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Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice
Open accessAbstract
SUMMARY Autism spectrum disorder (ASD) manifests as alterations in complex human behaviors including social communication and stereotypies. In addition to genetic risks, the gut microbiome differs between typically-developing (TD) and ASD individuals, though it remains unclear whether the microbiome contributes to symptoms. We transplanted gut microbiota from human donors with ASD or TD controls into germ-free mice, and reveal that colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors. The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes. Microbiome and metabolome profiles of mice harboring human microbiota predict that specific bacterial taxa and their metabolites modulate ASD behaviors. Indeed, treatment of an ASD mouse model with candidate microbial metabolites improves behavioral abnormalities and modulates neuronal excitability in the brain. We propose that the gut microbiota regulates behaviors in mice via production of neuroactive metabolites, suggesting that gut-brain connections contribute to the pathophysiology of ASD.
Overview
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TL;DR
Transplanting gut microbiota from children with ASD into germ-free mice was sufficient to induce ASD-like behavioral symptoms in offspring, relative to TD microbiota. The authors link these behaviors to altered brain gene splicing and microbial metabolites, especially lower taurine and 5-aminovaleric acid (5AV), and show that administering these metabolites improves behaviors in BTBR mice.
Key findings
- Germ-free C57BL/6J mice colonized with ASD donor microbiota produced offspring (oASD) with increased repetitive behavior, decreased locomotion, and decreased communication versus oTD controls; direct social interaction also showed decreased sociability, and effects were more pronounced in male mice.
- Microbiome analysis identified 31 differentially abundant amplicon sequence variants between oTD and oASD mice, including *Bacteroides ovatus* and *Parabacteroides merdae* enriched in oTD and *Eisenbergiella tayi* enriched in oASD; *E. tayi* correlated with increased repetitive behavior and social deficits.
- RNA-seq/rMATS found 560 genes with differential alternative splicing events between oASD and oTD brains (PFC: 265, STR: 257, full dataset: 243), with 52 of 560 events in autism-associated genes and 11 present in both SPARK and SFARI datasets.
- Metabolomics found 27 of 313 detected colon metabolites significantly different in oASD versus oTD mice, including ~50% less taurine and lower 5AV; oral taurine or 5AV from conception reduced repetitive behavior and increased social duration in BTBR mice, and 5AV decreased L5 pyramidal neuron excitability in medial prefrontal cortex.
Methods
- Human fecal samples from TD and ASD donors, selected using ADOS and GI severity index scores, were transplanted into germ-free C57BL/6J mice; recipient mice were bred, and offspring were behaviorally tested (open field, marble burying, three-chamber sociability, direct social interaction, ultrasonic vocalization) and sampled at P45.
- The study used 16S rRNA gene sequencing, shotgun metagenomics, RNA-seq with rMATS splicing analysis, untargeted NMR/GC-MS metabolomics, and MIMOSA metabolic modeling; candidate metabolites were administered to BTBR T+ tf/J mice, followed by slice electrophysiology and calcium imaging.
- Behavioral outcomes were analyzed with longitudinal linear mixed-effects models; microbiome differential abundance used DESeq2 and Random Forest; correlations used Spearman’s rank; splicing events used FDR < 0.1.
Limitations
- The paper states it is a limited study with 16 donor samples from a pediatric cohort, and that it cannot conclude gut bacteria are entirely causal for ASD symptoms; host genetics and perinatal events may compound risk.
- The paper states that only human male donor samples were used, so the observed male bias in mouse behavioral effects may be a true effect or an artifact of experimental design; future studies with male and female donors are needed.
- The paper notes that GI co-morbidities in ASD donors and their correlation with some behaviors may impact mouse outcomes after microbiota transplant; evident from the text, the mechanistic work relies heavily on mouse models, including BTBR mice and germ-free humanized mice, and on correlational predictions from microbiome-metabolome integration.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes.”
- Also stated in: § ASD Microbiota Promote Extensive Alternative Splicing of ASD-relevant Genes in the Brain · plain
“These data reveal a major shift in alternative splicing patterns of genes in the brains of oASD mice relative to oTD mice, with an enrichment for ASD-related genes in the differentially spliced subset that mirror findings from human brains.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § ASD Microbiota Promote Extensive Alternative Splicing of ASD-relevant Genes in the Brain · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We transplanted gut microbiota from human donors with ASD or TD controls into germ-free mice, and reveal that colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors.”
- Also stated in: § Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice · plain
“Thus, microbiota transplantation from human ASD donors into mice can transfer ASD relevant behavioral deficits.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The behavioral differences observed in mice colonized with ASD microbiota are due to the microbiota itself and not to other donor-derived factors such as diet, genetics, or GI comorbidities.
- Rests on an assumption: The human donor fecal samples are representative of the donor's gut microbiota and of ASD/TD status, without other confounding differences between donor groups.
- Rests on an assumption: The mouse behavioral tests used (marble burying, open-field, ultrasonic vocalization, direct social interaction) measure ASD-relevant behaviors that translate to human ASD symptoms.
- Also stated in: § Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Conversely, female oASD mice traveled shorter distances than oTD females in OFT (Figures S2C’, S2H).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: The behavioral differences observed in mice colonized with ASD microbiota are due to the microbiota itself and not to other donor-derived factors such as diet, genetics, or GI comorbidities.
- Rests on an assumption: The mouse behavioral tests used (marble burying, open-field, ultrasonic vocalization, direct social interaction) measure ASD-relevant behaviors that translate to human ASD symptoms.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we observed increased repetitive behavior, decreased locomotion, and decreased communication in oASD mice compared to mice colonized with samples from TD controls (oTD), as tested by marble burying (MB), open-field testing (OFT), and ultrasonic vocalization (USV), respectively.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The behavioral differences observed in mice colonized with ASD microbiota are due to the microbiota itself and not to other donor-derived factors such as diet, genetics, or GI comorbidities.
- Rests on an assumption: The mouse behavioral tests used (marble burying, open-field, ultrasonic vocalization, direct social interaction) measure ASD-relevant behaviors that translate to human ASD symptoms.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“oASD mice “humanized” with fecal microbiota from ASD donors showed increased repetitive behavior, decreased sociability, and decreased locomotion compared to mice colonized with samples from TD controls (Figures 1E–G).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The behavioral differences observed in mice colonized with ASD microbiota are due to the microbiota itself and not to other donor-derived factors such as diet, genetics, or GI comorbidities.
- Rests on an assumption: The mouse behavioral tests used (marble burying, open-field, ultrasonic vocalization, direct social interaction) measure ASD-relevant behaviors that translate to human ASD symptoms.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“oASD offspring displayed different bacterial profiles from oTD controls, driven by various taxa such as Bacteriodetes, β-Proteobacteria, Lactobacillales, Clostridiaceae, and Enterobacteriaceae (Figure 1K).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed a slight shift in α- and β-diversity in offspring compared to recipients (Figures S1C–E).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The trained classifier assigned all offspring samples correctly by group.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we observed increased repetitive behavior, decreased locomotion, and decreased communication in oASD mice compared to mice colonized with samples from TD controls (oTD), as tested by marble burying (MB), open-field testing (OFT), and ultrasonic vocalization (USV), respectively.”
- Also stated in: § Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice · plain
“oASD mice “humanized” with fecal microbiota from ASD donors showed increased repetitive behavior, decreased sociability, and decreased locomotion compared to mice colonized with samples from TD controls (Figures 1E–G).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The behavioral differences observed in mice colonized with ASD microbiota are due to the microbiota itself and not to other donor-derived factors such as diet, genetics, or GI comorbidities.
- Rests on an assumption: The mouse behavioral tests used (marble burying, open-field, ultrasonic vocalization, direct social interaction) measure ASD-relevant behaviors that translate to human ASD symptoms.
- Also stated in: § Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We find that the distance traveled in OFT negatively correlates with the donor age, indicating that some donor age-related microbiota changes may affect locomotion (Figure 1H).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: The germ-free mouse model and humanization procedure do not introduce artifacts that confound the behavioral or molecular results.
- It may state two separate claims as one. 34
- Probably not a substantial claim. 33
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, treatment of an ASD mouse model with candidate microbial metabolites improves behavioral abnormalities and modulates neuronal excitability in the brain.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Conversely, Eisenbergiela tayi (02b40_Lachnospiraceae and 29857_Lachnospiraceae) was prevalent among all oASD mice, and absent from oTD groups (Figure 2B).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we found no differences in mouse weight and intestinal barrier function between oTD and oASD mice (Figure S3A–B, Figure S3C–H).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Specifically, Bacteroides ovatus (970ed_Bacteroides ovatus and 054dc_Bacteroides ovatus) and Parabacteroides merdae (4ae7e_Parabacteroides) were prevalent in all oTD samples, and absent from most or all oASD samples.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“Sixty percent of the taxa in donor samples engrafted on average in recipient mice with no differences in engraftment or bacterial loads between oTD and oASD mice (Figure S1H–I, S1J–L).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“Moreover, specific taxa, such as Actinobacteria and some Firmicutes, failed to engraft in mice, while others such as some Bacteriodetes thrived (Figure S1F–G).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These core features of ASD were not the result of anxiety or other locomotion deficits, as colonized mice spent the same amount of time in the center of an open-field arena and male mice traveled similar distances (Figures S2C–D).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Gut Microbiota from Individuals with ASD is Sufficient to Promote Altered Behaviors in Mice
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The mouse behavioral tests used (marble burying, open-field, ultrasonic vocalization, direct social interaction) measure ASD-relevant behaviors that translate to human ASD symptoms.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The Bacteroides (b20cd_Bacteroides) species and P. merdae (4ae7e_Parabacteroides) both correlated with reduced repetitive behavior and increased social behavior.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The germ-free mouse model and humanization procedure do not introduce artifacts that confound the behavioral or molecular results.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, we found that this dataset of differentially spliced genes was highly enriched for various ribosome binding protein (RBP) targets, but under-enriched in activity dependent transcripts (Figure 3E), suggesting that the gut microbiome can alter splicing programs at the RBP level.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > ASD Microbiota Promote Extensive Alternative Splicing of ASD-relevant Genes in the Brain
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In the paper
“Fifty two of the 560 AS events occurred within genes associated with autism, with 11 present in both the SPARK gene list and SFARI Gene dataset, and 52 present in the SFARI gene list (Figure 3C).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > ASD Microbiota Promote Extensive Alternative Splicing of ASD-relevant Genes in the Brain
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In the paper
“Differential splicing events were enriched for genes highly expressed in neurons, and under-enriched for in microglia in oASD mice compared to oTD animals (Figure 3D).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > ASD Microbiota Promote Extensive Alternative Splicing of ASD-relevant Genes in the Brain
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In the paper
“Accordingly, we validated that 16S rRNA gene ASVs that map to E. tayi, but not those that map to P. merdae, were more abundant in ASD individuals from large human cohort studies (Figure 2F–G).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
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In the paper
“Three long-noncoding RNAs of unknown function from the PFC, and two additional genes from the combined PFC and STR dataset, displayed differential expression between groups of mice (Figures S4A–C, Figure S4D).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > ASD Microbiota Promote Extensive Alternative Splicing of ASD-relevant Genes in the Brain
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In the paper
“However, we found a significant increase in K13821 (Figure 5H) and a significant decrease in P5C reductase (K00286) abundance (Figure 5I) in oASD mice.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Microbiota from TD and ASD-colonized Mice Produce Discrete Metabolite Profiles
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In the paper
“While 5AV reached the fetal compartment and the fetal brain (Figure 6B), taurine concentrations did not change with administration suggesting it may act locally in the gut.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Administration of Metabolites Depleted in ASD Improve Behaviors in a Mouse Model
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In the paper
“Hydroxyproline concentrations varied consistently with K00286 abundance (Figure S5B), and hypD levels were not significantly decreased in oASD samples (Figure 5G).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Microbiota from TD and ASD-colonized Mice Produce Discrete Metabolite Profiles
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“Interestingly, MIMOSA analysis predicted that taurine concentrations may result from differential synthesis potential by three specific species: Alistipes sp. HGB5, Alistipes finegoldii, and Bacteroides xylanisolvens (Figure S5A).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Microbiota from TD and ASD-colonized Mice Produce Discrete Metabolite Profiles
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Mice administered 5AV showed increased locomotion, decreased center duration (Figure S6F), and increased sociability (Figure S6H), with no significant difference in repetitive behavior (Figure S6G).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Administration of Metabolites Depleted in ASD Improve Behaviors in a Mouse Model
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In the paper
“However, L5 pyramidal neurons from mice treated with 5AV, but not taurine, showed significantly decreased excitability as measured by the number of spikes observed as a result of injection of stepwise increasing currents”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > 5AV Reduces Neuronal Excitability in the Prefrontal Cortex of BTBR Mice
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In the paper
“Neither 5AV nor taurine affected the intrinsic membrane properties of neurons or the frequency or amplitude of mEPSCs and mIPSCs, compared to controls (Figure S6I, Figure 6F–G).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > 5AV Reduces Neuronal Excitability in the Prefrontal Cortex of BTBR Mice
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In the paper
“Analysis of gene splicing revealed extensive differences between oTD and oASD mice, with 11 alternative splicing events in validated high-risk ASD genes.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
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In the paper
“Two examples are taurine, the metabolic product of cysteate or taurocholic acid, and 5AV, the fermentation product of proline—both GABAA receptor agonists that are increased in the colons of oTD mice.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
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In the paper
“In serum, a total of 130 metabolites were identified by GC-MS (out of a total of 255 detected).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“and 67 metabolites were detected and identified by NMR”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
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In the paper
“In colon contents, a total of 122 metabolites were identified by GC-MS (out of a total of 246 detected)”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
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In the paper
“Specific gut microbes have demonstrated therapeutic potential in animal models of ASD (Buffington et al., 2016; Hsiao et al., 2013; Sgritta et al., 2018; Tabouy et al., 2018).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > INTRODUCTION
What the sources say
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“changes in the microbiome often result in altered metabolic profiles, impacting the availability and diversity of nutrients and microbial metabolites (Dodd et al., 2017; Melnik et al., 2017; Sharon et al., 2014; Wikoff et al., 2009).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > INTRODUCTION
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In the paper
“as well as in mouse models of ASD (Buffington et al., 2016; Coretti et al., 2017; Hsiao et al., 2013; Kim et al., 2017; Liu et al., 2018; de Theije et al., 2014).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > INTRODUCTION
What the sources say
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In the paper
“microbial-based interventions, including fecal transplantation, antibiotics, and probiotics, have shown promise in a limited number of human trials (Grimaldi et al., 2018; Kang et al., 2017b; Sandler et al., 2000).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > INTRODUCTION
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In the paper
“Fecal microbiome profiles are most divergent in ASD subjects with GI dysfunction, a common comorbidity of autism (Chaidez et al., 2014; Gorrindo et al., 2012).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > INTRODUCTION
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In the paper
“amino-acid transport and degradation differ between TD and ASD individuals (Aldred et al., 2003; Evans et al., 2008)”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > INTRODUCTION
What the sources say
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In the paper
“Collectively, fecal transplantation from human donors into GF recipient mice maintained differences between TD and ASD microbiome profiles, which are vertically transmitted to offspring with fidelity.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
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In the paper
“We observe a decrease in α-diversity upon colonization of mice (donor to recipients), indicating loss of bacterial species due to sample processing and/or host-incompatibility (Figure S1D).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > TD and ASD Colonized Mice Harbor Different Bacterial Species that Correlate with Behaviors
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In the paper
“These data reveal a major shift in alternative splicing patterns of genes in the brains of oASD mice relative to oTD mice, with an enrichment for ASD-related genes in the differentially spliced subset that mirror findings from human brains.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > ASD Microbiota Promote Extensive Alternative Splicing of ASD-relevant Genes in the Brain
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In the paper
“While 5AV reached the fetal compartment and the fetal brain (Figure 6B), taurine concentrations did not change with administration suggesting it may act locally in the gut.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Administration of Metabolites Depleted in ASD Improve Behaviors in a Mouse Model
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In the paper
“These data suggest that, in oTD microbiota, L-proline is produced from Hyp via P5C and subsequently serves as an electron acceptor to produce 5AV (Figure 5F–I). Conversely, in oASD microbiota, the balance shifts towards production of P5C and glutamate, and away from 5AV (Figure 5F–I).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Microbiota from TD and ASD-colonized Mice Produce Discrete Metabolite Profiles
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In the paper
“In addition, we predict that genistein and daidzein (or the absence of their degradation products) contribute to repetitive behavior effects while lysine, 3AIBA, and genistein are predicted to influence locomotion (Figure 6A).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > Administration of Metabolites Depleted in ASD Improve Behaviors in a Mouse Model
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- Rests on an assumption: The germ-free mouse model and humanization procedure do not introduce artifacts that confound the behavioral or molecular results.
None of the sources cited for this claim have been checked yet.
In the paper
“The high prevalence of GI dysfunction (Adams et al., 2011; Chaidez et al., 2014; McElhanon et al., 2014), along with evidence of immune imbalance (Onore et al., 2012), further suggest microbiota involvement in ASD.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
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In the paper
“The transcriptional program in ASD brains is distinct from that of TD brains (Gandal et al., 2018; Parikshak et al., 2016; Voineagu et al., 2011).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
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In the paper
“Factors such as altered host genetics and perinatal events, coupled with an altered microbiota, may together influence the etiology of ASD by compounding risks that enhance symptom severity.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
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In the paper
“We propose that the human microbiota can modulate complex behaviors in mice via the production of neuroactive microbial metabolites, with mechanisms that include regulation of E-I balances in the brain.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > RESULTS > 5AV Reduces Neuronal Excitability in the Prefrontal Cortex of BTBR Mice
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In the paper
“Taurine is essential for brain development (Kilb and Fukuda, 2017; Tochitani, 2017) and can be produced by neurons and astrocytes (Vitvitsky et al., 2011) or transported through the blood-brain-barrier via the Taurine transporter TauT (Benrabh et al., 1995).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
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In the paper
“Gut bacteria can affect gene expression and host behavior through various pathways, including the production of neuroactive small molecules (Hsiao et al., 2013).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
What the sources say
- Not checked yetcites Hsiao et al., 2013 source
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In the paper
“Recent studies have highlighted the importance of aberrant alternative splicing of mRNA in the brains of subjects with an ASD diagnosis (Corominas et al., 2014; Gandal et al., 2018; Irimia et al., 2014; Parikshak et al., 2016; Voineagu et al., 2011).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
What the sources say
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In the paper
“These findings suggest that gut microbes not only regulate gene expression in the mouse brain (Hoban et al., 2016; Neufeld et al., 2011; Stilling et al., 2015), but also affect alternative splicing (Stilling et al., 2018), and can regulate the production of specific isoforms of genes that have been implicated in ASD.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
What the sources say
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In the paper
“All samples were then assigned an identification number that prevented from direct identification of the groups to facilitate blinded analysis of samples downstream.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
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In the paper
“Consistent with these results, social deficits in the CNTNP2-deficient mouse model of autism could be rescued by modulating the excitability of pyramidal neurons (Selimbeyoglu et al., 2017).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
What the sources say
- Not checked yetcites Selimbeyoglu et al., 2017 source
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In the paper
“Mice were tested during the light phase of the light cycle; to control for time of day effects, cages of different groups were alternated.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
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In the paper
“During the initial discovery phase, the experimenter was blinded to the donor but not to the group. In the subsequent validation phase, the experimenter was blinded.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
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None of the sources cited for this claim have been checked yet.
In the paper
“Extensive evidence highlight the importance of the E-I balance in neurodevelopmental disorders (Lee et al., 2017; Nelson and Valakh, 2015; Rubenstein and Merzenich, 2003).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
What the sources say
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In the paper
“To control for effects by the time of collection, mice from different groups were sacrificed in an alternated fashion.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
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In the paper
“Sample outliers were identified and removed based on the RMD-PAV algorithm (Matzke et al., 2011) and a p-value threshold of 0.0001; based on this criterion, three samples were removed.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
What the sources say
- Not checked yetcites Matzke et al., 2011 source
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In the paper
“These GABAA receptor agonists may act to perturb the E-I balance in the brain, specifically during development.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
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In the paper
“When the experimenter was not blinded to the treatment or group, the number of buried marbles was scored by a second experimenter blinded to the treatment/group from overhead images taken after the second 10 min session.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
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In the paper
“Accordingly, we propose that the etiology of ASD may lie in the human genome, the human microbiota, or both via gene-environment interactions.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: Both human and microbial genes are vertically heritable across generations.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A set of reference videos was used to ensure consistency over time.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
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In the paper
“The high concordance rates observed between monozygotic twins implicate a strong genetic basis for ASD (Tick et al., 2016).”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > DISCUSSION
What the sources say
- Not checked yetcites Tick et al., 2016 source
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In the paper
“Throughout the procedure, the experimenter was blinded to mouse groups.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Subsequently, we tested and analyzed a subset of representative samples (two TD and three ASD) along with additional previously untested samples (one TD and two ASD), to ensure there is no bias in sample selection.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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In the paper
“Enrichment of known autism risk genes (SFARI: https://gene.sfari.org/, SPARK for Autism: http://spark-sf.s3.amazonaws.com/SPARK_gene_list.pdf) among those exhibiting DS was assessed using logistic regression, controlling for gene length.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All metabolite identification and quantification ions were validated and confirmed to reduce deconvolution errors during automated dataprocessing and to eliminate false identifications.”
§ Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
The behavioral differences observed in mice colonized with ASD microbiota are due to the microbiota itself and not to other donor-derived factors such as diet, genetics, or GI comorbidities.
“It is possible that GI co-morbidities in the ASD donors and their correlation with some behaviors (Figure 1B, Table S1) may impact outcomes in experimental mice after microbiota transplant.”
The paper relies on this without support.
The human donor fecal samples are representative of the donor's gut microbiota and of ASD/TD status, without other confounding differences between donor groups.
“Fecal samples from human TD and ASD donors were selected based on Autism Diagnostic Observation Schedule (ADOS) (Gotham et al., 2007) and GI severity index (GSI) scores (Schneider et al., 2006) (Figure 1A–B, Table S1), and transplanted into GF wild-type mice, i.e., “humanized microbiome” mice.”
The paper relies on this without support.
The mouse behavioral tests used (marble burying, open-field, ultrasonic vocalization, direct social interaction) measure ASD-relevant behaviors that translate to human ASD symptoms.
“oASD mice, colonized with samples from ASD donors, displayed behavioral deficits relevant to ASD, while oMild-ASD mice behaved similar to oTD controls (Figure S2A–E).”
The paper relies on this without support.
Correlations between bacterial taxa or metabolites and behavioral outcomes indicate a potential causal or modulatory relationship rather than mere association.
“The association of specific bacterial species with oTD or oASD samples, which are also highly correlated with ASD-relevant behaviors, supports the hypothesis that specific bacteria may contribute to various symptoms of ASD.”
The paper relies on this without support.
The germ-free mouse model and humanization procedure do not introduce artifacts that confound the behavioral or molecular results.
“We transplanted gut microbiota from human donors with ASD or TD controls into germ-free mice, and reveal that colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors.”
The paper relies on this without support.
A direct contribution by the microbiota to the pathophysiology and behavioral outcomes of ASD has not been described previously.
“While these compelling association studies in humans suggest gut bacteria may impact behavioral symptoms, a direct contribution by the microbiota to the pathophysiology and behavioral outcomes of ASD has not been described previously.”
The paper relies on this without support.
Both human and microbial genes are vertically heritable across generations.
“However, it is important to consider that both human and microbial genes are vertically heritable across generations.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“gut microbiota dysbiosis has been implicated in behavioral and neurologic pathologies, such as depression, Alzheimer's (AD) and Parkinson's (PD) diseases and autism spectrum disorder (ASD) (9, 21, 25–27).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [27]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Recently, Sharon and collaborators showed that microbiota transplantation from human ASD donors into mice could transfer ASD-relevant behavioral deficits (27).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [27]
In the citing paper
“Research on them [114] shows that transplanting fecal microflora from ASD donors to GF mice induced autistic behavior, specifically increased repetitive behavior, decreased locomotion, and communication, compared to mice with NT donors microbiota.”
From Unraveling the Connections: Eating Issues, Microbiome, and Gastrointestinal Symptoms in Autism Spectrum Disorder (2025) · cites this paper as [114]
In the citing paper
“Of extreme relevance, the altered microbiota of patients could transfer the disease from a human host to a mouse host (113, 116–120).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [113]
In the citing paper
“The microbiota composition differs significantly between healthy controls and patients affected by neurodegenerative disorders (such as multiple sclerosis (MS), Alzheimer’s (AD) and Parkinson’s (PD) diseases) (20, 22, 23, 32, 111–115), and neuropsychiatric disorders (NPS) (30), like major depressive and mood disorders.”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [113]
In the citing paper
“Colonizing GF mice with fecal microbiota from patients affected by ASD was sufficient to promote ASD-like behaviors in the animals (113).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [113]
In the citing paper
“This approach seemed to be due to a deficit in the production of two bacterial metabolites, 5-aminovaleric acid (5-AV) and taurine, both being weak GABAA agonists, in ASD individuals compared to controls (113).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [113]
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Metadata
- Authors
- Sharon, G., Cruz, N. J., Kang, D.-W., Gandal, M. J., Wang, B., Kim, Y.-M., Zink, E. M., Casey, C. P., Taylor, B. C., Lane, C. J., Bramer, L. M., Isern, N. G., Hoyt, D. W., Noecker, C., Sweredoski, M. J., Moradian, A., Borenstein, E., Jansson, J. K., Knight, R., Metz, T. O., Lois, C., Geschwind, D. H., Krajmalnik-Brown, R., & Mazmanian, S. K.
- Affiliations
- California Institute of Technology (US)
- Arizona State University (US)
- University of California, Los Angeles (US)
- Pacific Northwest National Laboratory (US)
- University of California San Diego (US)
- University of Southern California (US)
- University of Washington (US)
- Santa Fe Institute (US)
- Corresponding author
- Sharon, Gil
- Mazmanian, Sarkis K.
- ORCID
- Sharon, Gil
- Kang, Dae-Wook
- Gandal, Michael J.
- Wang, Bo
- Kim, Young-Mo
- Zink, Erika M.
- Casey, Cameron P.
- Taylor, Bryn C.
- Lane, Christianne J.
- Bramer, Lisa M.
- Isern, Nancy G.
- Hoyt, David W.
- Noecker, Cecilia
- Sweredoski, Michael J.
- Moradian, Annie
- Borenstein, Elhanan
- Jansson, Janet K.
- Knight, Rob
- Metz, Thomas O.
- Lois, Carlos
- Geschwind, Daniel H.
- Mazmanian, Sarkis K.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 177
- Issue
- 6
- Pages
- 1600-1618.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6993574
- OpenAlex
- W2948003108
- Semantic Scholar
- afd469685e7754bfd52bfa454d808bbbec849f79
- Cited by
- 1,182
- References
- 196
- Citations by year
- 2026: 128 · 2025: 187 · 2024: 163 · 2023: 166 · 2022: 189 · 2021: 155 · 2020: 153 · 2019: 37
- FWCI
- 44.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Simons Foundation Autism Research Initiative
- Heritage Medical Research Institute
- Simons Foundation
- Autism Speaks
- University of California, San Diego
- National Institutes of Health
- Emch Foundation
- Autism Research Institute
- Pacific Northwest National Laboratory
- Brenen Hornstein Autism Research & Education Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, gut microbiota, microbiota transplantation, germ-free mice, autistic behavior, alternative splicing, microbial metabolites, gut-brain axis, neuronal excitability, social communication, stereotypy
- MeSH terms
- Autism Spectrum Disorder, Gastrointestinal Microbiome, Animals, Bacteria, Behavior, Animal, Behavioral Symptoms, Brain, Disease Models, Animal, Humans, Risk Factors, Mice, Microbiota
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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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