scholarly journals Effect of Dietary Zinc Supplementation on the Gastrointestinal Microbiota and Host Gene Expression in the Shank3B-/- Mouse Model of Autism Spectrum Disorder

2021 ◽  
Author(s):  
Giselle C Wong ◽  
Yewon Jung ◽  
Kevin Lee ◽  
Chantelle Fourie ◽  
Kim M. Handley ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Autism Spectrum ◽  
Wild Type ◽  
Dietary Zinc ◽  
Knock Out ◽  
Gastrointestinal Problems ◽  
Host Metabolism

Abstract Background: Shank genes are implicated in ~1% of people with autism and mice with Shank3 knock out mutations exhibit autism-like behaviours. Zinc deficiency and gastrointestinal problems can be common among people with autism, and zinc is a key element required for SHANK protein function and gut development. In Shank3B-/- mice, a supplementary zinc diet reverses autism behaviours. We hypothesise that dietary zinc may alter the gut microbiome, potentially affecting the gut-microbiota-brain axis, which may contribute to changes in autism-like behaviours. Methods: Four types of gastrointestinal samples (ileum, caecum, colon, faecal) were collected from wild-type and knock-out Shank3B-/- mice on either control or supplemented-zinc diets. Bacterial 16S rRNA gene and fungal ITS2 genomic region amplicons were sequenced on the Illumina MiSeq platform and RNA on the Illumina HiSeq platform.Results: Cage, genotype and zinc diet each contributed significantly to bacterial community variation (accounting for 12.8%, 3.9% and 2.3% of the variation, respectively). Fungal diversity differed significantly between wild-type and knock-out Shank3B-/- mice on the control zinc diet, and the fungal biota differed among gut locations. RNA-seq analysis of host (mouse) transcripts revealed differential expression of genes involved in host metabolism that may be regulated by the gut microbiota and genes involved in anti-microbial interactions. Limitations: This study used the Shank3B-/- mouse model of autism spectrum disorder. Heterozygous and homozygous Shank3 gene mutations are found in 1% of the ASD population, only homozygous Shank3 mice were utilised in this study. Any translational conclusions should consider these limitations.Conclusions: By utilising the Shank3B-/- knock-out mouse model we were able to examine the influence of – and interactions between – dietary zinc and ASD-linked host genotype. Differential expression of host antimicrobial interaction genes as well as gut microbiota-regulated host metabolism genes among the treatment groups, suggests that the interplay between gut microbes, the gastrointestinal tract and the brain may play a major role towards the observed amelioration of ASD behaviours seen previously with supplemented dietary zinc. These data broaden understanding of the gut microbiome in autism and pave the way towards potential microbial therapeutics for gastrointestinal problems in people with autism.

scholarly journals Effect of dietary zinc supplementation on the gastrointestinal microbiota and host gene expression in the Shank3B−/− mouse model of autism spectrum disorder

2021 ◽  
Author(s):  
Giselle C. Wong ◽  
Yewon Jung ◽  
Kevin Lee ◽  
Chantelle Fourie ◽  
Kim M. Handley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gut Microbiome ◽  
Autism Spectrum ◽  
Wild Type ◽  
Dietary Zinc ◽  
Host Genotype ◽  
Knock Out ◽  
Treatment Groups ◽  
Gastrointestinal Problems ◽  
Host Metabolism

AbstractShank genes are implicated in ~1% of people with autism and mice with Shank3 knock out mutations exhibit autism-like behaviours. Zinc deficiency and gastrointestinal problems can be common among people with autism, and zinc is a key element required for SHANK protein function and gut development. In Shank3B−/− mice, a supplementary zinc diet reverses autism behaviours. We hypothesise that dietary zinc may alter the gut microbiome, potentially affecting the gut-microbiome-brain axis, which may contribute to changes in autism-like behaviours. To test this, four types of gastrointestinal samples (ileum, caecum, colon, faecal) were collected from wild-type and knock-out Shank3B−/− mice on either control or supplemented-zinc diets. Cage, genotype and zinc diet each contributed significantly to bacterial community variation (accounting for 12.8%, 3.9% and 2.3% of the variation, respectively). Fungal diversity differed significantly between wild-type and knock-out Shank3B−/− mice on the control zinc diet, and the fungal biota differed among gut locations. RNA-seq analysis of host (mouse) transcripts revealed differential expression of genes involved in host metabolism that may be regulated by the gut microbiota and genes involved in anti-microbial interactions. By utilising the Shank3B−/− knock-out mouse model we were able to examine the influence of – and interactions between – dietary zinc and ASD-linked host genotype. These data broaden understanding of the gut microbiome in autism and pave the way towards potential microbial therapeutics for gastrointestinal problems in people with autism.ImportancePreviously, supplemental dietary zinc in the Shank3B−/− mouse model of autism spectrum disorder resulted in observations of ASD behaviours reversal; in this study we also used the Shank3B−/− mouse model to examine the influence of – and interaction between – dietary zinc and ASD-linked host genotype. Sample location along the gastrointestinal tract, genotype and zinc diet explained some of the variation in the microbiota data, with notable bacterial differences between treatment groups. Differential expression of host genes between treatment groups, including antimicrobial interaction genes and gut microbiota-regulated host metabolism genes, suggests that the interplay between gut microbes, the gastrointestinal tract and the brain may play a major role towards the observed amelioration of ASD behaviours seen previously with supplemented dietary zinc. These results widen the scope towards manipulating both dietary zinc and the microbiota itself to ameliorate ASD-related behaviours and associated gastrointestinal issues.

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 Gut Microbiome-Based Analysis of Lipid A Biosynthesis in Individuals with Autism Spectrum Disorder: An In Silico Evaluation

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 688
Author(s):  
Abdulkadir Yusif Maigoro ◽  
Soojin Lee
Keyword(s):  
Autism Spectrum Disorder ◽  
Gut Microbiome ◽  
In Silico ◽  
Lipid A ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Synthesis Rate ◽  
Special Focus ◽  
Control Subjects ◽  
Gastrointestinal Problems

The link between autism spectrum disorder (ASD) and the gut microbiome has received much attention, with special focus on gut–brain-axis immunological imbalances. Gastrointestinal problems are one of the major symptoms of ASD and are thought to be related to immune dysregulation. Therefore, in silico analysis was performed on mined data from 36 individuals with ASD and 21 control subjects, with an emphasis on lipid A endotoxin-producing bacteria and their lipopolysaccharide (LPS) metabolic pathways. Analysis of enzyme distribution among the 15 most abundant genera in both groups revealed that almost all these genera utilized five early-stage enzymes responsible for catalyzing the nine conserved lipid A synthesis steps. However, Haemophilus and Escherichia, which were significantly more abundant in individuals with ASD than in the control subjects, possess a complete set of essential lipid A synthesis enzymes. Furthermore, the 10 genera with the greatest increase in individuals with ASD showed high potential for producing late-stage lipid A products. Collectively, these results suggested that the synthesis rate of immunogenic LPS end products is likely to increase in individuals with ASD, which may be related to their gastrointestinal symptoms and elevated inflammatory conditions.

Underdevelopment of the gut microbiota and bacteria species as non-invasive markers of prediction in children with autism spectrum disorder

Gut ◽  
2021 ◽  
pp. gutjnl-2020-324015
Author(s):  
Yating Wan ◽  
Tao Zuo ◽  
Zhilu Xu ◽  
Fen Zhang ◽  
Hui Zhan ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Chinese Children ◽  
Chronological Age ◽  
Microbiome Composition ◽  
Children With Asd ◽  
Faecal Microbiome

ObjectiveThe gut microbiota has been suggested to play a role in autism spectrum disorder (ASD). We postulate that children with ASD harbour an altered developmental profile of the gut microbiota distinct from that of typically developing (TD) children. Here, we aimed to characterise compositional and functional alterations in gut microbiome in association with age in children with ASD and to identify novel faecal bacterial markers for predicting ASD.DesignWe performed deep metagenomic sequencing in faecal samples of 146 Chinese children (72 ASD and 74 TD children). We compared gut microbial composition and functions between children with ASD and TD children. Candidate bacteria markers were identified and validated by metagenomic analysis. Gut microbiota development in relation to chronological age was assessed using random forest model.ResultsASD and chronological age had the most significant and largest impacts on children’s faecal microbiome while diet showed no correlation. Children with ASD had significant alterations in faecal microbiome composition compared with TD children characterised by increased bacterial richness (p=0.021) and altered microbiome composition (p<0.05). Five bacterial species were identified to distinguish gut microbes in ASD and TD children, with areas under the receiver operating curve (AUC) of 82.6% and 76.2% in the discovery cohort and validation cohort, respectively. Multiple neurotransmitter biosynthesis related pathways in the gut microbiome were depleted in children with ASD compared with TD children (p<0.05). Developing dynamics of growth-associated gut bacteria (age-discriminatory species) seen in TD children were lost in children with ASD across the early-life age spectrum.ConclusionsGut microbiome in Chinese children with ASD was altered in composition, ecological network and functionality compared with TD children. We identified novel bacterial markers for prediction of ASD and demonstrated persistent underdevelopment of the gut microbiota in children with ASD which lagged behind their respective age-matched peers.

scholarly journals Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Lorena Coretti ◽  
Claudia Cristiano ◽  
Ermanno Florio ◽  
Giovanni Scala ◽  
Adriano Lama ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Microbiota Composition ◽  
Btbr Mouse ◽  
Gut Microbiota Composition

scholarly journals Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder

2020 ◽  
Author(s):  
Aya Osman ◽  
Nicholas L. Mervosh ◽  
Ana N. Strat ◽  
Katherine R. Meckel ◽  
Tanner J. Euston ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Environmental Factors ◽  
Mouse Model ◽  
Translational Research ◽  
Gut Microbiome ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Research Strategies ◽  
Stage Of Development

AbstractAutism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a very high prevalence rate and a chronic disease course beginning in early childhood. Despite the tremendous burden of ASD, there are currently no disease-modifying treatments. Like many neuropsychiatric illnesses ASD has a complex pathophysiology driven by genetic and environmental factors. There is interest in identifying modifiable environmental factors as potential translational research strategies for development of therapeutics for ASD. A rapidly growing body of research demonstrates that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, have profound influence on brain and behavior. This gut-brain signaling pathway is highly relevant to ASD as the microbiome begins to form at birth, is heavily influenced by environmental factors throughout early life, and begins to stabilize at the same stage of development that symptoms of ASD begin to develop. To investigate potential gene x microbiome interactions in a model of ASD, we utilized mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO), which clinically manifests as Phelan-McDermid syndrome, as a model for genetic risk of ASD. Analysis of the gut microbiome of Shank3KO mice demonstrated genotype effects on both microbiome composition and metabolite production. Behaviorally, Shank3KO mice demonstrate decreased social interactions and have altered anxiety and compulsive-like behaviors. Disruption of the microbiome with broad spectrum antibiotics lead to an exacerbation of all behavioral phenotypes in Shank3KO mice. Additionally, we found that Shank3KO mice had markedly increased changes in gene expression in the prefrontal cortex following microbiome depletion. Taken together, our results suggest a gene x microbiome interaction in this mouse model for ASD and raise the possibility that targeting the microbiome may be a valid translational research strategy in developing therapeutics for ASD.

scholarly journals Changes in Receptive Field Size in Syngap1 +/- Mouse Model of Autism Spectrum Disorder

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Evan Anderson ◽  
Charles A Martin ◽  
Maria Dadarlat
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Receptive Field ◽  
Mouse Model ◽  
Neural Activity ◽  
Autism Spectrum ◽  
Field Size ◽  
Wild Type ◽  
Receptive Field Size ◽  
Field Area

Background and Hypothesis:  Autism spectrum disorder (ASD) is a form of intellectual disability with impairments in social functioning and cognition. Mutations within the SynGAP1 gene are associated with ASD due to over activation of RAS-GTP causing insertion of AMPA receptors onto the post synaptic membrane, and thus early maturation of dendrites. These mutations lead to an excitatory/inhibitory imbalance within the brain, and patients often present with intellectual disability, seizures, and issues of cognition. Research has shown that Syngap1 +/- mice have decreased cortical gray matter brain volume throughout areas involved in the visual system pathway. However, hierarchal visual processing has not been well characterized in a Syngap1 +/- mouse model of autism.   Project Methods:  Using 64 and 128 channel microelectrodes, we recorded the neural activity within V1 of four mice. Neural activity was recorded in response to visual stimuli - testing receptive field size between two wild-type and two Syngap1 +/- mice. Data was run through spike sorting algorithms to identify neurons. Receptive field area for each neuron was then calculated and compared between the two genotypes.   Results:  The receptive field areas of Syngap1 +/- mice were statistically larger (p < 0.01) compared to wild type mice. Syngap1 +/- mice had a mean receptive field area of 450.5 visual degrees (±443.7) and WT mice had a mean receptive field area of 261.1 visual degrees (±187.21). Most of the neurons within Syngap +/- had no distinct receptive field, 67.9%, while only 25.7% of wild type neurons lacked a distinct receptive field.   Conclusion and Potential Impact:  Overall, Syngap1 +/- mice had larger, and less distinct receptive fields compared to wild type mice. Deficiencies in the Syngap1 protein may impair refinement of visual stimuli. Understanding the mechanism of response of missing SynGAP1 can inform directed therapies and interventions to treat patients with the missing gene and manage their intellectual disability.

scholarly journals Serum Oxytocin Level Correlates With Gut Microbiome Dysbiosis in Children With Autism Spectrum Disorder

2021 ◽  
Vol 15 ◽  
Author(s):  
Minshi Huang ◽  
Kevin Liu ◽  
Zhen Wei ◽  
Zhe Feng ◽  
Jierong Chen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Children With Autism ◽  
Preliminary Evidence ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Enzyme Linked Immunosorbent Assay ◽  
Children With Asd ◽  
New Findings

To investigate the levels of serum oxytocin (OT) in children with autism spectrum disorder (ASD) and explore the association between OT levels and gut microbiota relative abundances, we recruited 39 children with ASD children–mother dyads and 44 healthy controls. Serum OT levels were determined via enzyme-linked immunosorbent assay and gut microbiota abundances were determined by 16S rRNA sequencing. We found that the OT level of ASD was lower than the healthy control group overall (P &lt; 0.05). Furthermore, we present preliminary evidence of gut microbiome dysbiosis observed among children with ASD to lower levels of OT based on correlational analysis between serum OT and specific gut microbiota abundances (P &lt; 0.05). We also found sex-related differences in serum OT levels and GIS index (P &lt; 0.05). However, the generalizability of findings relevant to females with ASD require further validation in future studies involving larger sample sizes and balanced sex distributions due to the small number of females involved in this study. Nonetheless, these new findings further our understanding of the effects of low serum OT levels among individuals with ASD, which provides preliminary evidence in hopes of guiding future study design or mechanistic studies. The findings of the present study may be suggestive of potential ASD subtypes based on ASD severity and gut microbiome composition that may facilitate the prediction of the therapeutic responses of OT among those with ASD.

scholarly journals The Possible Role of the Microbiota-Gut-Brain-Axis in Autism Spectrum Disorder

2019 ◽  
Vol 20 (9) ◽  
pp. 2115 ◽  
Author(s):  
Piranavie Srikantha ◽  
M. Hasan Mohajeri
Keyword(s):  
Autism Spectrum Disorder ◽  
Gut Microbiota ◽  
Structural Changes ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Gut Health ◽  
Autistic Children ◽  
Bacterial Metabolites ◽  
Autistic People ◽  
Gastrointestinal Problems

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.

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