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Cited by 149Gut microbiota and healthAutism Spectrum Disorder ResearchGastrointestinal motility and disorders

Gut microbiota changes in children with autism spectrum disorder: a systematic review

Open access
Ho, Lucius Kang Hua, Tong, Valerie Jia Wei, Syn, Nicholas, Nagarajan, Niranjan, Tham, Elizabeth Huiwen, Tay, Stacey K., Shorey, Shefaly, Tambyah, Paul Anantharajah +1 more·2020·Gut Pathogens
DOI 10.1186/s13099-020-0346-1PMC PMC6996179
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Abstract

Background: As more animal studies start to disentangle pathways linking the gut microbial ecosystem and neurobehavioral traits, human studies have grown rapidly. Many have since investigated the bidirectional communication between the gastrointestinal tract and the central nervous system, specifically on the effects of microbial composition on the brain and development. Methods: Our review at the initial stage aimed to evaluate literature on gut microbial alterations in pediatric neurobehavioral conditions. We searched five literature databases (Embase, PubMed, PsychInfo, Scopus, and Medline) and found 4489 published work. As the mechanisms linking gut microbiota to these conditions are divergent, the scope of this review was narrowed to focus on describing gut dysbiosis in children with autism spectrum disorder (ASD). Results: Among the final 26 articles, there was a lack of consistency in the reported gut microbiome changes across ASD studies, except for distinguishable patterns, within limits, for Prevotella , Firmicutes at the phylum level, Clostridiales clusters including Clostridium perfringens , and Bifidobacterium species. Conclusions: These results were inadequate to confirm a global microbiome change in children with ASD and causality could not be inferred to explain the etiology of the behaviors associated with ASD. Mechanistic studies are needed to elucidate the specific role of the gut microbiome in the pathogenesis of ASD.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review of 26 studies found no consistent global gut microbiome signature in children with autism spectrum disorder (ASD), although some patterns emerged for Prevotella, Firmicutes, Clostridiales clusters including Clostridium perfringens, and Bifidobacterium. The authors conclude that current evidence is inadequate to confirm a global microbiome change or infer causality in ASD.

Key findings

  • Among 26 final articles, most gut microbiome changes were inconsistent across ASD studies, except for distinguishable patterns, within limits, for Prevotella, Firmicutes at the phylum level, Clostridiales clusters including Clostridium perfringens, and Bifidobacterium species.
  • Alpha diversity results from 11 papers showed no consistent pattern: 2 studies showed increases, 6 showed no significant changes, and 3 showed decreases, all from one laboratory; among 7 papers reporting beta diversity, 4 showed significant differences between ASD and sibling/healthy controls.
  • Bifidobacterium counts and proportions were consistently lower in children with ASD versus siblings or controls, except for one small study of 10 children with ASD; no study showed higher Prevotella relative abundance in ASD, with results either non-significant or lower.
  • Intervention findings were mixed: microbiota transfer therapy increased absolute abundance of Prevotella, Bifidobacterium, and Desulfovibrio and behavioral ASD symptoms improved and remained improved 8 weeks after treatment; vitamin A increased Bacteroidetes, Bacteroides, and Prevotella but produced no changes in ASD symptomatology; probiotic studies showed inconsistent bacterial and behavioral effects.

Methods

  • PRISMA systematic review searching Embase, Medline, PsycINFO, PubMed, and Scopus in three waves (September 2017, August 2018, April 2019), yielding 4489 published works and 26 final articles.
  • Inclusion criteria: children under 18 years with clinically diagnosed ASD, more than 10 enrolled participants, gut microbiota with descriptive and inferential statistics, and full-text peer-reviewed articles; exclusion criteria included non-human subjects, single case reports or reviews, genetic disorders with high ASD prevalence, major intestinal tract diseases, and publication before January 2000 or after May 2019.
  • Data were extracted into tables from phylum to species; observational data without inferential statistics were excluded, and when p-values or 95% confidence intervals were unavailable, the review authors conducted chi-square tests, t-tests, and one-way ANOVA using IBM SPSS Statistics Version 22.

Limitations

  • Stated in the paper: results were inadequate to confirm a global microbiome change in children with ASD, causality could not be inferred, and mechanistic studies are needed; heterogeneity in sampling, storage, processing, experimental protocols, and multiple testing may constrain interpretation, requiring external validation by independent laboratories.
  • Stated in the paper: studies did not report birth or pre-diagnosis microbiome, directionality with dietary habits is hard to determine, prospective studies are lacking, few studies involved developmental specialists or psychologists, and diagnostic criteria changed from DSM-IV to DSM-5.
  • Evident from the text: many species were described in only one study each, methodological differences rendered meta-analysis of Clostridium studies inconclusive, and intervention studies used different probiotic species, so purposeful conclusions cannot be drawn directly for comparison.

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

Integrity signals

Registry

Crossref · 10.1186/s13099-020-0346-1

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 160 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Based on 11 papers, there were no consistent patterns in alpha diversity when comparing children with ASD versus siblings and healthy controls.

    “Based on the results of 11 papers that examined alpha diversity, there were no consistent patterns when comparing alpha diversity in children with ASD versus alpha diversity in siblings (SIB) and healthy controls (HC; Additional file 1: Table S2).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the same study, the percentage of Bacteroidetes in children with mild ASD was still significantly increased compared to controls (p = 0.0012), based on the review authors' t-tests.

    “We found that despite having “mild” ASD in the study, the percentage of Bacteroidetes in these children was still significantly increased compared to controls (p = 0.0012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Finegold S, Dowd S, Gontcharova V, Liu C, Henley K, Wolcott R, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444–53. source

      Not checked in the free run.

  • Findingcitation

    Only one study demonstrated an increase in the percentage of Bacteroidetes in children with ASD classified as severe compared to healthy controls (p = 0.001).

    “Only one study [33] demonstrated an increase in the percentage of Bacteroidetes in children with ASD, classified as “severe”, compared to HC (p = 0.001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Finegold S, Dowd S, Gontcharova V, Liu C, Henley K, Wolcott R, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444–53. source

      Not checked in the free run.

  • Findingown data

    Among seven papers reporting beta diversity, four showed significant differences in beta diversity between ASD and SIB/HC while the rest did not.

    “Among the seven [31, 36, 40–42, 48, 50] papers that reported on beta diversity, four [31, 40, 41, 50] papers showed significant differences in beta diversity between ASD and SIB/HC while the rest did not (Additional file 1: Table S2).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [31] De Angelis MA, Piccolo M, Vannini L, Siragusa S, De AG, Serrazzanetti D, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE. 2013;8(10):e76993-e. source

      Not checked in the free run.

    • cites [36] Gondalia S, Palombo E, Knowles S, Cox S, Meyer D, Austin D. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res. 2012;5(6):419–27. source

      Not checked in the free run.

    • cites [40] Kang D, Adams J, Gregory A, Borody T, Chittick L, Fasano A, et al. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017;5(1):10. source

      Not checked in the free run.

    • cites [41] Kang D, Ilhan Z, Isern N, Hoyt D, Howsmon D, Shaffer M, et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe. 2018;49:121–31. source

      Not checked in the free run.

    • cites [42] Kushak R, Winter H, Buie T, Cox S, Phillips C, Ward N. Analysis of the duodenal microbiome in autistic individuals: association with carbohydrate digestion. J Pediatr Gastroenterol Nutr. 2017;64(5):e110–e11616. source

      Not checked in the free run.

    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

    • cites [50] Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome. 2017;1(5):1–11.

      Not checked in the free run.

  • Findingown data

    Among fifteen studies reporting genus and/or species level Bacteroidetes, results were not consistent.

    “Fifteen studies reported findings at the genus and/or species level of Bacteroidetes. Similar to the phylum Bacteroidetes as a whole, results from these studies were not consistent.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 27

  • May combine two claims.

    Findingnone given

    Among the final 26 articles, there was a lack of consistency in reported gut microbiome changes across ASD studies, except for distinguishable patterns, within limits, for Prevotella, Firmicutes at the phylum level, Clostridiales clusters including Clostridium perfringens, and Bifidobacterium species.

    “Among the final 26 articles, there was a lack of consistency in the reported gut microbiome changes across ASD studies, except for distinguishable patterns, within limits, for Prevotella, Firmicutes at the phylum level, Clostridiales clusters including Clostridium perfringens, and Bifidobacterium species.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There has not been a comprehensive review that systematically evaluates dysbiosis in children with ASD based on bacterial taxonomy from phylum to species, investigates whether results are congruous, and summarises both positive and negative findings down to species in all captured studies.

  • May combine two claims.

    Findingcitation

    The last three studies indicated decreases in alpha diversity, but the studies came from one laboratory.

    “The last three studies indicated decreases; however, the studies came from one laboratory [39–41].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Kang D, Park J, Ilhan Z, Wallstrom G, Labaer J, Adams J, et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS ONE. 2013;8(7):e68322-e. source

      Not checked in the free run.

    • cites [40] Kang D, Adams J, Gregory A, Borody T, Chittick L, Fasano A, et al. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017;5(1):10. source

      Not checked in the free run.

    • cites [41] Kang D, Ilhan Z, Isern N, Hoyt D, Howsmon D, Shaffer M, et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe. 2018;49:121–31. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Two studies showed increases in alpha diversity and six studies showed no significant changes in alpha diversity.

    “Two studies showed increases [31, 33] and six studies showed no significant changes in alpha diversity [36, 42, 43, 48, 50, 54].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [31] De Angelis MA, Piccolo M, Vannini L, Siragusa S, De AG, Serrazzanetti D, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE. 2013;8(10):e76993-e. source

      Not checked in the free run.

    • cites [33] Finegold S, Dowd S, Gontcharova V, Liu C, Henley K, Wolcott R, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444–53. source

      Not checked in the free run.

    • cites [36] Gondalia S, Palombo E, Knowles S, Cox S, Meyer D, Austin D. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res. 2012;5(6):419–27. source

      Not checked in the free run.

    • cites [42] Kushak R, Winter H, Buie T, Cox S, Phillips C, Ward N. Analysis of the duodenal microbiome in autistic individuals: association with carbohydrate digestion. J Pediatr Gastroenterol Nutr. 2017;64(5):e110–e11616. source

      Not checked in the free run.

    • cites [43] Liu J, Liu X, Xiong X, Yang T, Cui T, Hou N, et al. Effect of vitamin A supplementation on gut microbiota in children with autism spectrum disorders-a pilot study. BMC Microbiol. 2017;17(1):204. source

      Not checked in the free run.

    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

    • cites [50] Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome. 2017;1(5):1–11.

      Not checked in the free run.

    • cites [54] Williams B, Hornig M, Buie T, Bauman M, Cho MP, Wick I, et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. 2011;6(9):e24585-e. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The rest of the studies observed either a decrease in Bacteroidetes percentage or no significant differences between cases and controls.

    “The rest of the studies observed either a decrease in Bacteroidetes percentage [50, 54] or no significant differences between cases and controls [31, 36, 48].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [50] Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome. 2017;1(5):1–11.

      Not checked in the free run.

    • cites [54] Williams B, Hornig M, Buie T, Bauman M, Cho MP, Wick I, et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. 2011;6(9):e24585-e. source

      Not checked in the free run.

    • cites [31] De Angelis MA, Piccolo M, Vannini L, Siragusa S, De AG, Serrazzanetti D, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE. 2013;8(10):e76993-e. source

      Not checked in the free run.

    • cites [36] Gondalia S, Palombo E, Knowles S, Cox S, Meyer D, Austin D. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res. 2012;5(6):419–27. source

      Not checked in the free run.

    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

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

    Findingown data

    Six studies provided results on Bacteroidetes at the phylum level.

    “Six studies provided results on Bacteroidetes at the phylum level (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The other 24 detected species in Bacteroidetes were described in only one study each, so no summary could be made.

    “The other 24 detected species in the Bacteroidetes phyla were described in only one study each; hence, no summary could be made.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Seven out of fifteen studies described Prevotella and none showed a higher relative abundance in stools of children with ASD compared to controls.

    “Seven out of fifteen studies described Prevotella and none of them showed a higher relative abundance in the stools of children with ASD when compared to controls.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    These seven Prevotella studies showed either a non-significant result in relative abundance or a lower relative abundance in children classified as ASD versus SIB or HC.

    “Instead, these seven studies showed either a non-significant result in relative abundance [41, 48, 50, 52] or a lower relative abundance in children classified as ASD versus SIB or HC [31, 39, 42].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [41] Kang D, Ilhan Z, Isern N, Hoyt D, Howsmon D, Shaffer M, et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe. 2018;49:121–31. source

      Not checked in the free run.

    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

    • cites [50] Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome. 2017;1(5):1–11.

      Not checked in the free run.

    • cites [52] Wang L, Christophersen C, Sorich M, Gerber J, Angley M, Conlon M. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol. 2011;77(18):6718–21. source

      Not checked in the free run.

    • cites [31] De Angelis MA, Piccolo M, Vannini L, Siragusa S, De AG, Serrazzanetti D, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE. 2013;8(10):e76993-e. source

      Not checked in the free run.

    • cites [39] Kang D, Park J, Ilhan Z, Wallstrom G, Labaer J, Adams J, et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS ONE. 2013;8(7):e68322-e. source

      Not checked in the free run.

    • cites [42] Kushak R, Winter H, Buie T, Cox S, Phillips C, Ward N. Analysis of the duodenal microbiome in autistic individuals: association with carbohydrate digestion. J Pediatr Gastroenterol Nutr. 2017;64(5):e110–e11616. source

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    For all other Bacteroidetes genera and species, studies generally contradicted each other and different laboratories found varying composition.

    “For all other genera and species (Table 2), studies generally contradicted each other and different laboratories found varying composition of Bacteroidetes species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The general trend supports no alterations in E. coli for children with ASD in five studies versus one study documenting a decrease in E. coli percentage.

    “The general trend, however, supports no alterations in E. coli for children in ASD in five studies [30, 35, 42, 48, 52] vs one study [31] documenting a decrease in E. coli percentage among other microbiota.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [30] Adams J, Johansen L, Powell L, Quig D, Rubin R. Gastrointestinal flora and gastrointestinal status in children with autism—comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011;11:22. source

      Not checked in the free run.

    • cites [35] Gondalia SV, Palombo EA, Knowles SR, Austin DW. Faecal microbiota of individuals with autism spectrum disorder. E-J Appl Psychol Clin Soc Issues. 2010;6(2):24–9.

      Not checked in the free run.

    • cites [42] Kushak R, Winter H, Buie T, Cox S, Phillips C, Ward N. Analysis of the duodenal microbiome in autistic individuals: association with carbohydrate digestion. J Pediatr Gastroenterol Nutr. 2017;64(5):e110–e11616. source

      Not checked in the free run.

    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

    • cites [52] Wang L, Christophersen C, Sorich M, Gerber J, Angley M, Conlon M. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol. 2011;77(18):6718–21. source

      Not checked in the free run.

    • cites [31] De Angelis MA, Piccolo M, Vannini L, Siragusa S, De AG, Serrazzanetti D, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE. 2013;8(10):e76993-e. source

      Not checked in the free run.

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

    Findingnone given

    Staphylococcus species were not extensively studied.

    “Staphylococcus species were not extensively studied.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    An additional 83 species were reported, and because of a paucity of studies, no firm conclusions could be made.

    “An additional 83 species were reported in Additional file 1: Table S4. As there was a paucity of studies published on these species, no firm conclusions could be made.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Despite speculation that Sutterella was increased in children with ASD, this was not true in every study; three studies suggested no significant differences and one suggested a decrease.

    “Despite speculation that Sutterella was increased in children with ASD [53, 55], this was not true in every study. There were three studies suggesting no significant differences [38, 41, 48] and one suggesting a decrease [44], but this particular study included adolescents in their cohort.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [53] Wang L, Christophersen C, Sorich M, Gerber J, Angley M, Conlon M. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism. 2013;4(1):42. source

      Not checked in the free run.

    • cites [55] Williams BL, Hornig M, Parekh T, Lipkin WI. 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. 2012;3(1):e00261-11. source

      Not checked in the free run.

    • cites [38] Iovene M, Bombace F, Maresca R, Sapone A, Iardino P, Picardi A, et al. Intestinal dysbiosis and yeast isolation in stool of subjects with autism spectrum disorders. Mycopathologia. 2017;182(3–4):349–63. source

      Not checked in the free run.

    • cites [41] Kang D, Ilhan Z, Isern N, Hoyt D, Howsmon D, Shaffer M, et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe. 2018;49:121–31. source

      Not checked in the free run.

    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

    • cites [44] Luna R, Oezguen N, Balderas M, Venkatachalam A, Runge J, Versalovic J, et al. Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell Mol Gastroenterol Hepatol. 2017;3(2):218–30. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    At the Proteobacteria phylum level, no significant differences were observed between the two groups except one study indicated an increase in percentage.

    “At the phylum level, no significant differences were observed in Proteobacteria between the two groups except one study indicated an increase in percentage [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Finegold S, Dowd S, Gontcharova V, Liu C, Henley K, Wolcott R, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444–53. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    One study found that vitamin A administration to children with ASD increased Bacteroidetes at phylum level, with both Bacteroides and Prevotella species increasing post-treatment, while all other measured phyla and genera decreased.

    “One study investigated the effect of administering vitamin A [43] on children with ASD and found an increase in abundance on the Bacteroidetes phylum level (Table 5). Both Bacteroides species and Prevotella species levels increased post-treatment. On the other hand, all of the other phyla and genera measured showed a decrease in abundance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Liu J, Liu X, Xiong X, Yang T, Cui T, Hou N, et al. Effect of vitamin A supplementation on gut microbiota in children with autism spectrum disorders-a pilot study. BMC Microbiol. 2017;17(1):204. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Post-vitamin A administration, significant increases were seen in plasma retinol, CD38 and RORA mRNA levels, but no changes were seen in ASD symptomatology.

    “Post-vitamin A administration, significant increases were also seen in other forms of biomarkers, including plasma retinol, CD38 and RORA mRNA levels. However, no changes were seen in the ASD symptomatology of the study participants [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Liu J, Liu X, Xiong X, Yang T, Cui T, Hou N, et al. Effect of vitamin A supplementation on gut microbiota in children with autism spectrum disorders-a pilot study. BMC Microbiol. 2017;17(1):204. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    No specific findings were identified in the Verrucomicrobia phylum and in the Verrucomicrobiaceae family.

    “No specific findings were identified in the Verrucomicrobia phylum [31, 33, 36, 39, 48] and in the Verrucomicrobiaceae family [31, 37, 39, 41, 52].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [31] De Angelis MA, Piccolo M, Vannini L, Siragusa S, De AG, Serrazzanetti D, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE. 2013;8(10):e76993-e. source

      Not checked in the free run.

    • cites [33] Finegold S, Dowd S, Gontcharova V, Liu C, Henley K, Wolcott R, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444–53. source

      Not checked in the free run.

    • cites [36] Gondalia S, Palombo E, Knowles S, Cox S, Meyer D, Austin D. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res. 2012;5(6):419–27. source

      Not checked in the free run.

    • cites [39] Kang D, Park J, Ilhan Z, Wallstrom G, Labaer J, Adams J, et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS ONE. 2013;8(7):e68322-e. source

      Not checked in the free run.

    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

    • cites [37] Inoue R, Sakaue Y, Sawai C, Sawai T, Ozeki M, Romero-Pérez G, 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. 2016;80(12):2450–8. source

      Not checked in the free run.

    • cites [41] Kang D, Ilhan Z, Isern N, Hoyt D, Howsmon D, Shaffer M, et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe. 2018;49:121–31. source

      Not checked in the free run.

    • cites [52] Wang L, Christophersen C, Sorich M, Gerber J, Angley M, Conlon M. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol. 2011;77(18):6718–21. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Within these phyla, 42 additional bacterial species were described but were either unclassified or only measured by one study, and no comparisons or conclusions could be made.

    “Within these phyla, 42 additional bacterial species were described by the 26 studies, but were either unclassified or only measured by one study. We have listed positive and negative findings of each species in Additional file 1: Table S5. However, no comparisons or conclusions could be made from the limited number of studies on each species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Probiotics consisting of L. acidophilus, L. rhamnosus, and Bifidobacteria longum increased Lactobacillus and Bifidobacterium species, and significant improvements in autism severity by ATEC were found.

    “In another study where probiotics consisting of L. acidophilus, L. rhamnosus, and Bifidobacteria longum were used, both Lactobacillus and Bifidobacterium species increased [47]. Contrary to the first study, significant improvements in the severity of autism, as assessed by the Autism Treatment Evaluation Checklist (ATEC), were found in this second study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Shaaban SY, El Gendy YG, Mehanna NS, El-Senousy WM, El-Feki HSA, Saad K, et al. The role of probiotics in children with autism spectrum disorder: a prospective, open-label study. Nutr Neurosci. 2018;21(9):676–81. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Probiotics consisting of Lactobacillus plantarum WCSD1 decreased bacterial counts of Clostridium clusters XIVa and XIVb and increased Lactobacillus species, but behavioral improvements were not significantly different between probiotic and placebo regimes.

    “The first one [46] showed that probiotics consisting of Lactobacillus plantarum WCSD1 decreased the bacterial counts of Clostridium clusters XIVa and XIVb and increased Lactobacillus species. However, behavioral improvements on ASD children, as reported on the Development Behaviour Checklist, were not significantly different between the probiotic feeding and placebo regimes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Parracho H, Gibson G, Knott F, Bosscher D, Kleerebezem M, McCartney A. A double-blind, placebo-controlled, crossover-designed probiotic feeding study in children diagnosed with autistic spectrum disorders. Int J Probiot Prebiot. 2010;5(2):69–74.

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Fusobacteria phylum suggested a lower relative abundance in children with ASD versus unaffected siblings, although one study demonstrated the opposite in terms of Fusobacterium absolute numbers.

    “Fusobacteria phylum suggested a lower relative abundance in children with ASD vs unaffected siblings, although one study [48] demonstrated the opposite in terms of Fusobacterium absolute numbers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    After microbiota transfer therapy, an increase in absolute abundance of Prevotella, Bifidobacterium, and Desulfovibrio species was observed, and behavioral ASD symptoms improved significantly and remained improved 8 weeks after treatment ended.

    “After MTT intervention, an increase in the absolute abundance of Prevotella, Bifidobacterium, and Desulfovibrio species was observed. Additionally, clinical assessments showed that behavioral ASD symptoms improved significantly and remained improved 8 weeks after treatment ended [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Kang D, Adams J, Gregory A, Borody T, Chittick L, Fasano A, et al. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017;5(1):10. source

      Not checked in the free run.

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

    Findingown data

    In total, 26 papers were selected for this systematic review.

    “In total, 26 papers [30–55] were selected for this systematic review (PRISMA Fig. 1; search criteria Additional file 1: Table S1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30–55]

      Not checked in the free run.

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

    Findingown data

    Reference sections of all eligible articles were reviewed and an additional three studies were found, resulting in 26 articles.

    “Subsequently, the reference sections of all eligible articles were reviewed by E.C.L. and an additional three studies were found, which resulted in 26 articles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Probiotic supplementation with Lactobacillus 60%, Bifidumbacteria 25%, Streptococcus 15% resulted in a decrease in Firmicutes phylum and Desulfovibrio after intervention, a decrease in Bifidobacterium, and no significant changes in Lactobacillus species.

    “In the third study involving probiotic supplementation with Lactobacillus 60%, Bifidumbacteria 25%, Streptococcus 15% [51], a decrease in Firmicutes phylum and Desulfovibrio was observed after probiotics intervention. Surprisingly, a decrease in Bifidobacterium was found after probiotics and no significant changes were found in the Lactobacillus species, which contradicted aforementioned studies [”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B, Babinska K, et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav. 2015;138:179–87. source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    Relative and absolute abundances of Firmicutes at the phylum level, Streptococcus at the genus level, Prevotella species, and Bifidobacterium species are not increased in children with ASD versus non-sibling controls.

    “Similarly, the relative and absolute abundances of Firmicutes at the phylum level, Streptococcus at the genus level, Prevotella species, and Bifidobacterium species are not increased in children with ASD versus non-sibling controls.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Studies suggesting therapeutic potential for probiotic treatment have currently looked at individuals with the ASD profile as a whole.

    “Likewise, studies suggesting therapeutic potential for probiotic treatment has currently looked at individuals with the ASD profile as a whole.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    There is a paucity of research examining interactions of host genetics and microbial dysregulation in humans with ASD.

    “It is noteworthy to mention that there is a paucity of research examining the interactions of host genetics and microbial dysregulation in humans with ASD.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    High-throughput nucleic acid-based interrogation represents the most common technique used in included studies.

    “In terms of experimental procedures, high-throughput nucleic acid-based interrogation represent the most common technique used in included studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    General consistencies are found in composition changes of Prevotella, Firmicutes as a whole, three Clostridia clusters, C. perfringens, and Bifidobacterium in children with ASD.

    “However, researchers may take note of the general consistencies found in composition changes of Prevotella, Firmicutes as a whole, three Clostridia clusters, C. perfringens, and Bifidobacterium in children with ASD to design future studies”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    The studies reviewed have not reported on birth or pre-diagnosis microbiome of children with ASD; instead, studies generally report bacterial diversity after diagnosis.

    “The studies reviewed have not reported on the birth or pre-diagnosis microbiome of children with ASD. Instead, studies generally report bacterial diversity after children are diagnosed with ASD.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    The precise nature of how multiple systems interact or overlap in microbiome's role in neural development remains poorly defined.

    “Although mounting evidence is accumulating for microbiome’s role in neural development, the precise nature of how multiple systems interact or overlap remain poorly defined.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The review used a systematic search of five literature databases (Embase, Medline, PsycINFO, PubMed and Scopus) in three waves.

    “We conducted a systematic search of five literature databases to identify studies showing gut dysbiosis in neurological disorders. The databases searched were Embase, Medline, PsycINFO, PubMed and Scopus. All databases were searched in three waves, September 2017, August 2018, and April 2019, using the search criteria listed in Additional file 1: Table S1.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The 10-participant cutoff was chosen to ensure sufficient heterogeneity in the sample and to reduce the possibility of Type II errors.

    “We used 10 as the cutoff for the number of participants in our inclusion criteria. This parameter was chosen to ensure sufficient heterogeneity in the sample and to reduce the possibility of Type II errors.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Observational data without inferential statistics were not included.

    “To ensure a rigorous review, observational data without inferential statistics were not included.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Assessment of 23 articles for final inclusion was based on full text by two authors, disagreements on nine papers were resolved and arbitrated by two other authors, and consensus was reached in all cases.

    “Assessment of 23 articles for final inclusion was based on full text by authors L.H. and V.T. Disagreements on nine papers were resolved and arbitrated by authors E.C.L and N.S., and consensus was reached in all cases.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    When inferential statistics were completed yet no p-values or 95% confidence intervals could be found, the review authors used the original authors' data and conducted tests of statistical significance.

    “When inferential statistics were completed yet no p-values or 95% confidence intervals could be found, the authors of this review used the data generated by the original authors and conducted tests of statistical significance.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Two studies belonged to the same cohort but were both included because the gut microbes examined were different.

    “Two studies [52, 53] belonged to the same cohort but were both included in the synthesis of this systematic review because the gut microbes examined were different.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Wang L, Christophersen C, Sorich M, Gerber J, Angley M, Conlon M. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol. 2011;77(18):6718–21. source

      Not checked in the free run.

    • cites [53] Wang L, Christophersen C, Sorich M, Gerber J, Angley M, Conlon M. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism. 2013;4(1):42. source

      Not checked in the free run.

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

    Study design and conductnone given

    Inclusion criteria required children under 18 with clinically diagnosed ASD, more than 10 enrolled participants, gut microbiota with descriptive and inferential statistics, and full text peer-reviewed articles.

    “The inclusion criteria were studies pertaining to (1) children under the age of 18 years of age with clinically diagnosed ASD, (2) more than 10 enrolled participants, (3) gut microbiota with descriptive and inferential statistics, and (4) full text peer-viewed articles.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Gut microbiota influences the immune system directly via activation of the vagus nerve.

    “Interestingly, the gut microbiota has recently been shown to influence the immune system directly via activation of the vagus nerve [67, 68].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Bravo J, Julio-Pieper M, Forsythe P, Kunze W, Dinan T, Bienenstock J, et al. Communication between gastrointestinal bacteria and the nervous system. Curr Opin Pharmacol. 2012;12(6):667–72. source

      Not checked in the free run.

    • cites [68] Perez-Burgos A, Wang B, Mao Y, Mistry B, McVey KN, Bienenstock J, et al. Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents. Am J Physiol Gastrointest Liver Physiol. 2013;304(2):G211–G220220. source

      Not checked in the free run.

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

    Premisecitation

    Infections during pregnancy are correlated with increased frequency of neurodevelopmental disorders in offspring.

    “Prior literature has substantiated that infections during pregnancy have been correlated with increased frequency of neurodevelopmental disorders in offspring [16, 17, 76–78].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [16] Atladóttir H, Thorsen P, Østergaard L, Schendel D, Lemcke S, Abdallah M, et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord. 2010;40(12):1423–30. source

      Not checked in the free run.

    • cites [17] Brown A, Sourander A, Hinkka-Yli-Salomäki S, McKeague I, Sundvall J, Surcel H. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014;19(2):259–64. source

      Not checked in the free run.

    • cites [76] Patterson P. Maternal infection and immune involvement in autism. Trends Mol Med. 2011;17(7):389–94. source

      Not checked in the free run.

    • cites [77] Atladóttir H, Pedersen M, Thorsen P, Mortensen P, Deleuran B, Eaton W, et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics. 2009;124(2):687–94. source

      Not checked in the free run.

    • cites [78] Ashwood P, Wills S, de Water Van J. The immune response in autism: a new frontier for autism research. J Leukoc Biol. 2006;80(1):1–15. source

      Not checked in the free run.

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

    Premisecitation

    Gut microbiota-derived short-chain fatty acids such as propionic acid and butyric acid have immunomodulatory properties.

    “Furthermore, gut microbiota-derived short-chain fatty acids (SCFAs), such as propionic acid [69, 70] and butyric acid [71, 72], produced by bacterial fermentation of carbohydrates have immunomodulatory properties”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [69] Frye RE, Nankova B, Bhattacharyya S, Rose S, Bennuri SC, MacFabe DF. Modulation of immunological pathways in autistic and neurotypical lymphoblastoid cell lines by the enteric microbiome metabolite propionic acid. Front Immunol. 2017;8:1670. source

      Not checked in the free run.

    • cites [70] Frye RE, Rose S, Chacko J, Wynne R, Bennuri SC, Slattery JC, et al. Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. Transl Psychiatry. 2016;6(10):e927. source

      Not checked in the free run.

    • cites [71] Rose S, Bennuri SC, Davis JE, Wynne R, Slattery JC, Tippett M, et al. Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism. Transl Psychiatry. 2018;8(1):42. source

      Not checked in the free run.

    • cites [72] Rose S, Bennuri SC, Murray KF, Buie T, Winter H, Frye RE. Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: a blinded case–control study. PLoS ONE. 2017;12(10):e0186377. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with L. reuteri increased GABA receptor gene expression and protein levels in brain regions of mice and corresponded to improvements in social engagement.

    “Treatment with L. reuteri resulted in an increase of both GABA receptor gene expression and protein levels in brain regions of mice, which also corresponded to improvements in social engagement.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Tabouy L, Getselter D, Ziv O, Karpuj M, Tabouy T, Lukic I, et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav Immun. 2018;73:310–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a rodent model, L. reuteri was sensitive to an autism-related mutation, decreased in abundance, and positively correlated with GABA receptor expression in the brain.

    “In a rodent model, Tabouy et al. [84] used the Shank3 KO mice and demonstrated that specific bacterial species (i.e. L. reuteri) were sensitive to an autism-related mutation, were decreased in abundance, and positively correlated with the expression of gamma-aminobutyric acid (GABA) receptor in the brain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Tabouy L, Getselter D, Ziv O, Karpuj M, Tabouy T, Lukic I, et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav Immun. 2018;73:310–9. source

      Not checked in the free run.

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

    Premisecitation

    The gut microbiome's contribution to neurological development and regulation has been implicated and demonstrated in animal models.

    “Lastly, the gut microbiome’s contribution to neurological development and regulation has been implicated and demonstrated in animal models [85].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Rogers G, Keating D, Young R, Wong M, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry. 2016;21(6):738–48. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisenone given

    Parent-reported questionnaires are not as objective compared to experienced observations in standardized assessments by psychologists or developmental-behavioral pediatricians.

    “Parent-reported questionnaires, while important to provide a summary of behaviors within the home setting, are not as objective compared to experienced observations in standardized assessments by psychologists or developmental-behavioral pediatricians.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gnotobiotic animals demonstrate heightened hypothalamic-pituitary response, elevated plasma ACTH and corticosterone, and reduced BDNF expression in cortex and hippocampus.

    “For example, gnotobiotic animals demonstrate heightened hypothalamic-pituitary response, elevated plasma adrenocorticotropic hormone and corticosterone, and reduced brain-derived neurotrophic factor (BDNF) expression levels in the cortex and hippocampus [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu X, et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J Physiol. 2004;558(Pt 1):263–75. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The diagnostic criteria for ASD and classification into subtypes have been updated in 2013.

    “Further, the diagnostic criteria for ASD and classification of ASD into subtypes have been updated in 2013.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] American Psychiatric Association. DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Arlington: American Psychiatric Association; 2013. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gut microbiota manufactures neuroactive chemicals and influences levels of circulating 5-HT and serotonin, thereby altering fetal neuronal cell synaptogenesis and neuronal morphogenesis.

    “Furthermore, gut microbiota manufactures neuroactive chemicals and influences levels of circulating 5-hydroxytryptamine (5-HT) and serotonin, thereby altering fetal neuronal cell synaptogenesis [89] and neuronal morphogenesis [90], respectively.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci. 2003;4(12):1002–12. source

      Not checked in the free run.

    • cites [90] Côté F, Fligny C, Bayard E, Launay J, Gershon M, Mallet J, et al. Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci USA. 2007;104(1):329–34. source

      Not checked in the free run.

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

    Interpretationreasoning

    It is unlikely that the same environmental conditions (diet, antibiotics, pets, livestock, travel limits) may be imposed on participants in long prospective studies, complicating interpretation of microbial samples.

    “Given the long duration of such prospective studies, it is unlikely that the same environmental conditions such as diet, exposure to antibiotics or other medications, pets in the home, exposure to livestock, and limits on travel may be imposed on the participants, which will further complicate interpretation of microbial samples.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The issue of multiple testing looms large in comparison of microbial constituents between ASD cases and controls.

    “Finally, with regards to the comparison of microbial constituents between ASD cases and controls, the issue of multiple testing looms large.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Ongoing investigations such as NIH ECHO study have started collection of infant microbiotas with planned serial samples.

    “Nonetheless, ongoing investigations, such as the National Institutes of Health (NIH) Environmental influences on Child Health Outcomes (ECHO) study, have already started the collection of infant microbiotas with planned serial samples.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Interpretation of collective results across studies may be constrained by lack of standardization of experimental protocols and hampered by suboptimal inter-platform agreement and measurement reliability.

    “However, interpretation of the collective results across studies may be constrained by the lack of standardization of experimental protocols and is further hampered by suboptimal inter-platform agreement and measurement reliability.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human microbiome exhibits considerable spatial and temporal variability, so single samples from a specific anatomical site may not be representative of its true diversity and may fail to capture rarer or less abundant taxa.
    • Rests on an assumption: Shipping time and ambient temperature influence microbial composition in poorly-handled specimens.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    The relationship of the microbiome and social behaviors is multifaceted and complex involving environmental factors, immune responses, and host genetic background.

    “The relationship of the microbiome and social behaviors is multifaceted and complex involving not only environmental factors and immune responses, but also the genetic background of the host.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    One study suggests children with ASD may have increased intake of chia seeds in smoothies, associated with specific microbiome findings.

    “One study suggests that children with ASD may have an increased intake of chia seeds in smoothies, which is associated with specific microbiome findings [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Son J, Zheng L, Rowehl L, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE. 2015;10(10):e0137725-e. source

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    There has not been a comprehensive review that systematically evaluates dysbiosis in children with ASD based on bacterial taxonomy from phylum to species, investigates whether results are congruous, and summarises both positive and negative findings down to species in all captured studies.

    “However, there has not been a comprehensive review that systematically (1) evaluates the dysbiosis described in children with ASD based on bacterial taxonomy from phylum to species, (2) investigates whether results of dysbiosis are congruous in all cases, and (3) summarises both positive and negative findings down to species in all the studies captured.”

  • The paper relies on this without support.

    The human microbiome exhibits considerable spatial and temporal variability, so single samples from a specific anatomical site may not be representative of its true diversity and may fail to capture rarer or less abundant taxa.

    “Since the human microbiome exhibits considerable spatial and temporal variability, single samples obtained from a specific anatomical site may not be representative of its true diversity at any given time and may especially fail to capture rarer or less abundant taxa.”

  • The paper relies on this without support.

    Shipping time and ambient temperature influence microbial composition in poorly-handled specimens.

    “factors such as shipping time and ambient temperature are established to influence the microbial composition in poorly-handled specimens.”

  • The paper relies on this without support.

    Children with ASD are sometimes placed on non-specific gluten-free, casein-free diets, which easily change gut microbiome composition.

    “Children with ASD are also sometimes placed on non-specific gluten-free, casein-free diets, which easily change one’s gut microbiome composition.”
4 of 4

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?

  • Studies showing the importance of microbiota in ASD pathogenesis are few and mostly inconsistent, with some exceptions concerning differences in bacteria such as Prevotella, Firmicutes, Clostridiales (like Clostridium perfringens), and Bifidobacterium species between ASD patients and controls.

    “Regarding human autism spectrum disorder (ASD), studies showing the importance of the microbiota in the pathogenesis are few and mostly inconsistent, with some exceptions concerning the differences observed for bacteria, such as Prevotella, Firmicutes, Clostridiales, like Clostridium perfringens, and Bifidobacterium species (188), between the ASD patients and the controls.”

    From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [188]

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.

  • Bifidobacterium intervention result contradicts summary

    Minor

    The discussion says Bifidobacterium significantly increased after intervention, but the results describe a decrease after probiotic intervention in one included study.

1 of 1

The citation lists haven’t been fetched yet

References 95 · Cited by 149

Authors
Ho, L. K. H., Tong, V. J. W., Syn, N., Nagarajan, N., Tham, E. H., Tay, S. K., Shorey, S., Tambyah, P. A., & Law, E. C. N.
Affiliations
  • National University of Singapore (SG)
  • Agency for Science, Technology and Research (SG)
Corresponding author
Law, Evelyn Chung Ning
ORCID
Venue
Gut Pathogens
Publisher
Springer Science and Business Media LLC
Published
2020-02-03
Volume
12
Issue
1
Pages
6-6
ISSN
1757-4749 (ISSN-L)
DOI
10.1186/s13099-020-0346-1
PMC
PMC6996179
OpenAlex
W3009016294
Semantic Scholar
9cfead99b35d319528326a84c407f35fadad8dba
Cited by
149
References
95
Citations by year
2026: 17 · 2025: 19 · 2024: 23 · 2023: 24 · 2022: 25 · 2021: 28 · 2020: 12 · 2019: 1
FWCI
2.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Gut Pathogens (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
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
gut microbiota, autism spectrum disorder, gut dysbiosis, children, Prevotella, Firmicutes, Clostridium perfringens, Bifidobacterium, Clostridiales, microbiome-gut-brain axis, ASD pathogenesis

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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