Microbial ecology in health and disease : The Microbiome in Autism Spectrum Disorder (Mai 2015)

mercredi 19 août 2015

La revue Microbial ecology in health and disease propose dans son numéro de mai 2015 un focus sur le microbiome et l’autisme.

1. Bilbo SD, Nevison CD, Parker W. A model for the induction of autism in the ecosystem of the human body : the anatomy of a modern pandemic ?. Microb Ecol Health Dis ;2015 ;26:26253.

BACKGROUND : The field of autism research is currently divided based on a fundamental question regarding the nature of autism : Some are convinced that autism is a pandemic of modern culture, with environmental factors at the roots. Others are convinced that the disease is not pandemic in nature, but rather that it has been with humanity for millennia, with its biological and neurological underpinnings just now being understood. OBJECTIVE : In this review, two lines of reasoning are examined which suggest that autism is indeed a pandemic of modern culture. First, given the widely appreciated derailment of immune function by modern culture, evidence that autism is strongly associated with aberrant immune function is examined. Second, evidence is reviewed indicating that autism is associated with ’triggers’ that are, for the most part, a construct of modern culture. In light of this reasoning, current epidemiological evidence regarding the incidence of autism, including the role of changing awareness and diagnostic criteria, is examined. Finally, the potential role of the microbial flora (the microbiome) in the pathogenesis of autism is discussed, with the view that the microbial flora is a subset of the life associated with the human body, and that the entire human biome, including both the microbial flora and the fauna, has been radically destabilized by modern culture. CONCLUSIONS : It is suggested that the unequivocal way to resolve the debate regarding the pandemic nature of autism is to perform an experiment : monitor the prevalence of autism after normalizing immune function in a Western population using readily available approaches that address the well-known factors underlying the immune dysfunction in that population.

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2. Toh MC, Allen-Vercoe E. The human gut microbiota with reference to autism spectrum disorder : considering the whole as more than a sum of its parts. Microb Ecol Health Dis ;2015 ;26:26309.

The 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 (and continues to be) revealed. One of the more striking of these discoveries is the finding that the 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 brain and 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 of the gut microbiota in autism spectrum disorder to illustrate the concept.

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3. Rodakis J. An n=1 case report of a child with autism improving on antibiotics and a father’s quest to understand what it may mean. Microb Ecol Health Dis ;2015 ;26:26382.

The author, a parent of a child with autism, describes an n=1 case in which his child’s autism symptoms dramatically and rapidly improved following administration of a common antibiotic. The author asserts that this finding is not unusual in the autism population and that, when combined with prior recent medical research, suggests that a link between autism and the microbiome in some children is not just plausible, but in fact likely for some meaningful percentage of cases. The author argues for increased funding for a more thorough examination of links between autism and the microbiome and poses a series of questions to be further examined in future research.

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4. McDonald D, Hornig M, Lozupone C, Debelius J, Gilbert JA, Knight R. Towards large-cohort comparative studies to define the factors influencing the gut microbial community structure of ASD patients. Microb Ecol Health Dis ;2015 ;26:26555.

Differences 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.

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5. Frye RE, Slattery J, MacFabe DF, Allen-Vercoe E, Parker W, Rodakis J, Adams JB, Krajmalnik-Brown R, Bolte E, Kahler S, Jennings J, James J, Cerniglia CE, Midtvedt T. Approaches to studying and manipulating the enteric microbiome to improve autism symptoms. Microb Ecol Health Dis ;2015 ;26:26878.

There is a growing body of scientific evidence that the health of the microbiome (the trillions of microbes that inhabit the human host) plays an important role in maintaining the health of the host and that disruptions in the microbiome may play a role in certain disease processes. An increasing number of research studies have provided evidence that the composition of the gut (enteric) microbiome (GM) in at least a subset of individuals with autism spectrum disorder (ASD) deviates from what is usually observed in typically developing individuals. There are several lines of research that suggest that specific changes in the GM could be causative or highly associated with driving core and associated ASD symptoms, pathology, and comorbidities which include gastrointestinal symptoms, although it is also a possibility that these changes, in whole or in part, could be a consequence of underlying pathophysiological features associated with ASD. However, if the GM truly plays a causative role in ASD, then the manipulation of the GM could potentially be leveraged as a therapeutic approach to improve ASD symptoms and/or comorbidities, including gastrointestinal symptoms. One approach to investigating this possibility in greater detail includes a highly controlled clinical trial in which the GM is systematically manipulated to determine its significance in individuals with ASD. To outline the important issues that would be required to design such a study, a group of clinicians, research scientists, and parents of children with ASD participated in an interdisciplinary daylong workshop as an extension of the 1st International Symposium on the Microbiome in Health and Disease with a Special Focus on Autism (www.microbiome-autism.com). The group considered several aspects of designing clinical studies, including clinical trial design, treatments that could potentially be used in a clinical trial, appropriate ASD participants for the clinical trial, behavioral and cognitive assessments, important biomarkers, safety concerns, and ethical considerations. Overall, the group not only felt that this was a promising area of research for the ASD population and a promising avenue for potential treatment but also felt that further basic and translational research was needed to clarify the clinical utility of such treatments and to elucidate possible mechanisms responsible for a clinical response, so that new treatments and approaches may be discovered and/or fostered in the future.

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6. Krajmalnik-Brown R, Lozupone C, Kang DW, Adams JB. Gut bacteria in children with autism spectrum disorders : challenges and promise of studying how a complex community influences a complex disease. Microb Ecol Health Dis ;2015 ;26:26914.

Recent 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 chronic constipation 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.

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7. Frye RE, Rose S, Slattery J, MacFabe DF. Gastrointestinal dysfunction in autism spectrum disorder : the role of the mitochondria and the enteric microbiome. Microb Ecol Health Dis ;2015 ;26:27458.

Autism spectrum disorder (ASD) affects a significant number of individuals worldwide with the prevalence continuing to grow. It is becoming clear that a large subgroup of individuals with ASD demonstrate abnormalities in mitochondrial function as well as gastrointestinal (GI) symptoms. Interestingly, GI disturbances are common in individuals with mitochondrial disorders and have been reported to be highly prevalent in individuals with co-occurring ASD and mitochondrial disease. The majority of individuals with ASD and mitochondrial disorders do not manifest a primary genetic mutation, raising the possibility that their mitochondrial disorder is acquired or, at least, results from a combination of genetic susceptibility interacting with a wide range of environmental triggers. Mitochondria are very sensitive to both endogenous and exogenous environmental stressors such as toxicants, iatrogenic medications, immune activation, and metabolic disturbances. Many of these same environmental stressors have been associated with ASD, suggesting that the mitochondria could be the biological link between environmental stressors and neurometabolic abnormalities associated with ASD. This paper reviews the possible links between GI abnormalities, mitochondria, and ASD. First, we review the link between GI symptoms and abnormalities in mitochondrial function. Second, we review the evidence supporting the notion that environmental stressors linked to ASD can also adversely affect both mitochondria and GI function. Third, we review the evidence that enteric bacteria that are overrepresented in children with ASD, particularly Clostridia spp., produce short-chain fatty acid metabolites that are potentially toxic to the mitochondria. We provide an example of this gut-brain connection by highlighting the propionic acid rodent model of ASD and the clinical evidence that supports this animal model. Lastly, we discuss the potential therapeutic approaches that could be helpful for GI symptoms in ASD and mitochondrial disorders. To this end, this review aims to help better understand the underlying pathophysiology associated with ASD that may be related to concurrent mitochondrial and GI dysfunction.

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8. Frye RE, Slattery J. Introduction. Microb Ecol Health Dis ;2015 ;26:28168.

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9. Midtvedt T. Concluding remarks. Microb Ecol Health Dis ;2015 ;26:28169.

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