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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 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] [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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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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Bhusri B, Sutheeworapong S, Kittichotirat W, Kusonmano K, Thammarongtham C, Lertampaiporn S, Prommeenate P, Praphanphoj V, Kittitharaphan W, Dulsawat S, Paenkaew P, Cheevadhanarak S. Characterization of gut microbiota on gender and age groups bias in Thai patients with autism spectrum disorder. Sci Rep 2025; 15:2587. [PMID: 39833480 PMCID: PMC11747245 DOI: 10.1038/s41598-025-86740-2] [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] [Received: 08/03/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication and interaction problems. The prevalence of ASD is increasing globally, with a higher ratio of males to females. Gastrointestinal symptoms are common in individuals with ASD, and gut microbiota has been implicated in the disorder's development. This study aimed to investigate the gut microbiota alteration in Thai individuals with ASD compared to healthy controls using 16S rRNA gene sequencing. The influence of gender and age on gut microbiota composition and function was also examined. A total of 65 ASD individuals and 30 neurotypical (NT) individuals were included in the analysis. The results revealed notable differences in gut microbiota composition between the ASD and NT groups, with variations observed in microbial richness and the presence of enriched microbial taxa. These differences were influenced by both gender and age. Fusobacteriota, Fusobacteriaceae, and Fusobacterium were found to be enriched in individuals with ASD. Furthermore, the study identified gender-related taxa, such as Bacteroides plebeius, enriched in ASD females. Age-related taxa, including Veillonella, known to be associated with poor oral hygiene, were also observed in ASD children. The analysis of differentially abundant pathways highlighted the enrichment of various metabolic pathways in individuals with ASD, including those related to endocrine-disrupting chemicals. These findings underscore the importance of considering gender and age when studying gut microbiota in ASD. They provide valuable insights into the potential role of gut microbiota dysbiosis in ASD pathogenesis and highlight the influence of environmental factors.
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Affiliation(s)
- Benjaporn Bhusri
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology, and School of Information Technology, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
| | - Sawannee Sutheeworapong
- Systems Biology and Bioinformatics Unit, Pilot Plant Development and Training Institute, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
| | - Weerayuth Kittichotirat
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology, and School of Information Technology, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
- Systems Biology and Bioinformatics Unit, Pilot Plant Development and Training Institute, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
| | - Kanthida Kusonmano
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
| | - Chinae Thammarongtham
- Biochemical Engineering and Systems Biology Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
| | - Supatcha Lertampaiporn
- Biochemical Engineering and Systems Biology Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
| | - Peerada Prommeenate
- Biochemical Engineering and Systems Biology Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
| | | | - Wiranpat Kittitharaphan
- Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Ministry of Public Health, Samut Prakan, 10270, Thailand
| | - Sudarat Dulsawat
- Fungal Biotechnology Unit, Pilot Plant Development and Training Institute, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand
| | - Prasobsook Paenkaew
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Supapon Cheevadhanarak
- Systems Biology and Bioinformatics Unit, Pilot Plant Development and Training Institute, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand.
- Fungal Biotechnology Unit, Pilot Plant Development and Training Institute, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand.
- School of Bioresources and Technology, King Mongkut's University of Technology Thonburi, Bangkok, 10150, Thailand.
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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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Gilbert SF. "When does human life begin?" teaching human embryology in the context of the American abortion debate. Dev Biol 2024; 515:102-111. [PMID: 39004200 DOI: 10.1016/j.ydbio.2024.07.003] [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: 03/13/2024] [Revised: 07/02/2024] [Accepted: 07/11/2024] [Indexed: 07/16/2024]
Abstract
The Dobbs decision of the United States Supreme Court and the actions of several state legislatures have made it risky, if not outright dangerous, to teach factual material concerning human embryology. At some state universities, for instance, if a professor's lecture is felt to teach or discuss abortion (as it might when teaching about tubal pregnancies, hydatidiform moles, or eneuploidy), that instructor risks imprisonment for up to 14 years (Gyori, 2023). Some states' new censorship rules have thus caused professors to drop modules on abortion from numerous science and humanities courses. In most states, instructors can still teach about human embryonic development and not risk putting their careers or livelihoods in jeopardy. However, even in many of these institutions, students can bring a professor to a disciplinary hearing by claiming that the instructor failed to provide ample trigger warnings on such issues. This essay attempts to provide some strategies wherein human embryology and the ethical issues surrounding it might be taught and students may be given resources to counter unscientific falsehoods about fertilization and human development. This essay provides evidence for teaching the following propositions. Mis-information about human biology and medicine is rampant on the internet, and there are skills that can be taught to students that will help them determine which sites should trusted. This is a skill that needs to be taught as part of science courses.
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Affiliation(s)
- Scott F Gilbert
- Swarthmore College, Swarthmore, PA, 19081, USA; University of Helsinki, Helsinki, Finland.
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Kurokawa S, Nomura K, Sanada K, Miyaho K, Ishii C, Fukuda S, Iwamoto C, Naraoka M, Yoneda S, Imafuku M, Matsuzaki J, Saito Y, Mimura M, Kishimoto T. A comparative study on dietary diversity and gut microbial diversity in children with autism spectrum disorder, attention-deficit hyperactivity disorder, their neurotypical siblings, and non-related neurotypical volunteers: a cross-sectional study. J Child Psychol Psychiatry 2024; 65:1184-1195. [PMID: 38562118 DOI: 10.1111/jcpp.13962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/29/2023] [Indexed: 04/04/2024]
Abstract
BACKGROUND Previous research has shown a significant link between gut microbiota in children with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). However, much remains unknown because of the heterogeneity of disorders and the potential confounders such as dietary patterns and control group variations. METHODS Children aged 6-12 years who had been clinically diagnosed with ASD and/or ADHD, their unaffected neurotypical siblings, and non-related neurotypical volunteers were recruited cross-sectionally. The ASD diagnosis was confirmed using the Autism Diagnostic Observation Schedule-2 (ADOS-2) in all patients, including those with ADHD. Standardized DNA extraction and sequencing methods were used to compare gut microbial alpha-diversity among the groups. Dietary diversity was calculated from a standardized dietary questionnaire form. We compared the difference in gut microbiome between patients with ASD and/or ADHD with neurotypical siblings and non-related neurotypical controls. RESULTS Ninety-eight subjects were included in the study (18 with ASD, 19 with ADHD, 20 with both ASD and ADHD, 13 neurotypical siblings, and 28 non-related neurotypical controls). The alpha-diversity indices, such as Chao 1 and Shannon index, showed a significant difference between the groups in a Linear mixed-effect model (F(4, 93) = 4.539, p = .02), (F(4, 93) = 3.185, p = .017), respectively. In a post-hoc pairwise comparison, patients with ASD had lower alpha-diversity compared with non-related controls after Bonferroni correction. Dietary diversity shown in Shannon index did not differ among the groups (F(4, 84) = 1.494, p = .211). CONCLUSIONS Our study indicates disorder-specific microbiome differences in patients with ASD. In future research on gut microbiota in neurodevelopmental disorders, it is necessary to consider the impact of ASD and ADHD co-occurrence, and strictly control for background information such as diet, to elucidate the gut-microbiota interaction in ASD and ADHD for exploring the potential of therapeutic interventions.
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Affiliation(s)
- Shunya Kurokawa
- Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan
| | - Kensuke Nomura
- Department of Child Psychiatry, Shimada Ryoiku Medical Center for Challenged Children, Tokyo, Japan
| | - Kenji Sanada
- Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan
| | - Katsuma Miyaho
- Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan
| | - Chiharu Ishii
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan
| | - Shinji Fukuda
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan
- Laboratory for Regenerative Microbiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Gut Environmental Design Group, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Japan
- Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan
| | - Chiaki Iwamoto
- Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Minori Naraoka
- Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Shintaro Yoneda
- Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | | | - Juntaro Matsuzaki
- Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Yoshimasa Saito
- Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Masaru Mimura
- Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan
| | - Taishiro Kishimoto
- Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan
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You M, Chen N, Yang Y, Cheng L, He H, Cai Y, Liu Y, Liu H, Hong G. The gut microbiota-brain axis in neurological disorders. MedComm (Beijing) 2024; 5:e656. [PMID: 39036341 PMCID: PMC11260174 DOI: 10.1002/mco2.656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 06/15/2024] [Accepted: 06/17/2024] [Indexed: 07/23/2024] Open
Abstract
Previous studies have shown a bidirectional communication between human gut microbiota and the brain, known as the microbiota-gut-brain axis (MGBA). The MGBA influences the host's nervous system development, emotional regulation, and cognitive function through neurotransmitters, immune modulation, and metabolic pathways. Factors like diet, lifestyle, genetics, and environment shape the gut microbiota composition together. Most research have explored how gut microbiota regulates host physiology and its potential in preventing and treating neurological disorders. However, the individual heterogeneity of gut microbiota, strains playing a dominant role in neurological diseases, and the interactions of these microbial metabolites with the central/peripheral nervous systems still need exploration. This review summarizes the potential role of gut microbiota in driving neurodevelopmental disorders (autism spectrum disorder and attention deficit/hyperactivity disorder), neurodegenerative diseases (Alzheimer's and Parkinson's disease), and mood disorders (anxiety and depression) in recent years and discusses the current clinical and preclinical gut microbe-based interventions, including dietary intervention, probiotics, prebiotics, and fecal microbiota transplantation. It also puts forward the current insufficient research on gut microbiota in neurological disorders and provides a framework for further research on neurological disorders.
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Affiliation(s)
- Mingming You
- Xiamen Key Laboratory of Genetic TestingThe Department of Laboratory MedicineThe First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina
| | - Nan Chen
- Master of Public HealthSchool of Public HealthXiamen UniversityXiamenChina
| | - Yuanyuan Yang
- Xiamen Key Laboratory of Genetic TestingThe Department of Laboratory MedicineThe First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina
| | - Lingjun Cheng
- Xiamen Key Laboratory of Genetic TestingThe Department of Laboratory MedicineThe First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina
| | - Hongzhang He
- Xiamen Key Laboratory of Genetic TestingThe Department of Laboratory MedicineThe First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina
| | - Yanhua Cai
- Master of Public HealthSchool of Public HealthXiamen UniversityXiamenChina
| | - Yating Liu
- Xiamen Key Laboratory of Genetic TestingThe Department of Laboratory MedicineThe First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina
| | - Haiyue Liu
- Xiamen Key Laboratory of Genetic TestingThe Department of Laboratory MedicineThe First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina
| | - Guolin Hong
- Xiamen Key Laboratory of Genetic TestingThe Department of Laboratory MedicineThe First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen UniversityXiamenChina
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Phan J, Calvo DC, Nair D, Jain S, Montagne T, Dietsche S, Blanchard K, Treadwell S, Adams J, Krajmalnik-Brown R. Precision synbiotics increase gut microbiome diversity and improve gastrointestinal symptoms in a pilot open-label study for autism spectrum disorder. mSystems 2024; 9:e0050324. [PMID: 38661344 PMCID: PMC11097633 DOI: 10.1128/msystems.00503-24] [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: 04/08/2024] [Accepted: 04/08/2024] [Indexed: 04/26/2024] Open
Abstract
The efficacy of prebiotics and probiotics (synbiotics when combined) to improve symptoms associated with autism spectrum disorder (ASD) has shown considerable inter-study variation, likely due to the complex, heterogeneous nature of the disorder and its associated behavioral, developmental, and gastrointestinal symptoms. Here, we present a precision synbiotic supplementation study in 296 children and adults diagnosed with ASD versus 123 age-matched neurotypical controls. One hundred seventy ASD participants completed the study. Baseline and post-synbiotic assessment of ASD and gastrointestinal (GI) symptoms and deep metagenomic sequencing were performed. Within the ASD cohort, there were significant differences in microbes between subpopulations based on the social responsiveness scale (SRS2) survey (Prevotella spp., Bacteroides, Fusicatenibacter, and others) and gluten and dairy-free diets (Bifidobacterium spp., Lactococcus, Streptococcus spp., and others). At the baseline, the ASD cohort maintained a lower taxonomic alpha diversity and significant differences in taxonomic composition, metabolic pathways, and gene families, with a greater proportion of potential pathogens, including Shigella, Klebsiella, and Clostridium, and lower proportions of beneficial microbes, including Faecalibacterium compared to controls. Following the 3-month synbiotic supplementation, the ASD cohort showed increased taxonomic alpha diversity, shifts in taxonomy and metabolic pathway potential, and improvements in some ASD-related symptoms, including a significant reduction in GI discomfort and overall improved language, comprehension, cognition, thinking, and speech. However, the open-label study design may include some placebo effects. In summary, we found that precision synbiotics modulated the gut microbiome and could be used as supplementation to improve gastrointestinal and ASD-related symptoms. IMPORTANCE Autism spectrum disorder (ASD) is prevalent in 1 out of 36 children in the United States and contributes to health, financial, and psychological burdens. Attempts to identify a gut microbiome signature of ASD have produced varied results. The limited pre-clinical and clinical population sizes have hampered the success of these trials. To understand the microbiome associated with ASD, we employed whole metagenomic shotgun sequencing to classify microbial composition and genetic functional potential. Despite being one of the most extensive ASD post-synbiotic assessment studies, the results highlight the complexity of performing such a case-control supplementation study in this population and the potential for a future therapeutic approach in ASD.
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Affiliation(s)
- Joann Phan
- Sun Genomics, Inc., San Diego, California, USA
| | - Diana C. Calvo
- Department of Civil Engineering, Construction Management, and Environmental Engineering, Northern Arizona University, Flagstaff, Arizona, USA
| | - Divya Nair
- Sun Genomics, Inc., San Diego, California, USA
| | - Suneer Jain
- Sun Genomics, Inc., San Diego, California, USA
| | | | | | | | | | - James Adams
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, Arizona, USA
| | - Rosa Krajmalnik-Brown
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, Arizona, USA
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Korteniemi J, Karlsson L, Aatsinki A. Systematic Review: Autism Spectrum Disorder and the Gut Microbiota. FOCUS (AMERICAN PSYCHIATRIC PUBLISHING) 2024; 22:242-251. [PMID: 38680985 PMCID: PMC11046714 DOI: 10.1176/appi.focus.24022008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
Objective Autism spectrum disorders (ASD) are a varying group of disorders characterized by deficiency in social interaction and restrictive patterns of behavior and interests. While there are several studies focusing on the neuro-psychiatric pathogenesis of ASD, its etiology remains unclear. The role of gut-brain-axis in ASD has been studied increasingly and a correlation between symptoms and the composition of gut microbiota has been documented in various works. Despite this, the significance of individual microbes and their function is still widely unknown. This work aims to elucidate the current knowledge of the interrelations between ASD and the gut microbiota in children based on scientific evidence. Methods This is a systematic review done by a literature search focusing on the main findings concerning the gut microbiota composition, interventions targeting the gut microbiota, and possible mechanisms explaining the results in children aged between 2 and 18 years of age. Results Most studies in this review found significant differences between microbial communities, while there was notable variation in results regarding diversity indices or taxonomic level abundance. The most consistent results regarding taxa differences in ASD children's gut microbiota were higher levels of Proteobacteria, Actinobacteria and Sutterella compared to controls. Conclusion These results show that the gut microbiota of children with ASD is altered compared to one of neurotypically developed children. More research is needed to discover whether some of these features could be used as potential biomarkers for ASD and how the gut microbiota could be targeted in therapeutical interventions.Appeared originally in Acta Psychiatr Scand 2023;148:242-254.
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Affiliation(s)
- Jenni Korteniemi
- FinnBrain Birth Cohort Study, Turku Brain and Mind Center, Department of Clinical Medicine, Psychiatry, University of Turku, Turku, Finland (Korteniemi, Karlsson, Aatsinki); Centre for Population Health Research, Turku University Hospital, University of Turku, Turku, Finland (Karlsson, Aatsinki); Department of Clinical Medicine, Paediatrics and Adolescent Medicine, Turku University Hospital, University of Turku, Turku, Finland (Karlsson)
| | - Linnea Karlsson
- FinnBrain Birth Cohort Study, Turku Brain and Mind Center, Department of Clinical Medicine, Psychiatry, University of Turku, Turku, Finland (Korteniemi, Karlsson, Aatsinki); Centre for Population Health Research, Turku University Hospital, University of Turku, Turku, Finland (Karlsson, Aatsinki); Department of Clinical Medicine, Paediatrics and Adolescent Medicine, Turku University Hospital, University of Turku, Turku, Finland (Karlsson)
| | - Anna Aatsinki
- FinnBrain Birth Cohort Study, Turku Brain and Mind Center, Department of Clinical Medicine, Psychiatry, University of Turku, Turku, Finland (Korteniemi, Karlsson, Aatsinki); Centre for Population Health Research, Turku University Hospital, University of Turku, Turku, Finland (Karlsson, Aatsinki); Department of Clinical Medicine, Paediatrics and Adolescent Medicine, Turku University Hospital, University of Turku, Turku, Finland (Karlsson)
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10
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Hung LY, Margolis KG. Autism spectrum disorders and the gastrointestinal tract: insights into mechanisms and clinical relevance. Nat Rev Gastroenterol Hepatol 2024; 21:142-163. [PMID: 38114585 DOI: 10.1038/s41575-023-00857-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2023] [Indexed: 12/21/2023]
Abstract
Autism spectrum disorders (ASDs) are recognized as central neurodevelopmental disorders diagnosed by impairments in social interactions, communication and repetitive behaviours. The recognition of ASD as a central nervous system (CNS)-mediated neurobehavioural disorder has led most of the research in ASD to be focused on the CNS. However, gastrointestinal function is also likely to be affected owing to the neural mechanistic nature of ASD and the nervous system in the gastrointestinal tract (enteric nervous system). Thus, it is unsurprising that gastrointestinal disorders, particularly constipation, diarrhoea and abdominal pain, are highly comorbid in individuals with ASD. Gastrointestinal problems have also been repeatedly associated with increased severity of the core symptoms diagnostic of ASD and other centrally mediated comorbid conditions, including psychiatric issues, irritability, rigid-compulsive behaviours and aggression. Despite the high prevalence of gastrointestinal dysfunction in ASD and its associated behavioural comorbidities, the specific links between these two conditions have not been clearly delineated, and current data linking ASD to gastrointestinal dysfunction have not been extensively reviewed. This Review outlines the established and emerging clinical and preclinical evidence that emphasizes the gut as a novel mechanistic and potential therapeutic target for individuals with ASD.
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Affiliation(s)
- Lin Y Hung
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA
| | - Kara Gross Margolis
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA.
- Department of Cell Biology, NYU Grossman School of Medicine and Langone Medical Center, New York, NY, USA.
- Department of Pediatrics, NYU Grossman School of Medicine and Langone Medical Center, New York, NY, USA.
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11
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Hamrefors V, Kahn F, Holmqvist M, Carlson K, Varjus R, Gudjonsson A, Fedorowski A, Ohlsson B. Gut microbiota composition is altered in postural orthostatic tachycardia syndrome and post-acute COVID-19 syndrome. Sci Rep 2024; 14:3389. [PMID: 38336892 PMCID: PMC10858216 DOI: 10.1038/s41598-024-53784-9] [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] [Received: 05/24/2023] [Accepted: 02/05/2024] [Indexed: 02/12/2024] Open
Abstract
Postural Orthostatic Tachycardia Syndrome (POTS) reflects an autonomic dysfunction, which can occur as a complication to COVID-19. Our aim was to examine gastrointestinal symptoms and gut microbiota composition in patients with POTS and post-acute COVID-19 syndrome (PACS), compared with controls. POTS patients (n = 27), PACS patients (n = 32) and controls (n = 39) delivered fecal samples and completed a 4-day food diary, irritable bowel syndrome-severity scoring system (IBS-SSS), and visual analog scale for IBS (VAS-IBS). A total of 98 DNA aliquots were sequenced to an average depth of 28.3 million (M) read pairs (Illumina 2 × 150 PE) per sample. Diversity and taxonomic levels of the microbiome, as well as functional abundances were calculated for POTS and PACS groups, then compared with controls. There were several differences in taxonomic composition between POTS and controls, whereas only the abundance of Ascomycota and Firmicutes differed between PACS and controls. The clinical variables total IBS-SSS, fatigue, and bloating and flatulence significantly correlated with multiple individual taxa abundances, alpha diversity, and functional abundances. We conclude that POTS, and to a less extent PACS, are associated with differences in gut microbiota composition in diversity and at several taxonomic levels. Clinical symptoms are correlated with both alpha diversity and taxonomic and functional abundances.
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Affiliation(s)
- Viktor Hamrefors
- Department of Clinical Sciences, Lund University, Malmö, Sweden.
- Department of Cardiology, Skåne University Hospital, Malmö, Sweden.
| | - Fredrik Kahn
- Department of Infection Medicine, Skåne University Hospital, Malmö, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Madlene Holmqvist
- Department of Infection Medicine, Skåne University Hospital, Malmö, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Katherine Carlson
- Department of Infection Medicine, Skåne University Hospital, Malmö, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Roosa Varjus
- Clinical Microbiomics, Symbion, Copenhagen, Denmark
| | | | - Artur Fedorowski
- Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Bodil Ohlsson
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden
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12
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Li H, Liu C, Huang S, Wang X, Cao M, Gu T, Ou X, Pan S, Lin Z, Wang X, Zhu Y, Jing J. Multi-omics analyses demonstrate the modulating role of gut microbiota on the associations of unbalanced dietary intake with gastrointestinal symptoms in children with autism spectrum disorder. Gut Microbes 2023; 15:2281350. [PMID: 38010793 PMCID: PMC10730204 DOI: 10.1080/19490976.2023.2281350] [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: 07/14/2023] [Accepted: 11/06/2023] [Indexed: 11/29/2023] Open
Abstract
Our previous work revealed that unbalanced dietary intake was an important independent factor associated with constipation and gastrointestinal (GI) symptoms in children with autism spectrum disorder (ASD). Growing evidence has shown the alterations in the gut microbiota and gut microbiota-derived metabolites in ASD. However, how the altered microbiota might affect the associations between unbalanced diets and GI symptoms in ASD remains unknown. We analyzed microbiome and metabolomics data in 90 ASD and 90 typically developing (TD) children based on 16S rRNA and untargeted metabolomics, together with dietary intake and GI symptoms assessment. We found that there existed 11 altered gut microbiota (FDR-corrected P-value <0.05) and 397 altered metabolites (P-value <0.05) in children with ASD compared with TD children. Among the 11 altered microbiota, the Turicibacter, Coprococcus 1, and Lachnospiraceae FCS020 group were positively correlated with constipation (FDR-corrected P-value <0.25). The Eggerthellaceae was positively correlated with total GI symptoms (FDR-corrected P-value <0.25). More importantly, three increased microbiota including Turicibacter, Coprococcus 1, and Eggerthellaceae positively modulated the associations of unbalanced dietary intake with constipation and total GI symptoms, and the decreased Clostridium sp. BR31 negatively modulated their associations in ASD children (P-value <0.05). Together, the altered microbiota strengthens the relationship between unbalanced dietary intake and GI symptoms. Among the altered metabolites, ten metabolites derived from microbiota (Turicibacter, Coprococcus 1, Eggerthellaceae, and Clostridium sp. BR31) were screened out, enriched in eight metabolic pathways, and were identified to correlate with constipation and total GI symptoms in ASD children (FDR-corrected P-value <0.25). These metabolomics findings further support the modulating role of gut microbiota on the associations of unbalanced dietary intake with GI symptoms. Collectively, our research provides insights into the relationship between diet, the gut microbiota, and GI symptoms in children with ASD.
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Affiliation(s)
- Hailin Li
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Churui Liu
- School of Biological Engineering, Dalian Polytechnic University, Dalian, Liaoning, China
| | - Saijun Huang
- Department of Child Healthcare, Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, Guangdong, China
| | - Xin Wang
- Key Laboratory of Brain, Cognition and Education Science, Ministry of Education, Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, Guangdong, China
| | - Muqing Cao
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tingfeng Gu
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaoxuan Ou
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuolin Pan
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zongyu Lin
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaotong Wang
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yanna Zhu
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jin Jing
- Department of Maternal and Child Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
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13
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Schellekens H, Ribeiro G, Cuesta-Marti C, Cryan JF. The microbiome-gut-brain axis in nutritional neuroscience. Nutr Neurosci 2023; 26:1159-1171. [PMID: 36222323 DOI: 10.1080/1028415x.2022.2128007] [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] [Indexed: 12/02/2022]
Abstract
Emerging evidence is highlighting the microbiome as a key regulator of the effect of nutrition on gut-brain axis signaling. Nevertheless, it is not yet clear whether the impact of nutrition is moderating the microbiota-gut-brain interaction or if diet has a mediating role on microbiota composition and function to influence central nervous system function, brain phenotypes and behavior. Mechanistic evidence from cell-based in vitro studies, animal models and preclinical intervention studies are linking the gut microbiota to the effects of diet on brain function, but they have had limited translation to human intervention studies. While increasing evidence demonstrates the triangulating relationship between diet, microbiota, and brain function across the lifespan, future mechanistic and translational studies in the field of microbiota and nutritional neuroscience are warranted to inform potential strategies for prevention and management of several neurological, neurodevelopmental, neurodegenerative, and psychiatric disorders. This brief primer provides an overview of the most recent advances in the nutritional neuroscience - microbiome field, highlighting significant opportunities for future research.
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Affiliation(s)
- Harriët Schellekens
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | | | - Cristina Cuesta-Marti
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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Jayashankar A, Aziz-Zadeh L. Disgust Processing and Potential Relationships with Behaviors in Autism. Curr Psychiatry Rep 2023; 25:465-478. [PMID: 37672122 PMCID: PMC10627949 DOI: 10.1007/s11920-023-01445-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2023] [Indexed: 09/07/2023]
Abstract
PURPOSE OF REVIEW While there are reports of differences in emotion processing in autism, it is less understood whether the emotion of disgust, in particular, plays a significant role in these effects. Here, we review literature on potential disgust processing differences in autism and its possible associations with autistic traits. RECENT FINDINGS In autism, there is evidence for differences in physical disgust processing, pica behaviors, attention away from other's disgust facial expressions, and differences in neural activity related to disgust processing. In typically developing individuals, disgust processing is related to moral processing, but modulated by individual differences in interoception and alexithymia. Autistic individuals may experience atypical disgust, which may lead to difficulty avoiding contaminants and affect socio-emotional processing. In autism, such outcomes may lead to increased occurrences of illness, contribute to gastrointestinal issues, diminish vicarious learning of disgust expression and behaviors, and potentially contribute to differences in processes related to moral reasoning, though further research is needed.
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Affiliation(s)
- Aditya Jayashankar
- USC Mrs. T.H. Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, 90089, USA.
- Brain and Creativity Institute, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
| | - Lisa Aziz-Zadeh
- USC Mrs. T.H. Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, 90089, USA
- Brain and Creativity Institute, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
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15
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Olaguez-Gonzalez JM, Chairez I, Breton-Deval L, Alfaro-Ponce M. Machine Learning Algorithms Applied to Predict Autism Spectrum Disorder Based on Gut Microbiome Composition. Biomedicines 2023; 11:2633. [PMID: 37893007 PMCID: PMC10604849 DOI: 10.3390/biomedicines11102633] [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: 08/10/2023] [Revised: 09/01/2023] [Accepted: 09/18/2023] [Indexed: 10/29/2023] Open
Abstract
The application of machine learning (ML) techniques stands as a reliable method for aiding in the diagnosis of complex diseases. Recent studies have related the composition of the gut microbiota to the presence of autism spectrum disorder (ASD), but until now, the results have been mostly contradictory. This work proposes using machine learning to study the gut microbiome composition and its role in the early diagnosis of ASD. We applied support vector machines (SVMs), artificial neural networks (ANNs), and random forest (RF) algorithms to classify subjects as neurotypical (NT) or having ASD, using published data on gut microbiome composition. Naive Bayes, k-nearest neighbors, ensemble learning, logistic regression, linear regression, and decision trees were also trained and validated; however, the ones presented showed the best performance and interpretability. All the ML methods were developed using the SAS Viya software platform. The microbiome's composition was determined using 16S rRNA sequencing technology. The application of ML yielded a classification accuracy as high as 90%, with a sensitivity of 96.97% and specificity reaching 85.29%. In the case of the ANN model, no errors occurred when classifying NT subjects from the first dataset, indicating a significant classification outcome compared to traditional tests and data-based approaches. This approach was repeated with two datasets, one from the USA and the other from China, resulting in similar findings. The main predictors in the obtained models differ between the analyzed datasets. The most important predictors identified from the analyzed datasets are Bacteroides, Lachnospira, Anaerobutyricum, and Ruminococcus torques. Notably, among the predictors in each model, there is the presence of bacteria that are usually considered insignificant in the microbiome's composition due to their low relative abundance. This outcome reinforces the conventional understanding of the microbiome's influence on ASD development, where an imbalance in the composition of the microbiota can lead to disrupted host-microbiota homeostasis. Considering that several previous studies focused on the most abundant genera and neglected smaller (and frequently not statistically significant) microbial communities, the impact of such communities has been poorly analyzed. The ML-based models suggest that more research should focus on these less abundant microbes. A novel hypothesis explains the contradictory results in this field and advocates for more in-depth research to be conducted on variables that may not exhibit statistical significance. The obtained results seem to contribute to an explanation of the contradictory findings regarding ASD and its relation with gut microbiota composition. While some research correlates higher ratios of Bacillota/Bacteroidota, others find the opposite. These discrepancies are closely linked to the minority organisms in the microbiome's composition, which may differ between populations but share similar metabolic functions. Therefore, the ratios of Bacillota/Bacteroidota regarding ASD may not be determinants in the manifestation of ASD.
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Affiliation(s)
- Juan M. Olaguez-Gonzalez
- School of Engineering and Science, Tecnologico de Monterrey, Monterrey 64849, Mexico; (J.M.O.-G.); (I.C.)
| | - Isaac Chairez
- School of Engineering and Science, Tecnologico de Monterrey, Monterrey 64849, Mexico; (J.M.O.-G.); (I.C.)
- Institute of Advanced Materials for Sustainable Manufacturing, Tecnologico de Monterrey, Monterrey 64849, Mexico
| | - Luz Breton-Deval
- Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, Mexico;
- Consejo Nacional de Ciencia y Tecnologia, Mexico City 03940, Mexico
| | - Mariel Alfaro-Ponce
- School of Engineering and Science, Tecnologico de Monterrey, Monterrey 64849, Mexico; (J.M.O.-G.); (I.C.)
- Institute of Advanced Materials for Sustainable Manufacturing, Tecnologico de Monterrey, Monterrey 64849, Mexico
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Wang H, Liu S, Xie L, Wang J. Gut microbiota signature in children with autism spectrum disorder who suffered from chronic gastrointestinal symptoms. BMC Pediatr 2023; 23:476. [PMID: 37730588 PMCID: PMC10510216 DOI: 10.1186/s12887-023-04292-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 09/06/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Children diagnosed with autism spectrum disorder (ASD) frequently suffer from persistent gastrointestinal symptoms, such as constipation and diarrhea. Various studies have highlighted differences in gut microbiota composition between individuals with ASD and healthy controls of similar ages. However, it's essential to recognize that these disparities may be influenced by cultural practices, dietary habits, and environmental factors. METHODS In this study, we collected fecal samples from both children diagnosed with ASD (n = 42) and healthy individuals (n = 41) residing in the southeastern coastal region of China. Subsequently, 16 S rRNA gene sequencing and advanced bioinformatics analyses were conducted to investigate the distinctive features of gut microbial communities within each group. RESULTS The ASD group consisted of 28 males and 14 females, with a median age of 5.8 years, while the control group included 25 males and 16 females, with a median age of 6.8 years. Among the 83 sequenced fecal samples, a total of 1031 operational taxonomic units (OTUs) were identified. These included 122 unique OTUs specific to the control group and 285 unique OTUs specific to the ASD group. Analyses of α-diversity and β-diversity unveiled significant differences in the abundance and composition of gut microbiota between the two groups. It was found that the dominant bacterial taxa in healthy individuals were UBA1819, Flavonifractor, and Bradyrhizobium. In contrast, the ASD group exhibited a prevalence of Streptococcus, Ruminococcus, and Ruminiclostridium. Further analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Clusters of Orthologous Groups (COG) showed significant differences in the metabolic functionalities of the gut microbiota between the two groups. Notably, the metabolic pathway related to alpha-linolenic acid (ALA) in the gut microbiota of the ASD group was notably diminished compared to the control group. Conversely, the ASD group demonstrated significantly elevated levels of metabolic pathways involving uncharacterized conserved proteins, aminoglycoside phosphotransferase, and inorganic pyrophosphatase compared to the control group. CONCLUSIONS Overall, these results confirm that there are significant differences in the gut microbiota structure between children with ASD and healthy controls in the southeast coastal region of China. This underscores the critical significance of delving into clinical interventions capable of mitigating the gastrointestinal and psychological symptoms encountered by children with ASD. A particularly encouraging path for such interventions lies in the realm of fecal microbiota transplantation, a prospect that merits deeper inquiry.
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Affiliation(s)
- Hui Wang
- Child Healthcare Department, Xiamen Children's Hospital, Children's Hospital of Fudan University at Xiamen, Xiamen, 361006, China
| | - Shu Liu
- Child Healthcare Department, Xiamen Children's Hospital, Children's Hospital of Fudan University at Xiamen, Xiamen, 361006, China
| | - Liqing Xie
- Child Healthcare Department, Xiamen Children's Hospital, Children's Hospital of Fudan University at Xiamen, Xiamen, 361006, China
| | - Jinhui Wang
- Department of Clinical Laboratory, Xiamen Children's Hospital, Children's Hospital of Fudan University at Xiamen, No.92-98 Yibin Road, Huli District, Xiamen, 361006, China.
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17
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Morton JT, Jin DM, Mills RH, Shao Y, Rahman G, McDonald D, Zhu Q, Balaban M, Jiang Y, Cantrell K, Gonzalez A, Carmel J, Frankiensztajn LM, Martin-Brevet S, Berding K, Needham BD, Zurita MF, David M, Averina OV, Kovtun AS, Noto A, Mussap M, Wang M, Frank DN, Li E, Zhou W, Fanos V, Danilenko VN, Wall DP, Cárdenas P, Baldeón ME, Jacquemont S, Koren O, Elliott E, Xavier RJ, Mazmanian SK, Knight R, Gilbert JA, Donovan SM, Lawley TD, Carpenter B, Bonneau R, Taroncher-Oldenburg G. Multi-level analysis of the gut-brain axis shows autism spectrum disorder-associated molecular and microbial profiles. Nat Neurosci 2023; 26:1208-1217. [PMID: 37365313 PMCID: PMC10322709 DOI: 10.1038/s41593-023-01361-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 05/13/2023] [Indexed: 06/28/2023]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.
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Affiliation(s)
- James T Morton
- Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA
- Biostatistics & Bioinformatics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Dong-Min Jin
- Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
| | | | - Yan Shao
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK
| | - Gibraan Rahman
- Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA
- Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Daniel McDonald
- Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Qiyun Zhu
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, USA
| | - Metin Balaban
- Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA
| | - Yueyu Jiang
- Department of Electrical and Computer Engineering, University of California, San Diego, La Jolla, CA, USA
| | - Kalen Cantrell
- Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA, USA
| | - Antonio Gonzalez
- Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Julie Carmel
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | | | - Sandra Martin-Brevet
- Laboratory for Research in Neuroimaging, Centre for Research in Neurosciences, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Kirsten Berding
- Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA
| | - Brittany D Needham
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - María Fernanda Zurita
- Microbiology Institute and Health Science College, Universidad San Francisco de Quito, Quito, Ecuador
| | - Maude David
- Departments of Microbiology & Pharmaceutical Sciences, Oregon State University, Corvallis, OR, USA
| | - Olga V Averina
- Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
| | - Alexey S Kovtun
- Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
- Skolkovo Institute of Science and Technology, Skolkovo, Russia
| | - Antonio Noto
- Department of Biomedical Sciences, School of Medicine, University of Cagliari, Cagliari, Italy
| | - Michele Mussap
- Laboratory Medicine, Department of Surgical Sciences, School of Medicine, University of Cagliari, Cagliari, Italy
| | - Mingbang Wang
- Shanghai Key Laboratory of Birth Defects, Division of Neonatology, Children's Hospital of Fudan University, National Center for Children's Health, Shanghai, China
- Microbiome Therapy Center, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, China
| | - Daniel N Frank
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ellen Li
- Department of Medicine, Division of Gastroenterology and Hepatology, Stony Brook University, Stony Brook, NY, USA
| | - Wenhao Zhou
- Shanghai Key Laboratory of Birth Defects, Division of Neonatology, Children's Hospital of Fudan University, National Center for Children's Health, Shanghai, China
| | - Vassilios Fanos
- Neonatal Intensive Care Unit and Neonatal Pathology, Department of Surgical Sciences, School of Medicine, University of Cagliari, Cagliari, Italy
| | - Valery N Danilenko
- Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
| | - Dennis P Wall
- Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Paúl Cárdenas
- Institute of Microbiology, COCIBA, Universidad San Francisco de Quito, Quito, Ecuador
| | - Manuel E Baldeón
- Facultad de Ciencias Médicas, de la Salud y la Vida, Universidad Internacional del Ecuador, Quito, Ecuador
| | - Sébastien Jacquemont
- Sainte Justine Hospital Research Center, Montréal, QC, Canada
- Department of Pediatrics, Université de Montréal, Montréal, QC, Canada
| | - Omry Koren
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Evan Elliott
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA
| | - Sarkis K Mazmanian
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Rob Knight
- Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, California, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, California, USA
| | - Jack A Gilbert
- Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, California, USA
- Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA
| | - Sharon M Donovan
- Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA
| | - Trevor D Lawley
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK
| | - Bob Carpenter
- Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA
| | - Richard Bonneau
- Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA
- Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
- Prescient Design, a Genentech Accelerator, New York, NY, USA
| | - Gaspar Taroncher-Oldenburg
- Gaspar Taroncher Consulting, Philadelphia, PA, USA.
- Simons Foundation Autism Research Initiative, Simons Foundation, New York, NY, USA.
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Epigenetic Modifications Induced by the Gut Microbiota May Result from What We Eat: Should We Talk about Precision Diet in Health and Disease? Metabolites 2023; 13:metabo13030375. [PMID: 36984815 PMCID: PMC10051796 DOI: 10.3390/metabo13030375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
Diet is currently considered one of the most important adjustable determinants of human health. The gut microbiota, the collection of microorganisms that inhabit (mainly) the distal bowel, has recently been shown to ensure critical physiological functions, such as immune, metabolic and neuropsychiatric. Many of these biological effects result from the production of bacterial metabolites that may target host cells, tissues and organs. In line with this rationale, epigenetics has brought new insights to our understanding of how environmental factors influence gene expression and, interestingly, gut microbiota metabolites have recently been proposed as novel and significant inducers of epigenetic modifications. Efforts have been dedicated to unveil how the production of specific metabolites influences the activity of epigenetic writers and erasers in order to establish a mechanistic link between gut microbiota, epigenetic modifications and health. Recent data is now evidencing how specific microbial metabolites shape the epigenetic landscape of eukaryotic cells, paving new avenues for innovative therapeutic strategies relying on diet-driven microbiota: epigenetic interactions. Herein is discussed the impact of diet on gut microbiota and the molecular mechanisms underlying microbiota–host interactions, highlighting the influence of diet on microbiota metabolome and how this may induce epigenetic modifications in host cells. Furthermore, it is hypothesized that epigenetics may be a key process transducing the effects of diet on gut microbiota with consequences for health and disease. Accordingly, innovating strategies of disease prevention based on a “precision diet”, a personalized dietary planning according to specific epigenetic targets, are discussed.
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19
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Chen YC, Lin HY, Chien Y, Tung YH, Ni YH, Gau SSF. Altered gut microbiota correlates with behavioral problems but not gastrointestinal symptoms in individuals with autism. Brain Behav Immun 2022; 106:161-178. [PMID: 36058421 DOI: 10.1016/j.bbi.2022.08.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 08/09/2022] [Accepted: 08/28/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Despite inconsistent results across studies, emerging evidence suggests that the microbial micro-environment may be associated with autism spectrum disorder (ASD). Geographical and cultural factors highly impact microbial profiles, and there is a shortage of data from East Asian populations. This study aimed to comprehensively characterize microbial profiles in an East Asian sample and explore whether gut microbiota contributes to clinical symptoms, emotional/behavioral problems, and GI symptoms in ASD. METHODS We assessed 82 boys and young men with ASD and 31 typically developing controls (TDC), aged 6-25 years. We analyzed the stool sample of all participants with 16S V3-V4 rRNA sequencing and correlated its profile with GI symptoms, autistic symptoms, and emotional/behavioral problems. RESULTS Autistic individuals, compared to TDC, had worse GI symptoms. There were no group differences in alpha diversity of species richness estimates (Shannon-wiener and Simpson diversity indices). Participants with ASD had an increased relative abundance of Fusobacterium, Ruminococcus torques group (at the genus level), and Bacteroides plebeius DSM 17135 (at the species level), while a decreased relative abundance of Ruminococcaceae UCG 013, Ervsipelotrichaceae UCG 003, Parasutterella, Clostridium sensu stricto 1, Turicibacter (at the genus level), and Clostridium spiroforme DSM 1552 and Intestinimonas butyriciproducens (at the species level). Altered taxonomic diversity in ASD significantly correlated with autistic symptoms, thought problems, delinquent behaviors, self dysregulation, and somatic complaints. We did not find an association between gut symptoms and gut microbial dysbiosis. CONCLUSIONS Our findings suggest that altered microbiota are associated with behavioral phenotypes but not GI symptoms in ASD. The function of the identified microbial profiles mainly involves the immune pathway, supporting the hypothesis of a complex relationship between altered microbiome, immune dysregulation, and ASD that may advance the discovery of molecular biomarkers for ASD.
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Affiliation(s)
- Yu-Chieh Chen
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsiang-Yuan Lin
- Azrieli Adult Neurodevelopmental Centre, Centre for Addiction and Mental Health, Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yiling Chien
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Yu-Hung Tung
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - Susan Shur-Fen Gau
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
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20
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Jensen ET, Yi J, Jackson W, Singh R, Joseph RM, Kuban KCK, Msall ME, Washburn L, Fry R, South AM, O'Shea TM. Analysis of Neurodevelopment in Children Born Extremely Preterm Treated With Acid Suppressants Before Age 2 Years. JAMA Netw Open 2022; 5:e2241943. [PMID: 36378311 PMCID: PMC9667324 DOI: 10.1001/jamanetworkopen.2022.41943] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
Importance Children born preterm are at increased risk of adverse neurodevelopmental outcomes and may be particularly vulnerable to the effects of gastric acid suppression during infancy. Objective To assess whether early acid suppressant use in infants born extremely preterm is associated with poorer neurodevelopmental outcomes. Design, Setting, and Participants The Extremely Low Gestational Age Newborn study was a multicenter, longitudinal cohort study of infants born before 28 weeks' gestational age between March 22, 2002, and August 31, 2004. The current analyses were performed from September 12, 2020, through September 22, 2022. Of the 1506 infants enrolled, 284 died before discharge and 22 died before 24 months of age. An additional 2 died before age 10 years, leaving 1198 (79.5%) eligible for a visit. Of these, 889 (74%) participated in the visit at age 10. At age 10 years, the association of early-life acid suppressant use with neurocognitive, neurodevelopmental, and psychiatric symptomatology was assessed. Exposures Acid suppressant use before 24 months of age was determined from medical records and from questionnaires administered to mothers. Main Outcomes and Measures Neurodevelopmental assessments at age 10 years included the School-Age Differential Ability Scales-II, the Developmental Neuropsychological Assessment-II, the Autism Diagnostic Observation Schedule-2, the Social Responsiveness Scale-2, and the Child Symptom Inventory-4 for attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety. Results Of the 889 participants assessed at age 10 years (mean [SD] age, 9.97 [0.67] years; mean [SD] gestational age at birth, 26.1 [1.3] weeks; 455 [51.2%] male), 368 (41.4%) had received acid suppressants by 24 months of age. Associations were observed between acid suppressant use and decreased full-scale IQ z score (adjusted β, -0.29; 95% CI, -0.45 to -0.12), verbal IQ z score (adjusted β, -0.34; 95% CI, -0.52 to -0.15), nonverbal IQ z score (adjusted β, -0.22; 95% CI to -0.39 to -0.05), working memory z score (adjusted β, -0.26; 95% CI to -0.45, -0.08), autism spectrum disorder (adjusted relative risk, 1.84; 95% CI, 1.15-2.95), and epilepsy (adjusted relative risk, 2.07; 95% CI, 1.31 to 3.35). Results were robust to multiple sensitivity analyses. Use of acid suppressants was not associated with inhibitory control, ADHD, anxiety, or depression. Conclusions and Relevance The results of this cohort study suggest that early-life use of acid suppressants in extremely preterm infants may be associated with poorer neurodevelopmental outcomes and add to evidence indicating caution in use of these agents.
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Affiliation(s)
- Elizabeth T Jensen
- Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Joe Yi
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill
| | - Wesley Jackson
- Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill
| | - Rachana Singh
- Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts
| | - Robert M Joseph
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts
| | | | - Michael E Msall
- Kennedy Research Center on Intellectual and Neurodevelopmental Disabilities, University of Chicago Pritzker School of Medicine, Chicago, Illinois
| | - Lisa Washburn
- Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Rebecca Fry
- Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill
| | - Andrew M South
- Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina
- Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - T Michael O'Shea
- Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill
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21
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Watanangura A, Meller S, Suchodolski JS, Pilla R, Khattab MR, Loderstedt S, Becker LF, Bathen-Nöthen A, Mazzuoli-Weber G, Volk HA. The effect of phenobarbital treatment on behavioral comorbidities and on the composition and function of the fecal microbiome in dogs with idiopathic epilepsy. Front Vet Sci 2022; 9:933905. [PMID: 35990279 PMCID: PMC9386120 DOI: 10.3389/fvets.2022.933905] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 07/11/2022] [Indexed: 01/09/2023] Open
Abstract
Phenobarbital (PB) is one of the most important antiseizure drugs (ASDs) to treat canine idiopathic epilepsy (IE). The effect of PB on the taxonomic changes in gastrointestinal microbiota (GIM) and their functions is less known, which may explain parts of its pharmacokinetic and pharmacodynamic properties, especially its antiseizure effect and drug responsiveness or drug resistance as well as its effect on behavioral comorbidities. Fecal samples of 12 dogs with IE were collected prior to the initiation of PB treatment and 90 days after oral PB treatment. The fecal samples were analyzed using shallow DNA shotgun sequencing, real-time polymerase chain reaction (qPCR)-based dysbiosis index (DI), and quantification of short-chain fatty acids (SCFAs). Behavioral comorbidities were evaluated using standardized online questionnaires, namely, a canine behavioral assessment and research questionnaire (cBARQ), canine cognitive dysfunction rating scale (CCDR), and an attention deficit hyperactivity disorder (ADHD) questionnaire. The results revealed no significant changes in alpha and beta diversity or in the DI, whereas only the abundance of Clostridiales was significantly decreased after PB treatment. Fecal SCFA measurement showed a significant increase in total fecal SCFA concentration and the concentrations of propionate and butyrate, while acetate concentrations revealed an upward trend after 90 days of treatment. In addition, the PB-Responder (PB-R) group had significantly higher butyrate levels compared to the PB-Non-Responder (PB-NR) group. Metagenomics of functional pathway genes demonstrated a significant increase in genes in trehalose biosynthesis, ribosomal synthesis, and gluconeogenesis, but a decrease in V-ATPase-related oxidative phosphorylation. For behavioral assessment, cBARQ analysis showed improvement in stranger-directed fear, non-social fear, and trainability, while there were no differences in ADHD-like behavior and canine cognitive dysfunction (CCD) scores after 90 days of PB treatment. While only very minor shifts in bacterial taxonomy were detected, the higher SCFA concentrations after PB treatment could be one of the key differences between PB-R and PB-NR. These results suggest functional changes in GIM in canine IE treatment.
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Affiliation(s)
- Antja Watanangura
- Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Hannover, Germany
- Center for Systems Neuroscience (ZSN), Hannover, Germany
- Veterinary Research and Academic Service, Faculty of Veterinary Medicine, Kasetsart University, Kamphaeng Saen, Nakhon Pathom, Thailand
| | - Sebastian Meller
- Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Jan S. Suchodolski
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX, United States
| | - Rachel Pilla
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX, United States
| | - Mohammad R. Khattab
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX, United States
| | - Shenja Loderstedt
- Department for Small Animal, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Lisa F. Becker
- Department for Small Animal, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | | | - Gemma Mazzuoli-Weber
- Center for Systems Neuroscience (ZSN), Hannover, Germany
- Institute for Physiology and Cell Biology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Holger A. Volk
- Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Hannover, Germany
- Center for Systems Neuroscience (ZSN), Hannover, Germany
- *Correspondence: Holger A. Volk
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22
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Jones J, Reinke SN, Mousavi-Derazmahalleh M, Palmer DJ, Christophersen CT. Changes to the Gut Microbiome in Young Children Showing Early Behavioral Signs of Autism. Front Microbiol 2022; 13:905901. [PMID: 35966698 PMCID: PMC9371947 DOI: 10.3389/fmicb.2022.905901] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
The human gut microbiome has increasingly been associated with autism spectrum disorder (ASD), which is a neurological developmental disorder, characterized by impairments to social interaction. The ability of the gut microbiota to signal across the gut-brain-microbiota axis with metabolites, including short-chain fatty acids, impacts brain health and has been identified to play a role in the gastrointestinal and developmental symptoms affecting autistic children. The fecal microbiome of older children with ASD has repeatedly shown particular shifts in the bacterial and fungal microbial community, which are significantly different from age-matched neurotypical controls, but it is still unclear whether these characteristic shifts are detectable before diagnosis. Early microbial colonization patterns can have long-lasting effects on human health, and pre-emptive intervention may be an important mediator to more severe autism. In this study, we characterized both the microbiome and short-chain fatty acid concentrations of fecal samples from young children between 21 and 40 months who were showing early behavioral signs of ASD. The fungal richness and acetic acid concentrations were observed to be higher with increasing autism severity, and the abundance of several bacterial taxa also changed due to the severity of ASD. Bacterial diversity and SCFA concentrations were also associated with stool form, and some bacterial families were found with differential abundance according to stool firmness. An exploratory analysis of the microbiome associated with pre-emptive treatment also showed significant differences at multiple taxonomic levels. These differences may impact the microbial signaling across the gut-brain-microbiota axis and the neurological development of the children.
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Affiliation(s)
- Jacquelyn Jones
- Trace and Environmental DNA Laboratory, School of Molecular and Life Sciences, Curtin University, Bentley, WA, Australia
- The Western Australian Human Microbiome Collaboration Centre, Curtin University, Bentley, WA, Australia
- *Correspondence: Jacquelyn Jones
| | - Stacey N. Reinke
- Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Joondalup, WA, Australia
| | - Mahsa Mousavi-Derazmahalleh
- Trace and Environmental DNA Laboratory, School of Molecular and Life Sciences, Curtin University, Bentley, WA, Australia
- The Western Australian Human Microbiome Collaboration Centre, Curtin University, Bentley, WA, Australia
| | - Debra J. Palmer
- Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
- School of Medicine, University of Western Australia, Crawley, WA, Australia
| | - Claus T. Christophersen
- Trace and Environmental DNA Laboratory, School of Molecular and Life Sciences, Curtin University, Bentley, WA, Australia
- The Western Australian Human Microbiome Collaboration Centre, Curtin University, Bentley, WA, Australia
- Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Joondalup, WA, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
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23
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Unlocking the Potential of the Human Microbiome for Identifying Disease Diagnostic Biomarkers. Diagnostics (Basel) 2022; 12:diagnostics12071742. [PMID: 35885645 PMCID: PMC9315466 DOI: 10.3390/diagnostics12071742] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/10/2022] [Accepted: 07/14/2022] [Indexed: 02/07/2023] Open
Abstract
The human microbiome encodes more than three million genes, outnumbering human genes by more than 100 times, while microbial cells in the human microbiota outnumber human cells by 10 times. Thus, the human microbiota and related microbiome constitute a vast source for identifying disease biomarkers and therapeutic drug targets. Herein, we review the evidence backing the exploitation of the human microbiome for identifying diagnostic biomarkers for human disease. We describe the importance of the human microbiome in health and disease and detail the use of the human microbiome and microbiota metabolites as potential diagnostic biomarkers for multiple diseases, including cancer, as well as inflammatory, neurological, and metabolic diseases. Thus, the human microbiota has enormous potential to pave the road for a new era in biomarker research for diagnostic and therapeutic purposes. The scientific community needs to collaborate to overcome current challenges in microbiome research concerning the lack of standardization of research methods and the lack of understanding of causal relationships between microbiota and human disease.
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24
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Boussamet L, Rajoka MSR, Berthelot L. Microbiota, IgA and Multiple Sclerosis. Microorganisms 2022; 10:microorganisms10030617. [PMID: 35336190 PMCID: PMC8954136 DOI: 10.3390/microorganisms10030617] [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] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/11/2022] [Accepted: 03/11/2022] [Indexed: 12/16/2022] Open
Abstract
Multiple sclerosis (MS) is a neuroinflammatory disease characterized by immune cell infiltration in the central nervous system and destruction of myelin sheaths. Alterations of gut bacteria abundances are present in MS patients. In mouse models of neuroinflammation, depletion of microbiota results in amelioration of symptoms, and gavage with MS patient microbiota exacerbates the disease and inflammation via Th17 cells. On the other hand, depletion of B cells using anti-CD20 is an efficient therapy in MS, and growing evidence shows an important deleterious role of B cells in MS pathology. However, the failure of TACI-Ig treatment in MS highlighted the potential regulatory role of plasma cells. The mechanism was recently demonstrated involving IgA+ plasma cells, specific for gut microbiota and producing IL-10. IgA-coated bacteria in MS patient gut exhibit also modifications. We will focus our review on IgA interactions with gut microbiota and IgA+ B cells in MS. These recent data emphasize new pathways of neuroinflammation regulation in MS.
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Affiliation(s)
- Léo Boussamet
- Centre for Research in Transplantation and Translation Immunology, Nantes Université, Inserm, CR2TI UMR, 1064 Nantes, France;
| | - Muhammad Shahid Riaz Rajoka
- Laboratory of Animal Food Function, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan;
| | - Laureline Berthelot
- Centre for Research in Transplantation and Translation Immunology, Nantes Université, Inserm, CR2TI UMR, 1064 Nantes, France;
- Correspondence:
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25
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Tataru C, Martin A, Dunlap K, Peras M, Chrisman BS, Rutherford E, Deitzler GE, Phillips A, Yin X, Sabino K, Hannibal RL, Hartono W, Lin M, Raack E, Wu Y, DeSantis TZ, Iwai S, Wall DP, David MM. Longitudinal study of stool-associated microbial taxa in sibling pairs with and without autism spectrum disorder. ISME COMMUNICATIONS 2021; 1:80. [PMID: 37938270 PMCID: PMC9723651 DOI: 10.1038/s43705-021-00080-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/24/2021] [Accepted: 11/18/2021] [Indexed: 05/01/2023]
Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder influenced by both genetic and environmental factors. Recently, gut dysbiosis has emerged as a powerful contributor to ASD symptoms. In this study, we recruited over 100 age-matched sibling pairs (between 2 and 8 years old) where one had an Autism ASD diagnosis and the other was developing typically (TD) (432 samples total). We collected stool samples over four weeks, tracked over 100 lifestyle and dietary variables, and surveyed behavior measures related to ASD symptoms. We identified 117 amplicon sequencing variants (ASVs) that were significantly different in abundance between sibling pairs across all three timepoints, 11 of which were supported by at least two contrast methods. We additionally identified dietary and lifestyle variables that differ significantly between cohorts, and further linked those variables to the ASVs they statistically relate to. Overall, dietary and lifestyle features were explanatory of ASD phenotype using logistic regression, however, global compositional microbiome features were not. Leveraging our longitudinal behavior questionnaires, we additionally identified 11 ASVs associated with changes in reported anxiety over time within and across all individuals. Lastly, we find that overall microbiome composition (beta-diversity) is associated with specific ASD-related behavioral characteristics.
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Affiliation(s)
- Christine Tataru
- Department of Microbiology, Oregon State University, Corvallis, OR, USA.
| | - Austin Martin
- Department of Microbiology, Oregon State University, Corvallis, OR, USA
| | - Kaitlyn Dunlap
- Departments of Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | | | - Brianna S Chrisman
- Departments of Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | | | - Grace E Deitzler
- Department of Microbiology, Oregon State University, Corvallis, OR, USA
| | | | | | | | | | | | | | | | | | | | | | - Dennis P Wall
- Departments of Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Maude M David
- Department of Microbiology, Oregon State University, Corvallis, OR, USA.
- Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, USA.
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26
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Yap CX, Henders AK, Alvares GA, Wood DLA, Krause L, Tyson GW, Restuadi R, Wallace L, McLaren T, Hansell NK, Cleary D, Grove R, Hafekost C, Harun A, Holdsworth H, Jellett R, Khan F, Lawson LP, Leslie J, Frenk ML, Masi A, Mathew NE, Muniandy M, Nothard M, Miller JL, Nunn L, Holtmann G, Strike LT, de Zubicaray GI, Thompson PM, McMahon KL, Wright MJ, Visscher PM, Dawson PA, Dissanayake C, Eapen V, Heussler HS, McRae AF, Whitehouse AJO, Wray NR, Gratten J. Autism-related dietary preferences mediate autism-gut microbiome associations. Cell 2021; 184:5916-5931.e17. [PMID: 34767757 DOI: 10.1016/j.cell.2021.10.015] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 06/14/2021] [Accepted: 10/13/2021] [Indexed: 12/24/2022]
Abstract
There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.
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Affiliation(s)
- Chloe X Yap
- Mater Research Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Anjali K Henders
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Gail A Alvares
- Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia 6009, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - David L A Wood
- Microba Life Sciences, Brisbane, Queensland 4000, Australia
| | - Lutz Krause
- Microba Life Sciences, Brisbane, Queensland 4000, Australia
| | - Gene W Tyson
- Microba Life Sciences, Brisbane, Queensland 4000, Australia; Centre for Microbiome Research, School of Biomedical Sciences, Queensland University of Technology, Translational Research Institute, Woolloongabba, Queensland 4102, Australia
| | - Restuadi Restuadi
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Leanne Wallace
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Tiana McLaren
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Narelle K Hansell
- Queensland Brain Institute, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Dominique Cleary
- Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia 6009, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Rachel Grove
- Faculty of Health, University of Technology Sydney, Sydney, New South Wales 2007, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Claire Hafekost
- Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia 6009, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Alexis Harun
- Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia 6009, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Helen Holdsworth
- Mater Research Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Child Health Research Centre, The University of Queensland, South Brisbane, Queensland 4101, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Rachel Jellett
- Olga Tennison Autism Research Centre, La Trobe University, Bundoora, Victoria 3086, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Feroza Khan
- School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Lauren P Lawson
- Olga Tennison Autism Research Centre, La Trobe University, Bundoora, Victoria 3086, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Jodie Leslie
- Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia 6009, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Mira Levis Frenk
- Mater Research Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Child Health Research Centre, The University of Queensland, South Brisbane, Queensland 4101, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Anne Masi
- School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Nisha E Mathew
- School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Melanie Muniandy
- Olga Tennison Autism Research Centre, La Trobe University, Bundoora, Victoria 3086, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Michaela Nothard
- Mater Research Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Child Health Research Centre, The University of Queensland, South Brisbane, Queensland 4101, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Jessica L Miller
- Queensland Brain Institute, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Lorelle Nunn
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Gerald Holtmann
- Faculty of Medicine and Faculty of Health and Behavioural Science, University of Queensland, St Lucia, Queensland 4072, Australia; Department of Gastroenterology & Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia
| | - Lachlan T Strike
- Queensland Brain Institute, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Greig I de Zubicaray
- School of Psychology and Counselling, Faculty of Health, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia
| | - Paul M Thompson
- Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Katie L McMahon
- School of Clinical Sciences, Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, Queensland 4000, Australia
| | - Margaret J Wright
- Queensland Brain Institute, The University of Queensland, St Lucia, Queensland 4072, Australia; Centre for Advanced Imaging, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Peter M Visscher
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Paul A Dawson
- Mater Research Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Cheryl Dissanayake
- Olga Tennison Autism Research Centre, La Trobe University, Bundoora, Victoria 3086, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Valsamma Eapen
- School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia; Academic Unit of Child Psychiatry South West Sydney, Ingham Institute, Liverpool Hospital, Sydney, New South Wales, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Helen S Heussler
- Child Health Research Centre, The University of Queensland, South Brisbane, Queensland 4101, Australia; Child Development Program, Children's Health Queensland, South Brisbane, Queensland 4101, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Allan F McRae
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Andrew J O Whitehouse
- Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia 6009, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Naomi R Wray
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; Queensland Brain Institute, The University of Queensland, St Lucia, Queensland 4072, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia
| | - Jacob Gratten
- Mater Research Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; Cooperative Research Centre for Living with Autism (Autism CRC), Long Pocket, Queensland 4068, Australia.
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Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder. Brain Behav Immun 2021; 97:119-134. [PMID: 34252569 DOI: 10.1016/j.bbi.2021.07.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/17/2021] [Accepted: 07/03/2021] [Indexed: 12/13/2022] Open
Abstract
Autism spectrum disorder (ASD) is one of the most severe developmental disorders, affecting on average 1 in 150 children worldwide. There is a great need for more effective strategies to improve quality of life in ASD subjects. The gut microbiome has emerged as a potential therapeutic target in ASD. A novel modulator of the gut microbiome, the traditionally fermented milk drink kefir, has recently been shown to modulate the microbiota and decrease repetitive behaviour, one of the hallmarks of ASD, in mice. As such, we hypothesized that kefir could ameliorate behavioural deficits in a mouse model relevant to ASD; the BTBR T+ Itpr3tf/J mouse strain. To this end, adult mice were administered either kefir (UK4) or a milk control for three weeks as treatment lead-in, after which they were assessed for their behavioural phenotype using a battery of tests. In addition, we assessed systemic immunity by flow cytometry and the gut microbiome using shotgun metagenomic sequencing. We found that indeed kefir decreased repetitive behaviour in this mouse model. Furthermore, kefir prolonged stress-induced increases in corticosterone 60 min post-stress, which was accompanied by an ameliorated innate immune response as measured by LY6Chi monocyte levels. In addition, kefir increased the levels of anti-inflammatory Treg cells in mesenteric lymph nodes (MLNs). Kefir also increased the relative abundance of Lachnospiraceae bacterium A2, which correlated with reduced repetitive behaviour and increased Treg cells in MLNs. Functionally, kefir modulated various predicted gut microbial pathways, including the gut-brain module S-Adenosylmethionine (SAM) synthesis, as well as L-valine biosynthesis and pyruvate fermentation to isobutanol, which all correlated with repetitive behaviour. Taken together our data show that kefir modulates peripheral immunoregulation, can ameliorate specific ASD behavioural dysfunctions and modulates selective aspects of the composition and function of the gut microbiome, indicating that kefir supplementation might prove a viable strategy in improving quality of life in ASD subjects.
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Bai S, Xie J, Bai H, Tian T, Zou T, Chen JJ. Gut Microbiota-Derived Inflammation-Related Serum Metabolites as Potential Biomarkers for Major Depressive Disorder. J Inflamm Res 2021; 14:3755-3766. [PMID: 34393496 PMCID: PMC8354734 DOI: 10.2147/jir.s324922] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/28/2021] [Indexed: 12/14/2022] Open
Abstract
Background Although many works have been conducted to explore the biomarkers for diagnosing major depressive disorder (MDD), the widely accepted biomarkers are still not identified. Thus, the combined application of serum metabolomics and fecal microbial communities was used to identify gut microbiota-derived inflammation-related serum metabolites as potential biomarkers for MDD. Methods MDD patients and healthy controls (HCs) were included in this study. Both serum samples and fecal samples were collected. The liquid chromatography mass spectrometry (LC-MS) was used to detect the metabolites in serum samples, and the 16S rRNA gene sequencing was used to analyze the gut microbiota compositions in fecal samples. Results Totally, 60 MDD patients and 60 HCs were recruited. The 24 differential serum metabolites were identified, and 10 of these were inflammation-related metabolites. Three significantly affected inflammation-related pathways were identified using differential metabolites. The 17 differential genera were identified, and 14 of these genera belonged to phyla Firmicutes. Four significantly affected inflammation-related pathways were identified using differential genera. Five inflammation-related metabolites (LysoPC(16:0), deoxycholic acid, docosahexaenoic acid, taurocholic acid and LysoPC(20:0)) were identified as potential biomarkers. These potential biomarkers had significant correlations with genera belonged to phyla Firmicutes. The panel consisting of these biomarkers could effectively distinguish MDD patients from HCs with an area under the curve (AUC) of 0.95 in training set and 0.92 in testing set. Conclusion These findings suggested that the disturbance of phyla Firmicutes might be involved in the onset of depression by regulating host’s inflammatory response, and these potential biomarkers could be useful for future investigating the objective methods for diagnosing MDD.
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Affiliation(s)
- Shunjie Bai
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Jing Xie
- Department of Endocrinology, the Fourth People's Hospital of Chongqing, Chongqing University Central Hospital, Chongqing, People's Republic of China
| | - Huili Bai
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Tian Tian
- Department of Neurology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, People's Republic of China
| | - Tao Zou
- Department of Psychiatry, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, People's Republic of China.,Shanghai Key Laboratory of Forensic Medicine, Academy of Forensic Science, Shanghai, People's Republic of China
| | - Jian-Jun Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing, People's Republic of China
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Abstract
Autism spectrum disorder (ASD) is a remarkably complex disorder influenced by both genetic and environmental factors. Numerous microbial diversity surveys conducted over the past decade have attempted to link specific ASD biomarkers to gastrointestinal tract disturbances, but results generated across cohorts and studies remain inconsistent. This commentary discusses multidirectional interactions between the host, the microbiome, and external factors germane to autism. Recent studies posit the heritability of the gut microbiome itself, confounding attempts to discern heritable from nonheritable effectors in neurodevelopmental disorders. Elucidating the ever-evolving gut microbiome’s role in modulating the ASD phenotype will most certainly require new experimental methodologies and designs. In a recent paper published in mSystems (J. Fouquier, N. Moreno Huizar, J. Donnelly, C. Glickman, et al., mSystems e00848-20, 2021, https://doi.org/10.1128/mSystems.00848-20), the authors describe a web of interactions by collecting samples longitudinally, analyzing cross-sectional cohorts, and recording nonbinary phenotypic measurements.
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