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      Microbiota is essential for social development in the mouse

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          Abstract

          The microbiota–gut–brain axis is an emerging concept in modern medicine informed by the ability of gut microbiota to alter brain and behaviour. 1 Although some clinical studies have revealed altered gut microbiota composition in patients with neurodevelopmental disorders such as autism, 2, 3 the specific contributions of microbiota in early life to the development and programming of the various facets of social behaviour has not been investigated. Germ-free (GF) mice have been critical in assessing the role of microbiota in all aspects of physiology. Indeed, recent studies in GF mice report increases in neuroendocrine responses to stress, 4, 5 altered neurotrophin levels in the hippocampus and amygdala, 5, 6, 7 reduced anxiety 5, 6, 7 and non-spatial memory, 8 and altered monoamine neurotransmitter levels in the brain. 5, 6 Interestingly, many of the deficits are specific to males 4 in which there are higher incidence rates of neurodevelopmental disorders relative to females. Here, we examined the effects of GF rearing conditions through early life and adolescence on social behaviour in adulthood. Mice, like humans, are a social species and have a natural propensity to seek out the security and pleasure afforded by stable social scenarios. Social motivation and preference for social novelty in mice can be assessed in the three-chambered sociability test. 9 Our initial findings in this test revealed significant social impairments in GF mice, particularly in males, as indicated by a lack of the normal preference for time spent in a chamber containing a mouse versus the alternative empty chamber (GF × chamber interaction: F(1,57)=5.35, P<0.05; Supplementary Figures 1a–c). This was accompanied by reduced preference for novel social situations, where GF mice did not demonstrate the normal increase in time spent investigating a novel over a familiar mouse, which resembles social cognition deficits observed in patients with neurodevelopmental disorders (GF × chamber interaction: F(1,57)=5.86, P<0.01; Supplementary Figures 1d–f). To substantiate these results and to assess the capacity for post-weaning bacterial colonisation of the GF gut (GFC) to reverse the observed social deficits, we repeated the test in a different male cohort. As expected, GF mice exhibited robust deficits including social avoidance (GF × chamber interaction: F(1,20)=12.41, P<0.001; Figures 1a–c), and diminished preference for social novelty relative to conventionally colonised (CC) mice (GF × chamber interaction: F(1,20)=4.45, P<0.05; Figures 1d–f). These effects were not influenced by changes in general locomotor activity, as any decrease in chamber entries was specific to the social chamber (Supplementary Figure 2). Intriguingly, whereas GFC reversed the observed social avoidance, it had no effect on social cognition impairments. This indicates that although the effects of GF rearing on the latter behaviour are permanently established in the pre-weaning period, the development of social avoidance in GF mice is more amenable to microbial-based interventions in later life. In addition to symptoms of reduced social motivation, children with autism exhibit poor social and communication skills and repetitive behaviours. To establish whether the degree of information transfer during social interaction is disrupted in GF mice, performance in the social transmission of food preference test was assessed. GF mice spent a decreased proportion of time engaged in social investigation (F(2,20)=7.51, P<0.005; Figure 1g) and substantially greater proportion of time engaged in repetitive self-grooming behaviour (F(2,20)=11.91, P<0.001; Figure 1h) during social interaction. These behaviours were normalised following GF bacterial colonisation, confirming the involvement of microbiota in modulation of these behaviours. However, despite the reduction in social investigation times, the quality of information transfer during the interaction was not affected in GF mice, as they displayed normal preference for the novel food (food to which cage-mate was exposed prior to social interaction) in the subsequent food choice test conducted immediately after the social interaction and 24 h later (Figures 1i and j), indicating that the ability to process information per se during social interaction is not affected in GF mice. This study shows for, what is to our knowledge, the first time that microbiota are crucial for the programming and presentation of distinct normal social behaviours, including social motivation and preference for social novelty, while also being important regulators of repetitive behaviours. Given that these facets of behaviour are impaired in neurodevelopmental disorders such as schizophrenia and autism 10 and with a similar male preponderance, these data may have implications for our understanding of the genesis of neurodevelopmental disorders of altered sociability. A better understanding of the mechanisms underlying these social deficits, which may include modulation of immune cell cytokines release, changes in vagal nerve activity and neuroendocrine function, could potentially lead to the emergence of novel and more effective therapies to combat symptoms in the social domain.

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          Pyrosequencing study of fecal microflora of autistic and control children.

          There is evidence of genetic predisposition to autism, but the percent of autistic subjects with this background is unknown. It is clear that other factors, such as environmental influences, may play a role in this disease. In the present study, we have examined the fecal microbial flora of 33 subjects with various severities of autism with gastrointestinal symptoms, 7 siblings not showing autistic symptoms (sibling controls) and eight non-sibling control subjects, using the bacterial tag encoded FLX amplicon pyrosequencing (bTEFAP) procedure. The results provide us with information on the microflora of stools of young children and a compelling picture of unique fecal microflora of children with autism with gastrointestinal symptomatology. Differences based upon maximum observed and maximum predicted operational taxonomic units were statistically significant when comparing autistic and control subjects with p-values ranging from <0.001 to 0.009 using both parametric and non-parametric estimators. At the phylum level, Bacteroidetes and Firmicutes showed the most difference between groups of varying severities of autism. Bacteroidetes was found at high levels in the severely autistic group, while Firmicutes were more predominant in the control group. Smaller, but significant, differences also occurred in the Actinobacterium and Proteobacterium phyla. Desulfovibrio species and Bacteroides vulgatus are present in significantly higher numbers in stools of severely autistic children than in controls. If the unique microbial flora is found to be a causative or consequent factor in this type of autism, it may have implications with regard to a specific diagnostic test, its epidemiology, and for treatment and prevention. Copyright (c) 2010 Elsevier Ltd. All rights reserved.
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            Mouse behavioral assays relevant to the symptoms of autism.

            While the cause of autism remains unknown, the high concordance between monozygotic twins supports a strong genetic component. The importance of genetic factors in autism encourages the development of mutant mouse models, to advance our understanding of biological mechanisms underlying autistic behaviors. Mouse models of human neuropsychiatric diseases are designed to optimize (i) face validity (resemblance to the human symptoms) (ii) construct validity (similarity to the underlying causes of the disease) and (iii) predictive validity (expected responses to treatments that are effective in the human disease). There is a growing need for mouse behavioral tasks with all three types of validity, to define robust phenotypes in mouse models of autism. Ideal mouse models will incorporate analogies to the three diagnostic symptoms of autism: abnormal social interactions, deficits in communication and high levels of repetitive behaviors. Social approach is tested in an automated three chambered apparatus that offers the subject a choice between spending time with another mouse, with a novel object, or remaining in an empty familiar environment. Reciprocal social interaction is scored from videotapes of interactions between pairs of unfamiliar mice. Communication is evaluated by measuring emission and responses to vocalizations and olfactory cues. Repetitive behaviors are scored for measures of grooming, jumping, or stereotyped sniffing of one location or object. Insistence on sameness is modeled by scoring a change in habit, for example, reversal of the spatial location of a reinforcer in the Morris water maze or T-maze. Associated features of autism, for example, mouse phenotypes relevant to anxiety, seizures, sleep disturbances and sensory hypersensitivity, may be useful to include in a mouse model that meets some of the core diagnostic criteria. Applications of these assays include (i) behavioral phenotyping of transgenic and knockout mice with mutations in genes relevant to autism; (ii) characterization of inbred strains of mice; (iii) evaluation of environmental toxins; (iv) comparison of behavioral phenotypes with genetic factors, such as unusual expression patterns of genes or unusual single nucleotide polymorphisms; and (v) evaluation of proposed therapeutics for the treatment of autism.
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              Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management.

              Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, characterized by impairments in social interaction and communication and the presence of limited, repetitive and stereotyped interests and behavior. Bowel symptoms are frequently reported in children with ASD and a potential role for gastrointestinal disturbances in ASD has been suggested. This review focuses on the importance of (allergic) gastrointestinal problems in ASD. We provide an overview of the possible gut-to-brain pathways and discuss opportunities for pharmaceutical and/or nutritional approaches for therapy. Copyright © 2011. Published by Elsevier B.V.
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                Author and article information

                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group
                1359-4184
                1476-5578
                February 2014
                21 May 2013
                : 19
                : 2
                : 146-148
                Affiliations
                [1 ]Alimentary Pharmabiotic Centre, University College Cork , Cork, Ireland
                [2 ]Department of Psychiatry, University College Cork , Cork, Ireland
                [3 ]Department of Medicine, University College Cork , Cork, Ireland
                [4 ]Department of Anatomy and Neuroscience, University College Cork , Cork, Ireland
                Author notes
                Article
                mp201365
                10.1038/mp.2013.65
                3903109
                23689536
                Copyright © 2014 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/

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