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Cited by 336Gut microbiota and healthAutism Spectrum Disorder ResearchGastrointestinal motility and disorders

Altered composition and function of intestinal microbiota in autism spectrum disorders: A systematic review

Open access
Liu, Feitong, Li, Jie, Wu, Fan, Zheng, Huimin, Peng, Qiongling, Zhou, Hongwei·2019·Translational Psychiatry
DOI 10.1038/s41398-019-0389-6PMC PMC6351640
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Abstract

At present, the pathophysiology of autism spectrum disorder (ASD) remains unclear. Increasing evidence suggested that gut microbiota plays a critical role in gastrointestinal symptoms and behavioral impairment in ASD patients. The primary aim of this systematic review is to investigate potential evidence for the characteristic dysbiosis of gut microbiota in ASD patients compared with healthy controls (HCs). The MEDLINE, EMBASE, Web of Science and Scopus were systematically searched before March 2018. Human studies that compared the composition of gut microbiota in ASD patients and HCs using culture-independent techniques were included. Independent data extraction and quality assessment of studies were conducted according to PRISMA statement and Newcastle-Ottawa Scale. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to infer biological functional changes of the shifted microbiota with the available data in four studies. Sixteen studies with a total sample size of 381 ASD patients and 283 HCs were included in this systematic review. The quality of the studies was evaluated as medium to high. The overall changing of gut bacterial community in terms of β-diversity was consistently observed in ASD patients compared with HCs. Furthermore, 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. This systematic review demonstrated significant alterations of gut microbiota in ASD patients compared with HCs, strengthen the evidence that dysbiosis of gut microbiota may correlate with behavioral abnormality in ASD patients. However, results of inconsistent changing also existed and further big-sampled well-designed studies are needed. Generally, as a potential mediator of risk factors, the gut microbiota could be a novel target for ASD patients in the future.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review of 16 culture-independent studies found consistent evidence of altered gut microbiota composition in ASD patients versus healthy controls, especially differences in β-diversity and several bacterial genera. However, heterogeneity and conflicting findings across studies prevented meta-analysis and limit firm conclusions.

Key findings

  • Sixteen studies with 381 ASD patients and 283 healthy controls were included; study quality was medium to high by the Newcastle-Ottawa Scale.
  • β-diversity differed between ASD patients and controls: of ten studies analyzing β-diversity, six consistently reported that ASD microbiota clustered significantly apart from controls.
  • Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter were consistently decreased, while Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium were increased in ASD patients relative to controls in certain studies.
  • PICRUSt-based functional prediction in four studies showed substantial differences in microbial functional modules in three studies, but no difference in one study; enriched pathways in ASD included metabolism-related modules and some neurodegenerative disease pathways.

Methods

  • Systematic review following PRISMA, registered at PROSPERO (CRD42017060769), searching MEDLINE, EMBASE, Web of Science, and Scopus before March 2018.
  • Included human studies comparing gut microbiota in ASD patients and healthy controls using culture-independent techniques (metagenomic sequencing, 16S rDNA sequencing, qPCR, or FISH); participants were aged 2–18.
  • Data extraction and Newcastle-Ottawa Scale quality assessment were performed independently; PICRUSt and LEfSe were used for secondary functional analysis where raw sequencing data or OTU biome files were available.

Limitations

  • The paper states that methodological and clinical heterogeneity made it impossible to combine results into a meta-analysis, and that only four studies provided raw sequencing data or biome files for PICRUSt analysis.
  • The paper notes possible language bias because searches used English-language-dominated databases, and publication bias is a common challenge, though two included studies reported null findings.
  • Evident from the text: sample sizes ranged from 12 to 104, results for several taxa were conflicting across studies, and heterogeneity arose from sample source, DNA extraction, primers, sequencing platform, diet, control type (sibling vs non-sibling), and baseline GI symptoms.

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

Integrity signals

Registry

Crossref · 10.1038/s41398-019-0389-6

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 121 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    No systematic review has addressed the evidence of altered gut microbiota in ASD patients focusing on culture-independent methods, especially high-throughput sequencing techniques.

    “At present, no systematic review has addressed the evidence of the altered gut microbiota in ASD patients focusing on culture-independent methods especially the high-throughput sequencing techniques.”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    After exclusions, 17 articles corresponding to 16 studies were included in the systematic review.

    “Thus, a total of 17 articles (16 studies) were included.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Four studies consistently demonstrated a significant decrease of Bifidobacterium in ASD patients relative to healthy controls.

    “Further analysis of the alterations of genus and species in ASD, four studies consistently demonstrated a significantly decrease of Bifidobacterium in patients with ASD relative to HCs19,23,27,30.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Kang, D. W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5, 10 (2017). source

      Not checked in the free run.

    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

    • cites [27] Finegold, S. M. et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16, 444–453 (2010). source

      Not checked in the free run.

  • Findingnone given

    Results of inconsistent changing also existed across studies.

    “However, results of inconsistent changing also existed and further big-sampled well-designed studies are needed.”
    Quote in the paperSubstantial claim
  • Findingcitation

    De Angelis et al. reported increased α-diversity in both AD and PDD-NOS patients compared with sibling controls.

    “De Angelis et al.23 reported the increased α-diversity was found in both AD and PDD-NOS patients compared with their sibling control.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 36
  • May combine two claims. 53
  • The quote only partly states this claim. 1

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

    Findingown data

    A total of 381 ASD patients and 283 HCs were included, with sample size ranging from 12 to 104.

    “A total of 381 ASD patients and 283 HCs were included, with sample size ranged from 12 to 104.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The databases used for mapping sequences were GreenGenes, RDP-II, Silva, SSURef and GenBank, while one study did not report the database used.

    “Meanwhile, the database used for mapping the sequences were GreenGenes16,18–20,24, RDP-227, Silva17,21, SSURef22 and GenBank23, while one study26 did not report the database used.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The age of ASD patients ranged from 2-18 and the proportion of male ranged from 77.5-100%.

    “The age of ASD patients ranged from 2–18 and the proportion of male ranged from 77.5–100%.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    The remaining four studies consistently reported that some of the ASD patients had special diets, such as casein-free (CF) or gluten-free (GF) diet.

    “The remaining four studies consistently reported that some of the ASD patients had special diets, such as casein-free (CF) or gluten-free (GF) diet21,22,27,32.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Of 283 HCs, 107 subjects were healthy siblings.

    “Of 283 HCs, 107 subjects were healthy siblings21,23,26.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Different diagnostic criteria were used across studies, and two studies did not report the specific diagnostic criteria.

    “Different diagnostic criteria were used: ADOS, DSM-5, ABD, ADI-R, and CARS. However, two studies31,32 did not report the specific diagnostic criteria.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The electronic search identified 985 records.

    “In total, 985 records were identified through the electronic search.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Ten studies assessed gut microbiota by high-throughput molecular approaches (Illumina MiSeq, 454 pyrosequencing or bTEFAP using a 454 FLX Sequencer), three studies detected gut microbiota with qPCR, one with FISH, and one used both sequencing and qPCR.

    “Ten studies16–23,26,27 assessed gut microbiota by high-throughput molecular approaches: Illumina MiSeq platforms, 454 pyrosequencing or bTEFAP using a 454 FLX Sequencer. Three studies28–31 detected gut microbiota with qPCR and one32 with FISH approach. One study24,25 used both sequencing and qPCR method.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Concerning GI symptoms, five studies reported all ASD patients had GI symptoms, seven studies reported a part of ASD patients had GI symptoms, and three studies conducted in ASD patients without any GI symptoms.

    “Concerning about GI symptoms, five studies17,19,22,24,27 reported all of the ASD patients had GI symptoms, seven studies16,18,21,26,28,29,32 reported that a part of ASD patients had GI symptoms. And three studies20,23 conducted in ASD patients without any GI symptoms.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Son et al. conducted further nutritional analysis of one-week food diary and found no significant difference between the two groups with respect to daily intake of macronutrients (calories, protein, fats, carbohydrates, sugars or dietary fiber).

    “In addition, Son et al.21 conducted further nutritional analysis of one-week food diary, no significant difference between two group with respect to daily intake of macronutrients (calories, protein, fats, carbohydrates, sugars or dietary fiber) were noted.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Son, J. S. et al. Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection. PLoS. ONE. 10, e0137725 (2015). source

      Not checked in the free run.

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

    Findingown data

    Of the studies adopting 16S rDNA-based method, two studies did not report which hypervariable region of the 16S rDNA was targeted, and the remaining studies targeted varied sets of regions.

    “Of the studies adopting 16S rDNA-based method, two studies26,27 did not report which hypervariable region of the 16S rDNA was targeted and the remaining studies targeted varied sets of regions.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Only six studies reported dietary information.

    “As restricted diet is very common in ASD patients, we tried to extract the information of eating habit in ASD and control group. Whereas, only six studies reported dietary information.”
    Quote in the paperNot a substantial claim

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

    Findingreasoning

    Song et al. and Helena et al. lacked an adequate definition of the ASD patients, thus these two studies achieved 3 points in the selection assessment.

    “When assessing the quality of selection, the studies of Song et al.31 and Helena et al.32 lacked an adequate definition of the ASD patients, thus these two studies achieved 3 points in the selection assessment.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Song, Y., Liu, C. & Finegold, S. M. Real-time PCR quantitation of clostridia in feces of autistic children. Appl. Environ. Microbiol. 70, 6459–6465 (2004). source

      Not checked in the free run.

    • cites [32] Parracho, H. M., Bingham, M. O., Gibson, G. R. & McCartney, A. L. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J. Med. Microbiol. 54, 987–991 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Ten studies analyzed β-diversity, and six consistently reported that the microbiota of ASD patients clustered significantly apart from that of healthy controls.

    “In this systematic review, ten studies analyzed β-diversity (unweighted UniFrac distance, weighted UniFrac distances, and Bray-Curtis), six of them consistently reported that the microbiota of ASD patients clustered significantly apart from that of HCs16–18,23,27.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [16] Kang, D. W. et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe 49, 121–131 (2018). source

      Not checked in the free run.

    • cites [17] Luna, R. A. et al. Distinct Microbiome-Neuroimmune Signatures Correlate with Functional Abdominal Pain in Children with Autism Spectrum Disorder. Cell. Mol. Gastroenterol. Hepatol. 3, 218–230 (2017). source

      Not checked in the free run.

    • cites [18] Strati, F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5, 24 (2017). source

      Not checked in the free run.

    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

    • cites [27] Finegold, S. M. et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16, 444–453 (2010). source

      Not checked in the free run.

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

    Findingown data

    Although age structure varied greatly among studies, extensive overlap was found that age of all participants ranged from two to eighteen.

    “Although age structure varied greatly among studies, extensive overlap was found that age of all participants ranged from two to eighteen.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Possible clinical heterogeneity included age, gender, type of control (sibling vs non-sibling) and whether had GI symptoms.

    “Possible clinical heterogeneity included age, gender, type of control (sibling vs non-sibling) and whether had GI symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Methodological sources of heterogeneity included the type of sample (fecal or biopsy), the temperature samples stored, the methods of DNA extraction and the primer used to PCR.

    “Methodological sources of heterogeneity included the type of sample (fecal or biopsy), the temperature samples stored, the methods of DNA extraction and the primer used to PCR.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Son et al., De Angelis et al. and Gondalia et al. recruited healthy siblings as control, whereas other studies recruited normal control from the whole population.

    “Besides, Son et al.21, De Angelis et al.23 and Gondalia et al.26 recruited healthy siblings as control, whereas other studies recruited normal control from the whole population.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Son, J. S. et al. Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection. PLoS. ONE. 10, e0137725 (2015). source

      Not checked in the free run.

    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

    • cites [26] Gondalia, S. V. et al. Molecular characterization of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 5, 419–427 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The abundance of Blautia, Dialister, Prevotella, Turicibacter, and Veillonella were all decreased in ASD patients.

    “Consistent with this, the abundance of Blautia17,20, Dialister18,27, Prevotella16,22,23, Turicibacter23,27 and Veillonella18,22 were all decreased.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Luna, R. A. et al. Distinct Microbiome-Neuroimmune Signatures Correlate with Functional Abdominal Pain in Children with Autism Spectrum Disorder. Cell. Mol. Gastroenterol. Hepatol. 3, 218–230 (2017). source

      Not checked in the free run.

    • cites [20] Inoue, R. et al. 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. 80, 2450–2458 (2016). source

      Not checked in the free run.

    • cites [18] Strati, F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5, 24 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Luna et al. and William et al. only included male individuals, while the remaining studies included both male and female.

    “In terms of gender, Luna et al.17 and William et al.24 only included male individuals, the remaining studies included both male and female.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Luna, R. A. et al. Distinct Microbiome-Neuroimmune Signatures Correlate with Functional Abdominal Pain in Children with Autism Spectrum Disorder. Cell. Mol. Gastroenterol. Hepatol. 3, 218–230 (2017). source

      Not checked in the free run.

    • cites [24] Williams, B. L. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS. ONE. 6, e24585 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    Although the included studies had slight differences in primer selection, there was significant overlap in the key variable and constant regions of the 16S gene.

    “Although the included studies had slightly differences in primer selection, there was significant overlap in the key variable and constant regions of the 16S gene.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Luna et al., Inoue et al., De Angelis et al. and William et al. included case and control with better design, such as all participants had consistent GI symptoms at baseline, thus these studies achieved 2 points in the comparability assessment.

    “As for comparability, Luna et al.17, Inoue et al.20, De Angelis et al.23 and William et al.24,25 included case and control with better design, such as all participants has consistent GI symptoms at baseline, thus these studies achieved 2 points in the comparability assessment.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [17] Luna, R. A. et al. Distinct Microbiome-Neuroimmune Signatures Correlate with Functional Abdominal Pain in Children with Autism Spectrum Disorder. Cell. Mol. Gastroenterol. Hepatol. 3, 218–230 (2017). source

      Not checked in the free run.

    • cites [20] Inoue, R. et al. 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. 80, 2450–2458 (2016). source

      Not checked in the free run.

    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

    • cites [24] Williams, B. L. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS. ONE. 6, e24585 (2011). source

      Not checked in the free run.

    • cites [25] Williams, B. L., Hornig, M., Parekh, T. & Lipkin, W. I. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio 3, e00261–11 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Two sequencing studies reported Akkermansia elevated in ASD patients, while one qPCR study indicated lower Akkermansia muciniphila in feces of ASD patients than healthy controls.

    “Two sequencing studies reported that the abundance of Akkermansia was elevated in ASD patients22,23. Inconsistently, one qPCR study30 indicated that lower amount of Akkermansia muciniphila was found in feces of ASD patients than HCs.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Kang, D. W. et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS. ONE. 8, e68322 (2013). source

      Not checked in the free run.

    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

    • cites [30] Wang, L. et al. Low Relative Abundances of the Mucolytic Bacterium Akkermansia muciniphila and Bifidobacterium spp. in Feces of Children with Autism. Appl. Environ. Microbiol. 77, 6718–6721 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Dorea and Sutterella were reported increased significantly in ASD patients, but were reported decreased in another study.

    “Dorea18,23 and Sutterella25,29 were reported increased significantly in ASD patients, but they were reported decreased in another study17.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Strati, F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5, 24 (2017). source

      Not checked in the free run.

    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

    • cites [25] Williams, B. L., Hornig, M., Parekh, T. & Lipkin, W. I. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio 3, e00261–11 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Lactobacillus, Bacteroides, and Desulfovibrio were all increased in ASD patients rather than controls.

    “In contrast, Lactobacillus18,28, Bacteroides23,27, and Desulfovibrio27,28 were all increased in ASD patients rather than controls.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Strati, F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5, 24 (2017). source

      Not checked in the free run.

    • cites [28] Tomova, A. et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiol. Behav. 138, 179–187 (2015). source

      Not checked in the free run.

    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    William et al. and Finegold et al. both reported that Proteobacteria was elevated in ASD patients rather than healthy controls.

    “Consistently, William et al.24 and Finegold et al.27 both reported that the Proteobacteria was elevated in ASD patients rather than HCs.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Williams, B. L. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS. ONE. 6, e24585 (2011). source

      Not checked in the free run.

    • cites [27] Finegold, S. M. et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16, 444–453 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Enterobacter and Shigella were increased in ASD patients and were positively correlated with GI symptoms in autism.

    “De Angelis et al.23 indicated that Enterobacter and Shigella were increased in ASD patients, which were positively correlated with the GI symptoms in autism18.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

    • cites [18] Strati, F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5, 24 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Faecalibacterium and Ruminococcus were reported increased in ASD patients by three studies, but were reported reduced in another study.

    “Faecalibacterium20,23,24 and Ruminococcus23,24,29 were reported increased in ASD patients by three studies, but they were reported reduced in another study27.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] Inoue, R. et al. 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. 80, 2450–2458 (2016). source

      Not checked in the free run.

    • cites [23] De Angelis, M., Francavilla, R., Piccolo, M., De Giacomo, A. & Gobbetti, M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207–213 (2015). source

      Not checked in the free run.

    • cites [24] Williams, B. L. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS. ONE. 6, e24585 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In two studies of Kang et al., pathways of Cell Motility, Cellular Processes, and Bacterial motility proteins had consistent significant discriminative power in healthy controls; Bacterial chemotaxis and Flagellar assembly were also noted.

    “In two studies of Kang et al. (Figs. 2b, c)19,22, the pathways of “Cell Motility”, “Cellular Processes” and “Bacterial motility proteins” had consistent significant discriminative power in HCs. In addition, “Bacterial chemotaxis” and “Flagellar assembly” were also noted.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Kang, D. W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5, 10 (2017). source

      Not checked in the free run.

    • cites [22] Kang, D. W. et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS. ONE. 8, e68322 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Pathways of Huntingtons disease, Amyotrophic lateral sclerosis, and Glutamatergic synapse were increased in ASD patients.

    “It should be noted that pathways of “Huntingtons disease” and “Amyotrophic lateral sclerosis (ALS)” under Neurodegenerative Diseases category as well as “Glutamatergic synapse” under Nervous System category were also increased in ASD patients.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Kang, D. W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5, 10 (2017). source

      Not checked in the free run.

    • cites [22] Kang, D. W. et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS. ONE. 8, e68322 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    Several included studies reported the Firmicutes/Bacteroidetes ratio, but no concordant conclusions were reached.

    “Several included studies reported the Firmicutes/Bacteroidetes ratio due to the alteration of Firmicutes and Bacteroidetes, but has not reached to any concordant conclusions.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingcitation

    In Strati et al., the pathways with highest discriminative power in healthy controls were Glycan Biosynthesis and Metabolism, Membrane and intracellular structural molecules, Lipopolysaccharide biosynthesis proteins, Pores ion channels, and Lipopolysaccharide biosynthesis; in ASD patients, they were ABC transporters, Replication recombination and repair proteins, Lysine biosynthesis, Genetic信息处理,

    “In the study of Strati et al.18 (Fig. 2a), the pathways with the highest five discriminative power in HCs were “Glycan Biosynthesis and Metabolism”, “Membrane and intracellular structural molecules”, “Lipopolysaccharide biosynthesis proteins”, “Pores ion channels” and “Lipopolysaccharide biosynthesis”. The pathways with the highest discriminative power in ASD patients were “ABC transporters” under”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Strati, F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5, 24 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A randomized double-blind crossover trial showed that treatment with probiotics resulted in significant differences in stool consistency compared to placebo and behavior scores compared to baseline.

    “A randomized double-blind crossover trial showed that treatment with probiotics resulted in significant differences in the stool consistency compared to placebo and behavior scores compared to baseline65.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Parracho, H. M., Gibson, G. R., Bosscher, D., Kleerebezem, M. & McCartney, A. L. A double-blind, placebo-controlled, crossover-designed probiotic feeding study in children diagnosed with autistic spectrum disorders. Int J. Probiotics Prebiotics 5, 69–74 (2010).

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Buffington et al. reported that maternal high fat diet can induce abnormal social behavior through mediating the dysbiosis of gut microbiota, but reconstituting microbiota with probiotics can correct social deficits in MHFD offspring.

    “In addition, Buffington et al. reported that maternal high fat diet (MHFD) can induce abnormal social behavior through mediating the dysbiosis of gut microbiota, but reconstituting microbiota with probiotics can correct social deficits in MHFD offspring66.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Buffington, S. A. et al. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell 165, 1762–1775 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gastrointestinal symptoms are quite common in ASD and are correlated with the severity of the neurobehavioral disorder.

    “Among the comorbidities in ASD, gastrointestinal (GI) symptoms are quite common, such as diarrhea, constipation, and commutative diarrhea/constipation, they are also correlated with the severity of the neurobehavioral disorder7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] McElhanon, B. O., McCracken, C., Karpen, S. & Sharp, W. G. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics 133, 872–883 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gut microbiota reconstitution with probiotics could alter blood metabolic profiles, remediate gut permeability and improve ASD-related behaviors in mice model.

    “Conversely, gut microbiota reconstitution with probiotics could alter blood metabolic profiles, remediate gut permeability and improve ASD-related behaviors in mice model12.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic inflammation by LPS induced behavioral impairment and damaged the blood-brain barrier in animal models.

    “It has been confirmed that systematic inflammation by LPS induced behavioral impairment and damaged the blood-brain barrier in animal models10,11.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Stolp, H. B., Dziegielewska, K. M., Ek, C. J., Potter, A. M. & Saunders, N. R. Long-term changes in blood-brain barrier permeability and white matter following prolonged systemic inflammation in early development in the rat. Eur. J. Neurosci. 22, 2805–2816 (2005). source

      Not checked in the free run.

    • cites [11] Stolp, H. B. et al. Effects of neonatal systemic inflammation on blood-brain barrier permeability and behaviour in juvenile and adult rats. Cardiovasc. Psychiatry Neurol. 2011, 469046 (2011). source

      Not checked in the free run.

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

    Study design and conductnone given

    The systematic review was reported consistent with PRISMA guidelines and the protocol was registered at PROSPERO (CRD42017060769).

    “To report this systematic review, the method was consistent with the PRISMA statement guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analysis), and the protocol was registered at PROSPERO (registration number: CRD42017060769).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Two authors independently extracted data from selected articles and cross-checked for accuracy.

    “Two authors (FL and JL) independently extracted data from the selected articles, and the data was then cross-checked for accuracy (FW).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A recent open-label study indicated that fecal microbiota transfer (FMT) therapy alters gut ecosystem and improves GI and neurobehavioral symptoms in ASD patients.

    “Moreover, a recent open-label study has indicated that fecal microbiota transfer (FMT) therapy alters gut ecosystem and improves GI and neurobehavioral symptoms in ASD patients19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Kang, D. W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5, 10 (2017). source

      Not checked in the free run.

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

    Study design and conductown data

    Two independent authors assessed articles for eligibility and resolved disagreements by discussion until consensus.

    “Following the elimination of duplicates, two independent authors (FL and JL) assessed the articles for eligibility considering established criteria detailed above. Any disagreement between authors were resolved by discussion until consensus was achieved.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Studies were evaluated for methodological quality and risk of bias by two authors using the Newcastle-Ottawa Scale (NOS) for case-control studies.

    “Studies included in this systematic review were carefully evaluated for the methodological quality and the risk of bias by two authors (FL and JL). Study quality was assessed on the basis of Newcastle-Ottawa Scale (NOS) for case-control studies.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Considering the impact of GI symptoms on composition of gut microbiota, a potential source of heterogeneity may come from the varied baseline of GI symptoms.

    “Considering the impact of GI symptoms on composition of gut microbiota, a potential source of heterogeneity may come from the varied baseline of GI symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Bacteroides is the main producer of propionate in the gut, and the abundance of propionate in feces correlates strongly with the abundance of Bacteroides.

    “It is the main producer of propionate in the gut, and the abundance of propionate in feces correlates strongly with the abundance of Bacteroides47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Wang, L. et al. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig. Dis. Sci. 57, 2096–2102 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter were consistently decreased, while Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium were increased in ASD patients relative to healthy controls.

    “In addition, Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter were consistently decreased, while Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium were increased in ASD patients relative to HCs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Desulfovibrio produces LPS as well as hydrogen sulfide, which could be toxic to intestinal cells under certain circumstances.

    “Desulfovibrio produces LPS as well as hydrogen sulfide which could be toxic to intestinal cells under certain circumstance27,50.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Finegold, S. M. et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16, 444–453 (2010). source

      Not checked in the free run.

    • cites [50] Hughes, R., Magee, E. & Bingham, S. Protein degradation in the large intestine: relevance to colorectal cancer. Curr. Issues Intest. Microbiol. 1, 51–58 (2000).

      Not checked in the free run.

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

    Premisecitation

    Blautia plays an important role in nutrient assimilation and gut maturation in children.

    “Blautia plays an important role in nutrient assimilation44 and gut maturation in children45.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Eren, A. M. et al. A single genus in the gut microbiome reflects host preference and specificity. Isme. J. 9, 90–100 (2015). source

      Not checked in the free run.

    • cites [45] Hsiao, A. et al. Members of the human gut microbiota involved in recovery from Vibrio cholerae infection. Nature 515, 423–426 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Glutathione is a significant antioxidant and closely related to detoxification in the brain.

    “Glutathione is a significant antioxidant and closely related to detoxification in the brain39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Chauhan, A. & Chauhan, V. Oxidative stress in autism. Pathophysiology 13, 171–181 (2006). source

      Not checked in the free run.

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

    Premisecitation

    Bacteroides is an abundant genus at all ages, from infants to adults.

    “Indeed, Bacteroides is an abundant genus at all ages, from infants to adults46.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] MacFabe, D. F., Cain, N. E., Boon, F., Ossenkopp, K. P. & Cain, D. P. Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behav. Brain. Res. 217, 47–54 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Gram-negative bacteria produce a potent toxic factor LPS.

    “It is also remarkable that these Gram-negative bacteria produce a potent toxic factor LPS37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Finegold, S. M. et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16, 444–453 (2010). source

      Not checked in the free run.

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

    Premisecitation

    Bifidobacterium, Blautia, Veillonella, and Prevotella are known to be versatile carbohydrate metabolizers.

    “Notably, these particular species are known to be versatile carbohydrate metabolizers40.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Navarro, F., Liu, Y. & Rhoads, J. M. Can probiotics benefit children with autism spectrum disorders? World J. Gastroenterol. 22, 10093–10102 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some species belonging to Clostridium produce p-cresol; this chemical metabolite could cause the reduction of glutathione and is reported to be a possible urinary biomarker for autism.

    “In addition, some species belonging to the Clostridium produce p-cresol. This chemical metabolite could cause the reduction of glutathione and reported to be a possible urinary biomarker for autism54,55.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Altieri, L. et al. Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomarkers 16, 252–260 (2011). source

      Not checked in the free run.

    • cites [55] Persico, A. M. & Napolioni, V. Urinary p-cresol in autism spectrum disorder. Neurotoxicol. Teratol. 36, 82–90 (2013). source

      Not checked in the free run.

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

    Premisecitation

    These opportunistic pathogens have been previously reported to cause or underlie human infections such as bacteremia and intra-abdominal infection.

    “These opportunistic pathogens have been previously reported to cause or underlie human infections such as bacteremia and intra-abdominal infection56.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] McClean, K. L., Sheehan, G. J. & Harding, G. K. Intraabdominal infection: a review. Clin. Infect. Dis. 19, 100–116 (1994). source

      Not checked in the free run.

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

    Premisecitation

    Propionate produced by microbiota is used for gluconeogenesis in the liver and represents a source of glucose level for the host.

    “Propionate produced by microbiota is used for gluconeogenesis in liver and represents a source of glucose level for the host48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Wolever, T. M., Spadafora, P. & Eshuis, H. Interaction between colonic acetate and propionate in humans. Am. J. Clin. Nutr. 53, 681–687 (1991). source

      Not checked in the free run.

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

    Premisecitation

    Bifidobacterium can ferment complex polysaccharides to regulate host function and promote health.

    “It can ferment complex polysaccharides to regulate host function and promote health42,43,”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Menard, S. et al. Bifidobacterium breve and Streptococcus thermophilus secretion products enhance T helper 1 immune response and intestinal barrier in mice. Exp. Biol. Med. (Maywood). 230, 749–756 (2005). source

      Not checked in the free run.

    • cites [43] Furusawa, Y., Obata, Y. & Hase, K. Commensal microbiota regulates T cell fate decision in the gut. Semin. Immunopathol. 37, 17–25 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Elevated Firmicutes/Bacteroidetes ratio is correlated with inflammatory conditions such as inflammatory bowel diseases and obesity.

    “Some studies indicated that elevated Firmicutes /Bacteroidetes ratio was correlated with inflammatory conditions such as inflammation bowel diseases (IBDs)34 and obesity35.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–5 (2007). source

      Not checked in the free run.

    • cites [35] Turnbaugh, P. J., Backhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell. Host. Microbe 3, 213–223 (2008). source

      Not checked in the free run.

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

    Premisecitation

    Bifidobacterium is among the first colonizers of the human intestine and one of the dominant groups in the gut microbiota of breast-fed infants.

    “Bifidobacterium is among the first colonizers of human intestinal and one of the dominant groups in the gut microbiota of breast-fed infants41.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Garrido, D., Barile, D. & Mills, D. A. A molecular basis for bifidobacterial enrichment in the infant gastrointestinal tract. Adv. Nutr. 3, S415–S421 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Akkermansia and Ruminococcus are mucin-degrading bacteria and associated with gut permeability.

    “Akkermansia and Ruminococcus are mucin-degrading bacterium and associated with the gut permeability59,60.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Kang, D. W. et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS. ONE. 8, e68322 (2013). source

      Not checked in the free run.

    • cites [60] Quevrain, E. et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut 65, 415–425 (2016). source

      Not checked in the free run.

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

    Premisecitation

    Zoetendal et al. reported that using biopsies other than feces allowed to assess the mucosa-epithelia associated microbiota.

    “Zoetendal et al. reported that using biopsies other than feces allowed to assess the mucosa-epithelia associated microbiota.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Zoetendal, E. G. et al. Mucosa-associated bacteria in the human gastrointestinal tract are uniformly distributed along the colon and differ from the community recovered from feces. Appl. Environ. Microbiol. 68, 3401–3407 (2002). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Different results of gut microbiota may also arise from distinct techniques for DNA isolation, PCR and sequencing, and small-sample sized studies.

    “Besides, the different results of gut microbiota may also arise from distinct techniques for DNA isolation, PCR and sequencing, and small-sample sized studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The predicted biological functions of the observed microbial community in ASD patients were significantly different from those in healthy controls, but varied among studies.

    “The predicted biological functions of the observed microbial community in ASD patients were significantly different from that in HCs, but varied among studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Only four studies provided the raw sequencing data or biome file for doing PICRUSt analysis, which may result in the loss of bias.

    “In addition, only four studies provided the raw sequencing data or biome file for doing PICRUSt analysis, which may result in the loss of bias.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Lactobacillus has the ability of fermenting a series of carbon sources primarily to lactic acid and is widely recognized as probiotics.

    “Lactobacillus has the ability of fermenting a series of carbon sources primarily to lactic acid and is widely recognized as probiotics57.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Gibson, G. R. & Roberfroid, M. B. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J. Nutr. 125, 1401–1412 (1995). source

      Not checked in the free run.

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

    Premisecitation

    Lactobacillus was more abundant in T2DM patients than in healthy controls.

    “Nonetheless, a recent research indicated that Lactobacillus was more abundant in T2DM patients than in HCs58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Two studies included in the present review provided null findings, showing that the concern about publication bias may be solved to some extent.

    “However, two studies included in the present review provided null findings, showing that the concern about publication bias may be solved in some extent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    A number of issues resulted in heterogeneity, including dietary factors, the selection of controls, frequent occurrence of GI symptoms, and sample sources.

    “A number of issues resulted in heterogeneity has be drawn, including dietary factors, the selection of controls, frequent occurrence of GI symptoms and sample sources.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Geography and dietary habits are main factors that play a great role in microbiome composition.
    • Rests on an assumption: Implementation of restricted diet is very common in ASD subjects, such as gluten-free and casein-free diet.
    • Rests on an assumption: Frequent occurrence of GI symptoms in ASD patients may affect the composition of gut microbiota.

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

    Interpretationreasoning

    It can be an alternative explanation that studies using NT sibling controls did not find any significant difference, while other studies using non-sibling controls did.

    “It can be an alternative explanation that why studies21,26 using NT sibling controls did not find any significant difference, while other studies using non-sibling controls did.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Son, J. S. et al. Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection. PLoS. ONE. 10, e0137725 (2015). source

      Not checked in the free run.

    • cites [26] Gondalia, S. V. et al. Molecular characterization of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 5, 419–427 (2012). source

      Not checked in the free run.

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

    Premisecitation

    Faecalibacterium is regarded as commensal or even beneficial due to its function of producing anti-inflammation butyrate.

    “Faecalibacterium is regarded as commensal or even beneficial due to its function of producing anti-inflammation butyrate61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Ding, H. T., Taur, Y. & Walkup, J. T. Gut microbiota and autism: Key concepts and findings. J. Autism Dev. Disord. 47, 480–489 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sutterella can regulate mucosal metabolism and intestinal epithelial integrity.

    “Sutterella can regulate mucosal metabolism and intestinal epithelial integrity25,29.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Williams, B. L., Hornig, M., Parekh, T. & Lipkin, W. I. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio 3, e00261–11 (2012). source

      Not checked in the free run.

    • cites [29] Wang, L. et al. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol. Autism 4, 42 (2013). source

      Not checked in the free run.

69 of 69

  • The paper relies on this without support.

    16S rDNA sequencing can quantitatively identify all bacteria present in one sample, whereas qPCR and FISH only detected specific bacteria, lacking evaluation of the whole community.

    “16S rDNA sequencing can quantitatively identify all bacteria present in one sample. However, qPCR and FISH only detected the specific bacteria, which lacked the evaluation of the whole community.”

  • The paper relies on this without support.

    Gut microbiota makes a critical contribution to maintaining the integrity of intestinal epithelia, protecting the intestinal barrier and preventing bacterial LPS and other toxins into the bloodstream.

    “Gut microbiota makes critical contribution to maintaining the integrity of intestinal epithelia, protecting intestinal barrier and preventing bacterial LPS and other toxins into bloodstream.”

  • The paper relies on this without support.

    Gut microbiota may regulate the central nervous system (CNS) activities through neural, immune and endocrine pathways.

    “Moreover, gut microbiota may regulate the central nervous system (CNS) activities through neural, immune and endocrine pathways.”

  • The paper relies on this without support.

    Geography and dietary habits are main factors that play a great role in microbiome composition.

    “Geography and dietary habits are main factors that play a great role in microbiome composition.”

  • The paper relies on this without support.

    Implementation of restricted diet is very common in ASD subjects, such as gluten-free and casein-free diet.

    “Besides, implementation of restricted diet is very common in ASD subjects, such as GF and CF diet.”

  • The paper relies on this without support.

    Frequent occurrence of GI symptoms in ASD patients may affect the composition of gut microbiota.

    “Thirdly, the frequent occurrence of GI symptoms in ASD patients may affect the composition of gut microbiota.”

  • The paper relies on this without support.

    There is biogeographic variation of gut microbiota.

    “Another important consideration is that biogeographic variation of gut microbiota.”
7 of 7

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?

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.

  • Claim of increased Bacteroides conflicts with a cited subgroup

    Minor

    The text cites De Angelis et al. as finding increased Bacteroides in ASD, but its PDD-NOS subgroup is listed as having decreased Bacteroides.

  • Publication-year range excludes an included study

    Minor

    The study-characteristics section says the studies were published from 2005 onward, but Table 2 dates the included Song study to 2004.

  • Biopsy-study citations conflict with the sample-source table

    Minor

    The text identifies study 23 as using gut biopsy, whereas Table 1 identifies its sample as fecal.

  • De Angelis study has conflicting publication years

    Minor

    The study tables date De Angelis et al. to 2013, while the corresponding reference is dated 2015.

4 of 4

The citation lists haven’t been fetched yet

References 65 · Cited by 336

Research works printed but not linked: 4

  1. Finegold, S. M. et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16, 444–453 (2010). · DOI · Paper page
  2. Wang, L. et al. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig. Dis. Sci. 57, 2096–2102 (2012). · DOI · Paper page
  3. Williams, B. L. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS. ONE. 6, e24585 (2011). · DOI · Paper page
  4. Kang, D. W. et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS. ONE. 8, e68322 (2013). · DOI · Paper page

Authors
Liu, F., Li, J., Wu, F., Zheng, H., Peng, Q., & Zhou, H.
Affiliations
  • Zhujiang Hospital (CN)
  • Jinan University (CN)
Corresponding author
Zhou, Hongwei
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-01-29
Volume
9
Issue
1
Pages
43-43
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-019-0389-6
PMC
PMC6351640
OpenAlex
W2915174336
Semantic Scholar
0fa477b62a8517bde748a0097d4af905e58c466e
Cited by
336
References
65
Citations by year
2026: 26 · 2025: 55 · 2024: 34 · 2023: 44 · 2022: 49 · 2021: 63 · 2020: 41 · 2019: 24
FWCI
3.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (NSFC313220143)
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, dysbiosis, beta diversity, microbial community composition, gastrointestinal symptoms, behavioral impairment, Bifidobacterium, Lactobacillus, Prevotella, Veillonella, Clostridium, Bacteroides, Turicibacter, Blautia, Dialister, functional metagenomics
MeSH terms
Autism Spectrum Disorder, Gastrointestinal Microbiome, Animals, Humans, Dysbiosis

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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