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Cited by 309Gut microbiota and healthAutism Spectrum Disorder ResearchGastrointestinal motility and disorders

Association Between Gut Microbiota and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Open access
Xu, Mingyu, Xu, Xuefeng, Li, Jijun, Li, Fei·2019·Frontiers in Psychiatry
DOI 10.3389/fpsyt.2019.00473PMC PMC6673757
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Abstract

Autism spectrum disorders (ASD) are characterized by stereotyped behavior and deficits in communication and social interactions. Gastrointestinal (GI) dysfunction is an ASD-associated comorbidity, implying a potential role of the gut microbiota in ASD gastrointestinal pathophysiology. Several recent studies found that autistic individuals harbor an altered bacterial gut microbiota. In some cases, remodeling gut microbiota by antibiotics administration and microbiota transfer therapy reportedly alleviate the symptoms of ASD. However, there is little consensus on specific bacterial species that are similarly altered across individual studies. The aim of this study is to summarize previously published data, and analyze the relative abundance alteration of bacterial genera in gut microbiota in control and ASD individuals using meta-analysis. We analyzed nine studies including 254 ASD patients and found that children with ASD had lower percentages of Akkermansia, Bacteroides, Bifidobacterium, Parabacteroides, and a higher percentage of Faecalibacterium in the total detected microflora compared with control individuals. In contrast, the children with ASD had lower abundance of Enterococcus, E. coli, Bacteroides, Bifidobacteriums, and higher abundance of Lactobacillus. This meta-analysis suggests an association between ASD and microbiota composition alteration and warrants additional prospective cohort studies to evaluate associations of the bacterial changes with ASD symptoms, which would provide further evidence for precise microbiological treatment of ASD.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis of nine studies found that children with ASD show altered gut microbiota composition at the genus level compared with typically developing controls. The authors report lower Akkermansia, Bacteroides, Bifidobacterium, Parabacteroides, E. coli, and Enterococcus and higher Faecalibacterium and Lactobacillus in ASD, but conclude that prospective cohort studies are needed to clarify the association with ASD symptoms.

Key findings

  • Across nine studies including 254 participants with ASD and 167 age-matched controls (age range 6–11 years), children with ASD had lower percentages of Akkermansia (0.1% vs 0.2%; ratio 0.5), Bacteroides (10.2% vs 14.3%; ratio 0.71), Bifidobacterium (2.2% vs 4.2%; ratio 0.52), and Parabacteroides (0.3% vs 0.5%; ratio 0.6) in total detected microflora.
  • Children with ASD had a higher percentage of Faecalibacterium (10.2% vs 7.7%; ratio 1.32), with Ruminococcus slightly higher (3.4% vs 3.2%; ratio 1.06) and Clostridium similar (6.4% vs 6.3%).
  • Relative abundance analyses showed lower E. coli (SMD −0.33, 95% CI −1.18 to 0.52), Enterococcus (SMD −0.14, 95% CI −0.47 to 0.20), Bacteroides (SMD −0.35, 95% CI −1.2 to 0.51), and Bifidobacterium (SMD −1.05, 95% CI −2.27 to 0.18), and higher Lactobacillus (SMD 0.53, 95% CI −0.001 to 1.1) in ASD.
  • The authors state that neither significant changes in intestinal microbial diversity nor a single “ASD-promoting microbe” were found.

Methods

  • Systematic literature search of PubMed, Web of Science, and Cochrane databases up to July 2017 using PRISMA guidelines; inclusion required observational, case–control, or cohort studies of gut bacteria in children diagnosed with autism/ASD, with sample size and bacterial prevalence data, written in English.
  • Nine studies were included; gut microbiology was assessed by quantitative PCR/PCR, pyrosequencing, culture methods, or FISH, and analyses were restricted to bacterial percentages and relative abundance at the genus level.
  • Fixed-effects and random-effects models were used, with random effects applied when heterogeneity was notable (I² ≥ 50%); standardized mean difference (SMD) was used for continuous variables, and analyses were performed in Stata version 12.0.

Limitations

  • The paper states that study design, specificity, and sensitivity of detection methods varied across included studies, potentially underestimating gut microbiota complexity.
  • The paper states that many reports had relatively small sample sizes, with only two of nine studies recruiting more than 50 participants with ASD, and significant heterogeneity was found when data were pooled.
  • The paper states that analyses were limited to bacterial percentages and abundance at the genus level because of insufficient data for various bacterial taxonomies; the text also makes evident that the included observational/case–control designs cannot establish causality between microbiota changes and ASD.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fpsyt.2019.00473

Cites

Statistics

Claims the paper makes

0 of 66 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In children with ASD, the relative abundance of Enterococcus was lower than in controls (SMD −0.14, 95% CI: −0.47 to 0.20).

    “In contrast, children with ASD had lower abundance of Enterococcus, Escherichia coli, Bacteroides, and Bifidobacterium and higher abundance of Lactobacillus.”
    • Also stated in: § Characteristics of Included Studies · plain
      “The random-effects and fixed-effects models showed a lower relative abundance of E. coli and Enterococcus in children with ASD compared to controls (SMD −0.33, 95% CI: −1.18 to 0.52 and SMD −0.14, 95% CI: −0.47 to 0.20, respectively; Figure 4B and 4C ).”
    • Also stated in: § Alterations of the Gut Microbiota in Patients With ASD · plain
      “Our analyses showed that participants with ASD had a lower abundance of Akkermansia, Bacteroides, Bifidobacterium, E. coli, and Enterococcus, a higher abundance of Faecalibacterium and Lactobacillus, and a slightly increased abundance of Ruminococcus and Clostridium.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The percentage and relative abundance of bacterial genera are comparable across studies despite different detection methods.
    • Rests on an assumption: The ASD and control groups in the included studies are comparable except for ASD diagnosis, so observed microbiota differences are not due to confounding.
    • Rests on an assumption: The diagnosis of ASD based on parent report is valid for classifying participants.
  • Findingown data

    In children with ASD, the percentage of Bacteroides in the total detected microflora was lower (10.2%) than in typically developing controls (14.3%).

    “We analyzed nine studies, including 254 patients with ASD, and found that children with ASD had lower percentages of Akkermansia, Bacteroides, Bifidobacterium, and Parabacteroides and a higher percentage of Faecalibacterium in the total detected microflora compared to controls.”
    • Also stated in: § Characteristics of Included Studies · plain
      “A fixed-effects meta-analysis showed that the percentage of Bacteroides in the total detected microflora was 10.2% (95% CI: 0.041–0.163) in children with ASD but 14.3% in typically developing children (95% CI: 0.069–0.218).”
    • Also stated in: § Alterations of the Gut Microbiota in Patients With ASD · plain
      “Our analyses showed that participants with ASD had a lower abundance of Akkermansia, Bacteroides, Bifidobacterium, E. coli, and Enterococcus, a higher abundance of Faecalibacterium and Lactobacillus, and a slightly increased abundance of Ruminococcus and Clostridium.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The percentage and relative abundance of bacterial genera are comparable across studies despite different detection methods.
    • Rests on an assumption: The ASD and control groups in the included studies are comparable except for ASD diagnosis, so observed microbiota differences are not due to confounding.
    • Rests on an assumption: The diagnosis of ASD based on parent report is valid for classifying participants.
  • Findingown data

    In children with ASD, the percentage of Akkermansia in the total detected microflora was lower (0.1%) than in typically developing controls (0.2%).

    “We analyzed nine studies, including 254 patients with ASD, and found that children with ASD had lower percentages of Akkermansia, Bacteroides, Bifidobacterium, and Parabacteroides and a higher percentage of Faecalibacterium in the total detected microflora compared to controls.”
    • Also stated in: § Characteristics of Included Studies · plain
      “A fixed-effects meta-analysis showed that the percentage of Akkermansia in the total detected microflora was 0.1% in participants with ASD [95% confidence interval (CI): −0.005 to 0.007] compared to 0.2% in typically developing children (95% CI: −0.007 to 0.01).”
    • Also stated in: § Alterations of the Gut Microbiota in Patients With ASD · plain
      “Our analyses showed that participants with ASD had a lower abundance of Akkermansia, Bacteroides, Bifidobacterium, E. coli, and Enterococcus, a higher abundance of Faecalibacterium and Lactobacillus, and a slightly increased abundance of Ruminococcus and Clostridium.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The percentage and relative abundance of bacterial genera are comparable across studies despite different detection methods.
    • Rests on an assumption: The ASD and control groups in the included studies are comparable except for ASD diagnosis, so observed microbiota differences are not due to confounding.
    • Rests on an assumption: The diagnosis of ASD based on parent report is valid for classifying participants.
  • Findingown data

    In children with ASD, the relative abundance of Bifidobacterium was lower than in controls (SMD −1.05, 95% CI: −2.27 to 0.18).

    “In contrast, children with ASD had lower abundance of Enterococcus, Escherichia coli, Bacteroides, and Bifidobacterium and higher abundance of Lactobacillus.”
    • Also stated in: § Characteristics of Included Studies · plain
      “Furthermore, a random-effects model showed a lower abundance of Bifidobacterium in children with ASD (SMD −1.05, 95% CI: −2.27 to 0.18; Figure 4A ).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The percentage and relative abundance of bacterial genera are comparable across studies despite different detection methods.
    • Rests on an assumption: The ASD and control groups in the included studies are comparable except for ASD diagnosis, so observed microbiota differences are not due to confounding.
    • Rests on an assumption: The diagnosis of ASD based on parent report is valid for classifying participants.
  • Findingown data

    In children with ASD, the percentage of Parabacteroides in the total detected microflora was lower (0.3%) than in typically developing controls (0.5%).

    “We analyzed nine studies, including 254 patients with ASD, and found that children with ASD had lower percentages of Akkermansia, Bacteroides, Bifidobacterium, and Parabacteroides and a higher percentage of Faecalibacterium in the total detected microflora compared to controls.”
    • Also stated in: § Characteristics of Included Studies · plain
      “Additionally, the fixed-effects meta-analysis also showed that the percentage of Parabacteroides in the total detected microflora of children with ASD was 0.3% (95% CI: −0.008 to 0.014) compared to 0.5% in typically developing children (95% CI: −0.01 to 0.02; Figure 3B ).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The percentage and relative abundance of bacterial genera are comparable across studies despite different detection methods.
    • Rests on an assumption: The ASD and control groups in the included studies are comparable except for ASD diagnosis, so observed microbiota differences are not due to confounding.
    • Rests on an assumption: The diagnosis of ASD based on parent report is valid for classifying participants.
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 16

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The gut microbiota plays a major role in human physiology and pathology.

    “The gut microbiota plays a major role in human physiology and pathology (45–47).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Lei, 2016, Fatty acids and their therapeutic potential in neurological disorders, Neurochem Int source

      Not checked in the free run.

    • cites [46] Russo, 2017, Gut-brain axis: role of lipids in the regulation of inflammation, pain and CNS diseases, Curr Med Chem source

      Not checked in the free run.

    • cites [47] Slattery, 2016, The significance of the enteric microbiome on the development of childhood disease: a review of prebiotic and probiotic therapies in disorders of childhood, Clin Med Insights Pediatr source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Four investigators independently carried out data extraction.

    “Four investigators independently carried out data extraction of the following items: author(s), publication year, study design, country, study population age, diagnosis of ASD, and effect size.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    At least three studies were used to assess the bacteria in the meta-analyses.

    “To conduct the meta-analyses, at least three studies were used to assess the bacteria.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Discrepancies in extracted data were resolved by consensus discussion.

    “In case of disagreement regarding the extracted data, discrepancies were resolved by consensus discussion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bifidobacterium has long been used as a probiotic to alleviate various diseases by changing the gut microbiota composition.

    “Bifidobacterium has long been used as a probiotic to alleviate various diseases by changing the gut microbiota composition (34, 42).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Wang, 2011, Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism, Appl Environ Microbiol source

      Not checked in the free run.

    • cites [42] Mayer, 2014, Gut microbes and the brain: paradigm shift in neuroscience, J Neurosci source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    A random-effects model was applied when there was notable heterogeneity (I2 index ≥ 50%); otherwise, a fixed-effects model was used.

    “A random-effects model was applied when there was notable heterogeneity (I 2 index ≥ 50%); otherwise, a fixed-effects model was used.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The included studies were analyzed at the genus level for consistency.

    “For consistency, the included studies were analyzed at the genus level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Studies in rodents indicate that the gut microbiota appears to influence the development of emotional behaviors and brain neurotransmitter systems, suggesting the existence of a microbiota gut-brain axis.

    “Studies in rodents have indicated that the gut microbiota appears to influence the development of emotional behaviors and brain neurotransmitter systems, further suggesting the existence of a microbiota gut-brain axis (15–18).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [15] Bravo, 2011, Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [16] Desbonnet, 2014, Microbiota is essential for social development in the mouse, Mol Psychiatry source

      Not checked in the free run.

    • cites [17] Lim, 2017, Modeling environmental risk factors of autism in mice induces IBD-related gut microbial dysbiosis and hyperserotonemia, Mol Brain source

      Not checked in the free run.

    • cites [18] Mayer, 2015, Gut/brain axis and the microbiota, J Clin Invest source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The systematic literature search of PubMed, Web of Science, and Cochrane databases up to July 2017 was performed according to PRISMA guidelines.

    “We performed a systematic literature search of PubMed, Web of Science, and Cochrane databases up to July 2017 using the following terms: “autism (autism spectrum disorder) and microbiota” or “microbiome” or “dysbiosis” according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (31).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Shamseer, 2015, Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation, BMJ source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ruminococcus is an anaerobic Gram-positive coccus that can be found in the gastrointestinal tract.

    “Ruminococcus is an anaerobic Gram-positive coccus that can be found in the GI tract (43, 44).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Prosperi, 2017, Behavioral phenotype of ASD preschoolers with gastrointestinal symptoms or food selectivity, J Autism Dev Disord source

      Not checked in the free run.

    • cites [44] Wang, 2013, Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder, Mol Autism source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The percentage and relative abundance of bacterial genera were used to avoid potential variation caused by different detection methods.

    “The percentage and relative abundance of bacterial genera in the gut microbiota were used in the present analysis to avoid potential variation caused by different detection methods of the microbiota in the included papers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Bacteroides is a Gram-negative bacterium, one of the earliest colonizing and most abundant constituents of the gut microbiota, and may induce an anti-inflammatory milieu.

    “Bacteroides is a Gram-negative bacterium and is one of the earliest colonizing and most abundant constituents of the gut microbiota and may induce an anti-inflammatory milieu (41).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Bolte, 1998, Autism and clostridium tetani, Med Hypotheses source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The standardized mean difference (SMD) measure of effect was used for the continuous variables.

    “The standardized mean difference (SMD) measure of effect was used for the continuous variables (39).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Faraone, 2008, Interpreting estimates of treatment effects: implications for managed care, P T

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Gastrointestinal problems, including constipation, abdominal pain, gaseousness, diarrhea, and flatulence, are common symptoms associated with ASD in a prevalence range from 23% to 70%.

    “Gastrointestinal (GI) problems, including constipation, abdominal pain, gaseousness, diarrhea, and flatulence, are common symptoms associated with ASD in a prevalence range from 23% to 70% (4, 6–8).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Newschaffer, 2007, The epidemiology of autism spectrum disorders, Annu Rev Public Health source

      Not checked in the free run.

    • cites [6] Chaidez, 2014, Gastrointestinal problems in children with autism, developmental delays or typical development, J Autism Dev Disord source

      Not checked in the free run.

    • cites [7] Holingue, 2018, Gastrointestinal symptoms in autism spectrum disorder: a review of the literature on ascertainment and prevalence, Autism Res source

      Not checked in the free run.

    • cites [8] Myers, 2007, Management of children with autism spectrum disorders, Pediatrics source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Standardized data collection, strict inclusion criteria, and multiple statistical tools were used to ensure the most accurate assessment.

    “Standardized data collection, strict inclusion criteria, and multiple statistical tools were used to ensure the most accurate assessment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bifidobacteria are major producers of lactic acid.

    “Bifidobacteria are major producers of lactic acid, which suppress the growth of pathogens such as E. coli across the epithelium, reduce inflammation in the gut, and cooperate with the immune system (67, 68).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Hashemi, 2017, Dietary pea fiber supplementation improves glycemia and induces changes in the composition of gut microbiota, serum short chain fatty acid profile and expression of mucins in glucose intolerant rats, Nutrients source

      Not checked in the free run.

    • cites [68] Mudd, 2017, Serum cortisol mediates the relationship between fecal Ruminococcus and brain N-acetylaspartate in the young pig, Gut Microbes source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All bacterial information was reviewed and selected before the final analyses, including bacterial taxonomy, percentage, and relative abundance.

    “To maintain consistency within the present meta-analysis, all bacterial information were reviewed and selected before the final analyses, including bacterial taxonomy, percentage, and relative abundance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A set of structured criteria modified from previous studies was used to complete the quality assessment of publications.

    “A set of structured criteria modified from previous studies was used to complete the quality assessment of publications.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Statistical heterogeneity was assessed using the I2 value.

    “Statistical heterogeneity was assessed using the I 2 value, which represents the percentage of total variation across different studies, owing to heterogeneity rather than chance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Two reviewers completed the quality assessment independently.

    “Two reviewers completed the quality assessment independently.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Potential mechanisms by which microbiota impacts the gut-brain axis and ASD progression involve inflammatory and metabolic pathways and alteration of epithelial barrier integrity.

    “Potential mechanisms by which microbiota impacts the gut-brain axis and ASD progression involve inflammatory and metabolic pathways and alteration of epithelial barrier integrity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lactic acid produced by Bifidobacteria reduces inflammation in the gut and cooperates with the immune system.

    “Bifidobacteria are major producers of lactic acid, which suppress the growth of pathogens such as E. coli across the epithelium, reduce inflammation in the gut, and cooperate with the immune system (67, 68).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Hashemi, 2017, Dietary pea fiber supplementation improves glycemia and induces changes in the composition of gut microbiota, serum short chain fatty acid profile and expression of mucins in glucose intolerant rats, Nutrients source

      Not checked in the free run.

    • cites [68] Mudd, 2017, Serum cortisol mediates the relationship between fecal Ruminococcus and brain N-acetylaspartate in the young pig, Gut Microbes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gastroesophageal reflux, gastroenteritis, food allergies, and inflammatory bowel disease are more common in children with ASD, probably contributing to the development of GI symptoms.

    “Gastroesophageal reflux, gastroenteritis, food allergies, and inflammatory bowel disease are also more common in children with ASD, probably contributing to the development of GI symptoms (78).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] McElhanon, 2014, Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis, Pediatrics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    More than 50% of GI symptoms may be due to dysbiotic gut microbiota, including increased Ruminococcaceae.

    “More than 50% of GI symptoms may be due to dysbiotic gut microbiota, including increased Ruminococcaceae (76, 77).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [76] Mazefsky, 2014, The association between emotional and behavioral problems and gastrointestinal symptoms among children with high-functioning autism, Autism source

      Not checked in the free run.

    • cites [77] Saulnier, 2011, Gastrointestional microbome signatures of pediatric patients with irritable bowel syndrome, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The studies included in our analysis mainly used culture-based methods, PCR and pyrosequencing, to analyze the changes of particular bacterial groups, which might underestimate the complexity of the gut microbiota.

    “The studies included in our analysis mainly used culture-based methods, PCR and pyrosequencing, to analyze the changes of particular bacterial groups, which might underestimate the complexity of the gut microbiota.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductreasoning

    Suitable analytical and statistical methods are critical to detect the alterations of the abundance of some gut microbiota in patients with ASD.

    “Indeed, we found that suitable analytical and statistical methods are critical to detect the alterations of the abundance of some gut microbiota in patients with ASD.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Our study only analyzed bacterial percentages and abundance at the genus level due to the insufficiency of data for various bacterial taxonomies.

    “Finally, our study only analyzed bacterial percentages and abundance at the genus level due to the insufficiency of data for various bacterial taxonomies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Gut microbial populations in ASD may produce toxic products, including neurotoxins that influence distal sites such as the brain, and exert systemic effects.

    “Furthermore, gut microbial populations in ASD may produce toxic products, including neurotoxins that influence distal sites such as the brain, and exert systemic effects (35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Parracho, 2005, Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children, J Med Microbiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A low level of SCFA was possibly related to probiotic usage, lower saccharolytic fermentation by beneficial bacteria, or increased gut permeability, subsequently exacerbating autistic symptoms.

    “A low level of SCFA was possibly related to probiotic usage, lower saccharolytic fermentation by beneficial bacteria, or increased gut permeability, subsequently exacerbating autistic symptoms (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Adams, 2011, Gastrointestinal flora and gastrointestinal status in children with autism — comparisons to typical children and correlation with autism severity, BMC Gastroenterol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the present study, lower levels of Bifidobacterium and higher levels of Lactobacillus suggested an imbalance in beneficial bacteria.

    “In the present study, lower levels of Bifidobacterium and higher levels of Lactobacillus suggested an imbalance in beneficial bacteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Many reports had relatively small sample sizes with only two of the nine studies recruiting more than 50 participants with ASD.

    “Second, many reports had relatively small sample sizes with only two of the nine studies recruiting more than 50 participants with ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    In our meta-analysis, only two studies enrolled children with ASD who had no GI symptoms, and one study did not provide details about GI symptoms.

    “In our meta-analysis, only two studies enrolled children with ASD who had no GI symptoms (23, 37), and one study did not provide details about GI symptoms (33).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] De Angelis, 2013, Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified, PLoS One source

      Not checked in the free run.

    • cites [37] Inoue, 2016, A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders, Biosci Biotechnol Biochem source

      Not checked in the free run.

    • cites [33] Gondalia, 2010, Faecal microbiota of individuals with autism spectrum disorder, Electron J Appl Psychol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The meta-analysis is inherently limited by the included studies.

    “The meta-analysis is inherently limited by the included studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microbiota and their metabolites are essential in maintaining both white matter and epithelial barrier integrity, which is important for normal brain development and function.

    “Third, microbiota and their metabolites are essential in maintaining both white matter and epithelial barrier integrity, which is important for normal brain development and function (72).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Golubeva, 2017, Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism, EBioMedicine source

      Not checked in the free run.

34 of 34

  • The paper relies on this without support.

    The percentage and relative abundance of bacterial genera are comparable across studies despite different detection methods.

    “The percentage and relative abundance of bacterial genera in the gut microbiota were used in the present analysis to avoid potential variation caused by different detection methods of the microbiota in the included papers.”

  • The paper relies on this without support.

    The ASD and control groups in the included studies are comparable except for ASD diagnosis, so observed microbiota differences are not due to confounding.

    “In total, there were 254 participants with ASD and 167 age-matched typically developing controls with an age range from 6 to 11 years ( Table 1 ).”

  • The paper relies on this without support.

    The diagnosis of ASD based on parent report is valid for classifying participants.

    “The definition of ASD was based on a physician’s diagnosis according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision or a history of ASD reported by the parents of the children.”

  • The paper relies on this without support.

    Akkermansia is a mucin-degrading bacterium present in the gut of typically developing adults.

    “Akkermansia is a mucin-degrading bacterium present in the gut of typically developing adults.”

  • The paper relies on this without support.

    The role of the gut microbiota in development and disease is not yet well understood.

    “The role of the gut microbiota in development and disease is not yet well understood.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentz = 0.44reported p = .658 · recomputed p = .660

    “(Z = 0.44, p = .658”

  • Consistentz = 4.92reported p = 0 · recomputed p < .001

    “(Z = 4.92, p = .000”

  • Consistentz = 0.8reported p = .427 · recomputed p = .424

    “(Z = 0.8, p = .427”

  • Consistentz = 2.27reported p = .023 · recomputed p = .023

    “(Z = 2.27, p = .023”

  • Consistentz = 4.12reported p = 0 · recomputed p < .001

    “(Z = 4.12, p = .000”

  • Consistentz = 2.42reported p = .016 · recomputed p = .016

    “(Z = 2.42, p = .016”

6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported age range excludes ages in the included studies

    Minor

    The stated age range of 6 to 11 years conflicts with Table 1, which lists an included study with participants aged 3-5 years.

  • Species-level E. coli analyzed despite genus-level restriction

    Minor

    The methods say the included studies were analyzed at the genus level, but the results include an analysis of E. coli, a species.

2 of 2

The citation lists haven’t been fetched yet

References 78 · Cited by 309

Authors
Xu, M., Xu, X., Li, J., & Li, F.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Children's Hospital of Zhejiang University (CN)
Corresponding author
Li, Fei
ORCID
Venue
Frontiers in Psychiatry
Publisher
Frontiers Media SA
Published
2019-07-17
Volume
10
Pages
473-473
ISSN
1664-0640 (ISSN-L)
DOI
10.3389/fpsyt.2019.00473
PMC
PMC6673757
OpenAlex
W2952173081
Cited by
309
References
78
Citations by year
2026: 25 · 2025: 34 · 2024: 40 · 2023: 56 · 2022: 55 · 2021: 56 · 2020: 36 · 2019: 5
FWCI
3.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Shanghai Municipal Health Commission (2017ZZ02026)
  • National Natural Science Foundation of China (8171101223, 81571031)
  • Shanghai Municipal Education Commission (81571031, 20152234)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
autism spectrum disorder, gut microbiota, gastrointestinal dysfunction, Akkermansia, Bacteroides, Bifidobacterium, Parabacteroides, Faecalibacterium, Lactobacillus, Enterococcus, Escherichia coli, bacterial abundance, antibiotics, microbiological treatment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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