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Fabregat-Safont D, Coadic L, Haro N, Montané-Garcia M, Canaguier J, Mallaret G, Davidovic L, Pozo ÓJ. Improving the detectability of low-abundance p-cresol in biological matrices by chemical derivatization and LC-MS/MS determination. Talanta 2025; 290:127770. [PMID: 40010114 DOI: 10.1016/j.talanta.2025.127770] [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: 10/21/2024] [Revised: 02/14/2025] [Accepted: 02/17/2025] [Indexed: 02/28/2025]
Abstract
Gut microbiota produces a wide range of microbial metabolites with potential neuroactive properties. Among these, p-cresol, a by-product of tyrosine breakdown, has gained significant attention in various neuropsychiatric disorders, including autism spectrum disorder. However, current methods fail to detect p-cresol at trace levels in both the systemic circulation and brain, limiting the study of its role in neuropsychiatric disorders. There, the precise and accurate determination of p-cresol at low picogram levels is an unmet analytical need. To address this gap, we developed a highly-sensitive, validated method for quantifying p-cresol at low picogram levels in urine, plasma, and brain using chemical derivatization and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that derivatization with 1,2-dimethylimidazole-5-sulfonyl chloride (5-DMIS-Cl or 5-DMISC) increased up to 40-fold the sensitivity compared to traditional dansyl derivatization. Therefore, a method based on 5-DMISC derivatization and sum of transitions was selected for validation. The method was accurate (recoveries 91-100 %) and precise (RSD <15 %) in all tested matrices, enabling detection down to100 pg/mL for urine, 20 pg/mL for plasma, and 0.04 pg/mg for brain tissue. The method was applied to plasma and brain samples from control and p-cresol-treated mice, revealing significant increases in p-cresol levels in treated animals. For the first time, we successfully quantified p-cresol levels in the brain, demonstrating its ability to cross the blood-brain barrier. In summary, this validated method offers a powerful tool for exploring the role of p-cresol -and potentially other phenolic compounds-in the microbiota-gut-brain axis and neuropsychiatric disorders.
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Affiliation(s)
- David Fabregat-Safont
- Applied Metabolomics Research Group, Hospital del Mar Research Institute, Barcelona, Spain; Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water (IUPA), Univ. Jaume I, Castelló, Spain
| | - Lena Coadic
- Applied Metabolomics Research Group, Hospital del Mar Research Institute, Barcelona, Spain
| | - Noemí Haro
- Applied Metabolomics Research Group, Hospital del Mar Research Institute, Barcelona, Spain
| | | | - Juliette Canaguier
- Université Côte d'Azur, CNRS UMR7275, INSERM U1318, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
| | - Geoffroy Mallaret
- Université Côte d'Azur, CNRS UMR7275, INSERM U1318, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
| | - Laetitia Davidovic
- Université Côte d'Azur, CNRS UMR7275, INSERM U1318, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
| | - Óscar J Pozo
- Applied Metabolomics Research Group, Hospital del Mar Research Institute, Barcelona, Spain.
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Basra M, Miceli L, Mundra V, Stern-Harbutte A, Patel H, Haynes J, Parmar MS. Exploring the neurotoxic effects of microbial metabolites: A potential link between p-Cresol and autism spectrum disorders? Brain Res 2025; 1850:149427. [PMID: 39732158 DOI: 10.1016/j.brainres.2024.149427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 12/08/2024] [Accepted: 12/23/2024] [Indexed: 12/30/2024]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a complex etiology, including genetic and environmental factors. A growing body of evidence (preclinical and clinical studies) implicates a potential role of gut microbiome dysregulation in ASD pathophysiology. This review focuses on the microbial metabolite p-Cresol, produced by certain gut bacteria such as Clostridium, and its potential role in ASD. The review summarizes studies investigating the gut microbiome composition in ASD patients, particularly the increased abundance of Clostridium species and associated gastrointestinal symptoms. The potential neurotoxic effects of p-Cresol are explored, including its influence on neurotransmitter metabolism (especially dopamine), neuroinflammation, and brain development. The mechanistic findings from the preclinical studies of p-Cresol's induction of ASD-like behaviors and its impact on the dopaminergic system are discussed. Literature studies indicated increased levels of p-Cresol in the urine of patients with ASD. This increasing evidence suggests that p-Cresol may serve as a crucial biomarker for understanding the relationship between gut microbiota and ASD, opening avenues for potential diagnostic and therapeutic interventions.
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Affiliation(s)
- Mahi Basra
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Tampa Bay Campus, Clearwater, FL, United States
| | - Lauren Miceli
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Tampa Bay Campus, Clearwater, FL, United States
| | - Vatsala Mundra
- University of Texas Southwestern Medical School, Dallas, TX, United States
| | - Alison Stern-Harbutte
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Tampa Bay Campus, Clearwater, FL, United States
| | - Hemangi Patel
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Tampa Bay Campus, Clearwater, FL, United States
| | | | - Mayur S Parmar
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Tampa Bay Campus, Clearwater, FL, United States.
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Flynn CK, Adams JB, Krajmalnik-Brown R, Khoruts A, Sadowsky MJ, Nirmalkar K, Takyi E, Whiteley P. Review of Elevated Para-Cresol in Autism and Possible Impact on Symptoms. Int J Mol Sci 2025; 26:1513. [PMID: 40003979 PMCID: PMC11855632 DOI: 10.3390/ijms26041513] [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: 01/09/2025] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Para-cresol (p-cresol), and its primary human metabolite p-cresol sulfate (pCS), are among the most studied gut-derived metabolites relevant to autism spectrum disorder (ASD). P-cresol is produced by bacterial modification of phenylalanine or tyrosine and is one of many potentially deleterious metabolites produced by the gut microbiota. Seventeen studies have observed p-cresol and/or p-cresol sulfate as being higher in the urine of children with autism spectrum disorder (ASD) vs. controls. P-cresol has harmful effects on the body, including within the gut, brain, kidneys, liver, immune system, and mitochondria. Some of these effects may contribute to autism and comorbid symptoms. In the gut, p-cresol acts as an antibiotic, altering the gut microbiome to favor the bacteria that produce it. In the mitochondria, p-cresol disrupts ATP production and increases oxidative stress, which is also common in autism. In the brain, p-cresol impairs neuronal development. P-cresol inactivates dopamine beta-hydroxylase, which converts dopamine to noradrenaline. P-cresol sulfate impairs kidney function and is linked to chronic kidney disease (CKD), which is more common in ASD adults. P-cresol also interferes with immune function. Three animal studies have demonstrated that p-cresol causes autism-related symptoms in mice, and that mice can be recovered by the administration of fecal microbiota transplant from healthy mice. Similarly, it was found that microbiota transplant therapy treatment in children with ASD significantly reduced p-cresol sulfate levels to normal and led to significant improvements in gastrointestinal (GI) and ASD symptoms. In summary, p-cresol and pCS likely contribute to ASD core symptoms in a substantial subset of children with ASD.
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Affiliation(s)
- Christina K. Flynn
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ 85287, USA; (C.K.F.)
- School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85287, USA
| | - James B. Adams
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ 85287, USA; (C.K.F.)
- School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85287, USA
| | - Rosa Krajmalnik-Brown
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ 85287, USA; (C.K.F.)
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 85281, USA
| | - Alexander Khoruts
- Department of Medicine, Division of Gastroenterology, Center for Immunology and BioTechnology Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Michael J. Sadowsky
- Department of Medicine and BioTechnology Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Khemlal Nirmalkar
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ 85287, USA; (C.K.F.)
| | - Evelyn Takyi
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ 85287, USA; (C.K.F.)
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Bertarini L, Imbeni F, Vilella A, Alboni S, Pellati F. Targeted Metabolomics for the Analysis of p-Cresol in Mouse Brain: Impact of Biological Sex and Strain. ACS Chem Neurosci 2025; 16:452-461. [PMID: 39829036 DOI: 10.1021/acschemneuro.4c00698] [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: 01/22/2025] Open
Abstract
p-Cresol, an environmental contaminant and endogenous metabolite derived primarily from the conversion of l-tyrosine by intestinal microflora, is gaining increasing attention, due to its potential impact on human health. Recent studies have highlighted elevated levels of p-cresol and its metabolites, including p-cresyl sulfate and p-cresyl glucuronide, in various populations, suggesting a correlation with neurodevelopmental and neurodegenerative conditions. While the role of this compound as a uremic toxin is well established, its presence and concentration within the central nervous system (CNS) remain largely unexplored. To address this gap, an high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was optimized and validated for the first time in this work for the targeted metabolomics of p-cresol in brain tissues. This method enabled the quantification of this compound in different brain areas of adult male and female C57BL/6J mice and in the cortex of various mouse strains, including CD-1 and the idiopathic autism model BTBR T+Itpr3tf/J. Additionally, preliminary analyses of human cortex samples confirmed the presence of p-cresol, suggesting its relevance in human brain health. Moreover, metabolomic analyses have further explored the correlations between p-cresol and neurotransmitters, with a particular focus on dopaminergic and noradrenergic pathways. These findings pave the way for understanding the potential impact of p-cresol on neurochemical networks and its implications for neurodevelopmental and neurodegenerative disorders.
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Affiliation(s)
- Laura Bertarini
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103-287, 41125 Modena, Italy
- Clinical and Experimental Medicine PhD Program, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy
| | - Federico Imbeni
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103-287, 41125 Modena, Italy
| | - Antonietta Vilella
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy
- Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Silvia Alboni
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103-287, 41125 Modena, Italy
- Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Federica Pellati
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103-287, 41125 Modena, Italy
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K M M, Ghosh P, Nagappan K, Palaniswamy DS, Begum R, Islam MR, Tagde P, Shaikh NK, Farahim F, Mondal TK. From Gut Microbiomes to Infectious Pathogens: Neurological Disease Game Changers. Mol Neurobiol 2025; 62:1184-1204. [PMID: 38967904 DOI: 10.1007/s12035-024-04323-0] [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: 04/02/2024] [Accepted: 06/19/2024] [Indexed: 07/06/2024]
Abstract
Gut microbiota and infectious diseases affect neurological disorders, brain development, and function. Compounds generated in the gastrointestinal system by gut microbiota and infectious pathogens may mediate gut-brain interactions, which may circulate throughout the body and spread to numerous organs, including the brain. Studies shown that gut bacteria and disease-causing organisms may pass molecular signals to the brain, affecting neurological function, neurodevelopment, and neurodegenerative diseases. This article discusses microorganism-producing metabolites with neuromodulator activity, signaling routes from microbial flora to the brain, and the potential direct effects of gut bacteria and infectious pathogens on brain cells. The review also considered the neurological aspects of infectious diseases. The infectious diseases affecting neurological functions and the disease modifications have been discussed thoroughly. Recent discoveries and unique insights in this perspective need further validation. Research on the complex molecular interactions between gut bacteria, infectious pathogens, and the CNS provides valuable insights into the pathogenesis of neurodegenerative, behavioral, and psychiatric illnesses. This study may provide insights into advanced drug discovery processes for neurological disorders by considering the influence of microbial communities inside the human body.
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Affiliation(s)
- Muhasina K M
- Department of Pharmacognosy, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India.
| | - Puja Ghosh
- Department of Pharmacognosy, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India
| | - Krishnaveni Nagappan
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India
| | | | - Rahima Begum
- Department of Microbiology, Gono Bishwabidyalay, Dhaka, Bangladesh
| | - Md Rabiul Islam
- Tennessee State University Chemistry department 3500 John A Merritt Blvd, Nashville, TN, 37209, USA
| | - Priti Tagde
- PRISAL(Pharmaceutical Royal International Society), Branch Office Bhopal, Bhopal, Madhya Pradesh, 462042, India
| | - Nusrat K Shaikh
- Department of Quality Assurance, Smt. N. M, Padalia Pharmacy College, Navapura, Ahmedabad, 382 210, Gujarat, India
| | - Farha Farahim
- Department of Nursing, King Khalid University, Abha, 61413, Kingdom of Saudi Arabia
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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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Borrego-Ruiz A, Borrego JJ. Neurodevelopmental Disorders Associated with Gut Microbiome Dysbiosis in Children. CHILDREN (BASEL, SWITZERLAND) 2024; 11:796. [PMID: 39062245 PMCID: PMC11275248 DOI: 10.3390/children11070796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024]
Abstract
The formation of the human gut microbiome initiates in utero, and its maturation is established during the first 2-3 years of life. Numerous factors alter the composition of the gut microbiome and its functions, including mode of delivery, early onset of breastfeeding, exposure to antibiotics and chemicals, and maternal stress, among others. The gut microbiome-brain axis refers to the interconnection of biological networks that allow bidirectional communication between the gut microbiome and the brain, involving the nervous, endocrine, and immune systems. Evidence suggests that the gut microbiome and its metabolic byproducts are actively implicated in the regulation of the early brain development. Any disturbance during this stage may adversely affect brain functions, resulting in a variety of neurodevelopmental disorders (NDDs). In the present study, we reviewed recent evidence regarding the impact of the gut microbiome on early brain development, alongside its correlation with significant NDDs, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, cerebral palsy, fetal alcohol spectrum disorders, and genetic NDDs (Rett, Down, Angelman, and Turner syndromes). Understanding changes in the gut microbiome in NDDs may provide new chances for their treatment in the future.
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Affiliation(s)
- Alejandro Borrego-Ruiz
- Departamento de Psicología Social y de las Organizaciones, Universidad Nacional de Educación a Distancia (UNED), 28040 Madrid, Spain;
| | - Juan J. Borrego
- Departamento de Microbiología, Universidad de Málaga, 29071 Málaga, Spain
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA, Plataforma BIONAND, 29010 Málaga, Spain
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8
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Khoo SC, Zhang N, Luang-In V, Goh MS, Sonne C, Ma NL. Exploring environmental exposomes and the gut-brain nexus: Unveiling the impact of pesticide exposure. ENVIRONMENTAL RESEARCH 2024; 250:118441. [PMID: 38350544 DOI: 10.1016/j.envres.2024.118441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 01/20/2024] [Accepted: 02/06/2024] [Indexed: 02/15/2024]
Abstract
This review delves into the escalating concern of environmental pollutants and their profound impact on human health in the context of the modern surge in global diseases. The utilisation of chemicals in food production, which results in residues in food, has emerged as a major concern nowadays. By exploring the intricate relationship between environmental pollutants and gut microbiota, the study reveals a dynamic bidirectional interplay, as modifying microbiota profile influences metabolic pathways and subsequent brain functions. This review will first provide an overview of potential exposomes and their effect to gut health. This paper is then emphasis the connection of gut brain function by analysing microbiome markers with neurotoxicity responses. We then take pesticide as example of exposome to elucidate their influence to biomarkers biosynthesis pathways and subsequent brain functions. The interconnection between neuroendocrine and neuromodulators elements and the gut-brain axis emerges as a pivotal factor in regulating mental health and brain development. Thus, manipulation of gut microbiota function at the onset of stress may offer a potential avenue for the prevention and treatment for mental disorder and other neurodegenerative illness.
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Affiliation(s)
- Shing Ching Khoo
- Biological Security and Sustainability (BioSES) Research Interest Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030, Kuala Nerus, Terengganu, Malaysia
| | - Nan Zhang
- Synerk Biotech, BioBay, Suzhou, 215000, China; Neuroscience Program, Department of Neurology, Houston Methodist Research Institute, TX, 77030, USA; Department of Neurology, Weill Cornell Medicine, New York, 10065, USA
| | - Vijitra Luang-In
- Natural Antioxidant Innovation Research Unit, Department of Biotechnology, Faculty of Technology, Mahasarakham University, Khamriang, Kantharawichai, Mahasarakham, 44150, Thailand
| | - Meng Shien Goh
- Biological Security and Sustainability (BioSES) Research Interest Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030, Kuala Nerus, Terengganu, Malaysia
| | - Christian Sonne
- Aarhus University, Faculty of Science and Technology, Department of Bioscience, Arctic Research Centre (ARC), Danish Centre for Environment and Energy (DCE), Frederiksborgvej 399, PO Box 358, DK-4000, Roskilde, Denmark
| | - Nyuk Ling Ma
- Biological Security and Sustainability (BioSES) Research Interest Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030, Kuala Nerus, Terengganu, Malaysia; Center for Global Health Research (CGHR), Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India.
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D'Agostino GD, Chaudhari SN, Devlin AS. Host-microbiome orchestration of the sulfated metabolome. Nat Chem Biol 2024; 20:410-421. [PMID: 38347214 PMCID: PMC11095384 DOI: 10.1038/s41589-023-01526-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 12/08/2023] [Indexed: 04/01/2024]
Abstract
Recent studies have demonstrated that metabolites produced by commensal bacteria causally influence health and disease. The sulfated metabolome is one class of molecules that has recently come to the forefront due to efforts to understand the role of these metabolites in host-microbiome interactions. Sulfated compounds have canonically been classified as waste products; however, studies have revealed a variety of physiological roles for these metabolites, including effects on host metabolism, immune response and neurological function. Moreover, recent research has revealed that commensal bacteria either chemically modify or synthesize a variety of sulfated compounds. In this Review, we explore how host-microbiome collaborative metabolism transforms the sulfated metabolome. We describe bacterial and mammalian enzymes that sulfonate and desulfate biologically relevant carbohydrates, amino acid derivatives and cholesterol-derived metabolites. We then discuss outstanding questions and future directions in the field, including potential roles of sulfated metabolites in disease detection, prevention and treatment. We hope that this Review inspires future research into sulfated compounds and their effects on physiology.
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Affiliation(s)
- Gabriel D D'Agostino
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Snehal N Chaudhari
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
- Department of Biochemistry, University of Wisconsin, Madison, WI, USA.
| | - A Sloan Devlin
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
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Paul KC, Zhang K, Walker DI, Sinsheimer J, Yu Y, Kusters C, Del Rosario I, Folle AD, Keener AM, Bronstein J, Jones DP, Ritz B. Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson's disease. Mol Neurodegener 2023; 18:100. [PMID: 38115046 PMCID: PMC10731845 DOI: 10.1186/s13024-023-00694-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 12/06/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. OBJECTIVE Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics. METHODS We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation. RESULTS LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism. CONCLUSIONS Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.
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Affiliation(s)
- Kimberly C Paul
- Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
| | - Keren Zhang
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Douglas I Walker
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Janet Sinsheimer
- Department of Human Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
- Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Yu Yu
- Center for Health Policy Research, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Cynthia Kusters
- Department of Human Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Irish Del Rosario
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Aline Duarte Folle
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Adrienne M Keener
- Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
- Parkinson's Disease Research, Education, and Clinical Center, Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, USA
| | - Jeff Bronstein
- Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Dean P Jones
- Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA
| | - Beate Ritz
- Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
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11
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Myridakis A, Wen Q, Boshier PR, Parker AG, Belluomo I, Handakas E, Hanna GB. Global Urinary Volatolomics with (GC×)GC-TOF-MS. Anal Chem 2023; 95:17170-17176. [PMID: 37967208 PMCID: PMC10688225 DOI: 10.1021/acs.analchem.3c02523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 10/04/2023] [Accepted: 10/30/2023] [Indexed: 11/17/2023]
Abstract
Urinary volatolomics offers a noninvasive approach for disease detection and monitoring. Herein we present an improved methodology for global volatolomic profiling. Wide coverage was achieved by utilizing a multiphase sorbent for volatile organic compound (VOC) extraction. A single, midpolar column gas chromatography (GC) assay yielded substantially higher numbers of monitored VOCs compared to our previously reported single-sorbent method. Multidimensional GC (GC×GC) enhanced further biomarker discovery while data analysis was simplified by using a tile-based approach. At the same time, the required urine volume was reduced 5-fold from 2 to 0.4 mL. The applicability of the methodology was demonstrated in a pancreatic ductal adenocarcinoma cohort where previous findings were confirmed while a series of additional VOCs with diagnostic potential were discovered.
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Affiliation(s)
- Antonis Myridakis
- Department
of Surgery and Cancer, Imperial College
London, London W12 0HS, United
Kingdom
- Centre
for Pollution Research & Policy, Environmental Sciences, Brunel University, London UB8 3PH, United Kingdom
| | - Qing Wen
- Department
of Surgery and Cancer, Imperial College
London, London W12 0HS, United
Kingdom
- Department
of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Piers R. Boshier
- Department
of Surgery and Cancer, Imperial College
London, London W12 0HS, United
Kingdom
| | - Aaron G. Parker
- Department
of Surgery and Cancer, Imperial College
London, London W12 0HS, United
Kingdom
| | - Ilaria Belluomo
- Department
of Surgery and Cancer, Imperial College
London, London W12 0HS, United
Kingdom
| | - Evangelos Handakas
- Medical
Research Council Centre for Environment and Health, School of Public
Health, Imperial College London, London W12 0BZ, United Kingdom
| | - George B. Hanna
- Department
of Surgery and Cancer, Imperial College
London, London W12 0HS, United
Kingdom
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12
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Siracusano M, Arturi L, Riccioni A, Noto A, Mussap M, Mazzone L. Metabolomics: Perspectives on Clinical Employment in Autism Spectrum Disorder. Int J Mol Sci 2023; 24:13404. [PMID: 37686207 PMCID: PMC10487559 DOI: 10.3390/ijms241713404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/09/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Precision medicine is imminent, and metabolomics is one of the main actors on stage. We summarize and discuss the current literature on the clinical application of metabolomic techniques as a possible tool to improve early diagnosis of autism spectrum disorder (ASD), to define clinical phenotypes and to identify co-occurring medical conditions. A review of the current literature was carried out after PubMed, Medline and Google Scholar were consulted. A total of 37 articles published in the period 2010-2022 was included. Selected studies involve as a whole 2079 individuals diagnosed with ASD (1625 males, 394 females; mean age of 10, 9 years), 51 with other psychiatric comorbidities (developmental delays), 182 at-risk individuals (siblings, those with genetic conditions) and 1530 healthy controls (TD). Metabolomics, reflecting the interplay between genetics and environment, represents an innovative and promising technique to approach ASD. The metabotype may mirror the clinical heterogeneity of an autistic condition; several metabolites can be expressions of dysregulated metabolic pathways thus liable of leading to clinical profiles. However, the employment of metabolomic analyses in clinical practice is far from being introduced, which means there is a need for further studies for the full transition of metabolomics from clinical research to clinical diagnostic routine.
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Affiliation(s)
- Martina Siracusano
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Hospital, Viale Oxford 81, 00133 Rome, Italy; (L.A.); (A.R.); (L.M.)
| | - Lucrezia Arturi
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Hospital, Viale Oxford 81, 00133 Rome, Italy; (L.A.); (A.R.); (L.M.)
| | - Assia Riccioni
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Hospital, Viale Oxford 81, 00133 Rome, Italy; (L.A.); (A.R.); (L.M.)
| | - Antonio Noto
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, SS 554, Km 4.5, 09042 Monserrato, Italy
| | - Michele Mussap
- Department of Surgical Sciences, School of Medicine, University of Cagliari, Cittadella Universitaria, SS 554, Km 4.5, 09042 Monserrato, Italy
| | - Luigi Mazzone
- Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Hospital, Viale Oxford 81, 00133 Rome, Italy; (L.A.); (A.R.); (L.M.)
- Systems Medicine Department, University of Rome Tor Vergata, Montpellier Street 1, 00133 Rome, Italy
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13
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Shaw C, Hess M, Weimer BC. Microbial-Derived Tryptophan Metabolites and Their Role in Neurological Disease: Anthranilic Acid and Anthranilic Acid Derivatives. Microorganisms 2023; 11:1825. [PMID: 37512997 PMCID: PMC10384668 DOI: 10.3390/microorganisms11071825] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
The gut microbiome provides the host access to otherwise indigestible nutrients, which are often further metabolized by the microbiome into bioactive components. The gut microbiome can also shift the balance of host-produced compounds, which may alter host health. One precursor to bioactive metabolites is the essential aromatic amino acid tryptophan. Tryptophan is mostly shunted into the kynurenine pathway but is also the primary metabolite for serotonin production and the bacterial indole pathway. Balance between tryptophan-derived bioactive metabolites is crucial for neurological homeostasis and metabolic imbalance can trigger or exacerbate neurological diseases. Alzheimer's, depression, and schizophrenia have been linked to diverging levels of tryptophan-derived anthranilic, kynurenic, and quinolinic acid. Anthranilic acid from collective microbiome metabolism plays a complex but important role in systemic host health. Although anthranilic acid and its metabolic products are of great importance for host-microbe interaction in neurological health, literature examining the mechanistic relationships between microbial production, host regulation, and neurological diseases is scarce and at times conflicting. This narrative review provides an overview of the current understanding of anthranilic acid's role in neurological health and disease, with particular focus on the contribution of the gut microbiome, the gut-brain axis, and the involvement of the three major tryptophan pathways.
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Affiliation(s)
- Claire Shaw
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, University of California Davis, Davis, CA 95616, USA
- Department of Animal Science, College of Agricultural and Environmental Sciences, University of California Davis, Davis, CA 95616, USA
| | - Matthias Hess
- Department of Animal Science, College of Agricultural and Environmental Sciences, University of California Davis, Davis, CA 95616, USA
| | - Bart C Weimer
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, University of California Davis, Davis, CA 95616, USA
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14
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Sotelo-Orozco J, Schmidt RJ, Slupsky CM, Hertz-Picciotto I. Investigating the Urinary Metabolome in the First Year of Life and Its Association with Later Diagnosis of Autism Spectrum Disorder or Non-Typical Neurodevelopment in the MARBLES Study. Int J Mol Sci 2023; 24:9454. [PMID: 37298406 PMCID: PMC10254021 DOI: 10.3390/ijms24119454] [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] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/25/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Developmental disabilities are often associated with alterations in metabolism. However, it remains unknown how early these metabolic issues may arise. This study included a subset of children from the Markers of Autism Risks in Babies-Learning Early Signs (MARBLES) prospective cohort study. In this analysis, 109 urine samples collected at 3, 6, and/or 12 months of age from 70 children with a family history of ASD who went on to develop autism spectrum disorder (ASD n = 17), non-typical development (Non-TD n = 11), or typical development (TD n = 42) were investigated by nuclear magnetic resonance (NMR) spectroscopy to measure urinary metabolites. Multivariate principal component analysis and a generalized estimating equation were performed with the objective of exploring the associations between urinary metabolite levels in the first year of life and later adverse neurodevelopment. We found that children who were later diagnosed with ASD tended to have decreased urinary dimethylamine, guanidoacetate, hippurate, and serine, while children who were later diagnosed with Non-TD tended to have elevated urinary ethanolamine and hypoxanthine but lower methionine and homovanillate. Children later diagnosed with ASD or Non-TD both tended to have decreased urinary 3-aminoisobutyrate. Our results suggest subtle alterations in one-carbon metabolism, gut-microbial co-metabolism, and neurotransmitter precursors observed in the first year of life may be associated with later adverse neurodevelopment.
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Affiliation(s)
- Jennie Sotelo-Orozco
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA; (R.J.S.); (I.H.-P.)
| | - Rebecca J. Schmidt
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA; (R.J.S.); (I.H.-P.)
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
| | - Carolyn M. Slupsky
- Department of Nutrition, University of California, Davis, CA 95616, USA;
- Department of Food Science and Technology, University of California, Davis, CA 95616, USA
| | - Irva Hertz-Picciotto
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA; (R.J.S.); (I.H.-P.)
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
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15
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Osredkar J, Baškovič BŽ, Finderle P, Bobrowska-Korczak B, Gątarek P, Rosiak A, Giebułtowicz J, Vrhovšek MJ, Kałużna-Czaplińska J. Relationship between Excreted Uremic Toxins and Degree of Disorder of Children with ASD. Int J Mol Sci 2023; 24:7078. [PMID: 37108238 PMCID: PMC10138607 DOI: 10.3390/ijms24087078] [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: 03/10/2023] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Autism spectrum disorder (ASD) is a complex developmental disorder in which communication and behavior are affected. A number of studies have investigated potential biomarkers, including uremic toxins. The aim of our study was to determine uremic toxins in the urine of children with ASD (143) and compare the results with healthy children (48). Uremic toxins were determined with a validated high-performance liquid chromatography coupled to mass spectrometry (LC-MS/MS) method. We observed higher levels of p-cresyl sulphate (pCS) and indoxyl sulphate (IS) in the ASD group compared to the controls. Moreover, the toxin levels of trimethylamine N-oxide (TMAO), symmetric dimethylarginine (SDMA), and asymmetric dimethylarginine (ADMA) were lower in ASD patients. Similarly, for pCS and IS in children classified, according to the intensity of their symptoms, into mild, moderate, and severe, elevated levels of these compounds were observed. For mild severity of the disorder, elevated levels of TMAO and comparable levels of SDMA and ADMA for ASD children as compared to the controls were observed in the urine. For moderate severity of ASD, significantly elevated levels of TMAO but reduced levels of SDMA and ADMA were observed in the urine of ASD children as compared to the controls. When the results obtained for severe ASD severity were considered, reduced levels of TMAO and comparable levels of SDMA and ADMA were observed in ASD children.
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Affiliation(s)
- Joško Osredkar
- Institute of Clinical Chemistry and Biochemistry, University Medical Center Ljubljana, Njegoseva 4, 1000 Ljubljana, Slovenia; (B.Ž.B.); (P.F.)
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000 Ljubljana, Slovenia
| | - Barbara Žvar Baškovič
- Institute of Clinical Chemistry and Biochemistry, University Medical Center Ljubljana, Njegoseva 4, 1000 Ljubljana, Slovenia; (B.Ž.B.); (P.F.)
| | - Petra Finderle
- Institute of Clinical Chemistry and Biochemistry, University Medical Center Ljubljana, Njegoseva 4, 1000 Ljubljana, Slovenia; (B.Ž.B.); (P.F.)
| | - Barbara Bobrowska-Korczak
- Department of Toxicology and Food Science, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland;
| | - Paulina Gątarek
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland; (P.G.); (A.R.)
- CONEM Poland Chemistry and Nutrition Research Group, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
| | - Angelina Rosiak
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland; (P.G.); (A.R.)
- CONEM Poland Chemistry and Nutrition Research Group, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
| | - Joanna Giebułtowicz
- Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland;
| | - Maja Jekovec Vrhovšek
- Center for Autism, Unit of Child Psychiatry, University Children’s Hospital, University Medical Centre Ljubljana, Zaloška c.002, 1000 Ljubljana, Slovenia;
| | - Joanna Kałużna-Czaplińska
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland; (P.G.); (A.R.)
- CONEM Poland Chemistry and Nutrition Research Group, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
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16
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Zhang Y, Chen R, Zhang D, Qi S, Liu Y. Metabolite interactions between host and microbiota during health and disease: Which feeds the other? Biomed Pharmacother 2023; 160:114295. [PMID: 36709600 DOI: 10.1016/j.biopha.2023.114295] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/20/2023] [Accepted: 01/20/2023] [Indexed: 01/30/2023] Open
Abstract
Metabolites produced by the host and microbiota play a crucial role in how human bodies develop and remain healthy. Most of these metabolites are produced by microbiota and hosts in the digestive tract. Metabolites in the gut have important roles in energy metabolism, cellular communication, and host immunity, among other physiological activities. Although numerous host metabolites, such as free fatty acids, amino acids, and vitamins, are found in the intestine, metabolites generated by gut microbiota are equally vital for intestinal homeostasis. Furthermore, microbiota in the gut is the sole source of some metabolites, including short-chain fatty acids (SCFAs). Metabolites produced by microbiota, such as neurotransmitters and hormones, may modulate and significantly affect host metabolism. The gut microbiota is becoming recognized as a second endocrine system. A variety of chronic inflammatory disorders have been linked to aberrant host-microbiota interplays, but the precise mechanisms underpinning these disturbances and how they might lead to diseases remain to be fully elucidated. Microbiome-modulated metabolites are promising targets for new drug discovery due to their endocrine function in various complex disorders. In humans, metabolotherapy for the prevention or treatment of various disorders will be possible if we better understand the metabolic preferences of bacteria and the host in specific tissues and organs. Better disease treatments may be possible with the help of novel complementary therapies that target host or bacterial metabolism. The metabolites, their physiological consequences, and functional mechanisms of the host-microbiota interplays will be highlighted, summarized, and discussed in this overview.
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Affiliation(s)
- Yan Zhang
- Department of Anethesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - Rui Chen
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - DuoDuo Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.
| | - Shuang Qi
- Department of Anethesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - Yan Liu
- Department of Hand and Foot Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
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17
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Kim JK, Hong S, Park J, Kim S. Metabolic and Transcriptomic Changes in the Mouse Brain in Response to Short-Term High-Fat Metabolic Stress. Metabolites 2023; 13:metabo13030407. [PMID: 36984847 PMCID: PMC10051449 DOI: 10.3390/metabo13030407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/07/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
The chronic consumption of diets rich in saturated fats leads to obesity and associated metabolic disorders including diabetes and atherosclerosis. Intake of a high-fat diet (HFD) is also recognized to dysregulate neural functions such as cognition, mood, and behavior. However, the effects of short-term high-fat diets on the brain are elusive. Here, we investigated molecular changes in the mouse brain following an acute HFD for 10 days by employing RNA sequencing and metabolomics profiling. Aberrant expressions of 92 genes were detected in the brain tissues of acute HFD-exposed mice. The differentially expressed genes were enriched for various pathways and processes such as superoxide metabolism. In our global metabolomic profiling, a total of 59 metabolites were significantly altered by the acute HFD. Metabolic pathways upregulated from HFD-exposed brain tissues relative to control samples included oxidative stress, oxidized polyunsaturated fatty acids, amino acid metabolism (e.g., branched-chain amino acid catabolism, and lysine metabolism), and the gut microbiome. Acute HFD also elevated levels of N-acetylated amino acids, urea cycle metabolites, and uracil metabolites, further suggesting complex changes in nitrogen metabolism. The observed molecular events in the present study provide a valuable resource that can help us better understand how acute HFD stress impacts brain homeostasis.
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Affiliation(s)
- Ji-Kwang Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Sehoon Hong
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Jina Park
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Seyun Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
- KAIST Institute for the BioCentury, KAIST, Daejeon 34141, Republic of Korea
- KAIST Stem Cell Center, KAIST, Daejeon 34141, Republic of Korea
- Correspondence:
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18
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The interaction between intestinal bacterial metabolites and phosphatase and tensin homolog in autism spectrum disorder. Mol Cell Neurosci 2023; 124:103805. [PMID: 36592799 DOI: 10.1016/j.mcn.2022.103805] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/17/2022] [Accepted: 12/24/2022] [Indexed: 01/01/2023] Open
Abstract
Intestinal bacteria-associated para-cresyl sulfate (pCS) and 4-ethylphenyl sulfate (4EPS) are elevated in autism spectrum disorder (ASD). Both metabolites can induce ASD-like behaviors in mice, but the molecular mechanisms are not known. Phosphatase and tensin homolog (PTEN) is a susceptibility gene for ASD. The present study investigated the relation between pCS and 4EPS and PTEN in ASD in a valproic acid (VPA)-induced murine ASD model and an in vitro LPS-activated microglial model. The VPA-induced intestinal inflammation and compromised permeability in the distal ileum was not associated with changes of PTEN expression and phosphorylation. In contrast, VPA reduced PTEN expression in the hippocampus of mice. In vitro results show that pCS and 4EPS reduced PTEN expression and derailed innate immune response of BV2 microglial cells. The PTEN inhibitor VO-OHpic did not affect innate immune response of microglial cells. In conclusion, PTEN does not play a role in intestinal inflammation and compromised permeability in VPA-induced murine model for ASD. Although pCS and 4EPS reduced PTEN expression in microglial cells, PTEN is not involved in the pCS and 4EPS-induced derailed innate immune response of microglial cells. Further studies are needed to investigate the possible involvement of reduced PTEN expression in the ASD brain regarding synapse function and neuronal connectivity.
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19
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Gupta R, Raghuvanshi S. Human Microbiome and Autism-Spectrum Disorders. PROBIOTICS, PREBIOTICS, SYNBIOTICS, AND POSTBIOTICS 2023:347-360. [DOI: 10.1007/978-981-99-1463-0_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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An Updated Systematic Review and Meta-Analysis on the Effects of Probiotics, Prebiotics and Synbiotics in Autism Spectrum Disorder. REVIEW JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS 2022. [DOI: 10.1007/s40489-022-00348-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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21
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Timperio AM, Gevi F, Cucinotta F, Ricciardello A, Turriziani L, Scattoni ML, Persico AM. Urinary Untargeted Metabolic Profile Differentiates Children with Autism from Their Unaffected Siblings. Metabolites 2022; 12:metabo12090797. [PMID: 36144201 PMCID: PMC9503174 DOI: 10.3390/metabo12090797] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/16/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Autism Spectrum Disorder (ASD) encompasses a clinical spectrum of neurodevelopmental conditions that display significant heterogeneity in etiology, symptomatology, and severity. We previously compared 30 young children with idiopathic ASD and 30 unrelated typically-developing controls, detecting an imbalance in several compounds belonging mainly to the metabolism of purines, tryptophan and other amino acids, as well as compounds derived from the intestinal flora, and reduced levels of vitamins B6, B12 and folic acid. The present study describes significant urinary metabolomic differences within 14 pairs, including one child with idiopathic ASD and his/her typically-developing sibling, tightly matched by sex and age to minimize confounding factors, allowing a more reliable identification of the metabolic fingerprint related to ASD. By using a highly sensitive, accurate and unbiased approach, suitable for ensuring broad metabolite detection coverage on human urine, and by applying multivariate statistical analysis, we largely replicate our previous results, demonstrating a significant perturbation of the purine and tryptophan pathways, and further highlight abnormalities in the “phenylalanine, tyrosine and tryptophan” pathway, essentially involving increased phenylalanine and decreased tyrosine levels, as well as enhanced concentrations of bacterial degradation products, including phenylpyruvic acid, phenylacetic acid and 4-ethylphenyl-sulfate. The outcome of these within-family contrasts consolidates and extends our previous results obtained from unrelated individuals, adding further evidence that these metabolic imbalances may be linked to ASD rather than to environmental differences between cases and controls. It further underscores the excess of some gut microbiota-derived compounds in ASD, which could have diagnostic value in a network model differentiating the metabolome of autistic and unaffected siblings. Finally, it points toward the existence of a “metabolic autism spectrum” distributed as an endophenotype, with unaffected siblings possibly displaying a metabolic profile intermediate between their autistic siblings and unrelated typically-developing controls.
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Affiliation(s)
- Anna Maria Timperio
- Department of Ecological and Biological Sciences, University of Tuscia, 01100 Viterbo, Italy
- Correspondence: (A.M.T.); (A.M.P.)
| | - Federica Gevi
- Department of Ecological and Biological Sciences, University of Tuscia, 01100 Viterbo, Italy
| | - Francesca Cucinotta
- Interdepartmental Program “Autism 0-90”, “G. Martino” University Hospital, 98124 Messina, Italy
- IRCCS Centro Neurolesi “Bonino-Pulejo”, 98124 Messina, Italy
| | - Arianna Ricciardello
- Interdepartmental Program “Autism 0-90”, “G. Martino” University Hospital, 98124 Messina, Italy
- Villa Miralago, 21050 Cuasso al Monte, Italy
| | - Laura Turriziani
- Interdepartmental Program “Autism 0-90”, “G. Martino” University Hospital, 98124 Messina, Italy
| | - Maria Luisa Scattoni
- Research Coordination and Support Service, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Antonio M. Persico
- Child & Adolescent Neuropsychiatry Program, Modena University Hospital & Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
- Correspondence: (A.M.T.); (A.M.P.)
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22
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A combination of amino-functionalized fibrous silica (KCC-1-NH2)/effectively and efficiently oxidized graphene oxide (EEGO) nanocomposite for dispersive solid-phase extraction, pre-concentration and fluorescence determination of total para-cresol in plasma samples of chronic kidney disease patients. J Pharm Biomed Anal 2022; 214:114746. [DOI: 10.1016/j.jpba.2022.114746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 11/19/2022]
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23
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Guzmán Salas S, Weber A, Malci A, Lin X, Herrera-Molina R, Cerpa W, Dorador C, Signorelli J, Zamorano P. The metabolite p-cresol impairs dendritic development, synaptogenesis and synapse function in hippocampal neurons: Implications for autism spectrum disorder. J Neurochem 2022; 161:335-349. [PMID: 35257373 DOI: 10.1111/jnc.15604] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 02/21/2022] [Accepted: 03/01/2022] [Indexed: 11/29/2022]
Abstract
Autism spectrum disorder (ASD) is a heterogenous neurodevelopment disorder resulting from different etiological factors, both genetic and/or environmental. These factors can lead to abnormal neuronal development on dendrite and synaptic function at the central nervous system. Recent studies have shown that a subset of ASD patients display increased circulation levels of the tyrosine metabolite, p-cresol, related to chronic intestinal disorders due to dysbiosis of the intestinal microbiota. In particular, abnormal presence of intestinal Clostridium sp. has been linked to high levels of p-cresol in ASD children younger than 8 years. However, the role of p-cresol during development of the central nervous system is unknown. Here, we evaluated in vitro the effect of p-cresol on neurite outgrowth in N2a and PC12 cell lines and dendritic morphology, synaptic density, neuronal activity, and calcium responses in primary rat hippocampal neurons. p-cresol inhibits neural differentiation and neurites outgrowth in N2a and PC12 neuronal cell lines. In hippocampal neuronal cultures, Sholl´s analysis shows a decrease in the dendritic arborization of neurons treated with p-cresol. Synaptic density analyzed with the synaptic markers Piccolo and Shank2 is diminished in hippocampal neurons treated with p-cresol. Electrically-evoked intracellular calcium rise was drastically, but reversely, blocked by p-cresol, whereas that spontaneous neuronal activity was severely affected by early addition of the metabolite. These findings show that p-cresol alters dendrite development, synaptogenesis and synapse function of neurons in culture, therefore, neuronal alterations occurring in ASD children may be related to this metabolite and dysbiosis of the intestinal microbiota.
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Affiliation(s)
- Sheyla Guzmán Salas
- Departamento Biomédico, Universidad de Antofagasta, Antofagasta, Chile.,Centre for Biotechnology and Bioengineering CeBiB, Antofagasta
| | - André Weber
- Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Ayse Malci
- Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Xiao Lin
- Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Rodrigo Herrera-Molina
- Leibniz Institute for Neurobiology, Magdeburg, Germany.,Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O'Higgins, Santiago, Chile.,Center for Behavioral Brain Sciences and Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - Waldo Cerpa
- Laboratorio de Función y Patología Neuronal; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile.,Centro de Excelencia en Biomedicina de Magallanes (CEBIMA); Universidad de Magallanes, Punta Arenas, Chile.,Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Cristina Dorador
- Centre for Biotechnology and Bioengineering CeBiB, Antofagasta.,Instituto Antofagasta, Universidad de Antofagasta, Antofagasta, Chile
| | | | - Pedro Zamorano
- Departamento Biomédico, Universidad de Antofagasta, Antofagasta, Chile.,Instituto Antofagasta, Universidad de Antofagasta, Antofagasta, Chile
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24
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Duarte-Silva E, Oriá AC, Mendonça IP, de Melo MG, Paiva IHR, Maes M, Joca SRL, Peixoto CA. TINY IN SIZE, BIG IN IMPACT: EXTRACELLULAR VESICLES AS MODULATORS OF MOOD, ANXIETY AND NEURODEVELOPMENTAL DISORDERS. Neurosci Biobehav Rev 2022; 135:104582. [PMID: 35182538 DOI: 10.1016/j.neubiorev.2022.104582] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 01/17/2022] [Accepted: 02/12/2022] [Indexed: 12/13/2022]
Abstract
Extracellular Vesicles (EVs) are tiny vesicles used by cells as means of cellular communication, through which the function and state of a given cell can be changed. A body of evidence has suggested that EVs could be culprits in the development and progression of various types of diseases, including neurodegenerative diseases such as Multiple Sclerosis (MS) and Alzheimer's Disease (AD). Unsurprisingly, EVs have also been implicate in mood, anxiety and neurodevelopmental disorders, such as Major Depressive Disorder (MDD), anxiety disorder and Autism-Spectrum Disorder (ASD), respectively. Here, we review the state-of-art regarding the roles of EVs in the aforementioned diseases and focus on the mechanisms by which they can cause and worsen disease. Harnessing the knowledge of EVs is not only important to deliver different cargos to cells in a specific manner to treat these diseases, but also to establish reliable disease biomarkers, which will aid in the early disease diagnosis and treatment, increasing the chance of successful treatment.
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Affiliation(s)
- Eduardo Duarte-Silva
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil; Postgraduate Program in Biosciences and Biotechnology for Health (PPGBBS), Oswaldo Cruz Foundation (FIOCRUZ-PE)/Aggeu Magalhães Institute (IAM), Recife, PE, Brazil; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Recife, PE, Brazil; Department of Neurology, Medical Faculty, University Hospital Düsseldorf, 40255 Düsseldorf, Germany.
| | | | - Ingrid Prata Mendonça
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Michel Gomes de Melo
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Igor Henrique R Paiva
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria; IMPACT Strategic Research Center, Deakin University, Geelong, Australia
| | - Sâmia R L Joca
- School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Ribeirão Preto, Brazil; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Christina Alves Peixoto
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil; National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM, CNPq), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
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25
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Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial. Nat Med 2022; 28:528-534. [DOI: 10.1038/s41591-022-01683-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023]
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26
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Needham BD, Funabashi M, Adame MD, Wang Z, Boktor JC, Haney J, Wu WL, Rabut C, Ladinsky MS, Hwang SJ, Guo Y, Zhu Q, Griffiths JA, Knight R, Bjorkman PJ, Shapiro MG, Geschwind DH, Holschneider DP, Fischbach MA, Mazmanian SK. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature 2022; 602:647-653. [PMID: 35165440 PMCID: PMC9170029 DOI: 10.1038/s41586-022-04396-8] [Citation(s) in RCA: 227] [Impact Index Per Article: 75.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 01/02/2022] [Indexed: 12/14/2022]
Abstract
Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. The mechanisms that mediate the gut-brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes7,9-14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.
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Affiliation(s)
- Brittany D Needham
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
| | - Masanori Funabashi
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA, USA
- Translational Research Department, Daiichi Sankyo RD Novare Co Ltd, Tokyo, Japan
| | - Mark D Adame
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Zhuo Wang
- Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Joseph C Boktor
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Jillian Haney
- Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA
| | - Wei-Li Wu
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Claire Rabut
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Mark S Ladinsky
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Son-Jong Hwang
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Yumei Guo
- Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Qiyun Zhu
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | - Jessica A Griffiths
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
| | - Pamela J Bjorkman
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Mikhail G Shapiro
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Daniel H Geschwind
- Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA
| | - Daniel P Holschneider
- Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Viterbi School of Engineering, Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Michael A Fischbach
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA, USA
| | - Sarkis K Mazmanian
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
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27
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Alharthi A, Alhazmi S, Alburae N, Bahieldin A. The Human Gut Microbiome as a Potential Factor in Autism Spectrum Disorder. Int J Mol Sci 2022; 23:ijms23031363. [PMID: 35163286 PMCID: PMC8835713 DOI: 10.3390/ijms23031363] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/18/2022] [Accepted: 01/24/2022] [Indexed: 11/16/2022] Open
Abstract
The high prevalence of gastrointestinal (GI) disorders among autism spectrum disorder (ASD) patients has prompted scientists to look into the gut microbiota as a putative trigger in ASD pathogenesis. Thus, many studies have linked the gut microbial dysbiosis that is frequently observed in ASD patients with the modulation of brain function and social behavior, but little is known about this connection and its contribution to the etiology of ASD. This present review highlights the potential role of the microbiota–gut–brain axis in autism. In particular, it focuses on how gut microbiota dysbiosis may impact gut permeability, immune function, and the microbial metabolites in autistic people. We further discuss recent findings supporting the possible role of the gut microbiome in initiating epigenetic modifications and consider the potential role of this pathway in influencing the severity of ASD. Lastly, we summarize recent updates in microbiota-targeted therapies such as probiotics, prebiotics, dietary supplements, fecal microbiota transplantation, and microbiota transfer therapy. The findings of this paper reveal new insights into possible therapeutic interventions that may be used to reduce and cure ASD-related symptoms. However, well-designed research studies using large sample sizes are still required in this area of study.
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Affiliation(s)
- Amani Alharthi
- Department of Biology, Faculty of Science, Majmaah University, Al Zulfi 11932, Saudi Arabia
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.)
- Correspondence: (A.A.); (A.B.)
| | - Safiah Alhazmi
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.)
| | - Najla Alburae
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.)
| | - Ahmed Bahieldin
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.A.); (N.A.)
- Correspondence: (A.A.); (A.B.)
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28
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Alteration of the Intestinal Permeability Are Reflected by Changes in the Urine Metabolome of Young Autistic Children: Preliminary Results. Metabolites 2022; 12:metabo12020104. [PMID: 35208179 PMCID: PMC8875518 DOI: 10.3390/metabo12020104] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 12/11/2022] Open
Abstract
Several metabolomics-based studies have provided evidence that autistic subjects might share metabolic abnormalities with gut microbiota dysbiosis and alterations in gut mucosal permeability. Our aims were to explore the most relevant metabolic perturbations in a group of autistic children, compared with their healthy siblings, and to investigate whether the increased intestinal permeability may be mirrored by specific metabolic perturbations. We enrolled 13 autistic children and 14 unaffected siblings aged 2–12 years; the evaluation of the intestinal permeability was estimated by the lactulose:mannitol test. The urine metabolome was investigated by proton nuclear magnetic resonance (1H-NMR) spectroscopy. The lactulose:mannitol test unveiled two autistic children with altered intestinal permeability. Nine metabolites significantly discriminated the urine metabolome of autistic children from that of their unaffected siblings; however, in the autistic children with increased permeability, four additional metabolites—namely, fucose, phenylacetylglycine, nicotinurate, and 1-methyl-nicotinamide, strongly discriminated their urine metabolome from that of the remaining autistic children. Our preliminary data suggest the presence of a specific urine metabolic profile associated with the increase in intestinal permeability.
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29
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Lin X, Zhou R, Liang D, Xia L, Zeng L, Chen X. The role of microbiota in autism spectrum disorder: A bibliometric analysis based on original articles. Front Psychiatry 2022; 13:976827. [PMID: 36172516 PMCID: PMC9512137 DOI: 10.3389/fpsyt.2022.976827] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/22/2022] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Gastrointestinal (GI) symptoms can be observed in autism spectrum disorder (ASD) children. It is suggested that the gut microbiota and its metabolites are associated, not only with GI symptoms, but also with behaviors of ASD. The aim of this study was to explore the development context, research hotspots and frontiers of gut microbiota and ASD from January 1, 1980 to April 1, 2022 by bibliometric analysis. MATERIALS AND METHODS Publications of ASD and gut microbiota research from 1 January 1980 to 1 April 2022 were retrieved from the Web of Science Core Collection (WoSCC). Publications and citations trends were analyzed by Excel 2010. CiteSpace was used to analyze countries/regions, authors, institutes, references, and keywords and to visualize the knowledge map. RESULTS A total of 1027 studies were retrieved, and 266 original articles were included after screening. The most published countries and institutes were the United States and King Saud University. Afaf El-Aansary published the most articles, while Finegold SM had the highest co-citations. Hotspots and emerging trends in this area may be indicated by co-cited references and keywords and their clusters, including "gut-brain axis," "behavior," "chain fatty acid," "brain," "feces," "propionic acid," "clostridium perfringens," and "species clostridium innocuum." CONCLUSION The United States dominants the research in this field, which focuses on the alterations of gut microbiota composition and its metabolites, among which the roles of the genus Clostridium and metabolites of short-chain fatty acids, especially propionic acid, are priorities. Fecal microbiota transplantation (FMT) is a promising complementary therapy. In general, research in this area is sparse, but it still has great research prospects.
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Affiliation(s)
- Xiaoling Lin
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Runjin Zhou
- Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dandan Liang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lingling Xia
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liying Zeng
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaogang Chen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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30
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He X, Tu Y, Song Y, Yang G, You M. The relationship between pesticide exposure during critical neurodevelopment and autism spectrum disorder: A narrative review. ENVIRONMENTAL RESEARCH 2022; 203:111902. [PMID: 34416252 DOI: 10.1016/j.envres.2021.111902] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 06/13/2023]
Abstract
Agricultural pesticides have been one of the most extensively used compounds throughout the world. The main sources of contamination for humans are dietary intake and occupational exposure. The impairments caused by agricultural pesticide exposure have been a significant global public health problem. Recent studies have shown that low-level agricultural pesticide exposure during the critical period of neurodevelopment (pregnancy and lactation) is closely related to autism spectrum disorder (ASD). Inhibition of acetylcholinesterase, gut microbiota, neural dendrite morphology, synaptic function, and glial cells are targets for the effects of pesticides during nervous system development. In the present review, we summarize the associations between several highly used and frequently studied pesticides (e.g., glyphosate, chlorpyrifos, pyrethroids, and avermectins) and ASD. We also discusse future epidemiological and toxicological research directions on the relationship between pesticides and ASD.
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Affiliation(s)
- Xiu He
- School of Public Heath, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Ying Tu
- School of Public Heath, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Yawen Song
- School of Public Heath, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Guanghong Yang
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang, Guizhou, 550004, PR China.
| | - Mingdan You
- School of Public Heath, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China.
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31
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Turriziani L, Ricciardello A, Cucinotta F, Bellomo F, Turturo G, Boncoddo M, Mirabelli S, Scattoni ML, Rossi M, Persico AM. Gut mobilization improves behavioral symptoms and modulates urinary p-cresol in chronically constipated autistic children: A prospective study. Autism Res 2022; 15:56-69. [PMID: 34813183 PMCID: PMC9299106 DOI: 10.1002/aur.2639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 10/23/2021] [Accepted: 10/30/2021] [Indexed: 12/28/2022]
Abstract
Chronic constipation is common among children with ASD and is associated with more severe hyperactivity, anxiety, irritability, and repetitive behaviors. Young autistic children with chronic constipation display higher urinary, and foecal concentrations of p-cresol, an aromatic compound produced by gut bacteria, known to negatively affect brain function. Acute p-cresol administration to BTBR mice enhances anxiety, hyperactivity and stereotypic behaviors, while blunting social interaction. This study was undertaken to prospectively assess the behavioral effects of gut mobilization in young autistic children with chronic constipation, and to verify their possible correlation with urinary p-cresol. To this aim, 21 chronically constipated autistic children 2-8 years old were evaluated before (T0), 1 month (T1), and 6 months (T2) after intestinal mobilization, recording Bristol stool scale scores, urinary p-cresol concentrations, and behavioral scores for social interaction deficits, stereotypic behaviors, anxiety, and hyperactivity. Gut mobilization yielded a progressive and highly significant decrease in all behavioral symptoms over the 6-month study period. Urinary p-cresol levels displayed variable trends not significantly correlated with changes in behavioral parameters, mainly increasing at T1 and decreasing at T2. These results support gut mobilization as a simple strategy to ameliorate ASD symptoms, as well as comorbid anxiety and hyperactivity, in chronically constipated children. Variation in p-cresol absorption seemingly provides limited contributions, if any, to these behavioral changes. Further research will be needed to address the relative role of reduced abdominal discomfort following mobilization, as compared to specific modifications in microbiome composition and in gut bacteria-derived neuroactive compounds.
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Affiliation(s)
- Laura Turriziani
- Interdepartmental Program "Autism 0‐90""G. Martino" University Hospital of MessinaMessinaItaly
| | - Arianna Ricciardello
- Interdepartmental Program "Autism 0‐90""G. Martino" University Hospital of MessinaMessinaItaly
| | - Francesca Cucinotta
- Interdepartmental Program "Autism 0‐90""G. Martino" University Hospital of MessinaMessinaItaly
- IRCCS Centro Neurolesi "Bonino‐Pulejo"MessinaItaly
| | - Fabiana Bellomo
- Interdepartmental Program "Autism 0‐90""G. Martino" University Hospital of MessinaMessinaItaly
| | - Giada Turturo
- Interdepartmental Program "Autism 0‐90""G. Martino" University Hospital of MessinaMessinaItaly
| | - Maria Boncoddo
- Interdepartmental Program "Autism 0‐90""G. Martino" University Hospital of MessinaMessinaItaly
| | - Silvestro Mirabelli
- Interdepartmental Program "Autism 0‐90""G. Martino" University Hospital of MessinaMessinaItaly
| | - Maria Luisa Scattoni
- Research Coordination and Support Service, Istituto Superiore di SanitàRomeItaly
| | - Maddalena Rossi
- Department of Life Sciences & BIOGEST‐SITEIAUniversity of Modena and Reggio EmiliaModenaItaly
| | - Antonio M. Persico
- Child & Adolescent Neuropsychiatry Program, Modena University Hospital, & Department of Biomedical, Metabolic and Neural SciencesUniversity of Modena and Reggio EmiliaModenaItaly
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32
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Tu T, Zhao C. Treating autism spectrum disorder by intervening with gut microbiota. J Med Microbiol 2021; 70. [PMID: 34898421 DOI: 10.1099/jmm.0.001469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders with a high prevalence in childhood. The gut microbiota can affect human cognition and moods and has a strong correlation with ASD. Microbiota transplantation, including faecal microbiota transplantation (FMT), probiotics, breastfeeding, formula feeding, gluten-free and casein-free (GFCF) diet and ketogenic diet therapy, may provide satisfying effects for ASD and its related various symptoms. For instance, FMT can improve the core symptoms of ASD and gastrointestinal symptoms. Probiotics, breastfeeding and formula feeding, and GFCF diet can improve gastrointestinal symptoms. The core symptom score still needs to be confirmed by large-scale clinical randomized controlled studies. It is recommended to use a ketogenic diet to treat patients with epilepsy in ASD. At present, the unresolved problems include which of gut the microbiota are beneficial, which of the microorganisms are harmful, how to safely and effectively implant beneficial bacteria into the human body, and how to extract and eliminate harmful microorganisms before transplantation. In future studies, large sample and randomized controlled clinical studies are needed to confirm the mechanism of intestinal microorganisms in the treatment of ASD and the method of microbial transplantation.
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Affiliation(s)
- Tingting Tu
- Department of Rehabilitation Treatment, Health Science College, Guangdong Pharmaceutical University, Guangzhou 51006, PR China
| | - Changlin Zhao
- Department of Rehabilitation Treatment, Health Science College, Guangdong Pharmaceutical University, Guangzhou 51006, PR China
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Sudo N. Possible role of the gut microbiota in the pathogenesis of anorexia nervosa. Biopsychosoc Med 2021; 15:25. [PMID: 34844634 PMCID: PMC8630889 DOI: 10.1186/s13030-021-00228-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022] Open
Abstract
Anorexia nervosa (AN), an eating disorder, is characterized by extreme weight loss and fear of weight gain. Psychosocial factors are thought to play important roles in the development and progression of AN; however, biological factors also presumably contribute to eating disorders. Recent evidence has shown that the gut microbiota plays an important role in pathogenesis of neuropsychiatric disorders including AN. In this article, we describe the possible role of the gut microbiota in the development and persistence of AN, based on the latest research works, including those of our group.
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Affiliation(s)
- Nobuyuki Sudo
- Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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Zheng Y, Bek MK, Prince NZ, Peralta Marzal LN, Garssen J, Perez Pardo P, Kraneveld AD. The Role of Bacterial-Derived Aromatic Amino Acids Metabolites Relevant in Autism Spectrum Disorders: A Comprehensive Review. Front Neurosci 2021; 15:738220. [PMID: 34744609 PMCID: PMC8568365 DOI: 10.3389/fnins.2021.738220] [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: 07/08/2021] [Accepted: 09/30/2021] [Indexed: 12/27/2022] Open
Abstract
In recent years, the idea of the gut microbiota being involved in the pathogenesis of autism spectrum disorders (ASD) has attracted attention through numerous studies. Many of these studies report microbial dysregulation in the gut and feces of autistic patients and in ASD animal models. The host microbiota plays a large role in metabolism of ingested foods, and through the production of a range of metabolites it may be involved in neurodevelopmental disorders such as ASD. Two specific microbiota-derived host metabolites, p-cresol sulfate and 4-ethylphenyl sulfate, have been associated with ASD in both patients and animal models. These metabolites originate from bacterially produced p-cresol and 4-ethylphenol, respectively. p-Cresol and 4-ethylphenol are produced through aromatic amino acid fermentation by a range of commensal bacteria, most notably bacteria from the Clostridioides genus, which are among the dysregulated bacteria frequently detected in ASD patients. Once produced, these metabolites are suggested to enter the bloodstream, pass the blood–brain-barrier and affect microglial cells in the central nervous system, possibly affecting processes like neuroinflammation and microglial phagocytosis. This review describes the current knowledge of microbial dysbiosis in ASD and elaborates on the relevance and synthesis pathways of two specific ASD-associated metabolites that may form a link between the microbiota and the brain in autism. While the two discussed metabolites are promising candidates for biomarkers and (nutritional) intervention targets, more research into the role of these metabolites in ASD is required to causally connect these metabolites to ASD pathophysiology.
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Affiliation(s)
- Yuanpeng Zheng
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Marie K Bek
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Naika Z Prince
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Lucia N Peralta Marzal
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.,Global Centre of Excellence Immunology, Danone Nutricia Research, Utrecht, Netherlands
| | - Paula Perez Pardo
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Aletta D Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
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Moradi M, Soleymani J, Tayebi-Khosroshahi H, Khoubnasabjafari M, Jouyban A. Simple Determination of p-Cresol in Plasma Samples Using Fluorescence Spectroscopy Technique. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:68-78. [PMID: 34567147 PMCID: PMC8457733 DOI: 10.22037/ijpr.2020.114330.14799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The development of simple, fast, cheap and reliable analytical methods for tracing biological indicators is demanded through clinical investigations. Herein, we developed, for the first time, a cheap and specific method for the extraction and quantification of p-cresol (pC) in real plasma samples of chronic kidney disease (CKD). Plasma samples were prepared by hydrolyzing in an acidic medium to convert pCS (p-cresol sulfate) and p-Cresol glucuronide (pCG) to pC. Next, proteins of plasma samples were precipitated and then pC was extracted by acetonitrile (ACN) and saturated NaCl (as salting-out agent). Finally, fluorescence emissions were measured at λex/λem = 280/310 nm. The specificity of the method was checked by testing various possible interfering agents. The obtained results revealed a specific determination of pC. Under optimal conditions, a linear range was detected from 0.5 to 30 µg/mL of pC with a lower limit of detection (LLOQ) of 0.5 µg/mL. The reliability of the method was checked by calculating the repeatability, selectivity, and accuracy of the developed method for pC determination in plasma samples. The application of the developed method was investigated for the detection of pC in a number of CKD patients. Due to the simplicity and selectivity, the developed method could be applied for routine analysis of pC concentrations in the plasma samples of CKD patients. In addition, the developed method showed great potential for developing a point-of-care testing (POCT) device.
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Affiliation(s)
- Milad Moradi
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Soleymani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Tayebi-Khosroshahi
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Khoubnasabjafari
- Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolghasem Jouyban
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Kimia Idea Pardaz Azarbayjan (KIPA) Science-Based Company, Tabriz University of Medical Sciences, Tabriz, Iran
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36
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Peralta-Marzal LN, Prince N, Bajic D, Roussin L, Naudon L, Rabot S, Garssen J, Kraneveld AD, Perez-Pardo P. The Impact of Gut Microbiota-Derived Metabolites in Autism Spectrum Disorders. Int J Mol Sci 2021; 22:10052. [PMID: 34576216 PMCID: PMC8470471 DOI: 10.3390/ijms221810052] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders characterised by behavioural impairment and deficiencies in social interaction and communication. A recent study estimated that 1 in 89 children have developed some form of ASD in European countries. Moreover, there is no specific treatment and since ASD is not a single clinical entity, the identification of molecular biomarkers for diagnosis remains challenging. Besides behavioural deficiencies, individuals with ASD often develop comorbid medical conditions including intestinal problems, which may reflect aberrations in the bidirectional communication between the brain and the gut. The impact of faecal microbial composition in brain development and behavioural functions has been repeatedly linked to ASD, as well as changes in the metabolic profile of individuals affected by ASD. Since metabolism is one of the major drivers of microbiome-host interactions, this review aims to report emerging literature showing shifts in gut microbiota metabolic function in ASD. Additionally, we discuss how these changes may be involved in and/or perpetuate ASD pathology. These valuable insights can help us to better comprehend ASD pathogenesis and may provide relevant biomarkers for improving diagnosis and identifying new therapeutic targets.
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Affiliation(s)
- Lucía N. Peralta-Marzal
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
| | - Naika Prince
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
| | - Djordje Bajic
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA;
- Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA
| | - Léa Roussin
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; (L.R.); (S.R.)
| | - Laurent Naudon
- CNRS, Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France;
| | - Sylvie Rabot
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; (L.R.); (S.R.)
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands
| | - Aletta D. Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
| | - Paula Perez-Pardo
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
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Blachier F, Andriamihaja M. Effects of the L-tyrosine-derived bacterial metabolite p-cresol on colonic and peripheral cells. Amino Acids 2021; 54:325-338. [PMID: 34468872 DOI: 10.1007/s00726-021-03064-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 08/06/2021] [Indexed: 11/28/2022]
Abstract
Specific families of bacteria present within the intestinal luminal content produce p-cresol from L-tyrosine. Although the hosts do not synthesize p-cresol, they can metabolize this compound within their colonic mucosa and liver leading to the production of co-metabolites including p-cresyl sulfate (p-CS) and p-cresyl glucuronide (p-CG). p-Cresol and its co-metabolites are recovered in the circulation mainly conjugated to albumin, but also in their free forms that are excreted in the urine. An increased dietary protein intake raises the amount of p-cresol recovered in the feces and urine, while fecal excretion of p-cresol is diminished by a diet containing undigestible polysaccharides. p-Cresol in excess is genotoxic for colonocytes. In addition, in these cells, this bacterial metabolite decreases mitochondrial oxygen consumption, while increasing the anion superoxide production. In chronic kidney disease (CKD), marked accumulation of p-cresol and p-CS in plasma is measured, and in renal tubular cells, p-cresol and p-CS increase oxidative stress, affect mitochondrial function, and lead to cell death, strongly suggesting that these 2 compounds act as uremic toxins that aggravate CKD progression. p-Cresol and p-CS are also suspected to play a role in the CKD-associated adverse cardiovascular events, since they affect endothelial cell proliferation and migration, decrease the capacity of endothelial wound repair, and increase the senescence of endothelial cells. Finally, the fact that concentration of p-cresol is transiently increased in young autistic children biological fluids, and that intraperitoneal injection of p-cresol in animal models induces some behavioral characteristics observed in the autism spectrum disorders (ASD), raise the view that p-cresol may possibly represent one of the components involved in ASD etiology. Further pre-clinical and clinical studies are obviously needed to determine if the lowering of p-cresol and/or p-CS circulating concentrations, by dietary and/or pharmacological means, would allow, by itself or in combination with other interventions, to improve CKD progression and associated cardiovascular outcomes, as well as some neurological outcomes in children with an early diagnosis of autism.
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Affiliation(s)
- F Blachier
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Paris, France.
| | - M Andriamihaja
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Paris, France
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Bermudez-Martin P, Becker JAJ, Caramello N, Fernandez SP, Costa-Campos R, Canaguier J, Barbosa S, Martinez-Gili L, Myridakis A, Dumas ME, Bruneau A, Cherbuy C, Langella P, Callebert J, Launay JM, Chabry J, Barik J, Le Merrer J, Glaichenhaus N, Davidovic L. The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota. MICROBIOME 2021; 9:157. [PMID: 34238386 PMCID: PMC8268286 DOI: 10.1186/s40168-021-01103-z] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/27/2021] [Indexed: 05/06/2023]
Abstract
BACKGROUND Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. RESULTS Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. CONCLUSIONS The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. Video abstract.
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Affiliation(s)
- Patricia Bermudez-Martin
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
| | - Jérôme A J Becker
- Physiologie de la Reproduction et des Comportements, UMR0075 INRAE, UMR7247 CNRS, IFCE, Inserm, Université François Rabelais, 37380, Nouzilly, France
- UMR 1253, iBrain, Université de Tours, Inserm, CNRS, Tours, 37200, France
| | - Nicolas Caramello
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
- Current address: Structural Biology, Radiation Facility, European Synchrotron, Grenoble, France
| | - Sebastian P Fernandez
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
| | - Renan Costa-Campos
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
| | - Juliette Canaguier
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
| | - Susana Barbosa
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
| | - Laura Martinez-Gili
- Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK
| | - Antonis Myridakis
- Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK
| | - Marc-Emmanuel Dumas
- Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK
- Genomic and Environmental Medicine, National Heart & Lung Institute, Faculty of Medicine, Imperial College London, London, SW3 6KY, UK
- European Genomic Institute for Diabetes, CNRS UMR 8199, INSERM UMR 1283, Institut Pasteur de Lille, Lille University Hospital, University of Lille, 59045, Lille, France
- McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montréal, QC, H3A 0G1, Canada
| | - Aurélia Bruneau
- AgroParisTech, INRAE, Institut Micalis, Université Paris-Saclay, Jouy-en-Josas, France
| | - Claire Cherbuy
- AgroParisTech, INRAE, Institut Micalis, Université Paris-Saclay, Jouy-en-Josas, France
| | - Philippe Langella
- AgroParisTech, INRAE, Institut Micalis, Université Paris-Saclay, Jouy-en-Josas, France
| | - Jacques Callebert
- UMR-S 942, INSERM, Department of Biochemistry, Lariboisière Hospital, Paris, France
- Centre for Biological Resources, BB-0033-00064, Lariboisière Hospital, Paris, France
| | - Jean-Marie Launay
- UMR-S 942, INSERM, Department of Biochemistry, Lariboisière Hospital, Paris, France
- Centre for Biological Resources, BB-0033-00064, Lariboisière Hospital, Paris, France
| | - Joëlle Chabry
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
| | - Jacques Barik
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
| | - Julie Le Merrer
- Physiologie de la Reproduction et des Comportements, UMR0075 INRAE, UMR7247 CNRS, IFCE, Inserm, Université François Rabelais, 37380, Nouzilly, France
- UMR 1253, iBrain, Université de Tours, Inserm, CNRS, Tours, 37200, France
| | - Nicolas Glaichenhaus
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France
- Fondation FondaMental, Créteil, France
| | - Laetitia Davidovic
- Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France.
- Fondation FondaMental, Créteil, France.
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Goswami A, Wendt FR, Pathak GA, Tylee DS, De Angelis F, De Lillo A, Polimanti R. Role of microbes in the pathogenesis of neuropsychiatric disorders. Front Neuroendocrinol 2021; 62:100917. [PMID: 33957173 PMCID: PMC8364482 DOI: 10.1016/j.yfrne.2021.100917] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/25/2021] [Accepted: 04/29/2021] [Indexed: 02/08/2023]
Abstract
Microbes inhabit different anatomical sites of the human body including oral cavity, gut, and skin. A growing literature highlights how microbiome variation is associated with human health and disease. There is strong evidence of bidirectional communication between gut and brain mediated by neurotransmitters and microbial metabolites. Here, we review the potential involvement of microbes residing in the gut and in other body sites in the pathogenesis of eight neuropsychiatric disorders, discussing findings from animal and human studies. The data reported provide a comprehensive overview of the current state of the microbiome research in neuropsychiatry, including hypotheses about the mechanisms underlying the associations reported and the translational potential of probiotics and prebiotics.
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Affiliation(s)
- Aranyak Goswami
- Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Frank R Wendt
- Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Gita A Pathak
- Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Daniel S Tylee
- Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Flavio De Angelis
- Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Antonella De Lillo
- Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT 06516, USA
| | - Renato Polimanti
- Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT 06516, USA.
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40
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Davoli-Ferreira M, Thomson CA, McCoy KD. Microbiota and Microglia Interactions in ASD. Front Immunol 2021; 12:676255. [PMID: 34113350 PMCID: PMC8185464 DOI: 10.3389/fimmu.2021.676255] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Autism spectrum disorders (ASD) are serious, highly variable neurodevelopmental disorders, commonly characterized by the manifestation of specific behavioral abnormalities, such as stereotypic behaviors and deficits in social skills, including communication. Although the neurobiological basis for ASD has attracted attention in recent decades, the role of microglial cells, which are the main resident myeloid cell population in the brain, is still controversial and underexplored. Microglia play several fundamental roles in orchestrating brain development and homeostasis. As such, alterations in the intrinsic functions of these cells could be one of the driving forces responsible for the development of various neurodevelopmental disorders, including ASD. Microglia are highly sensitive to environmental cues. Amongst the environmental factors known to influence their intrinsic functions, the gut microbiota has emerged as a central player, controlling both microglial maturation and activation. Strikingly, there is now compelling data suggesting that the intestinal microbiota can play a causative role in driving the behavioural changes associated with ASD. Not only is intestinal dysbiosis commonly reported in ASD patients, but therapies targeting the microbiome can markedly alleviate behavioral symptoms. Here we explore the emerging mechanisms by which altered microglial functions could contribute to several major etiological factors of ASD. We then demonstrate how pre- and postnatal environmental stimuli can modulate microglial cell phenotype and function, underpinning the notion that reciprocal interactions between microglia and intestinal microbes could play a crucial role in ASD aetiology.
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Affiliation(s)
- Marcela Davoli-Ferreira
- Department of Physiology and Pharmacology, Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Carolyn A Thomson
- Department of Physiology and Pharmacology, Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Kathy D McCoy
- Department of Physiology and Pharmacology, Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Needham BD, Adame MD, Serena G, Rose DR, Preston GM, Conrad MC, Campbell AS, Donabedian DH, Fasano A, Ashwood P, Mazmanian SK. Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder. Biol Psychiatry 2021; 89:451-462. [PMID: 33342544 PMCID: PMC7867605 DOI: 10.1016/j.biopsych.2020.09.025] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental condition with hallmark behavioral manifestations including impaired social communication and restricted repetitive behavior. In addition, many affected individuals display metabolic imbalances, immune dysregulation, gastrointestinal dysfunction, and altered gut microbiome compositions. METHODS We sought to better understand nonbehavioral features of ASD by determining molecular signatures in peripheral tissues through mass spectrometry methods (ultrahigh performance liquid chromatography-tandem mass spectrometry) with broad panels of identified metabolites. Herein, we compared the global metabolome of 231 plasma and 97 fecal samples from a large cohort of children with ASD and typically developing control children. RESULTS Differences in amino acid, lipid, and xenobiotic metabolism distinguished ASD and typically developing samples. Our results implicated oxidative stress and mitochondrial dysfunction, hormone level elevations, lipid profile changes, and altered levels of phenolic microbial metabolites. We also revealed correlations between specific metabolite profiles and clinical behavior scores. Furthermore, a summary of metabolites modestly associated with gastrointestinal dysfunction in ASD is provided, and a pilot study of metabolites that can be transferred via fecal microbial transplant into mice is identified. CONCLUSIONS These findings support a connection between metabolism, gastrointestinal physiology, and complex behavioral traits and may advance discovery and development of molecular biomarkers for ASD.
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Affiliation(s)
- Brittany D. Needham
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Mark D. Adame
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA, 02114, USA
| | - Destanie R. Rose
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA,The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | | | | | | | | | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA, 02114, USA
| | - Paul Ashwood
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA,The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | - Sarkis K. Mazmanian
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
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42
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Tran SMS, Mohajeri MH. The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease. Nutrients 2021; 13:732. [PMID: 33669008 PMCID: PMC7996516 DOI: 10.3390/nu13030732] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/15/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
In the last decade, emerging evidence has reported correlations between the gut microbiome and human health and disease, including those affecting the brain. We performed a systematic assessment of the available literature focusing on gut bacterial metabolites and their associations with diseases of the central nervous system (CNS). The bacterial metabolites short-chain fatty acids (SCFAs) as well as non-SCFAs like amino acid metabolites (AAMs) and bacterial amyloids are described in particular. We found significantly altered SCFA levels in patients with autism spectrum disorder (ASD), affective disorders, multiple sclerosis (MS) and Parkinson's disease (PD). Non-SCFAs yielded less significantly distinct changes in faecal levels of patients and healthy controls, with the majority of findings were derived from urinary and blood samples. Preclinical studies have implicated different bacterial metabolites with potentially beneficial as well as detrimental mechanisms in brain diseases. Examples include immunomodulation and changes in catecholamine production by histone deacetylase inhibition, anti-inflammatory effects through activity on the aryl hydrocarbon receptor and involvement in protein misfolding. Overall, our findings highlight the existence of altered bacterial metabolites in patients across various brain diseases, as well as potential neuroactive effects by which gut-derived SCFAs, p-cresol, indole derivatives and bacterial amyloids could impact disease development and progression. The findings summarized in this review could lead to further insights into the gut-brain-axis and thus into potential diagnostic, therapeutic or preventive strategies in brain diseases.
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Affiliation(s)
| | - M. Hasan Mohajeri
- Department of Medicine, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland;
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García-Cabrerizo R, Carbia C, O Riordan KJ, Schellekens H, Cryan JF. Microbiota-gut-brain axis as a regulator of reward processes. J Neurochem 2021; 157:1495-1524. [PMID: 33368280 DOI: 10.1111/jnc.15284] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/08/2020] [Accepted: 12/21/2020] [Indexed: 12/14/2022]
Abstract
Our gut harbours trillions of microorganisms essential for the maintenance of homeostasis and host physiology in health and disease. In the last decade, there has been a growing interest in understanding the bidirectional pathway of communication between our microbiota and the central nervous system. With regard to reward processes there is accumulating evidence from both animal and human studies that this axis may be a key factor in gating reward valence. Focusing on the mesocorticolimbic pathway, we will discuss how the intestinal microbiota is involved in regulating brain reward functions, both in natural (i.e. eating, social or sexual behaviours) and non-natural reinforcers (drug addiction behaviours including those relevant to alcohol, psychostimulants, opioids and cannabinoids). We will integrate preclinical and clinical evidence suggesting that the microbiota-gut-brain axis could be implicated in the development of disorders associated with alterations in the reward system and how it may be targeted as a promising therapeutic strategy. Cover Image for this issue: https://doi.org/10.1111/jnc.15065.
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Affiliation(s)
| | - Carina Carbia
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | - Harriet Schellekens
- 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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Mesleh AG, Abdulla SA, El-Agnaf O. Paving the Way toward Personalized Medicine: Current Advances and Challenges in Multi-OMICS Approach in Autism Spectrum Disorder for Biomarkers Discovery and Patient Stratification. J Pers Med 2021; 11:jpm11010041. [PMID: 33450950 PMCID: PMC7828397 DOI: 10.3390/jpm11010041] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 02/06/2023] Open
Abstract
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by impairments in two main areas: social/communication skills and repetitive behavioral patterns. The prevalence of ASD has increased in the past two decades, however, it is not known whether the evident rise in ASD prevalence is due to changes in diagnostic criteria or an actual increase in ASD cases. Due to the complexity and heterogeneity of ASD, symptoms vary in severity and may be accompanied by comorbidities such as epilepsy, attention deficit hyperactivity disorder (ADHD), and gastrointestinal (GI) disorders. Identifying biomarkers of ASD is not only crucial to understanding the biological characteristics of the disorder, but also as a detection tool for its early screening. Hence, this review gives an insight into the main areas of ASD biomarker research that show promising findings. Finally, it covers success stories that highlight the importance of precision medicine and the current challenges in ASD biomarker discovery studies.
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Affiliation(s)
- Areej G. Mesleh
- Division of Genomics and Precision Medicine (GPM), College of Health & Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha 34110, Qatar;
| | - Sara A. Abdulla
- Neurological Disorder Center, Qatar Biomedical Research Institute (QBRI), HBKU, Doha 34110, Qatar
- Correspondence: (S.A.A.); (O.E.-A.)
| | - Omar El-Agnaf
- Division of Genomics and Precision Medicine (GPM), College of Health & Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha 34110, Qatar;
- Neurological Disorder Center, Qatar Biomedical Research Institute (QBRI), HBKU, Doha 34110, Qatar
- Correspondence: (S.A.A.); (O.E.-A.)
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Mussap M, Siracusano M, Noto A, Fattuoni C, Riccioni A, Rajula HSR, Fanos V, Curatolo P, Barberini L, Mazzone L. The Urine Metabolome of Young Autistic Children Correlates with Their Clinical Profile Severity. Metabolites 2020; 10:metabo10110476. [PMID: 33238400 PMCID: PMC7700197 DOI: 10.3390/metabo10110476] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 11/10/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022] Open
Abstract
Autism diagnosis is moving from the identification of common inherited genetic variants to a systems biology approach. The aims of the study were to explore metabolic perturbations in autism, to investigate whether the severity of autism core symptoms may be associated with specific metabolic signatures; and to examine whether the urine metabolome discriminates severe from mild-to-moderate restricted, repetitive, and stereotyped behaviors. We enrolled 57 children aged 2–11 years; thirty-one with idiopathic autism and twenty-six neurotypical (NT), matched for age and ethnicity. The urine metabolome was investigated by gas chromatography-mass spectrometry (GC-MS). The urinary metabolome of autistic children was largely distinguishable from that of NT children; food selectivity induced further significant metabolic differences. Severe autism spectrum disorder core deficits were marked by high levels of metabolites resulting from diet, gut dysbiosis, oxidative stress, tryptophan metabolism, mitochondrial dysfunction. The hierarchical clustering algorithm generated two metabolic clusters in autistic children: 85–90% of children with mild-to-moderate abnormal behaviors fell in cluster II. Our results open up new perspectives for the more general understanding of the correlation between the clinical phenotype of autistic children and their urine metabolome. Adipic acid, palmitic acid, and 3-(3-hydroxyphenyl)-3-hydroxypropanoic acid can be proposed as candidate biomarkers of autism severity.
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Affiliation(s)
- Michele Mussap
- Department of Surgical Sciences, School of Medicine, University of Cagliari, 09042 Monserrato, Italy; (H.S.R.R.); (V.F.)
- Correspondence: ; Tel.: +39-070-51093403
| | - Martina Siracusano
- Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy;
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Antonio Noto
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (A.N.); (L.B.)
| | - Claudia Fattuoni
- Department of Chemical and Geological Sciences, University of Cagliari, 09042 Monserrato, Italy;
| | - Assia Riccioni
- Child Neurology and Psychiatry Unit, System Medicine Department, Tor Vergata University Hospital of Rome, 00133 Rome, Italy; (A.R.); (P.C.); (L.M.)
| | - Hema Sekhar Reddy Rajula
- Department of Surgical Sciences, School of Medicine, University of Cagliari, 09042 Monserrato, Italy; (H.S.R.R.); (V.F.)
| | - Vassilios Fanos
- Department of Surgical Sciences, School of Medicine, University of Cagliari, 09042 Monserrato, Italy; (H.S.R.R.); (V.F.)
| | - Paolo Curatolo
- Child Neurology and Psychiatry Unit, System Medicine Department, Tor Vergata University Hospital of Rome, 00133 Rome, Italy; (A.R.); (P.C.); (L.M.)
| | - Luigi Barberini
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (A.N.); (L.B.)
| | - Luigi Mazzone
- Child Neurology and Psychiatry Unit, System Medicine Department, Tor Vergata University Hospital of Rome, 00133 Rome, Italy; (A.R.); (P.C.); (L.M.)
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Effects of gut microbial-based treatments on gut microbiota, behavioral symptoms, and gastrointestinal symptoms in children with autism spectrum disorder: A systematic review. Psychiatry Res 2020; 293:113471. [PMID: 33198044 DOI: 10.1016/j.psychres.2020.113471] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 09/20/2020] [Indexed: 02/06/2023]
Abstract
Many studies have identified some abnormalities in gastrointestinal (GI) physiology (e.g., increased intestinal permeability, overall microbiota alterations, and gut infection) in children with autism spectrum disorder (ASD). Furthermore, changes in the intestinal flora may be related to GI and ASD symptom severity. Thus, we decided to systematically review the effects of gut microbial-based interventions on gut microbiota, behavioral symptoms, and GI symptoms in children with ASD. We reviewed current evidence from the Cochrane Library, EBSCO PsycARTICLES, PubMed, Web of Science, and Scope databases up to July 12, 2020. Experimental studies that used gut microbial-based treatments among children with ASD were included. Independent data extraction and quality assessment of studies were conducted according to the PRISMA statement. Finally, we identified 16 articles and found that some interventions (i.e., prebiotic, probiotic, vitamin A supplementation, antibiotics, and fecal microbiota transplantation) could alter the gut microbiota and improve behavioral symptoms and GI symptoms among ASD patients. Our findings highlight that the gut microbiota could be a novel target for ASD patients in the future. However, we only provided suggestive but not conclusive evidence regarding the efficacy of interventions on GI and behavioral symptoms among ASD patients. Additional rigorous trials are needed to evaluate the effects of gut microbial-based treatments and explore potential mechanisms.
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Distinct Fecal and Plasma Metabolites in Children with Autism Spectrum Disorders and Their Modulation after Microbiota Transfer Therapy. mSphere 2020; 5:5/5/e00314-20. [PMID: 33087514 PMCID: PMC7580952 DOI: 10.1128/msphere.00314-20] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Despite the prevalence of autism and its extensive impact on our society, no U.S. Food and Drug Administration-approved treatment is available for this complex neurobiological disorder. Based on mounting evidences that support a link between autism and the gut microbiome, we previously performed a pioneering open-label clinical trial using intensive fecal microbiota transplant. The therapy significantly improved gastrointestinal and behavioral symptoms. Comprehensive metabolomic measurements in this study showed that children with autism spectrum disorder (ASD) had different levels of many plasma metabolites at baseline compared to those in typically developing children. Microbiota transfer therapy (MTT) had a systemic effect, resulting in substantial changes in plasma metabolites, driving a number of metabolites to be more similar to those from typically developing children. Our results provide evidence that changes in metabolites are one mechanism of the gut-brain connection mediated by the gut microbiota and offer plausible clinical evidence for a promising autism treatment and biomarkers. Accumulating evidence has strengthened a link between dysbiotic gut microbiota and autism. Fecal microbiota transplant (FMT) is a promising therapy to repair dysbiotic gut microbiota. We previously performed intensive FMT called microbiota transfer therapy (MTT) for children with autism spectrum disorders (ASD) and observed a substantial improvement of gastrointestinal and behavioral symptoms. We also reported modulation of the gut microbiome toward a healthy one. In this study, we report comprehensive metabolite profiles from plasma and fecal samples of the children who participated in the MTT trial. With 619 plasma metabolites detected, we found that the autism group had distinctive metabolic profiles at baseline. Eight metabolites (nicotinamide riboside, IMP, iminodiacetate, methylsuccinate, galactonate, valylglycine, sarcosine, and leucylglycine) were significantly lower in the ASD group at baseline, while caprylate and heptanoate were significantly higher in the ASD group. MTT drove global shifts in plasma profiles across various metabolic features, including nicotinate/nicotinamide and purine metabolism. In contrast, for 669 fecal metabolites detected, when correcting for multiple hypotheses, no metabolite was significantly different at baseline. Although not statistically significant, p-cresol sulfate was relatively higher in the ASD group at baseline, and after MTT, the levels decreased and were similar to levels in typically developing (TD) controls. p-Cresol sulfate levels were inversely correlated with Desulfovibrio, suggesting a potential role of Desulfovibrio on p-cresol sulfate modulation. Further studies of metabolites in a larger ASD cohort, before and after MTT, are warranted, as well as clinical trials of other therapies to address the metabolic changes which MTT was not able to correct. IMPORTANCE Despite the prevalence of autism and its extensive impact on our society, no U.S. Food and Drug Administration-approved treatment is available for this complex neurobiological disorder. Based on mounting evidences that support a link between autism and the gut microbiome, we previously performed a pioneering open-label clinical trial using intensive fecal microbiota transplant. The therapy significantly improved gastrointestinal and behavioral symptoms. Comprehensive metabolomic measurements in this study showed that children with autism spectrum disorder (ASD) had different levels of many plasma metabolites at baseline compared to those in typically developing children. Microbiota transfer therapy (MTT) had a systemic effect, resulting in substantial changes in plasma metabolites, driving a number of metabolites to be more similar to those from typically developing children. Our results provide evidence that changes in metabolites are one mechanism of the gut-brain connection mediated by the gut microbiota and offer plausible clinical evidence for a promising autism treatment and biomarkers.
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48
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Gut microbial molecules in behavioural and neurodegenerative conditions. Nat Rev Neurosci 2020; 21:717-731. [DOI: 10.1038/s41583-020-00381-0] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2020] [Indexed: 02/07/2023]
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Roussin L, Prince N, Perez-Pardo P, Kraneveld AD, Rabot S, Naudon L. Role of the Gut Microbiota in the Pathophysiology of Autism Spectrum Disorder: Clinical and Preclinical Evidence. Microorganisms 2020; 8:microorganisms8091369. [PMID: 32906656 PMCID: PMC7563175 DOI: 10.3390/microorganisms8091369] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/06/2023] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 160 people in the world. Although there is a strong genetic heritability to ASD, it is now accepted that environmental factors can play a role in its onset. As the prevalence of gastrointestinal (GI) symptoms is four-times higher in ASD patients, the potential implication of the gut microbiota in this disorder is being increasingly studied. A disturbed microbiota composition has been demonstrated in ASD patients, accompanied by altered production of bacterial metabolites. Clinical studies as well as preclinical studies conducted in rodents have started to investigate the physiological functions that gut microbiota might disturb and thus underlie the pathophysiology of ASD. The first data support an involvement of the immune system and tryptophan metabolism, both in the gut and central nervous system. In addition, a few clinical studies and a larger number of preclinical studies found that modulation of the microbiota through antibiotic and probiotic treatments, or fecal microbiota transplantation, could improve behavior. Although the understanding of the role of the gut microbiota in the physiopathology of ASD is only in its early stages, the data gathered in this review highlight that this role should be taken in consideration.
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Affiliation(s)
- Léa Roussin
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France;
- Correspondence:
| | - Naika Prince
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; (N.P.); (P.P.-P.); (A.D.K.)
| | - Paula Perez-Pardo
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; (N.P.); (P.P.-P.); (A.D.K.)
| | - Aletta D. Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; (N.P.); (P.P.-P.); (A.D.K.)
| | - Sylvie Rabot
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France;
| | - Laurent Naudon
- Université Paris-Saclay, INRAE, AgroParisTech, CNRS, Micalis Institute, 78350 Jouy-en-Josas, France;
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50
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Guo Y, Bian X, Liu J, Zhu M, Li L, Yao T, Tang C, Ravichandran V, Liao P, Papadimitriou K, Yin J. Dietary Components, Microbial Metabolites and Human Health: Reading between the Lines. Foods 2020; 9:E1045. [PMID: 32756378 PMCID: PMC7466307 DOI: 10.3390/foods9081045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
Trillions of bacteria reside in the human gut and they metabolize dietary substances to obtain nutrients and energy while producing metabolites. Therefore, different dietary components could affect human health in various ways through microbial metabolism. Many such metabolites have been shown to affect human physiological activities, including short-chain fatty acids metabolized from carbohydrates; indole, kynurenic acid and para-cresol, metabolized from amino acids; conjugated linoleic acid and linoleic acid, metabolized from lipids. Here, we review the features of these metabolites and summarize the possible molecular mechanisms of their metabolisms by gut microbiota. We discuss the potential roles of these metabolites in health and diseases, and the interactions between host metabolism and the gut microbiota. We also show some of the major dietary patterns around the world and hope this review can provide insights into our eating habits and improve consumers' health conditions.
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Affiliation(s)
- Yao Guo
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410006, China; (Y.G.); (X.B.); (J.L.); (M.Z.); (L.L.); (T.Y.); (C.T.)
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha 410006, China
| | - Xiaohan Bian
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410006, China; (Y.G.); (X.B.); (J.L.); (M.Z.); (L.L.); (T.Y.); (C.T.)
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha 410006, China
| | - Jiali Liu
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410006, China; (Y.G.); (X.B.); (J.L.); (M.Z.); (L.L.); (T.Y.); (C.T.)
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha 410006, China
| | - Ming Zhu
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410006, China; (Y.G.); (X.B.); (J.L.); (M.Z.); (L.L.); (T.Y.); (C.T.)
| | - Lin Li
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410006, China; (Y.G.); (X.B.); (J.L.); (M.Z.); (L.L.); (T.Y.); (C.T.)
| | - Tingyu Yao
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410006, China; (Y.G.); (X.B.); (J.L.); (M.Z.); (L.L.); (T.Y.); (C.T.)
| | - Congjia Tang
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410006, China; (Y.G.); (X.B.); (J.L.); (M.Z.); (L.L.); (T.Y.); (C.T.)
| | - Vinothkannan Ravichandran
- State Key Laboratory of Microbial Technology, Shandong University–Helmholtz Institute of Biotechnology, Shandong University, Qingdao 266237, China;
| | - Peng Liao
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China;
| | - Konstantinos Papadimitriou
- Department of Food Science and Technology, School of Agriculture and Food, University of Peloponnese, 22131 Antikalamos, Greece;
| | - Jia Yin
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410006, China; (Y.G.); (X.B.); (J.L.); (M.Z.); (L.L.); (T.Y.); (C.T.)
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha 410006, China
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