosis. Probiotics, postbiotics, and vitamin B therapies in kids with ASD should be investigated in future studies.
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Affiliation(s)
- Esma Karahmet Farhat
- Faculty of Food Technology, Josip Juraj Strossmayer University of Osijek, Osijek 31000, Croatia; International Society of Engineering Science and Technology UK, United Kingdom
| | - Ines Banjari
- Department of Food and Nutrition Research, Faculty of Food Technology, Josip Juraj Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Amina Džidić-Krivić
- Department of Neurology, Cantonal Hospital Zenica, Zenica 72000, Bosnia and Herzegovina; International Society of Engineering Science and Technology UK, United Kingdom
| | - Malik Ejubović
- Department of Internal Medicine, Cantonal Hospital Zenica, Zenica 72000, Bosnia and Herzegovina
| | - Emina Karahmet Sher
- School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, United Kingdom; International Society of Engineering Science and Technology UK, United Kingdom.
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Zarimeidani F, Rahmati R, Mostafavi M, Darvishi M, Khodadadi S, Mohammadi M, Shamlou F, Bakhtiyari S, Alipourfard I. Gut Microbiota and Autism Spectrum Disorder: A Neuroinflammatory Mediated Mechanism of Pathogenesis? Inflammation 2025; 48:501-519. [PMID: 39093342 PMCID: PMC12053372 DOI: 10.1007/s10753-024-02061-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/28/2024] [Accepted: 05/21/2024] [Indexed: 08/04/2024]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and behavior, frequently accompanied by restricted and repetitive patterns of interests or activities. The gut microbiota has been implicated in the etiology of ASD due to its impact on the bidirectional communication pathway known as the gut-brain axis. However, the precise involvement of the gut microbiota in the causation of ASD is unclear. This study critically examines recent evidence to rationalize a probable mechanism in which gut microbiota symbiosis can induce neuroinflammation through intermediator cytokines and metabolites. To develop ASD, loss of the integrity of the intestinal barrier, activation of microglia, and dysregulation of neurotransmitters are caused by neural inflammatory factors. It has emphasized the potential role of neuroinflammatory intermediates linked to gut microbiota alterations in individuals with ASD. Specifically, cytokines like brain-derived neurotrophic factor, calprotectin, eotaxin, and some metabolites and microRNAs have been considered etiological biomarkers. We have also overviewed how probiotic trials may be used as a therapeutic strategy in ASD to reestablish a healthy balance in the gut microbiota. Evidence indicates neuroinflammation induced by dysregulated gut microbiota in ASD, yet there is little clarity based on analysis of the circulating immune profile. It deems the repair of microbiota load would lower inflammatory chaos in the GI tract, correct neuroinflammatory mediators, and modulate the neurotransmitters to attenuate autism. The interaction between the gut and the brain, along with alterations in microbiota and neuroinflammatory biomarkers, serves as a foundational background for understanding the etiology, diagnosis, prognosis, and treatment of autism spectrum disorder.
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Affiliation(s)
- Fatemeh Zarimeidani
- Students Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Rahem Rahmati
- Students Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mehrnaz Mostafavi
- Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Darvishi
- School of Aerospace and Subaquatic Medicine, Infectious Diseases & Tropical Medicine Research Center (IDTMC), AJA University of Medical Sciences, Tehran, Iran
| | - Sanaz Khodadadi
- Student Research Committee, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Mahya Mohammadi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farid Shamlou
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Salar Bakhtiyari
- Feinberg Cardiovascular and Renal Research Institute, North Western University, Chicago. Illinois, USA
| | - Iraj Alipourfard
- Institute of Physical Chemistry, Polish Academy of Sciences, Marcin Kasprzaka 44/52, 01-224, Warsaw, Poland.
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Tu P, Halili X, Zhang S, Yang J, Xiao Y. The effectiveness of hyperbaric oxygen therapy in children and adolescents and with autism spectrum disorders: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2025; 137:111257. [PMID: 39826608 DOI: 10.1016/j.pnpbp.2025.111257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/24/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Hyperbaric oxygen therapy (HBOT) is considered a potential treatment for autism spectrum disorders, aiming to improve the underlying pathophysiological mechanisms. It has been studied in several clinical trials, but the effectiveness is still controversial. PURPOSE This systematic review aimed to systematically evaluate the effectiveness of hyperbaric oxygen therapy in the treatment of autism in children and adolescents. METHODS We systematically searched seven databases (PubMed, Embase, Cochrane Libraries, Web of Science, CNKI, Wanfang, and SinoMed) up to March 20, 2024, as well as references lists. The included studies evaluated the effect of HBOT on improving the core symptoms of autism and other specific symptoms (e.g., communication, sociability, cognitive awareness, behavior), including RCTs and quasiexperimental studies. The Cochrane Collaboration's Risk of Bias Assessment Tool for Randomized Trials (RoB2.0) and the JBI Risk of Bias Tool for Quasi-Experimental Studies were used as quality assessment tools. A random effects model was used to conduct a meta-analysis of the core and specific symptoms of autism. Sensitivity analyses and meta-regression were performed to identify sources of heterogeneity and assess result robustness. A Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence certainty analysis was performed for outcomes. This systematic review is registered with PROSPERO (CRD42024527220). RESULTS A total of 17 studies with 890 patients were ultimately included in the metaanalysis. The meta-analysis revealed moderately large, significant effects of hyperbaric oxygen therapy, reducing core symptoms of autism [SMD = -0.66, 95 % CI (-1.04, -0.28), P = 0.0006], and improving three aspects of daily performances (communication [SMD = -0.88, 95 % CI (-1.71,-0.04), P = 0.04], cognitive awareness [SMD = -0.93, 95 % CI (-1.51, -0.35), P = 0.002], and behavior [SMD = -0.80, 95 % CI (- 1.46, -0.13), P = 0.02] in children and adolescents with autism. This systematic review and meta-analysis have limitations such as poor quality and high heterogeneity of the included study. CONCLUSION These findings underscore the potential benefits of hyperbaric oxygen therapy in managing autism-related symptoms and improving daily functioning in affected children and adolescents. Future rigorously designed, high-quality studies are required to confirm the efficacy of hyperbaric oxygen therapy and establish standard treatment protocols.
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Affiliation(s)
- Ping Tu
- Xiang Ya School of Nursing, Central South University, Changsha, Hunan, China
| | - Xirongguli Halili
- Xiang Ya Research Center of Evidence-based Healthcare, Central South University, Changsha, Hunan, China; Xiang Ya Center for Evidence-Based Nursing Practice & Healthcare Innovation: A JBI Centre of Excellence, Central South University, Changsha, Hunan, China
| | - Siyi Zhang
- Clinical Nursing Teaching and Research Section, The Second Xiang Ya Hospital, Central South University, Changsha, Hunan, China; Department of Pediatrics, The Second Xiang Ya Hospital, Central South University, Changsha, Hunan, China
| | - Jing Yang
- Clinical Nursing Teaching and Research Section, The Second Xiang Ya Hospital, Central South University, Changsha, Hunan, China; Department of Pediatrics, The Second Xiang Ya Hospital, Central South University, Changsha, Hunan, China
| | - Yongbei Xiao
- Clinical Nursing Teaching and Research Section, The Second Xiang Ya Hospital, Central South University, Changsha, Hunan, China; Department of Pediatrics, The Second Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
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Cui Y, Okyere SK, Guan H, Hua Z, Deng Y, Deng H, Deng J. Ablation of Gut Microbiota Alleviates DON-Induced Neurobehavioral Abnormalities and Brain Damage in Mice. Toxins (Basel) 2025; 17:144. [PMID: 40137917 PMCID: PMC11946315 DOI: 10.3390/toxins17030144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/20/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Deoxynivalenol (DON) poses a threat to animal and human health, particularly causing damage to the nervous system. Intestinal flora can regulate the nervous system through the gut-brain axis; however, there is currently a lack of evidence on the effect of changing the intestinal flora on the damage to the nervous system caused by DON. Therefore, this study aims to investigate the effect of gut microbiota ablation on neurotoxicity induced by exposure to deoxynivalenol. METHODS One hundred-twenty (120) specific pathogen-free (SPF) male C57BL/6j mice were randomly divided into four groups (control group, microbiota-uncleaned group + 5 mg/kg/BW DON, microbiota-cleared group, and microbiota-cleared group + 5 mg/kg/BW DON). The open field and Morris behavior tests were used to evaluate behavior changes after DON exposure. After 14 days of treatment, the mice were euthanized and brain tissues were collected for further analysis. RESULTS The tests showed that DON exposure led to anxiety and decreased learning ability in mice with no gut microbiota ablation. We also observed pathological changes including neuronal shrinkage, degeneration, and cortical edema in the mice with no microbiota ablation after DON exposure. In addition, the protein and mRNA levels of tight junction proteins and anti-inflammatory factors were decreased in the mice with no microbiota ablation after DON exposure compared with mice with ablated microbiota. CONCLUSIONS We concluded that the presence of microbiota plays a key role in the neurotoxicity induced by DON; thus, ablation of the intestinal microbiota can effectively improve brain damage caused by DON.
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Affiliation(s)
- Yujing Cui
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (S.K.O.); (H.G.); (Z.H.); (Y.D.); (H.D.)
| | - Samuel Kumi Okyere
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (S.K.O.); (H.G.); (Z.H.); (Y.D.); (H.D.)
- Department of Pharmaceutical Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA
| | - Haoyue Guan
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (S.K.O.); (H.G.); (Z.H.); (Y.D.); (H.D.)
| | - Zixuan Hua
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (S.K.O.); (H.G.); (Z.H.); (Y.D.); (H.D.)
| | - Youtian Deng
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (S.K.O.); (H.G.); (Z.H.); (Y.D.); (H.D.)
| | - Huidan Deng
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (S.K.O.); (H.G.); (Z.H.); (Y.D.); (H.D.)
| | - Junliang Deng
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (S.K.O.); (H.G.); (Z.H.); (Y.D.); (H.D.)
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Xiao HL, Zhu H, Zeng TA, Xu F, Yu SH, Yang CJ. Potential similarities in gut microbiota composition between autism spectrum disorder and neurotypical siblings: Insights from a comprehensive meta-analysis. Neuroscience 2025; 567:172-181. [PMID: 39788315 DOI: 10.1016/j.neuroscience.2025.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/22/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
BACKGROUND Previous studies have explored the differences in gut microbiota (GM) between individuals with autism spectrum disorder (ASD) and neurotypical controls. However, factors such as diet, lifestyle, and environmental exposure influence GM, leading to significant variability, even among neurotypical individuals. Comparing the GM of ASD individuals with neurotypical siblings, who share similar genes and living conditions, may offer better insights into the GM mechanisms associated with ASD. Therefore, this study aims to analyze the GM composition in ASD by comparing it to that of neurotypical siblings, potentially identifying microbiota that influence ASD. METHODS We explored electronic databases up to July 2024, including EBSCOhost, PubMed, ScienceDirect, Web of Science, and Scopus. Meta-analysis using RevMan 5.4 assessed the relative abundance (RA) of gut bacteria from 8 phyla and 4 genera in ASD individuals and neurotypical siblings. RESULTS Eight studies were included, involving 248 people with ASD and 197 neurotypical siblings. Significant but unstable differences were observed in the RA of Bacteroidetes, Firmicutes, and Fusobacteria. No significant differences were found in the RA of Proteobacteria, Cyanobacteria, Actinobacteria, Verrucomicrobia, Tenericutes, or Bacteroides, Roseburia, Sutterella, Bifidobacterium. CONCLUSIONS GM composition in ASD individuals closely resembles that of neurotypical siblings, with only a few unstable differences. This suggests that other crucial bacteria or certain interacting environmental factors play a role. Further studies are needed to gather stronger evidence to uncover the differences in GM and their mechanisms in ASD people.
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Affiliation(s)
- Hong-Li Xiao
- Faculty of Education, East China Normal University, Shanghai, China
| | - Han Zhu
- Faculty of Education, East China Normal University, Shanghai, China
| | - Tong-Ao Zeng
- Faculty of Education, East China Normal University, Shanghai, China
| | - Fang Xu
- Faculty of Education, East China Normal University, Shanghai, China; Hangzhou Health Experimental School, Zhejiang, China
| | - Su-Hong Yu
- Faculty of Education, East China Normal University, Shanghai, China.
| | - Chang-Jiang Yang
- Faculty of Education, East China Normal University, Shanghai, China; China Research Institute of Care and Education of Infants and Young, ECNU, Shanghai, China.
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Barba-Vila O, García-Mieres H, Ramos B. Probiotics in autism spectrum disorders: a systematic review of clinical studies and future directions. Nutr Rev 2025; 83:329-343. [PMID: 38497979 DOI: 10.1093/nutrit/nuae010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2024] Open
Abstract
CONTEXT It is hypothesized that gut dysbiosis, a typical feature of patients with autism spectrum disorder (ASD), could be involved in the origin of this neurodevelopmental disorder. Therefore, the use of probiotics to restore gastrointestinal (GI) equilibrium might be a promising therapeutic strategy due to its capacity to balance the gut-brain axis and behavioral responses. OBJECTIVE To summarize current knowledge on the use of probiotics to treat core clinical ASD symptoms and concomitant GI signs, compare the design of published studies with those of ongoing trials, assess the near future of this field, and provide recommendations for improving novel studies. DATA SOURCES The literature search was conducted in February 2020 and updated in March 2021, using a broad range of bibliographic and clinical trial-specific databases. DATA EXTRACTION Data were extracted using a standardized form, and articles reporting on 28 clinical studies (already published or still ongoing) were included. The risk of bias in clinical studies was evaluated using the Cochrane Collaboration Risk of Bias Assessment tool for randomized trials and the Risk of Bias in Nonrandomized Studies-Interventions tool for nonrandomized trials. RESULTS The results suggest that probiotics improve ASD-like social deficits, GI symptoms, and gut microbiota profile. However, inconsistencies among studies and their methodological limitations make it difficult to draw any conclusions regarding the efficacy of probiotics in ASD. This review provides specific suggestions for future research to improve the quality of the studies. CONCLUSIONS Although ongoing studies have improved designs, the available knowledge does not permit solid conclusions to be made regarding the efficacy of probiotics in ameliorating the symptoms (psychiatric and/or GI) associated with ASD. Thus, more high-quality research and new approaches are needed to design effective probiotic strategies for ASD.
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Affiliation(s)
- Olga Barba-Vila
- Department de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona Bellaterra, Barcelona, Spain
| | - Helena García-Mieres
- Etiopathogenesis and Treatment of Severe Mental Disorders, Teaching, Research, and Innovation Unit, Institut de Recerca Sant Joan de Déu, Parc Sanitari Sant Joan de Déu Sant Boi de Llobregat, Barcelona, Spain
- Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain
- Health Services Research Unit, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain
- CIBER Epidemiología y Salud Pública, Madrid, Spain
- Department of Medicine and Health Sciences, Pompeu Fabra University, Barcelona, Spain
- Faculty of Medicine, University of Vic-Central University of Catalonia, Vic, Spain
| | - Belén Ramos
- Department de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona Bellaterra, Barcelona, Spain
- Etiopathogenesis and Treatment of Severe Mental Disorders, Teaching, Research, and Innovation Unit, Institut de Recerca Sant Joan de Déu, Parc Sanitari Sant Joan de Déu Sant Boi de Llobregat, Barcelona, Spain
- Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain
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Mamun AA, Geng P, Wang S, Shao C, Xiao J. IUPHAR review: Targeted therapies of signaling pathways based on the gut microbiome in autism spectrum disorders: Mechanistic and therapeutic applications. Pharmacol Res 2025; 211:107559. [PMID: 39733842 DOI: 10.1016/j.phrs.2024.107559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 12/22/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by impairments in social interaction, communication and repetitive activities. Gut microbiota significantly influences behavior and neurodevelopment by regulating the gut-brain axis. This review explores gut microbiota-influenced treatments for ASD, focusing on their therapeutic applications and mechanistic insights. In addition, this review discusses the interactions between gut microbiota and the immune, metabolic and neuroendocrine systems, focusing on crucial microbial metabolites including short-chain fatty acids (SCFAs) and several neurotransmitters. Furthermore, the review explores various therapy methods including fecal microbiota transplantation, dietary modifications, probiotics and prebiotics and evaluates their safety and efficacy in reducing ASD symptoms. The discussion shows the potential of customized microbiome-based therapeutics and the integration of multi-omics methods to understand the underlying mechanisms. Moreover, the review explores the intricate relationship between gut microbiota and ASD, aiming to develop innovative therapies that utilize the gut microbiome to improve the clinical outcomes of ASD patients. Microbial metabolites such as neurotransmitter precursors, tryptophan metabolites and SCFAs affect brain development and behavior. Symptoms of ASD are linked to changes in these metabolites. Dysbiosis in the gut microbiome may impact neuroinflammatory processes linked to autism, negatively affecting immune signaling pathways. Research indicates that probiotics and prebiotics can improve gut microbiota and alleviate symptoms in ASD patients. Fecal microbiota transplantation may also improve behavioral symptoms and restore gut microbiota balance. The review emphasizes the need for further research on gut microbiota modification as a potential therapeutic approach for ASD, highlighting its potential in clinical settings.
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Affiliation(s)
- Abdullah Al Mamun
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Peiwu Geng
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Shuanghu Wang
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Chuxiao Shao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China.
| | - Jian Xiao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
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Shi L, Feng Y, Wang J, Xiao R, Wang L, Tian P, Jin X, Zhao J, Wang G. Innovative mechanisms of micro- and nanoplastic-induced brain injury: Emphasis on the microbiota-gut-brain axis. Life Sci 2024; 357:123107. [PMID: 39369844 DOI: 10.1016/j.lfs.2024.123107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/21/2024] [Accepted: 10/01/2024] [Indexed: 10/08/2024]
Abstract
Micro- and nanoplastics (MNPs), emerging environmental pollutants, infiltrate marine, terrestrial, and freshwater systems via diverse pathways, culminating in their accumulation in the human body through food chain transmission, posing potential health risks. Researches have demonstrated that MNPs disrupt gut microbiota equilibrium and compromise intestinal barrier integrity, as well as traverse the blood-brain barrier, leading to brain damage. Moreover, the complex interaction between the gut and the nervous system, facilitated by the "gut-brain axis," indicates an additional pathway for MNPs-induced brain damage. This has intensified scientific interest in the intercommunication between MNPs and the gut-brain axis. While existing studies have documented microbial imbalances and metabolic disruptions subsequent to MNPs exposure, the precise mechanisms by which the microbiota-gut-brain axis contributes to MNPs-induced central nervous system damage remain unclear. This review synthesizes current knowledge on the microbiota-gut-brain axis, elucidating the pathogenesis of MNPs-induced gut microbiota dysbiosis and its consequent brain injury. It emphasizes the complex interrelation between MNPs and the microbiota-gut-brain axis, advocating for the gut microbiota as a novel therapeutic target to alleviate MNP-induced brain harm.
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Affiliation(s)
- Liuting Shi
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | | | - Jialiang Wang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Rui Xiao
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Linlin Wang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China; National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Peijun Tian
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China; National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xing Jin
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China; Yixing People's Hospital, Jiangsu, Wuxi 214200, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China; National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China; (Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou 225004, China
| | - Gang Wang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China; National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China; (Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou 225004, China.
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Palanivelu L, Chen YY, Chang CJ, Liang YW, Tseng HY, Li SJ, Chang CW, Lo YC. Investigating brain-gut microbiota dynamics and inflammatory processes in an autistic-like rat model using MRI biomarkers during childhood and adolescence. Neuroimage 2024; 302:120899. [PMID: 39461606 DOI: 10.1016/j.neuroimage.2024.120899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/11/2024] [Accepted: 10/22/2024] [Indexed: 10/29/2024] Open
Abstract
Autism spectrum disorder (ASD) is characterized by social interaction deficits and repetitive behaviors. Recent research has linked that gut dysbiosis may contribute to ASD-like behaviors. However, the exact developmental time point at which gut microbiota alterations affect brain function and behavior in patients with ASD remains unclear. We hypothesized that ASD-related brain microstructural changes and gut dysbiosis induce metabolic dysregulation and proinflammatory responses, which collectively contribute to the social behavioral deficits observed in early childhood. We used an autistic-like rat model that was generated via prenatal valproic acid exposure. We analyzed brain microstructural changes using diffusion tensor imaging (DTI) and examined microbiota, blood, and fecal samples for inflammation biomarkers. The ASD model rats exhibited significant brain microstructural changes in the anterior cingulate cortex, hippocampus, striatum, and thalamus; reduced microbiota diversity (Prevotellaceae and Peptostreptococcaceae); and altered metabolic signatures. The shift in microbiota diversity and density observed at postnatal day (PND) 35, which is a critical developmental period, underscored the importance of early ASD interventions. We identified a unique metabolic signature in the ASD model, with elevated formate and reduced acetate and butyrate levels, indicating a dysregulation in short-chain fatty acid (SCFA) metabolism. Furthermore, increased astrocytic and microglial activation and elevated proinflammatory cytokines-interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)-were observed, indicating immune dysregulation. This study provided insights into the complex interplay between the brain and the gut, and indicated DTI metrics as potential imaging-based biomarkers in ASD, thus emphasizing the need for early childhood interventions.
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Affiliation(s)
- Lalitha Palanivelu
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, 7F., No. 250, Wuxing St., Xinyi Dist., Taipei city 110, Taiwan
| | - You-Yin Chen
- Department of Biomedical Engineering, National Yang Ming Chiao Tung University, No.155, Sec.2, Linong St., Taipei 11221, Taiwan; Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University. 12F., Education and Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., New Taipei City 23564, Taiwan
| | - Chih-Ju Chang
- Department of Neurosurgery, Cathay General Hospital, No. 280, Sec. 4, Renai Rd., Taipei 10629, Taiwan; School of Medicine, Fu Jen Catholic University, No.510, Zhongzheng Rd., New Taipei City 242062, Taiwan
| | - Yao-Wen Liang
- Department of Biomedical Engineering, National Yang Ming Chiao Tung University, No.155, Sec.2, Linong St., Taipei 11221, Taiwan
| | - Hsin-Yi Tseng
- Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, 12F., Education and Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., New Taipei City 23564, Taiwan
| | - Ssu-Ju Li
- Department of Biomedical Engineering, National Yang Ming Chiao Tung University, No.155, Sec.2, Linong St., Taipei 11221, Taiwan
| | - Ching-Wen Chang
- Department of Biomedical Engineering, National Yang Ming Chiao Tung University, No.155, Sec.2, Linong St., Taipei 11221, Taiwan
| | - Yu-Chun Lo
- Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University. 12F., Education and Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., New Taipei City 23564, Taiwan.
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Ahmadi S, Hasani A, Khabbaz A, Poortahmasbe V, Hosseini S, Yasdchi M, Mehdizadehfar E, Mousavi Z, Hasani R, Nabizadeh E, Nezhadi J. Dysbiosis and fecal microbiota transplant: Contemplating progress in health, neurodegeneration and longevity. Biogerontology 2024; 25:957-983. [PMID: 39317918 DOI: 10.1007/s10522-024-10136-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 08/30/2024] [Indexed: 09/26/2024]
Abstract
The gut-brain axis plays an important role in mental health. The intestinal epithelial surface is colonized by billions of commensal and transitory bacteria, known as the Gut Microbiota (GM). However, potential pathogens continuously stimulate intestinal immunity when they find the place. The last two decades have witnessed several studies revealing intestinal bacteria as a key factor in the health-disease balance of the gut, as well as disease-emergent in other parts of the body. Various neurological processes, such as cognition, learning, and memory, could be affected by dysbiosis in GM. Additionally, the aging process and longevity are related to systemic inflammation caused by dysbiosis. Commensal GM affects brain development, behavior, and healthy aging suggesting that building changes in GM might be a potential therapeutic method. The innovation in GM dysbiosis is intervention by Fecal Microbiota Transplantation (FMT), which has been confirmed as a therapy for recurrent Clostridium difficile infections and is promising for other clinical disorders, such as Parkinson's disease, Multiple Sclerosis (MS), Alzheimer's disease, and depression. Additionally, FMT may be possible to promote healthy aging, and extend longevity. This review aims to connect dysbiosis, neurological disorders, and aging and the potential of FMT as a therapeutic strategy to treat these disorders, and to enhance the quality of life in the elderly.
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Affiliation(s)
- Somayeh Ahmadi
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Students Research Committee, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alka Hasani
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Clinical Research Development Unit, Sina Educational, Research and Treatment Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Aytak Khabbaz
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahdat Poortahmasbe
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samaneh Hosseini
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Yasdchi
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Mehdizadehfar
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Mousavi
- Department of Psychology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roqaiyeh Hasani
- School of Medicine, Istanbul Okan University, Tuzla, 34959, Istanbul, Turkey
| | - Edris Nabizadeh
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Nezhadi
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Peterson T, Dodson J, Burgin S, Sherwin R, Strale F. Impacts of Hyperbaric Oxygen Therapy (HBOT) on Verbal Scores in Children With Autism: A Secondary Analysis of the HBOT Trial Using Multivariate Analysis of Variance (MANOVA). Cureus 2024; 16:e69421. [PMID: 39411644 PMCID: PMC11473219 DOI: 10.7759/cureus.69421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 09/14/2024] [Indexed: 10/19/2024] Open
Abstract
Introduction A secondary analysis employing advanced statistical methodologies constitutes a robust means of validating initial findings in systematic empiricism. The current research will undertake a secondary analysis of the impacts of Hyperbaric Oxygen Therapy (HBOT) on verbal behaviors in children with autism using the original dataset. This approach aims to enhance the robustness of the initial results, thereby providing a deeper understanding of the data and potentially uncovering additional insights. Materials and methods From January 2018 to July 2021, all cohorts of autistic children (n = 65) were scheduled, evaluated, and treated at The Oxford Center (TOC) in Brighton and Troy, Michigan, USA. Trained research assistants retrospectively extracted pretest and posttest data from electronic medical records from the Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP) and the Assessment of Basic Language and Learning Skills (ABLLS). This data collection focused on children with autism who received either non-HBOT control with Applied Behavior Analysis (ABA) treatment only or ABA + HBOT interventions. For the VB-MAPP, the experimental group (ABA + HBOT) included 23 children, while the control group (ABA only) included 12 children. For the ABLLS, the experimental group (ABA + HBOT) consisted of nine children, compared to 21 children in the control group (ABA only). Demographic information was systematically summarized. Two independent sample t-tests were recomputed from the original study. Multivariate Analysis of Variance (MANOVA) were conducted, followed by one-way Analyses of Variance (ANOVA) post hoc analyses to elucidate the findings. Results The ages in both groups ranged from 2 to 17 years (M = 5.7 years ± 3.08), with median ages of four years for the experimental group and five years for the control group. The p-values and effect sizes indicated that the two independent sample t-tests from the original study and the MANOVAs from the current research are in agreement. This concordance provided confirmatory evidence for the validity of the pretest and posttest differences in VB-MAPP and ABLLS scores for the control group (ABA only) and the experimental group (ABA + HBOT), highlighting the impact of HBOT on verbal scores in children with autism. Conclusions The results from the two independent sample t-tests from the initial study exhibited high alignment with those derived from the current study's MANOVAs. Both statistical methodologies were applied to the same VB-MAPP and ABLLS datasets. The convergence of results from these two distinct statistical analyses may reinforce the credibility of the original research findings. It supports the hypothesis that the combined ABA and HBOT intervention may offer additional benefits over ABA therapy alone, with verbal milestone behaviors in children with autism.
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Affiliation(s)
- Tami Peterson
- Hyperbaric Oxygen Therapy, The Oxford Center, Brighton, USA
| | - Jessica Dodson
- Applied Behavior Analysis, The Oxford Center, Brighton, USA
| | - Sheila Burgin
- Hyperbaric Oxygen Therapy, The Oxford Center, Brighton, USA
| | - Robert Sherwin
- Hyperbaric Oxygen Therapy, Wayne State University School of Medicine, Detroit, USA
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Li S, Zhang N, Li W, Zhang HL, Wang XX. Gastrointestinal problems in a valproic acid-induced rat model of autism: From maternal intestinal health to offspring intestinal function. World J Psychiatry 2024; 14:1095-1105. [PMID: 39050201 PMCID: PMC11262932 DOI: 10.5498/wjp.v14.i7.1095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/13/2024] [Accepted: 06/04/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a developmental disorder characterized by social deficits and repetitive behavior. Gastrointestinal (GI) problems, such as constipation, diarrhea, and inflammatory bowel disease, commonly occur in patients with ASD. Previously, GI problems of ASD patients were attributed to intestinal inflammation and vertical mother-to-infant microbiome transmission. AIM To explore whether GI problems in ASD are related to maternal intestinal inflammation and gut microbiota abnormalities. METHODS An ASD rat model was developed using valproic acid (VPA). Enzyme-linked immunosorbent assay and fecal 16S rRNA sequencing were used to test GI changes. RESULTS VPA exposure during pregnancy led to pathological maternal intestinal changes, resulting in alterations in maternal gut microbiota. Additionally, the levels of inflammatory factors also increased. Moreover, prenatal exposure to VPA resulted in impaired duodenal motility in the offspring as well as increased levels of inflammatory factors. CONCLUSION GI problems in ASD may be associated with maternal intestinal inflammation and microbiota abnormality. Future research is required to find more evidence on the etiology and treatment of GI problems in ASD.
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Affiliation(s)
- Sha Li
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100000, China
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100000, China
| | - Nan Zhang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100000, China
| | - Wang Li
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100000, China
| | - Han-Lai Zhang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100000, China
| | - Xiao-Xi Wang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100000, China
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14
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Borrego-Ruiz A, Borrego JJ. Neurodevelopmental Disorders Associated with Gut Microbiome Dysbiosis in Children. CHILDREN (BASEL, SWITZERLAND) 2024; 11:796. [PMID: 39062245 PMCID: PMC11275248 DOI: 10.3390/children11070796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024]
Abstract
The formation of the human gut microbiome initiates in utero, and its maturation is established during the first 2-3 years of life. Numerous factors alter the composition of the gut microbiome and its functions, including mode of delivery, early onset of breastfeeding, exposure to antibiotics and chemicals, and maternal stress, among others. The gut microbiome-brain axis refers to the interconnection of biological networks that allow bidirectional communication between the gut microbiome and the brain, involving the nervous, endocrine, and immune systems. Evidence suggests that the gut microbiome and its metabolic byproducts are actively implicated in the regulation of the early brain development. Any disturbance during this stage may adversely affect brain functions, resulting in a variety of neurodevelopmental disorders (NDDs). In the present study, we reviewed recent evidence regarding the impact of the gut microbiome on early brain development, alongside its correlation with significant NDDs, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, cerebral palsy, fetal alcohol spectrum disorders, and genetic NDDs (Rett, Down, Angelman, and Turner syndromes). Understanding changes in the gut microbiome in NDDs may provide new chances for their treatment in the future.
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Affiliation(s)
- Alejandro Borrego-Ruiz
- Departamento de Psicología Social y de las Organizaciones, Universidad Nacional de Educación a Distancia (UNED), 28040 Madrid, Spain;
| | - Juan J. Borrego
- Departamento de Microbiología, Universidad de Málaga, 29071 Málaga, Spain
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA, Plataforma BIONAND, 29010 Málaga, Spain
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15
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Feng P, Zhang Y, Zhao Y, Zhao P, Li E. Combined repetitive transcranial magnetic stimulation and gut microbiota modulation through the gut-brain axis for prevention and treatment of autism spectrum disorder. Front Immunol 2024; 15:1341404. [PMID: 38455067 PMCID: PMC10918007 DOI: 10.3389/fimmu.2024.1341404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/07/2024] [Indexed: 03/09/2024] Open
Abstract
Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions characterized by enduring impairments in social communication and interaction together with restricted repetitive behaviors, interests, and activities. No targeted pharmacological or physical interventions are currently available for ASD. However, emerging evidence has indicated a potential association between the development of ASD and dysregulation of the gut-brain axis. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive diagnostic and therapeutic approach, has demonstrated positive outcomes in diverse psychiatric disorders; however, its efficacy in treating ASD and its accompanying gastrointestinal effects, particularly the effects on the gut-brain axis, remain unclear. Hence, this review aimed to thoroughly examine the existing research on the application of rTMS in the treatment of ASD. Additionally, the review explored the interplay between rTMS and the gut microbiota in children with ASD, focusing on the gut-brain axis. Furthermore, the review delved into the integration of rTMS and gut microbiota modulation as a targeted approach for ASD treatment based on recent literature. This review emphasizes the potential synergistic effects of rTMS and gut microbiota interventions, describes the underlying mechanisms, and proposes a potential therapeutic strategy for specific subsets of individuals with ASD.
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Affiliation(s)
- Pengya Feng
- Department of Children Rehabilitation, Key Laboratory of Rehabilitation Medicine in Henan, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- The American Psychiatric Association, Key Laboratory of Helicobacter pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yangyang Zhang
- Department of Children Rehabilitation, Key Laboratory of Rehabilitation Medicine in Henan, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yonghong Zhao
- Department of Children Rehabilitation, Key Laboratory of Rehabilitation Medicine in Henan, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Pengju Zhao
- Department of Children Rehabilitation, Key Laboratory of Rehabilitation Medicine in Henan, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Enyao Li
- Department of Children Rehabilitation, Key Laboratory of Rehabilitation Medicine in Henan, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Borrego-Ruiz A, Borrego JJ. An updated overview on the relationship between human gut microbiome dysbiosis and psychiatric and psychological disorders. Prog Neuropsychopharmacol Biol Psychiatry 2024; 128:110861. [PMID: 37690584 DOI: 10.1016/j.pnpbp.2023.110861] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/06/2023] [Accepted: 09/06/2023] [Indexed: 09/12/2023]
Abstract
There is a lot of evidence establishing that nervous system development is related to the composition and functions of the gut microbiome. In addition, the central nervous system (CNS) controls the imbalance of the intestinal microbiota, constituting a bidirectional communication system. At present, various gut-brain crosstalk routes have been described, including immune, endocrine and neural circuits via the vagal pathway. Several empirical data have associated gut microbiota alterations (dysbiosis) with neuropsychiatric diseases, such as Alzheimer's disease, autism and Parkinson's disease, and with other psychological disorders, like anxiety and depression. Fecal microbiota transplantation (FMT) therapy has shown that the gut microbiota can transfer behavioral features to recipient animals, which provides strong evidence to establish a causal-effect relationship. Interventions, based on prebiotics, probiotics or synbiotics, have demonstrated an important influence of microbiota on neurological disorders by the synthesis of neuroactive compounds that interact with the nervous system and by the regulation of inflammatory and endocrine processes. Further research is needed to demonstrate the influence of gut microbiota dysbiosis on psychiatric and psychological disorders, and how microbiota-based interventions may be used as potential therapeutic tools.
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Affiliation(s)
- Alejandro Borrego-Ruiz
- Departamento de Psicología Social y de las Organizaciones, Facultad de Psicología, UNED, Madrid, Spain
| | - Juan J Borrego
- Departamento de Microbiología, Universidad de Málaga, Málaga, Spain.
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Peterson T, Sherwin R, Hosey T, Close N, Strale F. The Effects of Hyperbaric Oxygen Treatment on Verbal Scores in Children With Autism Spectrum Disorder: A Retrospective Trial. Cureus 2024; 16:e51654. [PMID: 38318543 PMCID: PMC10839432 DOI: 10.7759/cureus.51654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/03/2024] [Indexed: 02/07/2024] Open
Abstract
Introduction Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects millions worldwide. Suggested pathophysiology includes cerebral hypoperfusion, inflammation, mitochondrial and immune dysregulation, and oxidative stress. Debate exists concerning the benefit of hyperbaric oxygen therapy (HBOT) in treating ASD and its impacts on verbal behavior. The present study directly assesses the impacts of HBOT treatments on verbal behavior using a novel and unique manner. Materials and methods A two-group quasi-experimental trial using a pretest and a posttest was designed to retrospectively assess (n = 65) any association between HBOT and change in verbal scores in children (n = 65) with ASD. All children completed two verbal tests six months apart, either the Verbal Behavior Milestones Assessment and Placement Program (VBMAPP) or the Assessment of Basic Language and Learning Skills (ABLLS), based on their developmental age. The control cohort received applied behavior analysis (ABA) without HBOT. The experimental cohort received ABA and a minimum of 40 HBOT treatments, breathing 100% oxygen at 2.0 atmosphere absolute (ATA) for 60 minutes. Results Sixty-five children were included, of which 32 received HBOT (mean (M) = 5.1, standard deviation (SD) = 2.93), with an age range of two to 17 years. More than 63% of the subjects had an autism severity level of three. The 23 children administered VBMAPP who received HBOT showed substantial mean differences with high effect sizes (ESs) (-0.743 to -1.65) and a total score (TS) ES equal to -1.23 as measured by Cohen's d. There was a statistically significant improvement (p < 0.05) in all VBMAPP milestone domains and TS. TS change from baseline versus those in the non-HBOT (Control-ABA) group (n=12) was 46.41 ± 20.14 vs 14.42 ± 6.99; p < 0.0001, ES = -1.23. The 30 children administered the ABLLS showed substantial mean difference (TS) change from baseline 268.89 ± 182.05 vs 190.81 ± 135.26 and exhibited small to medium (-.114 to -.773) ESs with a TS ES = -0.487. Due to the high within-group variability (low statistical power) within the ABLLS cohort, there was a non-significant mean difference between the control (ABA) and experimental (ABA + HBO2) groups' difference scores (p > 0.2024), despite the medium (TS) ES. Conclusions The child cohorts administered the VBMAPP and the ABLLS demonstrated substantial improvements between the non-HBOT (control-ABA) and HBOT (experimental-ABA + HBO2) groups as measured by the significant mean differences and small to large ESs. Simply put, the children in the experimental cohort acquired more verbal skills than their counterparts in the control group.
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Affiliation(s)
- Tami Peterson
- Hyperbaric Oxygen Therapy, The Oxford Center, Brighton, USA
| | - Robert Sherwin
- Hyperbaric Oxygen Therapy, Wayne State University School of Medicine, Detroit, USA
| | - Tiffany Hosey
- Hyperbaric Oxygen Therapy, The Oxford Center, Brighton, USA
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Gomes de Oliveira LI, Clementino JR, Salgaço MK, de Oliveira SPA, Dos Santos Lima M, Mesa V, de Souza EL, Vinderola CG, Magnani M, Sivieri K. Revealing the beneficial effects of a dairy infant formula on the gut microbiota of early childhood children with autistic spectrum disorder using static and SHIME® fermentation models. Food Funct 2023; 14:8964-8974. [PMID: 37724612 DOI: 10.1039/d3fo01156a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/21/2023]
Abstract
This study evaluated the impact of the Milnutri Profutura® (MNP) dairy infant formula on the gut microbiota of early childhood children (three to five years) with Autistic Spectrum Disorder (ASD) using static fermentation (time zero, 24, and 48 h) and the Simulator of the Human Intestinal Microbiol Ecosystem (SHIME®) (time zero, 72 h, and 7 days). The relative abundance of selected intestinal bacterial groups, pH values, organic acids, and sugars were verified at time zero, 24, and 48 h using flow cytometry and measurements. In addition, the diversity and changes in the gut microbiota, and the amounts of acetic, butyric, and propionic acids and ammonium ions (NH4+) in fermentation using the SHIME® were measured at time zero, 72 h, and 7 days. MNP increased Lactobacillus/Enterococcus and Bifidobacterium populations and decreased Bacteroides/Prevotella, Clostridium histolyticum and Eubacterium rectale/Clostridium coccoides populations (p < 0.05) at 24 and 48 h of static fermentation, showing a positive prebiotic activity score (65.18 ± 0.07). The pH, fructose and glucose decreased, while lactic, butyric, and propionic acids increased (p < 0.05) at 48 h of static fermentation. MNP increased (p < 0.05) the Firmicutes phylum during the fermentation in SHIME®. MNP decreased the diversity at 72 h of fermentation, mostly by the increase (p < 0.05) in the Lactobacillus genus. Microbial groups considered harmful such as Lachnospiraceae, Negativicoccus, and Lachnoclostridium were inhibited after administration with MNP. Propionic and butyric acids increased at 72 h and NH4+ decreased (p < 0.05) at the end of fermentation with MNP. The results indicate MNP as an infant formula which may benefit the gut microbiota of children with ASD.
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Affiliation(s)
- Louise Iara Gomes de Oliveira
- Post-Graduate Program in Nutritional Sciences, Health Sciences Center, Federal University of Paraíba (Universidade Federal da Paraíba - UFPB), Brazil.
| | - Jéssika Rodrigues Clementino
- Post-Graduate Program in Nutritional Sciences, Health Sciences Center, Federal University of Paraíba (Universidade Federal da Paraíba - UFPB), Brazil.
| | - Mateus Kawata Salgaço
- Department of Food and Nutrition, Laboratory of Food Microbiology, School of Pharmaceutical Sciences, São Paulo State University, Brazil
| | - Sônia Paula Alexandrino de Oliveira
- Post-Graduate Program in Nutritional Sciences, Health Sciences Center, Federal University of Paraíba (Universidade Federal da Paraíba - UFPB), Brazil.
| | - Marcos Dos Santos Lima
- Department of Food Technology, Federal Institute of Sertão de Pernambuco, Campus Petrolina, Brazil
| | - Victoria Mesa
- Food and Human Nutrition Research Group, School of Nutrition and Dietetics, Universidad de Antioquia (UdeA), Medellín 050010, Colombia
| | - Evandro Leite de Souza
- Post-Graduate Program in Nutritional Sciences, Health Sciences Center, Federal University of Paraíba (Universidade Federal da Paraíba - UFPB), Brazil.
| | - Celso Gabriel Vinderola
- Department of Biotechnology and Food Technology, Faculty of Chemical Engineering, Universidad Nacional del Litoral
| | - Marciane Magnani
- Post-Graduate Program in Nutritional Sciences, Health Sciences Center, Federal University of Paraíba (Universidade Federal da Paraíba - UFPB), Brazil.
| | - Katia Sivieri
- Department of Food and Nutrition, Laboratory of Food Microbiology, School of Pharmaceutical Sciences, São Paulo State University, Brazil
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Morin C, Bokobza C, Fleiss B, Hill-Yardin EL, Van Steenwinckel J, Gressens P. Preterm Birth by Cesarean Section: The Gut-Brain Axis, a Key Regulator of Brain Development. Dev Neurosci 2023; 46:179-187. [PMID: 37717575 DOI: 10.1159/000534124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/11/2023] [Indexed: 09/19/2023] Open
Abstract
Understanding the long-term functional implications of gut microbial communities during the perinatal period is a bourgeoning area of research. Numerous studies have revealed the existence of a "gut-brain axis" and the impact of an alteration of gut microbiota composition in brain diseases. Recent research has highlighted how gut microbiota could affect brain development and behavior. Many factors in early life such as the mode of delivery or preterm birth could lead to disturbance in the assembly and maturation of gut microbiota. Notably, global rates of cesarean sections (C-sections) have increased in recent decades and remain important when considering premature delivery. Both preterm birth and C-sections are associated with an increased risk of neurodevelopmental disorders such as autism spectrum disorders, with neuroinflammation a major risk factor. In this review, we explore links between preterm birth by C-sections, gut microbiota alteration, and neuroinflammation. We also highlight C-sections as a risk factor for developmental disorders due to alterations in the microbiome.
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Affiliation(s)
- Cécile Morin
- Université Paris Cité, Inserm, NeuroDiderot, Paris, France
- Hôpital Robert Debré, Assistance Publique, Hôpitaux de Paris (APHP), Paris, France
| | - Cindy Bokobza
- Université Paris Cité, Inserm, NeuroDiderot, Paris, France
| | - Bobbi Fleiss
- Université Paris Cité, Inserm, NeuroDiderot, Paris, France
- School of Health and Biomedical Sciences, STEM College, RMIT University, Bundoora, Victoria, Australia
| | - Elisa L Hill-Yardin
- School of Health and Biomedical Sciences, STEM College, RMIT University, Bundoora, Victoria, Australia
| | | | - Pierre Gressens
- Université Paris Cité, Inserm, NeuroDiderot, Paris, France
- Hôpital Robert Debré, Assistance Publique, Hôpitaux de Paris (APHP), Paris, France
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Panchal H, Athalye-Jape G, Rao S, Patole S. Growth and neuro-developmental outcomes of probiotic supplemented preterm infants-a systematic review and meta-analysis. Eur J Clin Nutr 2023; 77:855-871. [PMID: 36788356 PMCID: PMC10473962 DOI: 10.1038/s41430-023-01270-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 02/16/2023]
Abstract
Gut dysbiosis is associated with sepsis and necrotizing enterocolitis in preterm infants, which can adversely affect long-term growth and neurodevelopment. We aimed to synthesise evidence for the effect of probiotic supplementation on growth and neurodevelopmental outcomes in preterm infants. MEDLINE, EMBASE, EMCARE, Cochrane CENTRAL, and grey literature were searched in February 2022. Only randomized controlled trials (RCTs) were included. Meta-analysis was performed using random effects model. Effect sizes were expressed as standardized mean difference (SMD), mean difference (MD) or risk ratio (RR) and their corresponding 95% confidence intervals (CI). Risk of Bias (ROB) was assessed using the ROB-2 tool. Certainty of Evidence (CoE) was summarized using GRADE guidelines. Thirty RCTs (n = 4817) were included. Meta-analysis showed that probiotic supplementation was associated with better short-term weight gain [SMD 0.24 (95%CI 0.04, 0.44); 22 RCTs (n = 3721); p = 0.02; I2 = 88%; CoE: low]. However, length [SMD 0.12 (95%CI -0.13, 0.36); 7 RCTs, (n = 899); p = 0.35; I2 = 69%; CoE: low] and head circumference [SMD 0.09 (95%CI -0.15, 0.34); 8 RCTs (n = 1132); p = 0.46; I2 = 76%; CoE: low] were similar between the probiotic and placebo groups. Probiotic supplementation had no effect on neurodevelopmental impairment [RR 0.91 (95%CI 0.76, 1.08); 5 RCTs (n = 1556); p = 0.27; I2 = 0%; CoE: low]. Probiotic supplementation was associated with better short-term weight gain, but did not affect length, head circumference, long-term growth, and neurodevelopmental outcomes of preterm infants. Adequately powered RCTs are needed in this area. Prospero Registration: CRD42020064992.
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Affiliation(s)
- Harshad Panchal
- Neonatal Directorate, King Edward Memorial Hospital for Women, Perth, WA, Australia
| | - Gayatri Athalye-Jape
- Neonatal Directorate, King Edward Memorial Hospital for Women, Perth, WA, Australia.
- School of Medicine, University of Western Australia, Perth, WA, Australia.
| | - Shripada Rao
- School of Medicine, University of Western Australia, Perth, WA, Australia
- Neonatal Directorate, Perth Children's Hospital, Perth, WA, Australia
| | - Sanjay Patole
- Neonatal Directorate, King Edward Memorial Hospital for Women, Perth, WA, Australia
- School of Medicine, University of Western Australia, Perth, WA, Australia
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21
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Feng P, Zhao S, Zhang Y, Li E. A review of probiotics in the treatment of autism spectrum disorders: Perspectives from the gut–brain axis. Front Microbiol 2023; 14:1123462. [PMID: 37007501 PMCID: PMC10060862 DOI: 10.3389/fmicb.2023.1123462] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/07/2023] [Indexed: 03/18/2023] Open
Abstract
Autism spectrum disorders (ASD) are a class of neurodevelopmental conditions with a large societal impact. Despite existing evidence suggesting a link between ASD pathogenesis and gut–brain axis dysregulation, there is no systematic review of the treatment of probiotics on ASD and its associated gastrointestinal abnormalities based on the gut–brain axis. Therefore, we performed an analysis for ASD based on preclinical and clinical research to give a comprehensive synthesis of published evidence of a potential mechanism for ASD. On the one hand, this review aims to elucidate the link between gastrointestinal abnormalities and ASD. Accordingly, we discuss gut microbiota dysbiosis regarding gut–brain axis dysfunction. On the other hand, this review suggests that probiotic administration to regulate the gut–brain axis might improve gastrointestinal symptoms, restore ASD-related behavioral symptoms, restore gut microbiota composition, reduce inflammation, and restore intestinal barrier function in human and animal models. This review suggests that targeting the microbiota through agents such as probiotics may represent an approach for treating subsets of individuals with ASD.
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Affiliation(s)
- Pengya Feng
- Department of Children Rehabilitation, Key Laboratory of Rehabilitation Medicine in Henan, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Laboratory of Helicobacter pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuai Zhao
- College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Yangyang Zhang
- Department of Children Rehabilitation, Key Laboratory of Rehabilitation Medicine in Henan, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Enyao Li
- Department of Children Rehabilitation, Key Laboratory of Rehabilitation Medicine in Henan, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Enyao Li,
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22
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Long J, Wang J, Li Y, Chen S. Gut microbiota in ischemic stroke: Where we stand and challenges ahead. Front Nutr 2022; 9:1008514. [PMID: 36532541 PMCID: PMC9756810 DOI: 10.3389/fnut.2022.1008514] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 11/07/2022] [Indexed: 01/05/2025] Open
Abstract
Gut microbiota is increasingly recognized to affect host health and disease, including ischemic stroke (IS). Here, we systematically review the current understanding linking gut microbiota as well as the associated metabolites to the pathogenesis of IS (e.g., oxidative stress, apoptosis, and neuroinflammation). Of relevance, we highlight that the implications of gut microbiota-dependent intervention could be harnessed in orchestrating IS.
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Affiliation(s)
- Jiaxin Long
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Jinlong Wang
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Yang Li
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Shuai Chen
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
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23
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Kim A, Zisman CR, Holingue C. Influences of the Immune System and Microbiome on the Etiology of ASD and GI Symptomology of Autistic Individuals. Curr Top Behav Neurosci 2022; 61:141-161. [PMID: 35711026 DOI: 10.1007/7854_2022_371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Autism Spectrum Disorder is a developmental condition associated with impairments in communication and social interactions, and repetitive and restricted behavior or interests. Autistic individuals are more likely to experience gastrointestinal (GI) symptoms than neurotypical individuals. This may be partially due to dysbiosis of the gut microbiome. In this article, we describe the interaction of the microbiome and immune system on autism etiology. We also summarize the links between the microbiome and gastrointestinal and related symptoms among autistic individuals. We report that microbial interventions, including diet, probiotics, antibiotics, and fecal transplants, and immune-modulating therapies such as cytokine blockade during the preconception, pregnancy, and postnatal period may impact the neurodevelopment, behavior, and gastrointestinal health of autistic individuals.
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Affiliation(s)
- Amanda Kim
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Corina R Zisman
- Department of Psychology, Pennsylvania State University, University Park, PA, USA
| | - Calliope Holingue
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. .,Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, MD, USA.
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24
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[Functional feeding to alleviate gastrointestinal disorders associated with autism spectrum disorders: A systematic review]. NUTR HOSP 2022; 39:663-677. [PMID: 35485378 DOI: 10.20960/nh.03898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
BACKGROUND gastrointestinal disorders (GIDs) are common comorbidities in patients with autism spectrum disorders (ASD); treatments with gluten- and casein-free (LGLC) diets or prebiotic/probiotic supplements may reduce the severity of GIDs. OBJECTIVE to integrate and discuss the evidence on the effectiveness of LGLC diet therapies and prebiotic/probiotic supplements on GIDs in patients with ASD. METHODOLOGY the guidelines for the publication of systematic reviews and meta-analyses (PRISMA) were used. Participant characteristics, dietary interventions, prebiotic/prebiotic supplementation, effects of interventions on GIDs, risk of bias, and safety of treatments were analyzed. RESULTS fifteen investigations were analyzed; the prevalence of GIDs among patients with ASD was high (58 %; range, 27-83 %). In more than 20 % of the patients managed with LGLC diets or supplements GID severity decreased (mainly constipation, diarrhea, and abdominal pain). Increases in the counts of beneficial bacteria and a decrease in the proportion of pathogenic bacteria were reported after supplement use. However, all these investigations had significant methodological biases. CONCLUSIONS although reductions in the frequency and severity of some GIDs have been found, the effectiveness of these treatments has not been proven yet. Given the methodological differences in the investigations, the design of rigorous studies to evaluate the therapeutic effects of these treatments on gastrointestinal health in patients with ASD is warranted.
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25
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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. [PMID: 35438624 DOI: 10.1099/jmm.0.001510] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Introduction. Autism spectrum disorder (ASD) is a neurodevelopmental disorder. The discovery of the influence of gut microbiota on mental illness opens up new research avenues for the role of gut microbiota modifiers, such as probiotics or prebiotics, as a potential course of treatment. Potential treatments have received considerable attention in recent years.Aim. The meta-analysis only included clinical controlled trials to explore whether probiotics and prebiotics can improve the overall severity of ASD symptoms in children, the severity of gastrointestinal (GI) problems and the comorbid psychopathlology in ASD.Gap statement. Although systematic reviews have been conducted in this area in the past, most of them are mixed experimental designs, and the reliability of the conclusions remains to be determined. To the best of our knowledge, no systematic review of randomized controlled trials (RCTs) has been conducted.Methodology. A meta analysis used a combination of subject terms and free words, or used keywords, titles, and abstracts to conduct in PubMed, Web of Science, Embase, and Cochrane Library to identify studies relevant to the current review.Result. The results of the meta-analysis showed that probiotics and prebiotics did not significantly improve the severity of ASD patients, GI problems and comorbid psychopathlology in ASD, and the result is contradictory to the previous literatures.Conclusion. Since there are relatively few clinical controlled trials that can be included, the results of this study still need to be further verified in the clinic. In the future, more randomized controlled studies, more research populations, and the use of more professional clinicians may provide more robust research results.
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Affiliation(s)
- Wenjing Song
- Heilongjiang University of Chinese Medicine, Harbin, PR China
| | - Mei Zhang
- Heilongjiang University of Chinese Medicine, Harbin, PR China
| | - Lili Teng
- Heilongjiang University of Chinese Medicine, Harbin, PR China
| | - Yu Wang
- Heilongjiang University of Chinese Medicine, Harbin, PR China
| | - Luwen Zhu
- Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, PR China
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26
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Bacterial Atlas of Mouse Gut Microbiota. Cell Microbiol 2022. [DOI: 10.1155/2022/5968814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background. Mouse model is one of the most widely used animal models for exploring the roles of human gut microbiota, a complex system involving in human immunity and metabolism. However, the structure of mouse gut bacterial community has not been explored at a large scale. To address this concern, the diversity and composition of the gut bacteria of 600 mice were characterized in this study. Results. The results showed that the bacteria belonging to 8 genera were found in the gut microbiota of all mouse individuals, indicating that the 8 bacteria were the core bacteria of mouse gut microbiota. The dominant genera of the mouse gut bacteria contained 15 bacterial genera. It was found that the bacteria in the gut microbiota were mainly involved in host’s metabolisms via the collaborations between the gut bacteria. The further analysis demonstrated that the composition of mouse gut microbiota was similar to that of human gut microbiota. Conclusion. Our study presented a bacterial atlas of mouse gut microbiota, providing a solid basis for investing the bacterial communities of mouse gut microbiota.
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27
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Vellingiri B, Aishwarya SY, Benita Jancy S, Sriram Abhishek G, Winster Suresh Babu H, Vijayakumar P, Narayanasamy A, Mariappan S, Sangeetha R, Valsala Gopalakrishnan A, Parthasarathi R, Iyer M. An anxious relationship between Autism Spectrum Disorder and Gut Microbiota: A tangled chemistry? J Clin Neurosci 2022; 99:169-189. [PMID: 35286970 DOI: 10.1016/j.jocn.2022.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 12/27/2022]
Abstract
Autism spectrum disorder (ASD) is a serious multifactorial neurodevelopmental disorder often accompanied by strained social communication, repetitive behaviour, immune dysregulation, and gastrointestinal (GI) issues. Recent studies have recorded a link between dysbiosis in the gut microbiota (gm) and the primary stages of ASD. A bidirectional connection (also called microbiota-gut-brain-axis) exchanges information between the gut bacteria and central nervous system. When the homeostasis of the microenvironment of the gut is dysregulated, it causes oxidative stress, affecting neuronal cells and neurotransmitters, thereby causing neurodevelopmental disorders. Studies have confirmed a difference in the constitution of gut bacteria among ASD cases and their controls. Numerous studies on animal models of ASD have shown altered gm and its association with abnormal metabolite profile and altered behaviour phenotype. This process happens due to an abnormal metabolite production in gm, leading to changes in the immune system, especially in ASD. Hence, this review aims to question the current knowledge on gm dysbiosis and its related GI discomforts and ASD behavioural symptoms and shed light on the possible therapeutic approaches available to deal with this situation. Thereby, though it is understood that more research might be needed to prove an association or causal relationship between gm and ASD, therapy with the microbiome may also be considered as an effective strategy to combat this issue.
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Affiliation(s)
- Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India.
| | - S Y Aishwarya
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India
| | - S Benita Jancy
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India
| | - G Sriram Abhishek
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India
| | - Harysh Winster Suresh Babu
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India; Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Padmavathi Vijayakumar
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
| | - Arul Narayanasamy
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Sujitha Mariappan
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India
| | - R Sangeetha
- Department of Zoology and Wild Life Biology, Government Arts College, Udhagamandalam 643002, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632014 Tamil Nadu, India
| | - Ramakrishnan Parthasarathi
- Computational Toxicology Facility, Centre for Innovation and Translational Research, Environmental Monitoring and Intervention Hub (DSIR-CRTDH), CSIR-Indian Institute of Toxicology Research, Lucknow 226001 Uttar Pradesh, India
| | - Mahalaxmi Iyer
- Livestock Farming and Bioresource Technology, Tamil Nadu, India.
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28
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Mehra A, Arora G, Gaurav, Kaur M, Singh H, Singh B, Kaur S. Gut microbiota and Autism Spectrum Disorder: From pathogenesis to potential therapeutic perspectives. J Tradit Complement Med 2022; 13:135-149. [PMID: 36970459 PMCID: PMC10037072 DOI: 10.1016/j.jtcme.2022.03.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 01/19/2022] [Accepted: 03/03/2022] [Indexed: 02/08/2023] Open
Abstract
Autism is a complex neurodevelopmental disorder which disrupts communication, social and interactive skills followed by appearance of repetitive behavior. The underlying etiology remains incomprehensible but genetic and environmental factors play a key role. Accumulated evidence shows that alteration in level of gut microbes and their metabolites are not only linked to gastrointestinal problems but also to autism. So far the mix of microbes that is present in the gut affects human health in numerous ways through extensive bacterial-mammalian cometabolism and has a marked influence over health via gut-brain-microbial interactions. Healthy microbiota may even ease the symptoms of autism, as microbial balance influences brain development through the neuroendocrine, neuroimmune, and autonomic nervous systems. In this article, we focused on reviewing the correlation between gut microbiota and their metabolites on symptoms of autism by utilizing prebiotics, probiotics and herbal remedies to target gut microflora hence autism.
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29
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Sorboni SG, Moghaddam HS, Jafarzadeh-Esfehani R, Soleimanpour S. A Comprehensive Review on the Role of the Gut Microbiome in Human Neurological Disorders. Clin Microbiol Rev 2022; 35:e0033820. [PMID: 34985325 PMCID: PMC8729913 DOI: 10.1128/cmr.00338-20] [Citation(s) in RCA: 250] [Impact Index Per Article: 83.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The human body is full of an extensive number of commensal microbes, consisting of bacteria, viruses, and fungi, collectively termed the human microbiome. The initial acquisition of microbiota occurs from both the external and maternal environments, and the vast majority of them colonize the gastrointestinal tract (GIT). These microbial communities play a central role in the maturation and development of the immune system, the central nervous system, and the GIT system and are also responsible for essential metabolic pathways. Various factors, including host genetic predisposition, environmental factors, lifestyle, diet, antibiotic or nonantibiotic drug use, etc., affect the composition of the gut microbiota. Recent publications have highlighted that an imbalance in the gut microflora, known as dysbiosis, is associated with the onset and progression of neurological disorders. Moreover, characterization of the microbiome-host cross talk pathways provides insight into novel therapeutic strategies. Novel preclinical and clinical research on interventions related to the gut microbiome for treating neurological conditions, including autism spectrum disorders, Parkinson's disease, schizophrenia, multiple sclerosis, Alzheimer's disease, epilepsy, and stroke, hold significant promise. This review aims to present a comprehensive overview of the potential involvement of the human gut microbiome in the pathogenesis of neurological disorders, with a particular emphasis on the potential of microbe-based therapies and/or diagnostic microbial biomarkers. This review also discusses the potential health benefits of the administration of probiotics, prebiotics, postbiotics, and synbiotics and fecal microbiota transplantation in neurological disorders.
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Affiliation(s)
| | | | - Reza Jafarzadeh-Esfehani
- Blood Borne Infectious Research Center, Academic Center for Education, Culture and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Centre, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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30
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He X, Tu Y, Song Y, Yang G, You M. The relationship between pesticide exposure during critical neurodevelopment and autism spectrum disorder: A narrative review. ENVIRONMENTAL RESEARCH 2022; 203:111902. [PMID: 34416252 DOI: 10.1016/j.envres.2021.111902] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 06/13/2023]
Abstract
Agricultural pesticides have been one of the most extensively used compounds throughout the world. The main sources of contamination for humans are dietary intake and occupational exposure. The impairments caused by agricultural pesticide exposure have been a significant global public health problem. Recent studies have shown that low-level agricultural pesticide exposure during the critical period of neurodevelopment (pregnancy and lactation) is closely related to autism spectrum disorder (ASD). Inhibition of acetylcholinesterase, gut microbiota, neural dendrite morphology, synaptic function, and glial cells are targets for the effects of pesticides during nervous system development. In the present review, we summarize the associations between several highly used and frequently studied pesticides (e.g., glyphosate, chlorpyrifos, pyrethroids, and avermectins) and ASD. We also discusse future epidemiological and toxicological research directions on the relationship between pesticides and ASD.
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Affiliation(s)
- Xiu He
- School of Public Heath, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Ying Tu
- School of Public Heath, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Yawen Song
- School of Public Heath, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Guanghong Yang
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang, Guizhou, 550004, PR China.
| | - Mingdan You
- School of Public Heath, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China.
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31
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Erbescu A, Papuc SM, Budisteanu M, Arghir A, Neagu M. Re-emerging concepts of immune dysregulation in autism spectrum disorders. Front Psychiatry 2022; 13:1006612. [PMID: 36339838 PMCID: PMC9626859 DOI: 10.3389/fpsyt.2022.1006612] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by communication and social interaction deficits, and by restricted interests and stereotyped, repetitive behavior patterns. ASD has a strong genetic component and a complex architecture characterized by the interplay of rare and common genetic variants. Recently, increasing evidence suggest a significant contribution of immune system dysregulation in ASD. The present paper reviews the latest updates regarding the altered immune landscape of this complex disorder highlighting areas with potential for biomarkers discovery as well as personalization of therapeutic approaches. Cross-talk between the central nervous system and immune system has long been envisaged and recent evidence brings insights into the pathways connecting the brain to the immune system. Disturbance of cytokine levels plays an important role in the establishment of a neuroinflammatory milieu in ASD. Several other immune molecules involved in antigen presentation and inflammatory cellular phenotypes are also at play in ASD. Maternal immune activation, the presence of brain-reactive antibodies and autoimmunity are other potential prenatal and postnatal contributors to ASD pathophysiology. The molecular players involved in oxidative-stress response and mitochondrial system function, are discussed as contributors to the pro-inflammatory pattern. The gastrointestinal inflammation pathways proposed to play a role in ASD are also discussed. Moreover, the body of evidence regarding some of the genetic factors linked to the immune system dysregulation is reviewed and discussed. Last, but not least, the epigenetic traits and their interactions with the immune system are reviewed as an expanding field in ASD research. Understanding the immune-mediated pathways that influence brain development and function, metabolism, and intestinal homeostasis, may lead to the identification of robust diagnostic or predictive biomarkers for ASD individuals. Thus, novel therapeutic approaches could be developed, ultimately aiming to improve their quality of life.
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Affiliation(s)
- Alina Erbescu
- Victor Babes National Institute of Pathology, Bucharest, Romania.,Faculty of Biology, Doctoral School, University of Bucharest, Bucharest, Romania
| | | | - Magdalena Budisteanu
- Victor Babes National Institute of Pathology, Bucharest, Romania.,Prof. Dr. Alex. Obregia Clinical Hospital of Psychiatry, Bucharest, Romania.,Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
| | - Aurora Arghir
- Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Monica Neagu
- Victor Babes National Institute of Pathology, Bucharest, Romania.,Faculty of Biology, Doctoral School, University of Bucharest, Bucharest, Romania.,Colentina Clinical Hospital, Bucharest, Romania
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32
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Shah F, Dwivedi M. Pathophysiological Role of Gut Microbiota Affecting Gut–Brain Axis and Intervention of Probiotics and Prebiotics in Autism Spectrum Disorder. PROBIOTIC RESEARCH IN THERAPEUTICS 2022:69-115. [DOI: 10.1007/978-981-16-6760-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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33
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MCP-1 Signaling Disrupts Social Behavior by Modulating Brain Volumetric Changes and Microglia Morphology. Mol Neurobiol 2021; 59:932-949. [PMID: 34797523 DOI: 10.1007/s12035-021-02649-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/15/2021] [Indexed: 10/19/2022]
Abstract
Autism spectrum disorder (ASD) is a disease characterized by reduced social interaction and stereotypic behaviors and related to macroscopic volumetric changes in cerebellar and somatosensory cortices (SPP). Epidemiological and preclinical models have confirmed that a proinflammatory profile during fetal development increases ASD susceptibility after birth. Here, we aimed to globally identify the effect of maternal exposure to high-energy dense diets, which we refer to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring. We found a sex-dependent effect of maternal exposure to CAF diet or inoculation of the dsARN mimetic Poly (I:C) on peripheral proinflammatory and social interaction in the offspring. Notably, maternal exposure to CAF diet impairs social interaction and favors an increase in anxiety in male but not female offspring. Also, CAF diet exposure or Poly (I:C) inoculation during fetal programming promote peripheral proinflammatory profile in the ASD-diagnosed male but not in females. Selectively, we found a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to CAF during fetal development. Biological assessment of MCP-1 signaling in brain confirms that systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring. These data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.
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Ye L, Rawls JF. Microbial influences on gut development and gut-brain communication. Development 2021; 148:dev194936. [PMID: 34758081 PMCID: PMC8627602 DOI: 10.1242/dev.194936] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 10/07/2021] [Indexed: 12/15/2022]
Abstract
The developmental programs that build and sustain animal forms also encode the capacity to sense and adapt to the microbial world within which they evolved. This is abundantly apparent in the development of the digestive tract, which typically harbors the densest microbial communities of the body. Here, we review studies in human, mouse, zebrafish and Drosophila that are revealing how the microbiota impacts the development of the gut and its communication with the nervous system, highlighting important implications for human and animal health.
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Jackson-Cowan L, Cole EF, Arbiser JL, Silverberg JI, Lawley LP. TH2 sensitization in the skin-gut-brain axis: How early-life Th2-mediated inflammation may negatively perpetuate developmental and psychologic abnormalities. Pediatr Dermatol 2021; 38:1032-1039. [PMID: 34338364 DOI: 10.1111/pde.14657] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We recently reported children with comorbid atopic dermatitis (AD), asthma, allergic rhinitis, and food allergies displaying a 2.7-fold increase in developmental delays.2 To this end, we hypothesize unregulated increases in T helper-2 (Th2)-driven inflammation, such as those seen in atopic diseases, can exert deleterious effects on the developing brain. Recognizing that available information is incomplete and that many potential associations are not firmly established, we speculate these effects underlie the association between Th2 sensitization and cognitive dysfunction in children. In this review, we explore the role of Th2 sensitization in the skin-gut-brain axis and explain how it can lead to reduced connectivity and transmission in the developing brain. With a focus on AD, we explore the association between Th2 sensitization and developmental abnormalities such as developmental delays, memory impairment, autism spectrum disorder (ASD), and epilepsy/seizures. As such, we review the available literature to examine the impact of increased IL-4 exposure in early life on the brain. We explore the possible association between Th2 sensitization and psychologic dysfunction such as attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, and suicidal ideation. We also examine the impact that increased exposure to glucocorticoids and neurotrophins in early life exerts on the developing brain. Last, we discuss future directions for the advancement of our knowledge as a scientific community including possible interventions to reduce developmental and psychologic aberrations in children.
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Affiliation(s)
- LaDonya Jackson-Cowan
- AU/UGA Medical Partnership, The Medical College of Georgia at Augusta University, University of Georgia College of Pharmacy, Athens, GA, USA
| | - Emily F Cole
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
| | - Jack L Arbiser
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
| | - Jonathan I Silverberg
- Department of Dermatology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Leslie P Lawley
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
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Hyperbaric Oxygen Therapy for Children and Youth with Autism Spectrum Disorder: A Review. Brain Sci 2021; 11:brainsci11070916. [PMID: 34356150 PMCID: PMC8303909 DOI: 10.3390/brainsci11070916] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/02/2021] [Accepted: 07/08/2021] [Indexed: 01/07/2023] Open
Abstract
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder determined by a complex of factors (genetic and environmental). On a pathophysiological basis hyperbaric oxygen therapy (HBOT) has been suggested as an effective therapeutic method in ASD, and thus many parents/guardians attempt to treat their child with ASD using this method. Therefore, this review aimed to verify the significant therapeutic value of this method for individuals with ASD. The literature review included all articles from the last 5 years (2015-2021) that met the inclusion criteria-both original papers and literature reviews. None of the 10 literature reviews indicated that HBOT was a clearly effective form of therapy in the case of ASD. Two out of four papers presenting the results of the intervention studies also did not recommend the use of this form of therapy in children with ASD. The results of the other two studies were not entirely relevant to the purpose of this review because one study had no control group, while the other study focused solely on auditory processing disorders. A review of the literature on whether HBOT as a therapy significantly affects the symptoms of ASD does not confirm its effectiveness.
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Doenyas C, Ekici B, Unay ÖS, Gönen İ, Tatlı B. Autism in Turkey: demographics, behavior problems, and accompanying medical conditions in a sample of Turkish youth with autism spectrum disorder. INTERNATIONAL JOURNAL OF DEVELOPMENTAL DISABILITIES 2021; 69:179-189. [PMID: 37025343 PMCID: PMC10071939 DOI: 10.1080/20473869.2021.1937001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/27/2021] [Accepted: 05/27/2021] [Indexed: 06/19/2023]
Abstract
Autism spectrum disorder (ASD) is an etiologically heterogeneous neurodevelopmental condition that eludes a single explanation or cure. Epidemiological studies reveal risk factors, relevant comorbidities, and behavioral correlates to reach a better understanding of ASD. To contribute such data from an understudied ASD population, this paper presents epidemiological data from a Turkish sample of individuals with ASD (n = 911, 748 boys (82.1%) and 163 girls (17.9%) between 1 and 18 years of age). Average age at diagnosis was 31.06 ± 11.88 months, and the male-to-female ratio was 4.6:1. Three in 4 individuals with ASD had obsessive behaviors, and 1 in 4 had allergic conditions, inappropriate sexual behaviors, self-harming behaviors, and harmful behaviors towards others. One in 3 received a dietary treatment for at least 3 months; almost half received vitamin supplements; the majority (70%) did not experience constipation; and 2 in 3 were picky eaters. This paper presents data on the age of diagnosis, gender ratios, accompanying behaviors, and dietary interventions in Turkish individuals with ASD, which are topics of current research interest about ASD. Such data from non-Western populations may supplement epidemiological knowledge gained from Western populations to help reach a more comprehensive understanding of this condition with many unknowns.
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Affiliation(s)
- Ceymi Doenyas
- Koç University Research Center for Translational Medicine, Istanbul, Turkey
| | - Barış Ekici
- Pediatric Neurologist, Istanbul Special Child Neurology Clinic, Istanbul, Turkey
| | - Öykü Su Unay
- Occupational Therapist, Istanbul Special Child Neurology Clinic, Istanbul, Turkey
| | - İsmail Gönen
- Department of Pediatrics, İstinye University, Istanbul, Turkey
| | - Burak Tatlı
- Pediatric Neurologist, Istanbul Special Child Neurology Clinic, Istanbul, Turkey
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Guo Y, Zhu X, Zeng M, Qi L, Tang X, Wang D, Zhang M, Xie Y, Li H, Yang X, Chen D. A diet high in sugar and fat influences neurotransmitter metabolism and then affects brain function by altering the gut microbiota. Transl Psychiatry 2021; 11:328. [PMID: 34045460 PMCID: PMC8160265 DOI: 10.1038/s41398-021-01443-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 05/05/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota (GM) metabolites can modulate the physiology of the host brain through the gut-brain axis. We wished to discover connections between the GM, neurotransmitters, and brain function using direct and indirect methods. A diet with increased amounts of sugar and fat (high-sugar and high-fat (HSHF) diet) was employed to disturb the host GM. Then, we monitored the effect on pathology, neurotransmitter metabolism, transcription, and brain circularRNAs (circRNAs) profiles in mice. Administration of a HSHF diet-induced dysbacteriosis, damaged the intestinal tract, changed the neurotransmitter metabolism in the intestine and brain, and then caused changes in brain function and circRNA profiles. The GM byproduct trimethylamine-n-oxide could degrade some circRNAs. The basal level of the GM decided the conversion rate of choline to trimethylamine-n-oxide. A change in the abundance of a single bacterial strain could influence neurotransmitter secretion. These findings suggest that a new link between metabolism, brain circRNAs, and GM. Our data could enlarge the "microbiome-transcriptome" linkage library and provide more information on the gut-brain axis. Hence, our findings could provide more information on the interplay between the gut and brain to aid the identification of potential therapeutic markers and mechanistic solutions to complex problems encountered in studies of pathology, toxicology, diet, and nutrition development.
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Affiliation(s)
- Yinrui Guo
- grid.411866.c0000 0000 8848 7685School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangdong, Guangzhou 510120 China
| | - Xiangxiang Zhu
- grid.464309.c0000 0004 6431 5677State Key Laboratory of Applied Microbiology Southern China; Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application; Guangdong Open Laboratory of Applied Microbiology; Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070 China ,grid.258164.c0000 0004 1790 3548Academy of Life Sciences, Jinan University, Guangdong Province, Guangzhou, 510000 China
| | - Miao Zeng
- grid.464309.c0000 0004 6431 5677State Key Laboratory of Applied Microbiology Southern China; Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application; Guangdong Open Laboratory of Applied Microbiology; Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070 China ,grid.411304.30000 0001 0376 205XChengdu University of Traditional Chinese Medicine, Chengdu, 610075 China
| | - Longkai Qi
- grid.464309.c0000 0004 6431 5677State Key Laboratory of Applied Microbiology Southern China; Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application; Guangdong Open Laboratory of Applied Microbiology; Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070 China
| | - Xiaocui Tang
- grid.464309.c0000 0004 6431 5677State Key Laboratory of Applied Microbiology Southern China; Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application; Guangdong Open Laboratory of Applied Microbiology; Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070 China
| | - Dongdong Wang
- grid.464309.c0000 0004 6431 5677State Key Laboratory of Applied Microbiology Southern China; Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application; Guangdong Open Laboratory of Applied Microbiology; Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070 China
| | - Mei Zhang
- grid.411304.30000 0001 0376 205XChengdu University of Traditional Chinese Medicine, Chengdu, 610075 China
| | - Yizhen Xie
- grid.464309.c0000 0004 6431 5677State Key Laboratory of Applied Microbiology Southern China; Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application; Guangdong Open Laboratory of Applied Microbiology; Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070 China
| | - Hongye Li
- grid.258164.c0000 0004 1790 3548Academy of Life Sciences, Jinan University, Guangdong Province, Guangzhou, 510000 China
| | - Xin Yang
- The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
| | - Diling Chen
- State Key Laboratory of Applied Microbiology Southern China; Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application; Guangdong Open Laboratory of Applied Microbiology; Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070, China.
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Evaluation of Appetite-Regulating Hormones ın Young Children with Autism Spectrum Disorder. J Autism Dev Disord 2021; 51:632-643. [PMID: 32583136 DOI: 10.1007/s10803-020-04579-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
This study aimed to investigate the role of leptin, ghrelin, neuropeptide Y, and nesfatin-1 in young children with autism spectrum disorder (ASD). A total of 44 children with ASD and 44 healthy controls aged 18-60 months were included. Plasma levels of hormones were measured using commercial enzyme-linked immunosorbent assay kits. Plasma leptin and ghrelin levels were significantly higher in the ASD group than in the control group. However, no significant difference for plasma neuropeptide Y and nesfatin-1 levels was detected between the groups. No relation was found between the severity of ASD symptoms, severity of eating problems, and plasma levels of hormones. Leptin and ghrelin may play a potential role in the pathogenesis of ASD.
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Piccioni A, Franza L, Brigida M, Zanza C, Torelli E, Petrucci M, Nicolò R, Covino M, Candelli M, Saviano A, Ojetti V, Franceschi F. Gut Microbiota and Acute Diverticulitis: Role of Probiotics in Management of This Delicate Pathophysiological Balance. J Pers Med 2021; 11:298. [PMID: 33919818 PMCID: PMC8070761 DOI: 10.3390/jpm11040298] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 04/05/2021] [Accepted: 04/11/2021] [Indexed: 02/05/2023] Open
Abstract
How can the knowledge of probiotics and their mechanisms of action be translated into clinical practice when treating patients with diverticular disease and acute diverticulitis? Changes in microbiota composition have been observed in patients who were developing acute diverticulitis, with a reduction of taxa with anti-inflammatory activity, such as Clostridium cluster IV, Lactobacilli and Bacteroides. Recent observations supported that a dysbiosis characterised by decreased presence of anti-inflammatory bacterial species might be linked to mucosal inflammation, and a vicious cycle results from a mucosal inflammation driving dysbiosis at the same time. An alteration in gut microbiota can lead to an altered activation of nerve fibres, and subsequent neuronal and muscular dysfunction, thus favoring abdominal symptoms' development. The possible role of dysbiosis and mucosal inflammation in leading to dysmotility is linked, in turn, to bacterial translocation from the lumen of the diverticulum to perivisceral area. There, a possible activation of Toll-like receptors has been described, with a subsequent inflammatory reaction at the level of the perivisceral tissues. Being aware that bacterial colonisation of diverticula is involved in the pathogenesis of acute diverticulitis, the rationale for the potential role of probiotics in the treatment of this disease becomes clearer. For this review, articles were identified using the electronic PubMed database through a comprehensive search conducted by combining key terms such as "gut microbiota", "probiotics and gut disease", "probiotics and acute diverticulitis", "probiotics and diverticular disease", "probiotics mechanism of action". However, the amount of data present on this matter is not sufficient to draw robust conclusions on the efficacy of probiotics for symptoms' management in diverticular disease.
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Affiliation(s)
- Andrea Piccioni
- Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 1-00168 Rome, Italy; (M.C.); (M.C.); (V.O.); (F.F.)
| | - Laura Franza
- Università Cattolica del Sacro Cuore, 1-00168 Rome, Italy; (L.F.); (C.Z.); (E.T.); (M.P.); (R.N.); (A.S.)
| | - Mattia Brigida
- Unit of Gastroenterology, Department of Systems Medicine, Tor Vergata University, 2-00133 Rome, Italy;
| | - Christian Zanza
- Università Cattolica del Sacro Cuore, 1-00168 Rome, Italy; (L.F.); (C.Z.); (E.T.); (M.P.); (R.N.); (A.S.)
| | - Enrico Torelli
- Università Cattolica del Sacro Cuore, 1-00168 Rome, Italy; (L.F.); (C.Z.); (E.T.); (M.P.); (R.N.); (A.S.)
| | - Martina Petrucci
- Università Cattolica del Sacro Cuore, 1-00168 Rome, Italy; (L.F.); (C.Z.); (E.T.); (M.P.); (R.N.); (A.S.)
| | - Rebecca Nicolò
- Università Cattolica del Sacro Cuore, 1-00168 Rome, Italy; (L.F.); (C.Z.); (E.T.); (M.P.); (R.N.); (A.S.)
| | - Marcello Covino
- Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 1-00168 Rome, Italy; (M.C.); (M.C.); (V.O.); (F.F.)
| | - Marcello Candelli
- Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 1-00168 Rome, Italy; (M.C.); (M.C.); (V.O.); (F.F.)
| | - Angela Saviano
- Università Cattolica del Sacro Cuore, 1-00168 Rome, Italy; (L.F.); (C.Z.); (E.T.); (M.P.); (R.N.); (A.S.)
| | - Veronica Ojetti
- Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 1-00168 Rome, Italy; (M.C.); (M.C.); (V.O.); (F.F.)
- Università Cattolica del Sacro Cuore, 1-00168 Rome, Italy; (L.F.); (C.Z.); (E.T.); (M.P.); (R.N.); (A.S.)
| | - Francesco Franceschi
- Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 1-00168 Rome, Italy; (M.C.); (M.C.); (V.O.); (F.F.)
- Università Cattolica del Sacro Cuore, 1-00168 Rome, Italy; (L.F.); (C.Z.); (E.T.); (M.P.); (R.N.); (A.S.)
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Maiuolo J, Gliozzi M, Musolino V, Carresi C, Scarano F, Nucera S, Scicchitano M, Oppedisano F, Bosco F, Ruga S, Zito MC, Macri R, Palma E, Muscoli C, Mollace V. The Contribution of Gut Microbiota-Brain Axis in the Development of Brain Disorders. Front Neurosci 2021; 15:616883. [PMID: 33833660 PMCID: PMC8021727 DOI: 10.3389/fnins.2021.616883] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 02/05/2021] [Indexed: 12/19/2022] Open
Abstract
Different bacterial families colonize most mucosal tissues in the human organism such as the skin, mouth, vagina, respiratory, and gastrointestinal districts. In particular, the mammalian intestine hosts a microbial community of between 1,000 and 1,500 bacterial species, collectively called "microbiota." Co-metabolism between the microbiota and the host system is generated and the symbiotic relationship is mutually beneficial. The balance that is achieved between the microbiota and the host organism is fundamental to the organization of the immune system. Scientific studies have highlighted a direct correlation between the intestinal microbiota and the brain, establishing the existence of the gut microbiota-brain axis. Based on this theory, the microbiota acts on the development, physiology, and cognitive functions of the brain, although the mechanisms involved have not yet been fully interpreted. Similarly, a close relationship between alteration of the intestinal microbiota and the onset of several neurological pathologies has been highlighted. This review aims to point out current knowledge as can be found in literature regarding the connection between intestinal dysbiosis and the onset of particular neurological pathologies such as anxiety and depression, autism spectrum disorder, and multiple sclerosis. These disorders have always been considered to be a consequence of neuronal alteration, but in this review, we hypothesize that these alterations may be non-neuronal in origin, and consider the idea that the composition of the microbiota could be directly involved. In this direction, the following two key points will be highlighted: (1) the direct cross-talk that comes about between neurons and gut microbiota, and (2) the degree of impact of the microbiota on the brain. Could we consider the microbiota a valuable target for reducing or modulating the incidence of certain neurological diseases?
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Affiliation(s)
- Jessica Maiuolo
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Micaela Gliozzi
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Vincenzo Musolino
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Cristina Carresi
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Federica Scarano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Saverio Nucera
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Miriam Scicchitano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Francesca Oppedisano
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Francesca Bosco
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Stefano Ruga
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Maria Caterina Zito
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Roberta Macri
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Ernesto Palma
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Carolina Muscoli
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
- IRCCS San Raffaele, Rome, Italy
| | - Vincenzo Mollace
- IRC-FSH Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
- IRCCS San Raffaele, Rome, Italy
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Intestinal parasites may be associated with later behavioral problems in internationally adopted children. PLoS One 2021; 16:e0245786. [PMID: 33493225 PMCID: PMC7833226 DOI: 10.1371/journal.pone.0245786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 12/29/2020] [Indexed: 01/09/2023] Open
Abstract
Aim At arrival in new home country, internationally adopted children often have intestinal parasites. International adoptees also exhibit more behavioral problems than their biological peers. We examined whether intestinal parasite infections in international adoptees on arrival in Finland are associated with their later behavioral and emotional problems. Methods Data for this study were sourced from the Finnish Adoption Study (FinAdo) based on parental questionnaires for all internationally adopted children under 18 years (n = 1450) who arrived in Finland from 1985 to 2007. A total of 1293 families provided sufficient information on the adoptee’s background, parasitic status on arrival, and behavioral symptoms at the median time of 5 years after arrival (mean age = 7.8 years). Behavioral and emotional disorders were evaluated with the Child Behavior Checklist (CBCL). Statistical analyses were conducted using linear regression. Results Of the 1293 families, parents of 206 adoptive children reported intestinal parasites in their adopted children on arrival. Parasite-infected children had subsequently higher CBCL problem scores than the children without parasites (p < 0.001). The association between intestinal parasites and later behavioral problems was stronger than that between intestinal parasites and any other factors measured in this study, except disability. Limitations The control group was naturally provided by the adopted children without parasite infections, but we could not compare the adopted children to non-adopted children without a defined parasite infection. We were unable to specify the effects associated with a specific parasite type. It was not possible either to include multiple environmental factors that could have been associated with behavioral problems in the models, which indicated only modest explanatory values. Conclusions In this study, intestinal parasite infections in early childhood may be associated with children’s later psychological wellbeing, even in children who move to a country with a low prevalence of parasites. Our findings may support further developments pertaining to the gut-brain theory.
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Wu ML, Yang XQ, Xue L, Duan W, Du JR. Age-related cognitive decline is associated with microbiota-gut-brain axis disorders and neuroinflammation in mice. Behav Brain Res 2021; 402:113125. [PMID: 33422597 DOI: 10.1016/j.bbr.2021.113125] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 12/03/2020] [Accepted: 01/04/2021] [Indexed: 02/08/2023]
Abstract
Age-related cognitive decline is associated with chronic low grade neuroinflammation that may result from a complex interplay among many factors, such as bidirectional communication between the central nervous system (CNS) and gut microbiota. The present study used 2-month-old (young group) and 15-month-old (aged group) male C57BL/6 mice to explore the potential association between age-related cognitive decline and the microbiota-gut-brain axis disorder. We observed that aged mice exhibited significant deficits in learning and memory, neuronal and synaptic function compared with young mice. Aged mice also exhibited significant dysbiosis of the gut microbiota. Disruptions of the intestinal barrier and blood-brain barrier were also observed, including increases in intestinal, low-grade systemic and cerebral inflammation. Furthermore, plasma and brain levels of lipopolysaccharide (LPS) were significantly higher in aged mice compared with young mice, with increasing expression of Toll-like receptor 4 (TLR4) and myeloid differential protein-88 (MyD88) and the nuclear translocation of nuclear factor κB (NF-κB) in intestinal and brain tissues. These findings showed that microbiota-gut-brain axis dysfunction that occurs through LPS-induced activation of the TLR4/NF-κB signaling pathway is implicated in age-related neuroinflammation and cognitive decline.
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Affiliation(s)
- Mei-Ling Wu
- Departmen Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China
| | - Xue-Qin Yang
- Departmen Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China
| | - Li Xue
- Departmen Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Jun-Rong Du
- Departmen Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China.
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Zoccante L, Ciceri ML, Gozzi LA, Gennaro GD, Zerman N. The "Connectivome Theory": A New Model to Understand Autism Spectrum Disorders. Front Psychiatry 2021; 12:794516. [PMID: 35250650 PMCID: PMC8892379 DOI: 10.3389/fpsyt.2021.794516] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/23/2021] [Indexed: 12/20/2022] Open
Abstract
The classical approach to autism spectrum disorders (ASD) is often limited to considering their neuro-functional aspects. However, recent scientific literature has shown that ASDs also affect many body systems and apparatuses such as the immune system, the sensory-motor system, and the gut-brain axis. The connective tissue, a common thread linking all these structures, may have a pathogenetic role in the multisystem involvement of ASD. Depending on its different anatomical sites, the connective tissue performs functions of connection and support; furthermore, it acts as a barrier between the external and internal environments, regulating the interchange between the two and performing immunological surveillance. The connective tissue shares a close relationship with the central nervous system, the musculoskeletal system and the immune system. Alterations in brain connectivity are common to various developmental disorders, including ASD, and for this reason here we put forward the hypothesis that alterations in the physiological activity of microglia could be implicated in the pathogenesis of ASD. Also, muscle hypotonia is likely to clinically correlate with an altered sensoriality and, in fact, discomfort or early muscle fatigue are often reported in ASDs. Furthermore, patients with ASD often suffer from intestinal dysfunctions, malabsorption and leaky gut syndrome, all phenomena that may be linked to reduced intestinal connectivity. In addition, at the cutaneous and subcutaneous levels, ASDs show a greater predisposition to inflammatory events due to the lack of adequate release of anti-inflammatory mediators. Alveolar-capillary dysfunctions have also been observed in ASD, most frequently interstitial inflammations, immune-mediated forms of allergic asthma, and bronchial hyper-reactivity. Therefore, in autism, altered connectivity can result in phenomena of altered sensitivity to environmental stimuli. The following interpretative model, that we define as the "connectivome theory," considers the alterations in connective elements of common mesodermal origin located in the various organs and apparatuses and entails the evaluation and interpretation of ASDs through also highlighting somatic elements. We believe that this broader approach could be helpful for a more accurate analysis, as it is able to enrich clinical evaluation and define more multidisciplinary and personalized interventions.
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Affiliation(s)
- Leonardo Zoccante
- Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital Verona, Verona, Italy.,Autism Spectrum Disorders Regional Centre of Verona, Verona, Italy
| | - Marco Luigi Ciceri
- Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital Verona, Verona, Italy.,Autism Spectrum Disorders Regional Centre of Verona, Verona, Italy
| | - Luigi Alberto Gozzi
- Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital Verona, Verona, Italy.,Autism Spectrum Disorders Regional Centre of Verona, Verona, Italy
| | - Gianfranco Di Gennaro
- Department of Pathology and Diagnostics, Integrated University Hospital Verona, Verona, Italy
| | - Nicoletta Zerman
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, Verona, Italy
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Virulence factor-related gut microbiota genes and immunoglobulin A levels as novel markers for machine learning-based classification of autism spectrum disorder. Comput Struct Biotechnol J 2020; 19:545-554. [PMID: 33510860 PMCID: PMC7809157 DOI: 10.1016/j.csbj.2020.12.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/10/2020] [Accepted: 12/13/2020] [Indexed: 02/07/2023] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition for which early identification and intervention is crucial for optimum prognosis. Our previous work showed gut Immunoglobulin A (IgA) to be significantly elevated in the gut lumen of children with ASD compared to typically developing (TD) children. Gut microbiota variations have been reported in ASD, yet not much is known about virulence factor-related gut microbiota (VFGM) genes. Upon determining the VFGM genes distinguishing ASD from TD, this study is the first to utilize VFGM genes and IgA levels for a machine learning-based classification of ASD. Sequence comparisons were performed of metagenome datasets from children with ASD (n = 43) and TD children (n = 31) against genes in the virulence factor database. VFGM gene composition was associated with ASD phenotype. VFGM gene diversity was higher in children with ASD and positively correlated with IgA content. As Group B streptococcus (GBS) genes account for the highest proportion of 24 different VFGMs between ASD and TD and positively correlate with gut IgA, GBS genes were used in combination with IgA and VFGMs diversity to distinguish ASD from TD. Given that VFGM diversity, increases in IgA, and ASD-enriched VFGM genes were independent of sex and gastrointestinal symptoms, a classification method utilizing them will not pertain only to a specific subgroup of ASD. By introducing the classification value of VFGM genes and considering that VFs can be isolated in pregnant women and newborns, these findings provide a novel machine learning-based early risk identification method for ASD.
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Healing autism spectrum disorder with cannabinoids: a neuroinflammatory story. Neurosci Biobehav Rev 2020; 121:128-143. [PMID: 33358985 DOI: 10.1016/j.neubiorev.2020.12.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/28/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a multifactorial etiology. Latest researches are raising the hypothesis of a link between the onset of the main behavioral symptoms of ASD and the chronic neuroinflammatory condition of the autistic brain; increasing evidence of this connection is shedding light on new possible players in the pathogenesis of ASD. The endocannabinoid system (ECS) has a key role in neurodevelopment as well as in normal inflammatory responses and it is not surprising that many preclinical and clinical studies account for alterations of the endocannabinoid signaling in ASD. These findings lay the foundation for a better understanding of the neurochemical mechanisms underlying ASD and for new therapeutic attempts aimed at exploiting the renowned anti-inflammatory properties of cannabinoids to treat pathologies encompassed in the autistic spectrum. This review discusses the current preclinical and clinical evidence supporting a key role of the ECS in the neuroinflammatory state that characterizes ASD, providing hints to identify new biomarkers in ASD and promising therapies for the future.
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Saposnik FE, Huber JF. Trends in Web Searches About the Causes and Treatments of Autism Over the Past 15 Years: Exploratory Infodemiology Study. JMIR Pediatr Parent 2020; 3:e20913. [PMID: 33284128 PMCID: PMC7752533 DOI: 10.2196/20913] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/29/2020] [Accepted: 09/07/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Ninety percent of adults in the United States use the internet, and the majority of internet users report looking on the web for health information using search engines. The rising prevalence of autism spectrum disorder (ASD), uncertainty surrounding its etiology, and variety of intervention approaches contribute to questions about its causes and treatments. It is not known which terms people search most frequently about ASD and whether web search queries have changed over time. Infodemiology is an area of health informatics research using big data analytics to understand web search behavior. OBJECTIVE The objectives were to (1) use infodemiological data to analyze trends in web-based searches about the causes and treatments of ASD over time and (2) inform clinicians and ASD organizations about web queries regarding ASD. METHODS Google Trends was used to analyze web searches about the causes and treatments of ASD in the United States from 2004 to 2019. The search terms analyzed for queries about causes of ASD included vaccines, genetics, environmental factors, and microbiome and those for therapies included applied behavior analysis (ABA), gluten-free diet, chelation therapy, marijuana, probiotics, and stem cell therapy. RESULTS Google Trends results are normalized on a scale ranging from 0 to 100 to represent the frequency and relative interest of search topics. For searches about ASD causes, vaccines had the greatest frequency compared to other terms, with an initial search peak observed in 2008 (scaled score of 81), reaching the highest frequency in 2015 (scaled score of 100), and a current upward trend. In comparison, searches about genetics, environmental factors, and microbiome occurred less frequently. For web searches about ASD therapies, ABA consistently had a high frequency of search interest since 2004, reaching a maximum scaled score of 100 in 2019. The analyses of chelation therapy and gluten-free diet showed trending interest in 2005 (scaled score of 68) and 2007 (scaled score of 100), respectively, followed by a steady decline since (scaled scores of only 10 and 16, respectively, in 2019). Searches related to ASD and marijuana showed a rise in 2009 (scaled score of 35), and they continue to trend upward. Searches about probiotics and stem cell therapy have been relatively low (scaled scores of 22 and 18, respectively), but are gradually gaining interest. Web search volumes for stem cell therapy in 2019 surpassed both gluten-free diet and chelation therapy as web-searched interventions for ASD. CONCLUSIONS Google Trends is an effective infodemiology tool to analyze large-scale web search trends about ASD. The results showed informative variation in search trends over 15 years. These data are useful to inform clinicians and organizations about web queries on topics related to ASD, identify knowledge gaps, and target web-based education and knowledge translation strategies.
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Affiliation(s)
| | - Joelene F Huber
- Paediatric Medicine, The Hospital for Sick Children, Toronto, ON, Canada.,Division of Developmental Paediatrics, Department of Paediatrics, University of Toronto, Toronto, ON, Canada.,Surrey Place, Toronto, ON, Canada
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Bjørklund G, Pivina L, Dadar M, Meguid NA, Semenova Y, Anwar M, Chirumbolo S. Gastrointestinal alterations in autism spectrum disorder: What do we know? Neurosci Biobehav Rev 2020; 118:111-120. [DOI: 10.1016/j.neubiorev.2020.06.033] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/21/2020] [Accepted: 06/28/2020] [Indexed: 02/07/2023]
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Abstract
Food containing gluten and casein could play a role in autism spectrum disorders (ASD) symptoms. The present review aimed to update the evidence about the role of the gluten- and casein-free diet (GCFD) on the management of ASD. Web of Science, Science Direct, Google Scholar, and PubMed databases were used to search for randomized controlled trials (RCT) conducted between January 2000 and February 2020. In total, 9 RCT were included (521 participants) with age range between 2 to 18 years. Four of these studies did not show a significant improvement regarding the symptoms of ASD. The rest of these studies (n=5) showed improvement in communication, stereotyped movements, aggressiveness, language, hyperactivity, tantrums, and signs of attention deficit hyperactivity disorder compared to control group. Hence, the data remains insu cient to support the use of GCFD to improve the symptoms of ASD in children.
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Affiliation(s)
- Eman S Alamri
- Department of Nutrition and Food Science, Faculty of Home Economics, University of Tabuk, Tabuk, Kingdom of Saudi Arabia. E-mail.
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Carpita B, Marazziti D, Palego L, Giannaccini G, Betti L, Dell'Osso L. Microbiota, Immune System and Autism Spectrum Disorders: An Integrative Model towards Novel Treatment Options. Curr Med Chem 2020; 27:5119-5136. [PMID: 31448708 DOI: 10.2174/0929867326666190328151539] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/05/2019] [Accepted: 03/06/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Autism Spectrum Disorder (ASD) is a condition strongly associated with genetic predisposition and familial aggregation. Among ASD patients, different levels of symptoms severity are detectable, while the presence of intermediate autism phenotypes in close relatives of ASD probands is also known in literature. Recently, increasing attention has been paid to environmental factors that might play a role in modulating the relationship between genomic risk and development and severity of ASD. Within this framework, an increasing body of evidence has stressed a possible role of both gut microbiota and inflammation in the pathophysiology of neurodevelopment. The aim of this paper is to review findings about the link between microbiota dysbiosis, inflammation and ASD. METHODS Articles ranging from 1990 to 2018 were identified on PUBMED and Google Scholar databases, with keyword combinations as: microbiota, immune system, inflammation, ASD, autism, broad autism phenotype, adult. RESULTS Recent evidence suggests that microbiota alterations, immune system and neurodevelopment may be deeply intertwined, shaping each other during early life. However, results from both animal models and human samples are still heterogeneous, while few studies focused on adult patients and ASD intermediate phenotypes. CONCLUSION A better understanding of these pathways, within an integrative framework between central and peripheral systems, might not only shed more light on neural basis of ASD symptoms, clarifying brain pathophysiology, but it may also allow to develop new therapeutic strategies for these disorders, still poorly responsive to available treatments.
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Affiliation(s)
- Barbara Carpita
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Via Roma, 6756100 Pisa, Italy
| | - Donatella Marazziti
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Via Roma, 6756100 Pisa, Italy
| | - Lionella Palego
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Via Roma, 6756100 Pisa, Italy
| | - Gino Giannaccini
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Via Roma, 6756100 Pisa, Italy
| | - Laura Betti
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Via Roma, 6756100 Pisa, Italy
| | - Liliana Dell'Osso
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Via Roma, 6756100 Pisa, Italy
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