Mum's bacteria linked to baby's behaviour
Journal: Neuroscience
Pulished: Sep 13, 2017
Author: Craig M. Powell
Abstract: Infection during pregnancy increases the risk of neurodevelopmental disorders, such as autism, in offspring. Mouse studies now reveal a link between gut bacteria and atypical brain-circuit connections. See Article p.482 & Letter p.528
What do pregnancy, viral infection, gut bacteria, the immune response and the function of a neuronal circuit in the brain have in common? More than you might expect, according to a pair of studies, by Kim et al.1 and Yim et al.2, reported on pages 528 and 482, respectively.
Animal studies and epidemiological analysis in humans have shown that if a mother is infected by certain viruses during pregnancy, there is a risk that her offspring will develop autism or other neurodevelopmental disorders3,4. This phenomenon is often studied using a mouse model in which viral infection is mimicked by exposing pregnant animals to a synthetic molecule called poly(I:C) that is structurally similar to double-stranded RNA, a common hallmark of viral infection (Fig. 1). This exposure triggers an immune response in the mother that is termed maternal immune activation (MIA), which can lead to atypical social and repetitive behaviours in her offspring5. However, the molecular and cellular basis for this phenomenon has remained poorly understood until now.
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice
Journal: Cell
Pulished: May 30, 2019
Author: Gil Sharon, Nikki Jamie Cruz, Dae-Wook Kang, et al.
Abstract: Autism spectrum disorder (ASD) manifests as alterations in complex human behaviors including social communication and stereotypies. In addition to genetic risks, the gut microbiome differs between typically developing (TD) and ASD individuals, though it remains unclear whether the microbiome contributes to symptoms. We transplanted gut microbiota from human donors with ASD or TD controls into germ-free mice and reveal that colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors. The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes. Microbiome and metabolome profiles of mice harboring human microbiota predict that specific bacterial taxa and their metabolites modulate ASD behaviors. Indeed, treatment of an ASD mouse model with candidate microbial metabolites improves behavioral abnormalities and modulates neuronal excitability in the brain. We propose that the gut microbiota regulates behaviors in mice via production of neuroactive metabolites, suggesting that gut-brain connections contribute to the pathophysiology of ASD.
The Central Nervous System and the Gut Microbiome
Journal: Cell
Pulished: Nov 03, 2016
Author: Gil Sharon, Timothy R. Sampson, Daniel H. Geschwind, et al.
Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system and to the balance between mental health and disease.
Microbiota and neurodevelopmental windows: implications for brain disorders
Journal: Cell
Pulished: Sep 01, 2014
Author: Yuliya E. Borre, Gerard W. O'Keeffe, Gerard Clarke, et al.
Gut microbiota is essential to human health, playing a major role in the bidirectional communication between the gastrointestinal tract and the central nervous system. The microbiota undergoes a vigorous process of development throughout the lifespan and establishes its symbiotic rapport with the host early in life. Early life perturbations of the developing gut microbiota can impact neurodevelopment and potentially lead to adverse mental health outcomes later in life. This review compares the parallel early development of the intestinal microbiota and the nervous system. The concept of parallel and interacting microbial–neural critical windows opens new avenues for developing novel microbiota-modulating based therapeutic interventions in early life to combat neurodevelopmental deficits and brain disorders.
Toward Effective Probiotics for Autism and Other Neurodevelopmental Disorders
Journal: Cell
Pulished: Dec 19, 2013
Author: Jack A. Gilbert, Rosa Krajmalnik-Brown, Dorota L. Porazinska, et al.
Rapid advances in analytical and sequencing technologies have spurred a renaissance of research into connections between the microbial communities that inhabit our gut and physiological conditions. Given the complexity of gut microbial communities, estimated to contain 500–1,000 species that considerably expand our metabolic potential beyond what the human genome encodes, it is perhaps unsurprising that they can influence many aspects of our physiology and gut-linked health and disease. For example, TLR5 knockout mice can become obese because an altered microbial community, instead of affecting metabolic efficiency, increases its appetite (Vijay-Kumar et al., 2010), or in a mouse model of multiple sclerosis, demyelination only occurs in the context of the gut microbiota (Lee et al., 2011,
Berer et al., 2011). In addition, microbial impacts on neurology are also evident, including anxiety and sociability in mice (Collins et al., 2013) and changing emotions in humans who received fermented milk with probiotics (Tillisch et al., 2013). In this issue of Cell, Hsaio et al. (2013)make a striking contribution to our understanding of the influence of gut bacteria using an animal model that replicates autism-like behaviors in mouse offspring following maternal immune activation (Figure 1). They show that microbial shifts within the gut of a mouse resulted in changes of metabolites in the serum and that these lead to the onset of autism-like behaviors. Moreover, administering a beneficial bacterium, Bacteroides fragilis, reversed the physiological, neurological, and immunological anomalies.
The Microbiome and Host Behavior
Journal: Annual Review of Neuroscience
Pulished: July, 2017
Author: Helen E. Vuong, Jessica M. Yano, Thomas C. Fung, and Elaine Y. Hsiao
Main Text: The microbiota is increasingly recognized for its ability to influence the development and function of the nervous system and several complex host behaviors. In this review, we discuss emerging roles for the gut microbiota in modulating host social and communicative behavior, stressor-induced behavior, and performance in learning and memory tasks. We summarize effects of the microbiota on host neurophysiology, including brain microstructure, gene expression, and neurochemical metabolism across regions of the amygdala, hippocampus, frontal cortex, and hypothalamus. We further assess evidence linking dysbiosis of the gut microbiota to neurobehavioral diseases, such as autism spectrum disorder and major depression, drawing upon findings from animal models and human trials. Finally, based on increasing associations between the microbiota, neurophysiology, and behavior, we consider whether investigating mechanisms underlying the microbiota-gut-brain axis could lead to novel approaches for treating particular neurological conditions.
New evidences on the altered gut microbiota in autism spectrum disorders
Journal: Microbiome
Pulished: May 24, 2017
Author: Francesco Strati, Duccio Cavalieri, Davide Albanese, et al.
Astract:
Background: Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by social and behavioural impairments. In addition to neurological symptoms, ASD subjects frequently suffer from gastrointestinal abnormalities, thus implying a role of the gut microbiota in ASD gastrointestinal pathophysiology.
Results: Here, we characterized the bacterial and fungal gut microbiota in a cohort of autistic individuals demonstrating the presence of an altered microbial community structure. A fraction of 90% of the autistic subjects were classified as severe ASDs. We found a significant increase in the Firmicutes/Bacteroidetes ratio in autistic subjects due to a reduction of the Bacteroidetes relative abundance. At the genus level, we observed a decrease in the relative abundance of Alistipes, Bilophila, Dialister, Parabacteroides, and Veillonella in the ASD cohort, while Collinsella, Corynebacterium, Dorea, and Lactobacillus were significantly increased. Constipation has been then associated with different bacterial patterns in autistic and neurotypical subjects, with constipated autistic individuals characterized by high levels of bacterial taxa belonging to Escherichia/Shigella and Clostridium cluster XVIII. We also observed that the relative abundance of the fungal genus Candida was more than double in the autistic than neurotypical subjects, yet due to a larger dispersion of values, this difference was only partially significant.
Conclusions: The finding that, besides the bacterial gut microbiota, also the gut mycobiota contributes to the alteration of the intestinal microbial community structure in ASDs opens the possibility for new potential intervention strategies aimed at the relief of gastrointestinal symptoms in ASDs.
Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders
Journal: Pharmacological Research
Pulished: June, 2018
Author: NarekIsraelyan and Kara GrossMargolisb
Abstract: Autism-spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive patterns of behavior. ASD is, however, often associated with medical comorbidities and gastrointestinal (GI) dysfunction is among the most common. Studies have demonstrated a correlation between GI dysfunction and the degree of social impairment in ASD. The etiology of GI abnormalities in ASD is unclear, though the association between GI dysfunction and ASD-associated behaviors suggest that overlapping developmental defects in the brain and the intestine and/or a defect in communication between the enteric and central nervous systems (ENS and CNS, respectively), known as the gut-brain axis, could be responsible for the observed phenotypes. Brain-gut abnormalities have been increasingly implicated in several disease processes, including ASD. As a critical modulator of ENS and CNS development and function, serotonin may be a nexus for the gut-brain axis in ASD. This paper reviews the role of serotonin in ASD from the perspective of the ENS. A murine model that has been demonstrated to possess brain, behavioral and GI abnormalities mimicking those seen in ASD harbors the most common serotonin transporter (SERT) based mutation (SERT Ala56) found in children with ASD. Discussion of the gut-brain manifestations in the SERT Ala56 mice, and their correction with developmental administration of a 5-HT4 agonist, are also addressed in conjunction with other future directions for diagnosis and treatment.
The Possible Role of the Microbiota-Gut-Brain-Axis in Autism Spectrum Disorder
Journal: Int J Mol Sci.
Pulished: Apr 29, 2019
Author: Srikantha P., Mohajeri MH.
Abstract: New research points to a possible link between autism spectrum disorder (ASD) and the gut microbiota as many autistic children have co-occurring gastrointestinal problems. This review focuses on specific alterations of gut microbiota mostly observed in autistic patients. Particularly, the mechanisms through which such alterations may trigger the production of the bacterial metabolites, or leaky gut in autistic people are described. Various altered metabolite levels were observed in the blood and urine of autistic children, many of which were of bacterial origin such as short chain fatty acids (SCFAs), indoles and lipopolysaccharides (LPS). A less integrative gut-blood-barrier is abundant in autistic individuals. This explains the leakage of bacterial metabolites into the patients, triggering new body responses or an altered metabolism. Some other co-occurring symptoms such as mitochondrial dysfunction, oxidative stress in cells, altered tight junctions in the blood-brain barrier and structural changes in the cortex, hippocampus, amygdala and cerebellum were also detected. Moreover, this paper suggests that ASD is associated with an unbalanced gut microbiota (dysbiosis). Although the cause-effect relationship between ASD and gut microbiota is not yet well established, the consumption of specific probiotics may represent a side-effect free tool to re-establish gut homeostasis and promote gut health. The diagnostic and therapeutic value of bacterial-derived compounds as new possible biomarkers, associated with perturbation in the phenylalanine metabolism, as well as potential therapeutic strategies will be discussed.
Role of the Gut Microbiome in Autism Spectrum Disorders
Journal: Adv Exp Med Biol
Pulished: 2019
Author: Pulikkan J., Mazumder A., Grace T.
Abstract: Autism spectrum disorder (ASD) is a severe neurodevelopmental or neuropsychiatric disorder with elusive etiology and obscure pathophysiology. Cognitive inabilities, impaired communication, repetitive behavior pattern, and restricted social interaction and communication lead to a debilitating situation in autism. The pattern of co-occurrence of medical comorbidities is most intriguing in autism, compared to any other neurodevelopmental disorders. They have an elevated comorbidity burden among which most frequently are seizures, psychiatric illness, and gastrointestinal disorders. The gut microbiota is believed to play a pivotal role in human health and disease through involvement in physiological homoeostasis, immunological development, glutathione metabolism, amino acid metabolism, etc., which in a reasonable way explain the role of gut-brain axis in autism. Branded as a neurodevelopmental disorder with psychiatric impairment and often misclassified as a mental disorder, many experts in the field think that a therapeutic solution to autism is unlikely to emerge. As the pathophysiology is still elusive, taking into account of the various symptoms that are concurrent in autism is important. Gastrointestinal problems that are seen associated with most of the autism cases suggest that it is not just a psychiatric disorder as many claim but have a physiological base, and alleviating the gastrointestinal problems could help alleviating the symptoms by bringing out the much needed overall improvement in the affected victims. A gut disorder akin to Crohn's disease is, sometimes, reported in autistic children, an extremely painful gastrointestinal disease which is named as autistic enterocolitis. This disturbed situation hypothesized to be initiated by dysbiosis or microbial imbalance could in turn perturb the coordination of microbiota-gut-brain axis which is important in human mental health as goes the popular dictum: "fix your gut, fix your brain."
Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance
Journal: Cell
Pulished: Mar 19, 2019
Author: Kun Chen, Xiaoting Luan, Qisha Liu, et al.
Summary: Loss-of-function mutations in the histone demethylases KDM5A, KDM5B, or KDM5C are found in intellectual disability (ID) and autism spectrum disorders (ASD) patients. Here, we use the model organism Drosophila melanogaster to delineate how KDM5 contributes to ID and ASD. We show that reducing KDM5 causes intestinal barrier dysfunction and changes in social behavior that correlates with compositional changes in the gut microbiota. Therapeutic alteration of the dysbiotic microbiota through antibiotic administration or feeding with a probioticLactobacillus strain partially rescues the behavioral, lifespan, and cellular phenotypes observed in kdm5-deficient flies. Mechanistically, KDM5 was found to transcriptionally regulate component genes of the immune deficiency (IMD) signaling pathway and subsequent maintenance of host-commensal bacteria homeostasis in a demethylase-dependent manner. Together, our study uses a genetic approach to dissect the role of KDM5 in the gut-microbiome-brain axis and suggests that modifying the gut microbiome may provide therapeutic benefits for ID and ASD patients.