Disease ⇒ Autism {40000120}

Record Keys


Type:
Disease
Parent:[  ]
Definition:
Autism

Details


Initialisation date:
2019-06-23
Other Terms:
Autism Spectrum Disorders, ASD

Links


Meta Information


MedDra ID:
10080683
MedDra Level:[  ]
ICD:[  ]
Category:
Psychiatry, Pediatric
Zone:[  ]
Mechanism:[  ]

Notes:


- Twenty-seven of their 313 metabolites in faeces and serum were also different, and of the 313, two – 5-aminovaleric acid (5AV) and taurine – were also present in lower quantities. These two molecules are neurotransmitter agonists: their molecular structures resemble that of the GABA and glycine neurotransmitters, and they interfere with the latter’s functions.” As it happens, both GABA and glycine, help the brain develop normally.
And when the scientists injected the mice with 5AV and taurine, the rodents developed ASD-like symptoms. Ergo, bacteria probably interfere with brain functions using these molecules. (1)


- Members of the C. histolyticum group are recognized toxin-producers and may contribute towards gut dysfunction, with their metabolic products also exerting systemic effects.
- Strategies to reduce clostridial population levels harboured by ASD patients or to improve their gut microflora profile through dietary modulation may help to alleviate gut disorders common in such patients. (3)

- L. reuteri produces a metabolite that activates the vagus nerve to promote oxytocin, the cuddle hormone.This hormone then turns on the brain reward center for social behavior. Impeding the message at any point along this relay from bacteria to metabolite to vagus nerve to oxytocin receptors impairs the animals sociability (4)

- Blood of mice with autism symptoms had levels of a chemical called 4-ethylphenylsulphate (4EPS) that were 46 times higher than that of the control group. This substance is structurally similar to a chemical called para-cresol that is elevated in people with autism .
- When the researchers injected 4EPS into wild-type mice, they started behaving like the untreated autistic mice - obsessively repeating some behaviours and squeaking differently when greeting other mice. (5)

- ASD mice were fed with Bacteroides fragilis, a gut microbe with positive effects on the immune system, the abundance of 34% of these metabolites changed back, gut barrier integrity was improved, the gut-microbiome was restored to a non-ASD state, and ASD-related behavioral abnormalities were ameliorated. In addition, a 46-fold increase of 4-ethylphenylsulfate (4-EPS) in the serum of MIA offspring returned to normal levels.
-A second metabolite elevated in the MIA serum, and normalized by treatment with B. fragilis, was indolepyruvate. Indolepyruvate is generated by microbial tryptophan catabolism and is related to indolyl-3-acryloylglycine, another human autism marker. Indolepyruvate elevation could be linked to increased serum levels of serotonin, yet another human autism biomarker.
- Application of the B. fragilis probiotic, increased many other metabolites including N-acetylserine, which the authors hypothesize may provide protection against some ASD symptoms. (6)

- Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter were consistently decreased, while Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium were increased in patients with ASD relative to HCs in certain studies. (7)

- ASD patients reported a decrease in Bifidobacterium and increase in Faecalibacterium and Clostridium genera in ASD patients.
- In individuals with ASD > fecal metabolome > ncrease in p-cresol, a bacterial metabolite derived from tyrosine.

Shared Reference Notes


  • [1.1
    - There is a high coincidence of gastrointestinal (GI) symptoms and compositional changes within the gut microbiome in individuals with ASD. - The degree of GI symptomatology, including constipation and diarrhea, may correlate with the severity of ASD. - Microbiome-induced inflammation’s potential to alter the blood-brain barrier (BBB) permeability. - The same factors affecting gut permeability also affect the permeability of the BBB. - The translocation of pro-inflammatory molecules across the intestinal barrier causes a low-grade systemic inflammatory response, which can alter the BBB’s permeability
  • [1.2
    - Specifically, Bacteroidetes, Bacteroides, and Parabacteroides were decreased in oASD mice, with an increase in Akkermansia, Sutterella, and Lachnospiraceae, as has been reported in humans. - Both the Bacteroides spp. (b20cd_Bacteroides) and P. merdae (4ae7e_Parabacteroides) correlated with reduced repetitive behavior and increased social behavior. - E. tayi (02b40_Lachnospiraceae) showed the opposite effects, as it correlated with increased repetitive behavior and social interaction deficits - P. merdae, were more abundant in ASD individuals from human.
  • [1.3
    - In autism patient Bacteroides, Bifidobacterium, Escherichia coli are reduces and Faecalibacterium, Lactobacillus are increased. The presence of Clostridium remains substantially unchanged
  • [#Antibiotic Therapy] - Autism patients who have had their intestinal microbiota remodeled through the administration of antibiotics or bacterial transfer therapy in the intestine, presented with attenuated symptoms of ASD
  • [#Short Chain Fatty Acid] - The reduction of #Bifidobacterium also results in reduced levels of short-chain fatty acids (SCFAs), common in ASD children.
  • - Increase in #Faecalibacterium in ASD children is responsible for the progression of inflammatory processes, with increased levels of type I interferon, and the alteration of the intestinal barrier.
  • [1.4] [#Limosilactobacillus (Lactobacillus) reuteri
    - Treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. - The effects of L. reuteri on social behavior are not mediated by restoring the composition of the host gut microbiome, which is altered in all of these ASD models. - L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice
  • [1.5] [#Limosilactobacillus (Lactobacillus) reuteri
    - Host genetics and microbiota differentially regulate behaviors in an ASD mouse model - Microbe therapy (L. reuteri) rescues social deficits in ASD mouse model but not hyperactivity - Microbe-induced metabolite tetrahydrobiopterin (BH4) selectively rescues social deficits in ASD mouse model - L. reuteri and tetrahydrobiopterin (BH4) improves in ASD mouse model social-reward-mediated synaptic transmission
  • [1.6] [#Clostridioides difficile
    - Autism incidence has been found to be higher in the C. difficile diseased population.
  • [1.7] [#Para-cresol
    - The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. - Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition.
  • [1.8] [#Folic acid
    - There is an increased frequency of serum auto-antibodies against folate receptor alpha (FRAA) in autism spectrum disorder children.
  • [1.9] [#Indolyl-3-acryloylglycine
  • [#Indolepyruvate
  • [1.11] [#Para-cresol
  • [1.12
  • [1.13
    - #Beta-glucan food supplement > significant decrease in the Childhood Autism Rating Scale score in all of the children of the Nichi Glucan Gr.2 compared with the control. Plasma levels of #Alpha-synuclein were significantly higher in (Nichi Glucan) than in the control group.
  • [1.14] [#Alpha-synuclein, #Amyloid, #Beta-glucan, #Curli] [#Nichi Glucan
  • [1.15
    - children with autism, SCFA levels were differentially altered, with an increase in #Propionate and #Acetate and a decrease in #Butyrate levels. - rats fed with #Propionate exhibited phenotypic features similar to those of autism.
  • [1.16
    - Treatment with #Vitamin B12 in rats with experimental autism improved impaired markers of this neurologic condition
  • [1.17
    - Fecal microbiota transplant (FMT) via gavage from autistic children donors to mice, led to the colonization of ASD-like microbiota and autistic behaviors compared to the offspring of pregnant females exposed to #Valproic acid (VPA). - Such variations seemed to be tightly associated with increased populations of Tenericutes plus a notable reduction (p < 0.001) of Actinobacteria and Candidatus S. in the gastrointestinal region of FMT mice as compared to controls.
  • [1.18
    - up-regulation was found for some metaproteins associated with #Clostridia and with carbohydrate metabolism (glyceraldehyde-3-phosphate and glutamate dehydrogenases), while down-regulation was observed for others associated with #Bacteroidia
  • [1.19] [#Inflamatory bowel disease] [#Sutterella wadsworthensis
    - Sutterella, a Gram-negative genus from Proteobacteria, has been associated with various diseases including autism and inflammatory bowel disease (IBD)
  • - The depletion of #Bifidobacterium species has been reported widely in ASD. - #Bifidobacteria are SCFA producers, and “psychobiotics” , and they modulate the gut–brain signals via γ-aminobutyric acid (GABA) and #Glutamate metabolism. - #Bifidobacterium have been reported to improve behavior and prevent #Depression-like behaviors in mice.
  • - A higher relative abundance of #Alistipes species has been reported in children with autism, pervasive developmental disorder not otherwise specified (PDD-NOS) , and depression. - #Alistipes may disrupt the gut–brain axis by decreasing #Serotonin (indole-positive organism) and impair cognition by producing #Propionic acid in rats.
  • - lower levels of #Prevotella and #Bifidobacterium may lead to reduced levels of #Folate production due to diminished #Folate-dependent remethylation in ASD
  • - lower or depleted levels of #Prevotella in ASD compared to TD in fecal and oral microbiota. - Many gut #Prevotella species are fiber-consuming bacteria.
  • [1.21] [#Cancer
    - #Lachnoclostridium depleted in other psychiatric disorders including #Schizophrenia and autism and in patients with gastrointestinal tract neoplasms.
  • [1.22] [#Prevotella copri
    - P. copri and #Bacteroides fragilis both co-occurred with phages enriched in #Children with ASD or in neurotypical #Children
  • - #Bacteroides thetaiotaomicron was the second most highly elevated microbe when TGF-β was depleted and has been suggested to play a role modulating maternal immune activation-dependent metabolites that are linked to behavorial symptoms
  • - #Prevotella, #Bacteroides and #Bifidobacterium were predominantly associated with the cytokine differentials.
  • - #Bifidobacterium callitrichidarum was the sixth most enriched taxon when #IL-6 was in lower concentration.
  • - concentrations of the inflammatory cytokine transforming growth factor beta (TGF-β) are significantly elevated in #Children with ASD.
  • - Autistic children were less likely to consume foods high in #Glutamic acid, serine, #Choline, #Phenylalanine, #Leucine, #Tyrosine, #Valine and #Histidine, all compounds involved in neurotransmitter biosynthesis
  • [#Fecal Microbiota Transplantation] - children were subjected to a 2-week antibiotic treatment and a bowel cleanse, followed by 2 d of high-dose FMT treatment and 8 weeks of daily maintenance FMT doses. - based on the Childhood Autism Rating Scale (CARS), significant improvements were achieved after the 10-week course of treatment. - Two months later, the initial gains were largely maintained, and a 2-year follow-up showed signs of further improvement in most of the patients. - increase in #Prevotella sp. over the 2-year span of the study. - increase in #Desulfovibrio piger
  • - #Prevotella copri was the second most enriched taxon when #IL-6 was in lower concentration and the sixth most enriched taxon when TGF-β was in lower concentration.
  • [1.23] [#Clostridioides difficile] [#Para-cresol
    - p-Cresol is an aromatic derivative of #Tyrosine produced as a catabolite by many members of the gut microbiota, including some #Bifidobacteriaceae, #Enterobacteriaceae, #Clostridiaceae, #Lactobacillaceae, #Coriobacteriaceae, and #Bacteroidaceae. - #Clostridia difficile has displayed a particular growth advantage on p-cresol and people with autism spectrum disorders often have a gut microbiome that is enriched in #Clostridia.
  • [1.24] [#Bifidobacterium animalis, #Lactobacillus acidophilus, #Lactobacillus plantarum, #Streptococcus thermophilus
    - Sptreptococcus thermophilus, #Bifidobacterium breve, B. animalis, #Lactobacillus helveticus, L. plantarum, L. acidophilus, and L. paracacei > attenuated the inflammatory responses in a VPA-induced rodent ASD model. - psychobiotic treatment decreased serum pro-inflammatory cytokine, #IL-6 levels, and increased anti-inflammatory cytokine, #IL-10 levels, with the improved status of diverse behavior tests including social interaction, #Anxiety, and repetitive behaviors
  • [#GRO-α, #MIP-1α] - ASD > FMT > amelioration of #Anxiety actions and repetitive performance with lower serum levels of metabolites, such as GRO-α and MIP-1α, and a conversely higher level of #MCP-3, #RANTES, and #Eotaxin.
  • - #4-ethylphenylsulfate, which is a dietary #Tyrosine metabolite that is considered to induce ADS-like behavior
  • - The increased abundance of #Clostridia and #Desulfovibrio and #Bacteroidetes/#Firmicutes ratio were related to the severity of ASD and gastrointestinal symptoms.
  • - The levels of oxytocin and #DHEA-S, which have been considered to be etiologies of ASD, were significantly lower in the plasma of #Children with ASD - decreased #DHEA-S levels and a lower #Bacteroidetes/#Firmicutes ratio which increased after #Probiotic implementation
  • - the levels of #Bifidobacterium (known as beneficial bacteria, such as #Lactobacillus species) were significantly lower in the stool of #Children with ASD - After probiotic supplementation, there was a significant increase in the colony counts of #Bifidobacterium and #Lactobacillus with significant improvement in the severity of ASD and gastrointestinal symptoms.
  • - reduced #D-arabinitol levels, a metabolite of #Candida species, in the urine of #Children with ASD after #Probiotic supplementation
  • - TNF-α levels were strongly correlated with GI symptoms and showed a trend toward correlation with ASD severity. - #Probiotic supplementation significantly decreased TNF-α levels in the feces of #Children with ASD.
  • - FMT in the ASD cohort could decrease #GABA and #Serotonin in serum, but the #Dopamine level was increased by FMT.
  • [#Fecal Microbiota Transplantation] - ASD > FMT response significantly reduces the abundance of #Eubacterium coprostanoligenes. - These data also indicated that decrement in the population of #Eubacterium coprostanoligenes by FMT might be a curative technique for ASD symptoms and behaviors.
  • - FMT could exhibit a recovery effect on the serum levels of #Serotonin, #GABA, and DA in the ASD cohort, which means that FMT might be an effective technique in regulating #Neurotransmitters via the MGB axis
  • - rodent ASD model > induced by oral #Propionic acid ingestion. - Lactobacillus bulgaricus and Bifidobacterium infantis could ameliorate glutamate excitotoxicity, a major autistic feature in this model. The therapeutic effect of these psychobiotics might be due to the reduction of oxidative stress, restoration of the depleted #GABA signaling pathway, and upregulation of the #GABA receptor’s gene expression
  • [1.25
    - wheat fiber, may have therapeutic effects on patients with autism by decreasing the population of #Clostridium perfringens and increasing the rate of #Bifidobacteria
  • [1.26
    - presence of #Veillonella is negatively correlated with #Asthma, #Bronchiolitis, and autism
  • [1.27] [#Prevotella copri
    - #Prevotella and P. copri-like operational taxonomic units were absent in children with autism suffering from gastrointestinal problems unrelated to their diet. - in another study, the relative abundance of P. copri was significantly higher in children with ASD than that in healthy controls. - enrichment of P. copri in patients with T2D and suggested P. copri as a potential biomarker.
  • [1.28
  • [1.29
    - increasing #Serotonin synthesis from intestinal endocrine cells has been linked to #Depression and autism.
  • - in a mouse model known to display features of autism spectrum disorder,> concentration of 4-ethyl phenyl #Sulfate (chemically related to 4-methyl #Phenol) was 46-fold higher than in naive mice.
  • [#Gender, #Human breast milk] - boys diagnosed with autism were over three times more likely to have been born to mothers who reported daily consumption of diet soda or #Aspartame during #Pregnancy or breastfeeding.
  • [1.31
    - High blood concentrations of host-modified #4EP, 4-ethylphenol #Sulfate [#4EPS], are associated with an #Anxiety phenotype in autistic individuals. - accumulation of #4EPS in the brain of mice affects connectivity between subregions, particularly those linked to #Anxiety
  • [#Blood Brain Barrier Integrity] - increased intestinal permeability is common in autistic individuals, potentially explaining increased flux of #4EP and/or #4EPS across the gut epithelium and the Blood Brain Barrier [BBB].
  • [#4EPS] - #Clostridium spp. are highly abundant in autistic individuals and yield #4EP precursors.
  • [1.32
    - #Gluconobacter, Pseuodomonas, Kroppenstedtia, #Acinetobacter and #Megamonas were only present in feces from the GP #Children in despite to ASD #Children
  • - #Bifidobacteriaceae were significantly more abundant in the GP group than in ASD and SIB, while #Coriobacteriaceae were significantly more abundant in ASD than in GP and SIB
  • [#Propionic acid, #Valeric acid] - The lower abundance of #Bifidobacterium is the key feature of the microbiota composition associated with severe autism. ASD patients presented significantly higher levels of propionic and valeric acids than General Population at 4–7 years, but these differences disappeared at 8–10 years. - #Bifidobacterium being reduced in children with severe ASD.
  • [#Caproic acid, #Isobutyric acid, #Isovaleric acid, #Propionic acid, #Short Chain Fatty Acid, #Valeric acid] - higher levels of propionic and valeric acids as well as the sum of minor SCFA (isobutyric + isovaleric + valeric + caproic acids) were found in ASD at the age 4–7 years, but these differences disappeared at the age of 8–10 year
  • [#Eubacterium coprostanoligenes] - in contrast to ASD Patient > #Oscillospiraceae , #Christensenellaceae, Eubacterium coprostanoligenes_group, Oscillospirales__UCG-010and #Selenomonadaceae, generally enriched in SIB and GP groups were negatively correlated with #Propionic acid.
  • - significantly higher proportions of #Collinsella, #Coriobacteriaceae UCG-003, #Ruminococcus torques group, #Sarcina, #Slackia, #Solobacterium, #Methanosphera, and #Lachnospiraceae NKA3A20-group were found in ASD
  • [#Short Chain Fatty Acid] - #Coriobacteriaceae, microorganisms significantly increased in the ASD group, correlated positively with all SCFA
  • - #Sarcina, #Solobacterium and #Methanosphera also displaying higher relative abundances in ASD
  • - #Thermodesulfobacteriota displayed significantly higher abundance in #Children with severe ASD than in #Children with mild to moderate ASD
  • [1.33] [#Metabolic associated fatty liver disease, #Metabolic Dysfunction-associated Steatohepatitis
    - #Methyl isobutyl ketone, the highest ketone associated with ASD, we assume that its presence probably derived from the gut microbial imbalance of patients. This metabolite has also been described for nonalcoholic fatty liver disease (NAFLD)/nonalcoholic #Steatohepatitis (NASH) (Del Chierico et al., 2017) and for #Juvenile idiopathic arthritis (JIA)
  • - The GM volatilome of neurotypical ASD subjects was mainly characterized by butyl #Acetate and methyl #Acetate esters.
  • [#Aldehyde] - aldehydes such as benzenacetaldehyde were thought to be involved in the #Phenylalanine pathway > potential ASD biomarkers.
  • - increase of #Phenylacetylglycine has been detected in the urine of children with ASD children, indicating a consistent increase of gut permeability that could be linked to #Phenylalanine accumulation, stimulated by bacterial #Aromatic amino acid biosynthesis via the shikimate pathway.
  • - #Butanoic acid was detected by WGCNA and ML as a biomarker associated with ASD. > as a biomarker associated with ASD patients specifically over 5 years of age > hypothesis of pathogenetic effects triggered by #Butanoic acid in autism
  • [#Butanoic acid, #Propanoic acid] - GM core volatilome for all ASD patients was characterized by over-production of 1-pentanol, 1-butanol, phenyl ethyl alcohol; benzeneacetaldehyde, octadecanal, tetradecanal; #Methyl isobutyl ketone, 2-hexanone, acetone; acetic, propanoic, 3-methyl-butanoic and 2-methyl-propanoic acids; #Indole and #Skatole; and o-cymene.
  • [#Butanoic acid, #Propanoic acid, #Short Chain Fatty Acid] - a bi-directional perturbation of the dopaminergic pathways by both propanoic and butanoic acids has been described, suggesting that a similar dysregulation of brain catecholaminergic system occurs, as a response, in the presence of excessive concentrations of SCFA
  • - #Indole and #Skatole concentrations were increased in children with ASD. - #Indole was more represented in ASD subgroups characterized by low severity symptoms and without GI symptoms
  • - #Tryptophan derivatives such as #Indole and #Skatole were significantly increased (p ≤ 0.05) in #Children with ASD, particularly #Skatole, and thus were also identified as biomarkers by the ML predictive model.
  • [#Para-cresol] - #Phenol and p-cresol were higher in ASD patients
  • [#Para-cresol] [#Antibiotic Therapy] - p-cresol is hypothesized to exacerbate ASD severity and gut disorders, in the presence of intestinal infection, antibiotic consumption, and atypical intestinal permeability considered as potential p-cresol excess sources in ASD
  • - #Phenol compounds were increased in the stool of children with Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) and, especially, ASD.
  • - #Propanoic acid has been shown to induce hyperactivity, monotonous behaviors, impaired social behavior, increased repetitive locomotor activity, caudate spiking, and an innate neuroinflammatory response in ASD patients
  • [#Short Chain Fatty Acid] - #Propanoic acid was associated with the CBCL_EXT scale for ASDs with risk of symptoms, compared to ASDs without clinical symptoms, hence suggesting a role for SCFAs in the manifestation of behavioral problems.
  • [1.34] [#Kidney stone
    - #Desulfovibrio enriched in Nephrolithiasis > The intestinal #oxalate-#Sulfate antiporter (SAT-1) has been implicated in human CaOx nephrolithiasis; as #Sulfate-reducing bacteria, #Desulfovibrio spp. may reduce the bioavailability of the influx substrate leading to greater plasma #oxalate levels, as is observed in cohorts with Autism.
  • [1.35] [#Bacteroides fragilis
    - B. fragilis, was able to ameliorate autism spectrum disorder (ASD)–like symptoms in a mouse model by consuming a microbially dependent metabolite 4-ethylphenylsulfate (#4EPS)
  • [1.36
    - lower faecal #Bifidobacteria abundance in #Children with ASD compared to neurotypical #Children. - #Bifidobacterium was decreased in ASD cases compared to controls. - #Bifidobacteria changes correlated with differently abundant metabolites from derivatives of #Tryptophan metabolisms. - dietary interventions either with #Bifidobacterium strains or other bacterial strains and/or compounds that increase #Bifidobacteria levels in the gut have shown to improve, not only intestinal outcomes, but also ASD severity
  • - Autism > Reduced #Butyricicoccus and #Eubacterium eligens known to exert beneficial effects by modulating immune response and producing health-promoting compounds as short-chain fatty acids.
  • - increased bacterial taxa in ASD phenotype > #Clostridia, #Sarcina and #Parabacteroides, among others.
  • [#Antibiotic Therapy] - antibiotic usage against #Clostridia has shown beneficial effects in behavioural parameters of ASD studies
  • [1.37] [#Bacteroides fragilis
    - Treatment of #Adult offspring with B. fragilis attenuated the ASD-like behavioral phenotypes.
  • [#Bacteroides fragilis] - ASD > increased #Cholesterol biosynthesis genes in the cortices of B. fragilis treated mice.
  • [#Bacteroides fragilis] - The increase in #Bacteroides was initially rather surprising considering a previous rodent study demonstrating that a species of #Bacteroides, B. fragilis, may attenuate ASD-associated behavior.
  • [#Adult] - an increase of #Bacteroides in ASD, that also correlated with increases in interleukin-6. - The effects of this species could be solely exposure time dependent (infancy vs adulthood), as demonstrated here, or they could also be strain specific.
  • [#Gender] - ASD > males have a higher abundance of #Bacteroides than females > it is possible that males are more susceptible to the effects of a further increase in #Bacteroides abundance.
  • - dysregulation of serum #Cholesterol homeostasis in individuals with ASD, and hypocholesterolemia is the most common finding.
  • [1.38
    - L. reuteri produces a metabolite that activates the vagus nerve to promote oxytocin, the cuddle hormone.This hormone then turns on the brain reward center for social behavior. Impeding the message at any point along this relay from bacteria to metabolite to vagus nerve to oxytocin receptors impairs the animals sociability.
  • [1.39

References Notes


[  ]

Common References


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