scholarly journals The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice

2020 ◽  
Author(s):  
Jian-Ming Li ◽  
Ying Li ◽  
Zheng-Yi Luo ◽  
Yu-Ying Hu ◽  
Yue-Wei Bi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Vitamin B6 ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Cellular Level ◽  
Functional Link ◽  
Gut Homeostasis ◽  
Autistic Symptoms ◽  
Deficient Mice ◽  
New Strategies

Abstract Background Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, particularly that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. However, the mechanisms linking the gut microbiota with brain dysfunctions (gut-brain axis) in ASD have not yet been full elucidated. Due to its genetic mutations and downregulated expression in patients with ASD, EPHB6, which also plays important roles in gut homeostasis, is generally considered a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 in regulating the gut microbiota and the development of ASD are unclear.Results Here, we found that the deletion of EphB6 induced autism-like behavior and disturbed the gut microbiota in mice. More importantly, transplantation of the fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotic-treated C57BL/6J mice, and transplantation of the fecal microbiota from wild-type mice ameliorated the autism-like behavior in EphB6-deficient mice. At the metabolic level, the disturbed gut microbiota in EphB6-deficient mice led to vitamin B6 and dopamine defects. At the cellular level, the excitation/inhibition (E/I) balance in the medial prefrontal cortex was regulated by gut microbiota-mediated vitamin B6 in EphB6-deficient mice.Conclusions Our study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B6, dopamine and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD.

scholarly journals Gut microbiota regulates autism-like behavior by mediating vitamin B6 metabolism in EphB6-deficient mice

2020 ◽  
Author(s):  
Jian-Ming Li ◽  
Ying Li ◽  
Zheng-Yi Luo ◽  
Yu-Ying Hu ◽  
Yue-Wei Bi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Vitamin B6 ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Synthesis ◽  
Functional Link ◽  
Regulated Expression ◽  
Autistic Symptoms ◽  
Deficient Mice ◽  
New Strategies

Abstract Background Autism spectrum disorder (ASD) is a developmental disorder with limited effective pharmacological treatments for the core autistic symptoms so far. Increasing evidences, especially the clinical studies in ASD patients, suggest a functional link between gut microbiota and development of ASD. However, the mechanisms linking gut microbiota and brain dysfunctions (gut-brain axis) in ASD are still not well-established. With genetic mutations and down-regulated expression in patients with ASD, EPHB6, which is also important in homeostasis of gut, has been generally considered to be a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 involved in regulating gut microbiota and development of ASD have been unclear. Results Here, we found deletion of EphB6 induced autism-like behavior and disturbed gut microbiota in mice. More importantly, transplanting fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotics-treated C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice ameliorated autism-like behavior in EphB6-deficient mice. At the metabolic levels, disturbed gut microbiota led to vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was induced by gut microbiota-mediated defects of vitamin B6 metabolism in EphB6-deficient mice. Conclusions Our study uncovers a key role for gut microbiota in regulation of autism-like social behavior by mediating vitamin B6 metabolism, dopamine synthesis and E/I balance in EphB6-deficient mice, suggesting new strategies for understanding and treatment of ASD.

scholarly journals Gut microbiota regulates autism-like behavior by mediating vitamin B6 metabolism in EphB6-deficient mice

2020 ◽  
Author(s):  
Jian-Ming Li ◽  
Ying Li ◽  
Zheng-Yi Luo ◽  
Yu-Ying Hu ◽  
Yue-Wei Bi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Vitamin B6 ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Synthesis ◽  
Functional Link ◽  
Regulated Expression ◽  
Autistic Symptoms ◽  
Deficient Mice ◽  
New Strategies

Abstract Background Autism spectrum disorder (ASD) is a developmental disorder with limited effective pharmacological treatments for the core autistic symptoms so far. Increasing evidences, especially the clinical studies in ASD patients, suggest a functional link between gut microbiota and development of ASD. However, the mechanisms linking gut microbiota and brain dysfunctions (gut-brain axis) in ASD are still not well-established. With genetic mutations and down-regulated expression in patients with ASD, EPHB6 , which is also important in homeostasis of gut, has been generally considered to be a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 involved in regulating gut microbiota and development of ASD have been unclear. Results Here, we found deletion of EphB6 induced autism-like behavior and disturbed gut microbiota in mice. More importantly, transplanting fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotics-treated C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice ameliorated autism-like behavior in EphB6-deficient mice. At the metabolic levels, disturbed gut microbiota led to vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was induced by gut microbiota-mediated defects of vitamin B6 metabolism in EphB6-deficient mice. Conclusions Our study uncovers a key role for gut microbiota in regulation of autism-like social behavior by mediating vitamin B6 metabolism, dopamine synthesis and E/I balance in EphB6-deficient mice, suggesting new strategies for understanding and treatment of ASD.

scholarly journals EphB6 regulates social behavior through gut microbiota-mediated vitamin B6 metabolism and excitation/inhibition balance of medial prefrontal cortex in mice

2019 ◽  
Author(s):  
Ying Li ◽  
Zheng-Yi Luo ◽  
Yu-Ying Hu ◽  
Yue-Wei Bi ◽  
Jian-Ming Yang ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Social Behavior ◽  
Gut Microbiota ◽  
Medial Prefrontal Cortex ◽  
Vitamin B6 ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Synthesis ◽  
New Strategy ◽  
Deficient Mice

AbstractAutism spectrum disorder (ASD) is a developmental disorder with no effective pharmacological treatments so far. Gut microbiota has been suggested to contribute to autistic symptoms. However, the key genes and the mechanisms linking gut microbiota and brain dysfunctions in ASD are still unclear. Here, we found deletion of EphB6, an ASD-associated candidate gene, induced dysregulated gut microbiota and autism-like behavior in mice. More importantly, transplanting fecal microbiota from EphB6-deficient mice resulted in disturbed gut microbiota and autism-like behavior in antibiotics-treated C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice ameliorated disturbed gut microbiota and autism-like behavior in mice with deletion of EphB6. At the metabolic levels, dysregulated gut microbiota led to vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was induced by gut microbiota-mediated defects of vitamin B6 metabolism in EphB6-deficient mice. Our study uncovers a key role for EphB6 in regulation of social behavior by gut microbiota-mediated vitamin B6 metabolism, dopamine synthesis and E/I balance, suggesting a new strategy for treatment of ASD patients.

scholarly journals Fecal Supernatant from Adult with Autism Spectrum Disorder Alters Digestive Functions, Intestinal Epithelial Barrier, and Enteric Nervous System

2021 ◽  
Vol 9 (8) ◽  
pp. 1723
Author(s):  
Jacques Gonzales ◽  
Justine Marchix ◽  
Laetitia Aymeric ◽  
Catherine Le Berre-Scoul ◽  
Johanna Zoppi ◽  
...  
Keyword(s):  
Nervous System ◽  
Gut Microbiota ◽  
Enteric Nervous System ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Rrna Gene ◽  
Intestinal Epithelial ◽  
Microbiota Composition ◽  
Α Diversity

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders defined by impaired social interactions and communication with repetitive behaviors, activities, or interests. Gastrointestinal (GI) disturbances and gut microbiota dysbiosis are frequently associated with ASD in childhood. However, it is not known whether microbiota dysbiosis in ASD patients also occurs in adulthood. Further, the consequences of altered gut microbiota on digestive functions and the enteric nervous system (ENS) remain unexplored. Therefore, we studied, in mice, the ability offecal supernatant (FS) from adult ASD patients to induce GI dysfunctions and ENS remodeling. First, the analyses of the fecal microbiota composition in adult ASD patients indicated a reduced α-diversity and increased abundance of three bacterial 16S rRNA gene amplicon sequence variants compared to healthy controls (HC). The transfer of FS from ASD patients (FS–ASD) to mice decreased colonic barrier permeability by 29% and 58% compared to FS–HC for paracellular and transcellular permeability, respectively. These effects are associated with the reduced expression of the tight junction proteins JAM-A, ZO-2, cingulin, and proinflammatory cytokines TNFα and IL1β. In addition, the expression of glial and neuronal molecules was reduced by FS–ASD as compared to FS-HC in particular for those involved in neuronal connectivity (βIII-tubulin and synapsin decreased by 31% and 67%, respectively). Our data suggest that changes in microbiota composition in ASD may contribute to GI alterations, and in part, via ENS remodeling.

scholarly journals Do the Bugs in Your Gut Eat Your Memories? Relationship between Gut Microbiota and Alzheimer’s Disease

2020 ◽  
Vol 10 (11) ◽  
pp. 814
Author(s):  
Emily M. Borsom ◽  
Keehoon Lee ◽  
Emily K. Cope
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Dietary Intervention ◽  
Fecal Microbiota Transplantation ◽  
Neurological Diseases ◽  
Amyloid Β ◽  
Reproductive Organs ◽  
Fecal Microbiota ◽  
Autism Spectrum

The human microbiota is composed of trillions of microbial cells inhabiting the oral cavity, skin, gastrointestinal (GI) tract, airways, and reproductive organs. The gut microbiota is composed of dynamic communities of microorganisms that communicate bidirectionally with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites, known as the gut microbiota–brain axis. The gut microbiota–brain axis is suspected to be involved in the development of neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease, and Autism Spectrum Disorder. AD is an irreversible, neurodegenerative disease of the central nervous system (CNS), characterized by amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Microglia and astrocytes, the resident immune cells of the CNS, play an integral role in AD development, as neuroinflammation is a driving factor of disease severity. The gut microbiota–brain axis is a novel target for Alzheimer’s disease therapeutics to modulate critical neuroimmune and metabolic pathways. Potential therapeutics include probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. This review summarizes our current understanding of the role of the gut microbiota–brain axis and neuroinflammation in the onset and development of Alzheimer’s disease, limitations of current research, and potential for gut microbiota–brain axis targeted therapies.

scholarly journals The Brain-Gut-Microbiome System: Pathways and Implications for Autism Spectrum Disorder

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4497
Author(s):  
Michelle A. Chernikova ◽  
Genesis D. Flores ◽  
Emily Kilroy ◽  
Jennifer S. Labus ◽  
Emeran A. Mayer ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Preclinical Research ◽  
Gastrointestinal Problems ◽  
The Brain

Gastrointestinal dysfunction is one of the most prevalent physiological symptoms of autism spectrum disorder (ASD). A growing body of largely preclinical research suggests that dysbiotic gut microbiota may modulate brain function and social behavior, yet little is known about the mechanisms that underlie these relationships and how they may influence the pathogenesis or severity of ASD. While various genetic and environmental risk factors have been implicated in ASD, this review aims to provide an overview of studies elucidating the mechanisms by which gut microbiota, associated metabolites, and the brain interact to influence behavior and ASD development, in at least a subgroup of individuals with gastrointestinal problems. Specifically, we review the brain-gut-microbiome system and discuss findings from current animal and human studies as they relate to social-behavioral and neurological impairments in ASD, microbiota-targeted therapies (i.e., probiotics, fecal microbiota transplantation) in ASD, and how microbiota may influence the brain at molecular, structural, and functional levels, with a particular interest in social and emotion-related brain networks. A deeper understanding of microbiome-brain-behavior interactions has the potential to inform new therapies aimed at modulating this system and alleviating both behavioral and physiological symptomatology in individuals with ASD.

scholarly journals Establishment and Resilience of Transplanted Gut Microbiota in Aged Mice

2021 ◽  
Author(s):  
Ying Wang ◽  
Jinhui Tang ◽  
Qingqing Lv ◽  
Yuxiang Tan ◽  
Xiaoxiao Dong ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Fecal Microbiota ◽  
Long Term Effects ◽  
Aged Mice ◽  
Gut Homeostasis ◽  
Term Maintenance

Fecal microbiota transplantation (FMT), a procedure in which fecal material is transferred from a donor to a recipient, has been increasingly used as a treatment to restore healthy gut microbiota. There is a substantial difference in the composition of gut microbiota between young and aged hosts, but little is known about whether age matching between the FMT donor and recipient affects microbiota restoration and long-term maintenance. In the present investigation, we aimed to study the establishment and resilience of transplanted gut microbiota in aged recipients. We treated naturally aged mice (20 months old) with a broad-spectrum antibiotic cocktail and monitored the restoration of gut microbiota over 8 weeks. The diversity of gut microbiota in aged mice failed to reach the baseline level via spontaneous recovery; in contrast, FMT from either (age-)matched or unmatched donors facilitated the recovery of gut microbiota diversity. The microbiota transplanted from different donors successfully established in the aged recipients and had long-term effects on the gene expression profiles of the host colon. Finally, we evaluated the long-term maintenance of transplanted microbiota via intentional disruption of gut homeostasis. We found that lack of age matching between FMT donors and recipients may decrease the resilience of transplanted gut microbiota against colonic inflammation. The results from our study systematically examining the effects of FMT on the gut homeostasis of aged hosts suggest that the compatibility between donors and recipients should be taken into account when implementing FMT.

scholarly journals Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Ning Li ◽  
Hongyan Chen ◽  
Yi Cheng ◽  
Fenghua Xu ◽  
Guangcong Ruan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Gastrointestinal Symptoms ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Autism Symptoms ◽  
Clinical Trial Registry ◽  
Children With Asd ◽  
Gi Symptoms

Autism spectrum disorder (ASD) is a severe brain development disorder that is characterized by deficits in social communication and restricted, repetitive and stereotyped behaviors. Accumulating evidence has suggested that gut microbiota disorders play important roles in gastrointestinal symptoms and neurodevelopmental dysfunction in ASD patients. Manipulation of the gut microbiota by fecal microbiota transplantation (FMT) was recently shown to be a promising therapy for the treatment of various diseases. Here, we performed a clinical trial to evaluate the effect of FMT on gastrointestinal (GI) and ASD symptoms and gut microbiota alterations in children with ASD. We found that there was a large difference in baseline characteristics of behavior, GI symptoms, and gut microbiota between children with ASD and typically developing (TD) control children. FMT could improve GI symptoms and ASD symptoms without inducing any severe complications. Similarly, FMT significantly changed the serum levels of neurotransmitters. We further observed that FMT could promote the colonization of donor microbes and shift the bacterial community of children with ASD toward that of TD controls. The abundance of Eubacterium coprostanoligenes pre-FMT was positively correlated with high GSRS scores, whereas a decrease in Eubacterium coprostanoligenes abundance induced by FMT was associated with the FMT response. Our data suggest that FMT might be a promising therapeutic strategy to improve the GI and behavioral symptoms of patients with ASD, possibly due to its ability to alter gut microbiota and highlight a specific microbiota intervention that targets Eubacterium coprostanoligenes that can enhance the FMT response. This trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) (trial registration number ChiCTR1800014745).

scholarly journals Cage environment regulates gut microbiota independent of toll-like receptors

2021 ◽  
Author(s):  
J.H. Lipinski ◽  
X. Zhou ◽  
S.J Gurczynski ◽  
J.R. Erb-Downward ◽  
R.P. Dickson ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Fecal Microbiota ◽  
Toll Like Receptors ◽  
Wild Type ◽  
Immunological Responses ◽  
Epithelial Homeostasis ◽  
Changes Over Time ◽  
Deficient Mice

The gut microbiome orchestrates epithelial homeostasis and both local and remote immunological responses. Critical to these regulatory interactions are innate immune receptors termed toll-like receptors. Studies to date have implicated innate immunity and toll-like receptors in shaping key features of the gut microbiome. However, a variety of biological and environmental variables are also implicated in determining gut microbiota composition. In this report, we hypothesized that co-housing and environment dominated the regulation of gut microbiota in animal models independent of innate immunity. To determine the importance of these variables, innate immunity or environment in shaping gut microbiota, we used a randomized co-housing strategy and transgenic TLR-deficient mice. We have found that mice co-housed together by genotype exhibited limited changes over time in the composition of gut microbiota. However, in mice randomized to cage, we report extensive changes in gut microbiota, independent of TLR function whereby the fecal microbiota of TLR-deficient mice converge with wild type. TLR5-deficient mice in these experiments exhibit a greater susceptibility for comparative changes in microbiota to other TLR-deficient mice and wild type mice. Our work has broad implications for the study of innate immunity and host-microbiota interactions. Given the profound impact that gut dysbiosis may have on immunity, this report highlights the potential impact of co-housing on gut microbiota and indices of inflammation as outcomes in biological models of infectious or inflammatory disease.

scholarly journals Atherosclerosis Amelioration by Allicin in Raw Garlic through Gut Microbiota and Trimethylamine-N-Oxide Modulation

2021 ◽  
Author(s):  
Lee-Yan Sheen ◽  
Suraphan Panyod ◽  
Wei-Kai Wu ◽  
Pei-Chen Chen ◽  
Kent-Vui Chong ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Gut Microbiota ◽  
Human Subjects ◽  
Fecal Microbiota ◽  
Beneficial Bacteria ◽  
Cvd Risk ◽  
Deficient Mice ◽  
Primary Compound ◽  
Aortic Lesions

Abstract Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO) formed from ʟ-carnitine. Raw garlic juice, with allicin as its primary compound, has been shown to powerfully impact the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in ʟ-carnitine-fed C57BL/6J mice. It also reduced aortic lesions and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient mice. In human subjects exhibiting high TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro study, raw garlic juice inhibited γ-butyrobetaine (γBB) and trimethylamine (TMA) production by the gut microbiota. Thus, raw garlic juice can potentially prevent cardiovascular disease by decreasing TMAO production through gut microbiota modulation.

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