肠道菌群和自闭症

∙1a Department of Soil, Plant and Food Sciences , University of Bari Aldo Moro , Bari , Italy.AbstractThrough extensive microbial-mammalian co-metabolism, the intestinal microbiota have evolved to exert a marked influence on health and disease viagut-brain-microbiota interactions. In this addendum, wesummarize the findings of our recent study on the fecal microbiota and metabolomes of children with pervasive developmental disorder-not otherwise specified (PDD-NOS) or autism (AD) compared with healthy children (HC). Children with PDD-NOS or AD have altered fecal microbiota and metabolomes (including neurotransmitter molecules). We hypothesise that the degree of microbial alteration correlates with the severity of the disease since fecal microbiota and metabolomes alterations were higher inchildren with PDD-NOS and, especially, AD compared to HC. Our study indicates that the levels of free amino acids (FAA) and volatile organic compounds (VOC) differ in AD subjects compared to children with PDD-NOS, who are more similar to HC. Finally, we propose a new perspective on the implications for the interaction between intestinal microbiota and AD.∙1Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.∙2Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada ; Brain-Body Institute, St Joseph's Healthcare, Hamilton, ON, Canada.AbstractThe human intestine houses an astounding number and species of microorganisms, estimated at more than 10(14) gut microbiota and composed of over a thousand species. An individual's profileof microbiota is continually influenced by a variety of factors including but not limited to genetics, age, sex, diet, and lifestyle. Although each person's microbial profile is distinct, the relative abundance anddistribution of bacterial species is similar among healthy individuals, aiding in the maintenance of one's overall health. Consequently, the ability of gut microbiota to bidirectionally communicate with the brain, known as the gut-brain axis, in the modulation of human health is at the forefront of current research. At a basic level, the gutmicrobiota interacts with the human host in a mutualistic relationship - the hostintestine provides the bacteria with an environment to grow and the bacterium aids in governinghomeostasis within the host. Therefore, it is reasonable to think that the lack ofhealthy gut microbiota may also lead to a deterioration of these relationships and ultimately disease.Indeed, a dysfunction in the gut-brain axis has been elucidated by a multitude of studies linked toneuropsychological, metabolic, and gastrointestinal disorders. For instance, altered microbiota has been linked to neuropsychological disorders including depression and autism spectrum disorder, metabolic disorders such as obesity, and gastrointestinal disorders including inflammatory bowel disease andirritable bowel syndrome. Fortunately, studies have also indicated that gut microbiota may be modulated with the use of probiotics, antibiotics, and fecal microbiota transplants as a prospect for therapyin microbiota-associated diseases. This modulation of gutmicrobiota is currently a growing area ofresearch as it just might hold the key to treatment.∙1Department of Internal Medicine and Medical Specialties, University Sapienza, Rome (Marilia Carabotti, Annunziata Scirocco, Carola Severi), Italy.∙2Experimental Pharmacology Laboratory, Scientific Institute of Gastroenterology S. de Bellis, Castellana Grotte, Bari (Maria Antonietta Maselli), Italy.AbstractThe gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions.Recent advances in research have described the importance of gut microbiota in influencing theseinteractions. This interaction between microbiota and GBA appears to be bidirectional, namely through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of neural, endocrine, immune, and humoral links. In this review we summarize the available evidence supporting the existence of these interactions, as well as the possible pathophysiological mechanisms involved. Most of the data have been acquired using technical strategies consisting in germ-free animal models, probiotics,antibiotics, and infection studies. In clinical practice, evidence ofmicrobiota-GBA interactions comes from the association of dysbiosis with central nervous disorders (i.e. autism, anxiety-depressive behaviors) and functional gastrointestinal disorders. In particular, irritable bowel syndrome can be considered an example of the disruption of these complex relationships, and a better understanding of these alterations might provide new targeted therapies.∙1Alimentary Pharmabiotic Centre, University College, Cork, Ireland; Department of Psychiatry, University College Cork, Ireland. Electronic address: t.dinan@ucc.ie.∙2Alimentary Pharmabiotic Centre, University College, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Ireland.∙3Alimentary Pharmabiotic Centre, University College, Cork, Ireland; Department of Psychiatry, University College Cork, Ireland; Teagasc, Moorepark, Cork, Ireland.AbstractThe human gut harbors a dynamic and complex microbial ecosystem, consisting of approximately 1 kg of bacteria in the average adult, approximately the weight of the human brain. The evolutionary formation ofa complex gut microbiota in mammals has played an important role in enabling brain development andperhaps sophisticated social interaction. Genes within the human gut microbiota, termed the microbiome,significantly outnumber human genes in the body, and are capable of producing a myriad of neuroactive compounds. Gut microbes are part of the unconscious system regulating behavior. Recent investigations indicate that these microbes majorly impact on cognitive function and fundamental behavior patterns, such as social interaction and stress management. In the absence of microbes, underlyingneurochemistry is profoundly altered. Studies of gut microbes may play an important role in advancing understanding of disorders of cognitive functioning and social interaction, such as autism.∙1Swette Center for Environmental Biotechnology, Biodesign Institute, Arizona State University, Tempe, AZ, USA.∙2School of Sustainable Engineering and The Built Environment, Arizona State University, Tempe, AZ, USA; dr.rosy@.∙3Department of Medicine, University of Colorado-Denver, Aurora, CO, USA.∙4School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ, USA.AbstractRecent studies suggest a role for the microbiota in autism spectrum disorders (ASD), potentially arising from their role in modulating the immune system and gastrointestinal (GI) function or from gut-brain interactions dependent or independent from the immune system. GI problems such as chronicconstipation and/or diarrhea are common in children with ASD, and significantly worsen their behavior and their quality of life. Here we first summarize previously published data supporting that GI dysfunction is common in individuals with ASD and the role of the microbiota in ASD. Second, by comparing with other publically available microbiome datasets, we provide some evidence that the shifted microbiota can be a result of westernization and that this shift could also be framing an altered immune system. Third, we explore the possibility that gut-brain interactions could also be a direct result of microbially produced metabolites.∙1BioFrontiers Institute, University of Colorado, Boulder, CO, USA.∙2Department of Computer Science, University of Colorado, Boulder, CO, USA.∙3Center for Infection and Immunity, Columbia University Mailman School of Public Health, New York, NY, USA.∙4Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA.∙5Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.∙6Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO, USA.∙7Institute for Genomic and Systems Biology, Argonne National Laboratory, Argonne, IL, USA.∙8Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA.∙9Marine Biological Laboratory, Woods Hole, MA, USA.∙10College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, China;gilbertjack@.∙11Howard Hughes Medical Institute, Boulder, CO, USA.AbstractDifferences in the gut microbiota have been reported between individuals with autism spectrum disorders (ASD) and neurotypical controls, although direct evidence that changes in the microbiome contribute to causing ASD has been scarce to date. Here we summarize some considerations of experimental design that can help untangle causality in this complex system. In particular, large cross-sectional studies that can factor out important variables such as diet, prospective longitudinal studies that remove some of the influence of interpersonal variation in the microbiome (which is generally high, especially in children), and studies transferring microbial communities into germ-free mice may be especially useful. Controlling for the effects of technical variables, which have complicated efforts to combine existing studies, is critical when biological effect sizes are small. Large citizen-science studies with thousands of participants such as the American Gut Project have been effective at uncovering subtle microbiome effects in self-collected samples and with self-reported diet and behavior data, and may provide a useful complement to other types of traditionally funded and conducted studies in the case of ASD, especially in the hypothesis generation phase.J Clin Invest. 2015 Mar 2;125(3):926-38. doi: 10.1172/JCI76304. Epub 2015 Feb 17.Gut/brain axis and the microbiota.Mayer EA, Tillisch K, Gupta A.AbstractTremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocativepreclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions.Based on studies using rodents raised in a germ-free environment, the gut microbiota appears toinfluence the development of emotional behavior, stress- and pain-modulation systems, and brainneurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exertmodulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomicnervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.∙1Department of Biochemistry, Rush University Medical Center, Cohn Research Building, 1735 W.Harrison St., Room 506, Chicago, IL 60612, United States.∙2Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL 60637, United States.AbstractHumans have coevolved with their microbes over thousands of years, but this relationship, is now being dramatically affected by shifts in the collective human microbiome resulting from changes in theenvironment and societal norms. Resulting perturbations of intestinal host-microbe interactions can lead to miscues and altered host responses that increase the risk of pathogenic processes and promote"western" disorders such as inflammatory bowel diseases, cancers, obesity, diabetes, autism, andasthma. Given the current challenges and limitations in gene therapy, approaches that can reshapethe gut microbiome represent a reasonable strategy for restoring the balance between host and microbes.In this review and commentary, we highlight recent progress in our understanding of the intestinalmicrobiome in the context of health and diseases, focusing on mechanistic concepts that underlie the complex relationships between host and microbes. Despite these gains, many challenges lie ahead that make it difficult to close the gap between the basic sciences and clinical application. We will discuss the potential therapeutic strategies that can be used to manipulate the gutmicrobiota, recognizing that the promise of pharmabiotics ("bugs to drugs") is unlikely to be completely fulfilled without a greaterunderstanding of enteric microbiota and its impact on mammalian physiology. By leveraging theknowledge gained through these studies, we will be prepared to enter the era of personalized medicine where clinical inventions can be custom-tailored to individual patients to achieve better outcomes.∙1Department of Molecular and Cellular Biology, University of Guelph, Guelph, Canada.∙2Department of Molecular and Cellular Biology, University of Guelph, Guelph, Canada;eav@uoguelph.ca.AbstractThe human gut microbiota is a complex microbial ecosystem that contributes an important component towards the health of its host. This highly complex ecosystem has been underestimated in its importance until recently, when a realization of the enormous scope of gut microbiota function has been (andcontinues to be) revealed. One of the more striking of these discoveries is the finding thatthe gut microbiota and the brain are connected, and thus there is potential for the microbiota in the gut to influence behavior and mental health. In this short review, we outline the link between brainand gut microbiota and urge the reader to consider the gut microbiota as an ecosystem 'organ' rather than just as a collection of microbes filling a niche, using the hypothesized role ofthe gut microbiota in autism spectrum disorder to illustrate the concept.Ochratoxin A as possible factor trigging autism and its maleprevalence via epigenetic mechanism.Mezzelani A, Raggi ME, Marabotti A, Milanesi L.AbstractThe role of dysbiosis causing leaky gut with xenobiotic production and absorption is increasinglydemonstrated in autism spectrum disorder (ASD) pathogenesis. Among xenobiotics, we focused on ochratoxin A (one of the major food contaminating mycotoxin), that in vitro and in vivo exerts a male-specific neurotoxicity probably via microRNA modulation of a specific target gene. Among possible targets, we focused on neuroligin4X. Interestingly, this gene carries some SNPs already correlated with the disease and with illegitimate microRNA binding sites and, being located on X-chromosome, could explain the male prevalence. In conclusion, we propose a possible gene-environment interactiontriggering ASD explaining the epigenetic neurotoxic mechanism activated by ochratoxin A in genetically predisposed children. This mechanism offers a clue for male prevalence of the disease and may have an important impact on prevention and cure of ASD.∙1KU Leuven, Department of Microbiology and Immunology, Rega Institute, Herestraat 49, B-3000 Leuven, Belgium. VIB, Center for the Biology of Disease, Herestraat 49, B-3000 Leuven, Belgium.Microbiology Unit, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.∙2KU Leuven, Department of Microbiology and Immunology, Rega Institute, Herestraat 49, B-3000 Leuven, Belgium. VIB, Center for the Biology of Disease, Herestraat 49, B-3000 Leuven, Belgium.∙3KU Leuven, Department of Microbiology and Immunology, Rega Institute, Herestraat 49, B-3000 Leuven, Belgium. VIB, Center for the Biology of Disease, Herestraat 49, B-3000 Leuven, Belgium.Microbiology Unit, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. jeroen.raes@med.kuleuven.be.AbstractThe microbiota of the human gut is gaining broad attention owing to its association with a wide range of diseases, ranging from metabolic disorders (e.g. obesity and type 2 diabetes) to autoimmune diseases (such as inflammatory bowel disease and type 1 diabetes), cancer and even neurodevelopmentaldisorders (e.g. autism). Having been increasingly used in biomedical research, mice have become the model of choice for most studies in this emerging field. Mouse models allow perturbationsin gut microbiota to be studied in a controlled experimental setup, and thus help in assessing causality of the complex host-microbiota interactions and in developing mechanistic hypotheses. However, pitfalls should be considered when translating gut microbiome research results from mouse models to humans.In this Special Article, we discuss the intrinsic similarities and differences that exist between the two systems, and compare the human and murine core gut microbiota based on a meta-analysis of currently available datasets. Finally, we discuss the external factors that influence the capability of mouse models to recapitulate the gut microbiota shifts associated with human diseases, and investigate whichalternative model systems exist for gut microbiota research.。