scholarly journals Shared microbial community changes in female rats and humans with Rett syndrome

2019 ◽  
Author(s):  
Allison Gallucci ◽  
Kelsey Patterson ◽  
Abigael Weit ◽  
William Van Der Pol ◽  
Laura Dubois ◽  
...  
Keyword(s):  
Microbial Community ◽  
Rett Syndrome ◽  
Zinc Finger ◽  
Rat Model ◽  
Gut Microbiome ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Zinc Finger Nuclease ◽  
Female Rats ◽  
The Impact

Abstract Background Rett syndrome (RTT) is an X-linked neurodevelopmental disorder predominantly caused by alterations of the methyl-CpG-binding protein 2 (MECP2) gene. The gut microbiome has been implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) as a regulator of disease severity. Although the gut microbiome has been previously characterized in humans with RTT, the impact of MECP2 mutation on the composition of the gut microbiome in animal models where the host and diet can be experimentally controlled remains to be elucidated.Methods We evaluated the microbial community through 16S sequencing of fecal samples collected across postnatal development as behavioral symptoms appear and progress in a novel zinc-finger nuclease rat model of RTT. Additionally, we profiled fecal levels of fatty acids in MecP2 deficient rats. Lastly, we compared our results to predicted functional shifts in the microbiota of females with RTT compared to their mothers to further examine the translational potential of the current RTT rat model.Results We have identified microbial taxa that are differentially abundant across key timepoints in a zinc-finger nuclease rat model of RTT compared to WT. Furthermore, we have characterized functional categories of gut microbes that are similarly affected in females with RTT and female RTT rats, including similar alterations in pathways related to short chain fatty acid (SCFA) activity. Lastly, we have demonstrated that SCFA levels are decreased in the feces of RTT rats compared to WT.Limitations The current study is potentially limited by age related differences in the microbiome of RTT participants and controls as well as medication effects on the microbiome. Additionally, the current study did not assess male MeCP2-deficient rats, and it may be relevant in future studies to address potentially disparate microbial changes in male and female rats and humans with RTT.Conclusions The results of our studies establish distinct microbial community shifts that occur in RTT across developmental time points independently of diet or environmental factors. We identify p105 as a key translational timepoint at which microbial shifts most closely mirror reported microbiota communities in RTT patients. Overall, these results represent an important step in translational RTT research.

scholarly journals The gut-microbiota-brain axis in autism: what Drosophila models can offer?

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Safa Salim ◽  
Ayesha Banu ◽  
Amira Alwa ◽  
Swetha B. M. Gowda ◽  
Farhan Mohammad
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Neurological Disorders ◽  
Autism Spectrum ◽  
Brain Disorders ◽  
Mediated Communication ◽  
The Impact ◽  
Insight Into ◽  
Drosophila Models

AbstractThe idea that alterations in gut-microbiome-brain axis (GUMBA)-mediated communication play a crucial role in human brain disorders like autism remains a topic of intensive research in various labs. Gastrointestinal issues are a common comorbidity in patients with autism spectrum disorder (ASD). Although gut microbiome and microbial metabolites have been implicated in the etiology of ASD, the underlying molecular mechanism remains largely unknown. In this review, we have summarized recent findings in human and animal models highlighting the role of the gut-brain axis in ASD. We have discussed genetic and neurobehavioral characteristics of Drosophila as an animal model to study the role of GUMBA in ASD. The utility of Drosophila fruit flies as an amenable genetic tool, combined with axenic and gnotobiotic approaches, and availability of transgenic flies may reveal mechanistic insight into gut-microbiota-brain interactions and the impact of its alteration on behaviors relevant to neurological disorders like ASD.

The gap between parents’ knowledge and causal beliefs about etiology of autism: A key variable to understand parents’ anxiety

2014 ◽  
Vol 29 (S3) ◽  
pp. 598-599 ◽  
Author(s):  
C. Derguy ◽  
M. Bouvard ◽  
G. Michel ◽  
K. M’Bailara
Keyword(s):  
Cultural Values ◽  
Medical Information ◽  
Causal Attribution ◽  
Neurodevelopmental Disorder ◽  
Depression Scale ◽  
Parental Beliefs ◽  
Autism Spectrum ◽  
Developmental Trajectory ◽  
Knowledge And Beliefs ◽  
The Impact

Autism Spectrum Disorders (ASD) are associated with higher levels of anxiety for parents [1]. Provide medical information about autism etiology is the first step to help parents to understand the child disorder and to cope with it. The medical current community accepts that autism is a neurodevelopmental disorder in which genes play a role but that environmental factors likely contribute as well [2]. This conception can meet parent's beliefs constructed on their cultural values and personal experiences. In line with causal attribution theory [3], it is important to consider to parental beliefs because it can impact the treatment choices and the child developmental trajectory [4]. The Main purpose is to evaluate the consistency between parental knowledge and beliefs about ASD etiology. The second purpose is to explore the impact of consistency on parents’ anxiety. We interviewed through open-ended questions 89 parents of ASD children aged between 3 to 10 years about their knowledge and their beliefs about ASD etiology. A content analysis was performed using the Nvivo10 software. Anxiety is evaluated with the subscale of the Hospital Anxiety and Depression Scale (HADS). In agreement with previous work four categories of causes have been identified: biological (BIO), psychological (PSY), multifactorial etiology (BIO + PSY), others (OT). A percentage of 55.1% of parents is consistent between their knowledge and beliefs about ASD etiology while 43.8% are inconsistent. Parent anxiety is significantly higher (T (71.91) = 2.34; P < 0.05) when knowledge and beliefs are inconsistent than when they are consistent. This study demonstrates the deleterious impact of inconsistency between knowledge and beliefs about ASD etiology, on parental anxiety. In order to provide relevant support for parents, information delivered after diagnosis must consider pre-existing parental beliefs. A systematic assessment of parental beliefs would adjust the information provided after the diagnosis.

scholarly journals Rett syndrome: a sex-biased neurodevelopmental disorder

2017 ◽  
Vol 39 (1) ◽  
pp. 30-33 ◽  
Author(s):  
Eyleen Goh
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorders ◽  
Expression Profiles ◽  
Neurodevelopmental Disorder ◽  
Gene Expression Profiles ◽  
Autism Spectrum ◽  
Related Disorder ◽  
Genetic Sequences ◽  
Biochemical Profiles ◽  
Males And Females

Decades of research on neurodevelopmental disorders have focused on genetics. Although there has been significant progress, the aetiology of many neurodevelopmental disorders still remains unknown. Deciphering genetic sequences of the whole genome can identify disease-causing mutations in individuals. However, the same genetic sequences do not necessarily result in similar gene expression profiles, or the consequential biochemical profiles in every cell and in all individuals. In particular, studies have shown that differential biochemical profiles in males and females, possibly play a role in neurodevelopmental disorders being biased towards a different gender. Interestingly, autism spectrum disorder (ASD) is biased towards boys although it is not an X-linked disorder, whereas Rett syndrome, an ASD-related disorder where the disease-causing gene is located on the X-chromosome, is found almost exclusively in girls.

scholarly journals The relationship of Rett syndrome and MECP2 disorders to autism

2012 ◽  
Vol 14 (3) ◽  
pp. 253-262 ◽  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Protein Product ◽  
The Many ◽  
Clinical Conditions ◽  
Relationship Of ◽  
The Relationship ◽  
Clinical Problems ◽  
Insight Into

Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders.

scholarly journals Effects of Metformin on Reproductive, Endocrine, and Metabolic Characteristics of Female Offspring in a Rat Model of Letrozole-Induced Polycystic Ovarian Syndrome With Insulin Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Yidong Xie ◽  
Li Xiao ◽  
Shangwei Li
Keyword(s):  
Insulin Resistance ◽  
Rat Model ◽  
Polycystic Ovary ◽  
Body Weight Gain ◽  
Female Offspring ◽  
Female Rats ◽  
Metabolic Characteristics ◽  
Continuous Release ◽  
Reproductive Endocrine ◽  
The Impact

The beneficial effects of metformin, especially its capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), explains why it is widely prescribed. However, its effect on the offspring of patients with PCOS remains uncertain. This study investigated the impact of metformin treatment on the first- and second-generation female offspring born to letrozole-induced PCOS-IR rats. Forty-five female Wistar rats were implanted with continuous-release letrozole pellets or placebo and treated with metformin or vehicle control. Rats exposed to letrozole showed PCOS-like reproductive, endocrine, and metabolic phenotypes in contrast to the controls. Metformin significantly decreased the risk of body weight gain and increased INSR expression in F1 female offspring in PCOS-IR rats, contributing to the improvement in obesity, hyperinsulinemia, and IR. Decreased FSHR expression and increased LHCGR expression were observed in F1 female rats of the PCOS-IR and PCOS-IR+Metformin groups, suggesting that FSHR and LHCGR dysfunction might promote the development of PCOS. Nevertheless, we found no significant differences in INSR, FSHR, and LHCGR expression or other PCOS phenotypes in F2 female offspring of PCOS-IR rats. These findings indicated widespread reproductive, endocrine, and metabolic changes in the PCOS-IR rat model, but the PCOS phenotypes could not be stably inherited by the next generations. Metformin might have contributed to the improvement in obesity, hyperinsulinemia, and IR in F1 female offspring. The results of this study could be used as a theoretical basis in support of using metformin in the treatment of PCOS-IR patients.

scholarly journals Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1)

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Giorgio Pini ◽  
Laura Congiu ◽  
Alberto Benincasa ◽  
Pietro DiMarco ◽  
Stefania Bigoni ◽  
...  
Keyword(s):  
Clinical Study ◽  
Cognitive Ability ◽  
Rett Syndrome ◽  
Brain Activity ◽  
Neurodevelopmental Disorder ◽  
Preliminary Evidence ◽  
Autism Spectrum ◽  
Cognitive Testing ◽  
Clinical Severity ◽  
Recombinant Human Insulin

Rett Syndrome (RTT) is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1), which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p=0.0106) and RSS (p=0.0274) was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum.

scholarly journals Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
E. Golovina ◽  
T. Fadason ◽  
T. J. Lints ◽  
C. Walker ◽  
M. H. Vickers ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Protein Interactions ◽  
Ribosome Biogenesis ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Biological Pathways ◽  
Spectrum Disorder ◽  
Biological Information ◽  
Immune Pathways ◽  
The Impact

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Here, we integrated four distinct levels of biological information (GWAS, eQTL, spatial genome organization and protein–protein interactions) to identify potential regulatory impacts of ASD-associated SNPs (p < 5 × 10–8) on biological pathways within fetal and adult cortical tissues. We found 80 and 58 SNPs that mark regulatory regions (i.e. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. These eQTLs were also linked to other psychiatric disorders (e.g. schizophrenia, ADHD, bipolar disorder). Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. Furthermore, we constructed fetal and adult cortex-specific protein–protein interaction networks and identified that ASD-associated regulatory SNPs impact on immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome in the fetal cortex. By contrast, in the adult cortex they largely affect immune pathways. Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. This approach, in combination with clinical studies on ASD, will contribute to individualized mechanistic understanding of ASD development.

scholarly journals Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Kari Neier ◽  
Tianna E. Grant ◽  
Rebecca L. Palmer ◽  
Demario Chappell ◽  
Sophia M. Hakam ◽  
...  
Keyword(s):  
Mouse Model ◽  
Disease Progression ◽  
Rett Syndrome ◽  
Gut Microbiome ◽  
Neurodevelopmental Disorder ◽  
Molecular Pathways ◽  
Linked Gene ◽  
Disease Phenotypes ◽  
Altered Metabolism ◽  
Inflammatory Profile

AbstractRett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.

scholarly journals The development of animal models for autism: A gene-environment approach

2021 ◽  
Author(s):  
◽  
Peter Ranger
Keyword(s):  
Animal Models ◽  
Prenatal Exposure ◽  
Environmental Risk ◽  
Rat Model ◽  
Immune Activation ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Maternal Immune Activation ◽  
Gene Environment ◽  
Social Communicative

<p>Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterised by social, communicative, and behavioural deficits. Despite decades of research in this field, effective pharmacological treatments for ASD are still lacking and better animal models for this disorder are urgently needed. Although it is now well understood that both genetic and environmental influences play a role in the aetiology of ASD, most existing animal models for this disorder only take into account one of these aetiological contributors and have largely ignored investigating an interaction. The main aim of this thesis was to develop a novel animal model for ASD that demonstrated higher construct validity than traditional models by using a gene-environment approach. To this aim, two previously established environmental risk factor-based models for ASD were each combined with a genetic rat model that mimicked a genotype associated with ASD. Specifically, a maternal immune activation model (modelled via prenatal administration of lipopolysaccharide) and a prenatal exposure to valproate model (modelled via prenatal administration of valproate) were both combined with a serotonin transporter (SERT) knockout rat model. Next, experimental rats were investigated in a variety of paradigms designed to detect behavioural, biochemical, and immunological outcomes related to ASD. This thesis tested the hypothesis that rats with a genetically compromised SERT function would be more vulnerable to the impacts of the two environmental risk factors. Collectively, the data from this thesis show that rats with a genetically compromised SERT function are not more vulnerable to the impacts of a maternal immune activation or prenatal exposure to VPA. In fact, at least with regards to prenatal exposure to valproate, rats with a compromised SERT function actually appeared more resilient to ASD-like outcomes.</p>

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