Fecal Microbiome Transplantation from Children with Autism Spectrum Disorder Modulates Tryptophan and Serotonergic Synapse Metabolism and Induces Altered Behaviors in Germ-Free Mice
Open accessAbstract
The relationship between the gut microbiota and ASD is not yet fully understood. Numerous studies have focused on the differences in intestinal microbial and metabolism profiles between TD and ASD children.
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Written from the paper’s full text.
TL;DR
Fecal microbiota from children with ASD transferred into germ-free mice induced ASD-like behaviors, distinct cecal microbial communities, and altered tryptophan/serotonin metabolism relative to mice receiving microbiota from typically developing children. The same tryptophan and serotonergic synapse pathways were altered in fecal samples from children with ASD, and key serotonin synthesis/transport proteins changed in mouse colon and prefrontal cortex.
Key findings
- ASD-FMT mice showed ASD-like behaviors versus TD-FMT mice: shorter sniffing of mouse urine (P < 0.001), less time in the open-field center zone (P < 0.01), more self-grooming (P < 0.01), greater novel-object chamber preference (P < 0.001), and lesser strange-mouse chamber preference (P < 0.001) (n = 16).
- Cecal microbiota differed between groups: no significant α-diversity differences, but ANOSIM showed between-group separation (R² = 0.78; P = 0.001). Verrucomicrobia was lower (P < 0.05) and unidentified_Bacteria higher (P < 0.01) in ASD-FMT; genera increased in ASD-FMT included Parabacteroides (P < 0.05), Alistipes (P < 0.01), Anaerotruncus (P < 0.01), and Helicobacter (P < 0.01), while Parasutterella (P < 0.05), Akkermansia (P < 0.05), Lachnoclostridium (P < 0.01), and unidentified_Erysipelotrichaceae (P < 0.01) were decreased (n = 8).
- Untargeted metabolomics found 963 differential cecal metabolites (698 down, 265 up in ASD-FMT), 239 serum metabolites (122 down, 117 up), and 65 prefrontal cortex metabolites (36 down, 29 up). Tryptophan metabolism and serotonergic synapse pathways were enriched in cecal contents, serum, prefrontal cortex, and in feces from 120 children with ASD versus 60 TD children; picky eating differed (ASD 80/120 [66.7%] vs TD 26/60 [43.3%], P < 0.001).
- Protein expression in ASD-FMT versus TD-FMT mice: colon TPH1 was upregulated (P < 0.05), colon SERT (P < 0.01) and 5-HT1AR (P < 0.05) were downregulated; prefrontal cortex TPH2 and SERT were upregulated (P < 0.05 for both), while prefrontal cortex 5-HT1AR did not differ (P > 0.05) (n = 3).
Methods
- Thirty-two male germ-free BALB/c mice were randomized to receive 200 μl fecal suspension from 5 TD children or 5 children with ASD (boys aged 2–6 years); behavioral testing occurred after 3 weeks, and cecal contents, serum, prefrontal cortex, colon, and other tissues were collected.
- Cecal microbiota was analyzed by 16S rRNA gene V4 sequencing with α/β diversity, PCoA, Wilcoxon tests, and LEfSe (LDA > 4); untargeted LC-MS/MS metabolomics was performed on mouse cecal contents, serum, and prefrontal cortex, plus fecal samples from 120 children with ASD and 60 TD children, with KEGG pathway enrichment and Spearman correlation.
- Western blotting measured TPH1, SERT, and 5-HT1AR in mouse colon and TPH2, SERT, and 5-HT1AR in prefrontal cortex; differential metabolites were defined by VIP ≥ 1, P < 0.05, and fold change ≥ 1.25 or ≤ 0.8, with significance generally set at P < 0.05.
Limitations
- The paper states that it is difficult to distinguish whether mouse cecal metabolites were host-derived or microbiota-derived; the causal relationship between gut microbes, metabolites, and key metabolic proteins remains unclear; and multiple factors affecting the microbiome and metabolomics could not be fully controlled.
- Evident from the text: omics analyses used small mouse sample sizes (n = 8 per group; Western blot n = 3), and the mouse donors were only boys aged 2–6 years, limiting generalizability.
- Evident from the text: the human validation cohort was separate from the 5+5 mouse donors and provided only fecal metabolomics, so human causal or protein-level findings were not directly tested.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 23 cited sources checked · 0 supported · 0 flagged
- Findingown data
In cecal contents of mice, Trp-Trp, kynurenic acid, and indole-3-acetic acid were significantly higher in ASD-FMT mice than in TD-FMT mice.
“in the cecal contents of mice, the levels of Trp-Trp (a dipeptide of tryptophan), kynurenic acid, and indole-3-acetic acid were significantly higher and those of 6-hydroxymelatonin, indole-3-lactic acid, and 5-methoxy-indoleacetate were significantly lower in the ASD-FMT group than in the TD-FMT group”
Quote in the paperSubstantial claim - Findingown data
In the open-field test, the time of movement in the center zone was significantly shorter in ASD-FMT mice than in TD-FMT mice (P < 0.01).
“During this test, the time of movement in the center zone was significantly shorter in the ASD-FMT group than in the TD-FMT group (Fig. 1B) (P < 0.01).”
Quote in the paperSubstantial claim - Findingown data
239 differentially expressed metabolites were detected in serum samples, including 122 downregulated and 117 upregulated in ASD-FMT mice.
“a total of 239 differentially expressed metabolites were detected in the serum samples, including 122 downregulated metabolites and 117 upregulated metabolites in the ASD-FMT group”
Quote in the paperSubstantial claim - Findingown data
5-hydroxy-N-formylkynurenine, tryptamine, 5-hydroxytryptophan, and serotonin were more abundant in children with ASD than in TD children.
“5-hydroxy-N-formylkynurenine, tryptamine, 5-hydroxytryptophan, and serotonin were more abundant in children with ASD than in TD children”
Quote in the paperSubstantial claim - Findingown data
TPH2 expression in the prefrontal cortex was significantly upregulated in ASD-FMT mice compared with TD-FMT mice (P < 0.05).
“The expression levels of TPH2 and SERT in the prefrontal cortex were significantly upregulated in the ASD-FMT group compared with the TD-FMT group (P < 0.05 for both)”
Quote in the paperSubstantial claim
- Findingown data
At the genus level, Parabacteroides, Alistipes, Anaerotruncus, and Helicobacter were increased in ASD-FMT mice compared with TD-FMT mice.
“At the genus level, Parabacteroides (P < 0.05), Alistipes (P < 0.01), Anaerotruncus (P < 0.01), and Helicobacter (P < 0.01) were increased in the ASD-FMT group compared with the TD-FMT group”
Quote in the paperNot a substantial claim - Findingown data
Principal-coordinate analysis revealed conspicuous differences in microbial community structures between TD-FMT and ASD-FMT mice.
“Principal-coordinate analysis (PCoA) plots revealed conspicuous differences in microbial community structures between the TD-FMT and ASD-FMT groups”
Quote in the paperSubstantial claim - Findingown data
TPH1 protein expression in the colon was notably upregulated in ASD-FMT mice compared with TD-FMT mice (P < 0.05).
“The protein expression level of TPH1 in the colon was notably upregulated in the ASD-FMT group compared with the TD-FMT group (P < 0.05)”
Quote in the paperSubstantial claim - Findingown data
The time spent sniffing mouse urine was significantly shorter in ASD-FMT mice than in TD-FMT mice (P < 0.001).
“The time spent sniffing mouse urine was significantly shorter in the ASD-FMT group than in the TD-FMT group (P < 0.001) (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data
Bacteroidetes, Firmicutes, unidentified_Bacteria, Verrucomicrobia, and Proteobacteria were the most abundant bacteria in the cecum in both TD-FMT and ASD-FMT mice.
“Bacteroidetes, Firmicutes, unidentified_Bacteria, Verrucomicrobia, and Proteobacteria were the most abundant bacteria present in the cecum in the two groups.”
Quote in the paperNot a substantial claim - Findingown data
Analysis of similarities showed that differences between TD-FMT and ASD-FMT groups were significantly greater than differences within groups (R2 = 0.78; P = 0.001).
“Analysis of similarities showed that the differences between the two groups were significantly greater than the differences within the group (R2 = 0.78; P = 0.001)”
Quote in the paperSubstantial claim - Findingown data
Upregulated metabolites in cecal contents from ASD-FMT mice, including Trp-Trp, kynurenic acid, and indole-3-acetic acid, were positively correlated with the majority of genera in o_Clostridiales except Lachnoclostridium and Anaerostipes.
“the upregulated metabolites in the cecal contents from the ASD-FMT group, including Trp-Trp, kynurenic acid, and indole-3-acetic acid, were positively correlated with the majority of the genera in the order_Clostridiales (o_Clostridiales), except for Lachnoclostridium and Anaerostipes.”
Quote in the paperNot a substantial claim - Findingown data
6-hydroxymelatonin and 5-hydroxyindole-3-acetic acid were decreased in children with ASD relative to TD children.
“6-hydroxymelatonin and 5-hydroxyindole-3-acetic acid were decreased in the children with ASD relative to the TD children”
Quote in the paperSubstantial claim - Findingown data
Differential metabolites in prefrontal cortex and serum were enriched in the bile secretion pathway.
“The differential metabolites in the prefrontal cortex and serum were enriched in the pathway related to bile secretion”
Quote in the paperNot a substantial claim - Findingown data
5-HT1AR expression in the colon was downregulated in ASD-FMT mice compared with TD-FMT mice (P < 0.05).
“The expression levels of both SERT (P < 0.01) and 5-HT1AR (P < 0.05) in the colon were downregulated in the ASD-FMT group compared with the TD-FMT group”
Quote in the paperSubstantial claim - Findingown data
In the three-chamber sociability test, ASD-FMT mice displayed a significantly greater preference for the novel-object chamber than TD-FMT mice (P < 0.001).
“the ASD-FMT group displayed a significantly greater preference for the novel-object chamber (P < 0.001)”
Quote in the paperSubstantial claim - Findingown data
5-HT1AR protein expression in the prefrontal cortex did not differ between ASD-FMT and TD-FMT mice (P > 0.05).
“The protein expression levels of 5-HT1AR in the prefrontal cortex did not differ between the two groups (P > 0.05)”
Quote in the paperNot a substantial claim - Findingown data
SERT expression in the prefrontal cortex was significantly upregulated in ASD-FMT mice compared with TD-FMT mice (P < 0.05).
“The expression levels of TPH2 and SERT in the prefrontal cortex were significantly upregulated in the ASD-FMT group compared with the TD-FMT group (P < 0.05 for both)”
Quote in the paperSubstantial claim - Findingown data
There were significant between-group differences in enrichment of the biotin metabolism pathway in both cecal contents and serum samples.
“We found significant between-group differences in the enrichment of the biotin metabolism pathway in the cases of both the cecal contents and serum samples”
Quote in the paperNot a substantial claim - Findingown data
In the open-field test, the time of self-grooming was significantly longer in ASD-FMT mice than in TD-FMT mice (P < 0.01).
“In contrast, the time of self-grooming was significantly longer in the ASD-FMT group than in the TD-FMT group (Fig. 1C) (P < 0.01).”
Quote in the paperSubstantial claim - Findingown data
963 metabolites in cecal contents were differentially expressed between TD-FMT and ASD-FMT mice, including 698 downregulated and 265 upregulated in ASD-FMT mice.
“We identified 963 metabolites in the cecal contents that were differentially expressed between the TD-FMT and ASD-FMT groups, including 698 metabolites that were downregulated and 265 metabolites that were upregulated in the ASD-FMT group relative to the TD-FMT group”
Quote in the paperSubstantial claim - Findingown data
Differentially expressed metabolites in cecal contents of TD-FMT and ASD-FMT mice were significantly enriched in retinol, cholesterol, and biotin pathways.
“The differentially expressed metabolites in the cecal contents of the TD-FMT and ASD-FMT mice were significantly enriched in some metabolic pathways, including retinol, cholesterol, and biotin”
Quote in the paperNot a substantial claim - Findingown data
Differential metabolites in cecal contents, serum samples, and prefrontal cortex samples were enriched in tryptophan metabolism and serotonergic synapse pathways.
“our study found that the differential metabolites in the cecal contents, serum samples, and prefrontal cortex samples were enriched in the tryptophan metabolism and serotonergic synapse pathways”
Quote in the paperSubstantial claim - Findingown data
Cecal contents, serum samples, and prefrontal cortex samples from TD-FMT and ASD-FMT mice were largely separated according to principal-component analysis.
“The cecal contents, serum samples, and prefrontal cortex samples from the TD-FMT and ASD-FMT groups were largely separated according to principal-component analysis (PCA)”
Quote in the paperSubstantial claim - Findingown data
Metabolite enrichment analysis of fecal samples of children highlighted tryptophan metabolism and serotonergic synapse KEGG pathways.
“the metabolite enrichment analysis of the fecal samples of the children also highlighted the tryptophan metabolism and serotonergic synapse KEGG pathways”
Quote in the paperSubstantial claim - Findingown data
SERT expression in the colon was downregulated in ASD-FMT mice compared with TD-FMT mice (P < 0.01).
“The expression levels of both SERT (P < 0.01) and 5-HT1AR (P < 0.05) in the colon were downregulated in the ASD-FMT group compared with the TD-FMT group”
Quote in the paperSubstantial claim - Findingown data
The times spent sniffing water and beer did not differ between ASD-FMT and TD-FMT mice.
“In contrast, the times spent sniffing water and beer did not differ between the two groups”
Quote in the paperSubstantial claim - Findingown data
No statistically significant differences were found in α diversity indices between TD-FMT and ASD-FMT mice.
“no statistically significant differences were found in α diversity (Chao, abundance-based coverage estimator [ACE], Shannon, and Simpson diversity indices) between the two groups”
Quote in the paperNot a substantial claim - Findingown data
The abundance of Verrucomicrobia was significantly lower in ASD-FMT mice than in TD-FMT mice (P < 0.05).
“the abundance of Verrucomicrobia was significantly lower in the ASD-FMT group than in the TD-FMT group (Fig. 2F) (P < 0.05)”
Quote in the paperNot a substantial claim - Findingown data
N-acetyl-dl-tryptophan and 5-hydroxytryptophol levels were significantly increased in serum samples of ASD-FMT mice relative to TD-FMT mice.
“the N-acetyl-dl-tryptophan and 5-hydroxytryptophol levels were significantly increased in the serum samples”
Quote in the paperSubstantial claim - Findingown data
In cecal contents of mice, 6-hydroxymelatonin, indole-3-lactic acid, and 5-methoxy-indoleacetate were significantly lower in ASD-FMT mice than in TD-FMT mice.
“in the cecal contents of mice, the levels of Trp-Trp (a dipeptide of tryptophan), kynurenic acid, and indole-3-acetic acid were significantly higher and those of 6-hydroxymelatonin, indole-3-lactic acid, and 5-methoxy-indoleacetate were significantly lower in the ASD-FMT group than in the TD-FMT group”
Quote in the paperSubstantial claim - Findingown data
At the genus level, Parasutterella, Akkermansia, Lachnoclostridium, and unidentified_Erysipelotrichaceae were decreased in ASD-FMT mice compared with TD-FMT mice.
“while Parasutterella (P < 0.05), Akkermansia (P < 0.05), Lachnoclostridium (P < 0.01), and unidentified_Erysipelotrichaceae (P < 0.01) were decreased in the ASD-FMT group”
Quote in the paperNot a substantial claim - Findingown data
5-hydroxytryptophol was significantly decreased in prefrontal cortex samples of ASD-FMT mice relative to TD-FMT mice.
“5-hydroxytryptophol was significantly decreased in the prefrontal cortex samples of the ASD-FMT mice relative to the TD-FMT mice”
Quote in the paperSubstantial claim - Findingown data
In the three-chamber sociability test, ASD-FMT mice displayed a significantly lesser preference for the strange-mouse chamber than TD-FMT mice (P < 0.001).
“and a lesser preference for the strange-mouse chamber (P < 0.001)”
Quote in the paperSubstantial claim - Findingown data
Parabacteroides, Alistipes, Anaerotruncus, Helicobacter, Parasutterella, Akkermansia, Lachnoclostridium, and unidentified_Erysipelotrichaceae were related to certain differentially expressed metabolites involved in tryptophan and serotonin metabolism.
“Parabacteroides, Alistipes, Anaerotruncus, Helicobacter, Parasutterella, Akkermansia, Lachnoclostridium, and unidentified_Erysipelotrichaceae were identified as genera with significant differences between the ASD-FMT and TD-FMT groups (Fig. 2G) and were related to certain differentially expressed metabolites involved in tryptophan and serotonin metabolism.”
Quote in the paperSubstantial claim - Findingown data
The abundance of unidentified_Bacteria was higher in ASD-FMT mice than in TD-FMT mice (P < 0.01).
“while that of unidentified_Bacteria was higher in the ASD-FMT group than in the TD-FMT group (Fig. 2F) (P < 0.01)”
Quote in the paperNot a substantial claim - Findingown data
The fecal microbiome from children with ASD led to altered tryptophan and serotonin metabolism in germ-free mice.
“The fecal microbiome from children with ASD led to ASD-like behaviors, distinct microbial community structures, and altered tryptophan and serotonin metabolism in GF mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The 5 ASD donors are representative of children with ASD.
- Findingown data
The fecal microbiome from children with ASD led to ASD-like behaviors in germ-free mice.
“The fecal microbiome from children with ASD led to ASD-like behaviors, distinct microbial community structures, and altered tryptophan and serotonin metabolism in GF mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The 5 ASD donors are representative of children with ASD.
- Findingown data
The fecal microbiome from children with ASD led to distinct microbial community structures in germ-free mice.
“The fecal microbiome from children with ASD led to ASD-like behaviors, distinct microbial community structures, and altered tryptophan and serotonin metabolism in GF mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The 5 ASD donors are representative of children with ASD.
- Findingown data
Tryptophan and serotonin metabolism pathways were altered in children with ASD and TD children and in ASD-FMT and TD-FMT mice.
“The tryptophan and serotonin metabolism pathways were altered in both children with ASD and TD children and in ASD-FMT and TD-FMT mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The 5 ASD donors are representative of children with ASD.
- Rests on an assumption: The 5 TD donors are representative of typically developing children.
- Findingnone given
Some specific microbiota, namely o_Clostridiales, o_Bacteroidales, and f_Erysipelotrichaceae, were related to tryptophan and serotonin metabolism.
“Some specific microbiota, namely, o_Clostridiales, o_Bacteroidales, and f_Erysipelotrichaceae, were related to tryptophan and serotonin metabolism.”
Quote in the paperSubstantial claim- Rests on an assumption: The 5 ASD donors are representative of children with ASD.
- Premisecitation
Indigenous spore-forming bacteria, including Clostridiales, promote serotonin biosynthesis from colonic enterochromaffin cells.
“Indigenous spore-forming bacteria, including Clostridiales, promote serotonin biosynthesis from colonic enterochromaffin cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY. 2015. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161: 264– 276. doi: 10.1016/j.cell.2015.02.047. 25860609 PMC4393509 source
Not checked in the free run.
- Premisecitation
Butyrate-producing taxa belonging to the Erysipelotrichaceae were significantly decreased in the feces of individuals with ASD.
“butyrate-producing taxa belonging to the Erysipelotrichaceae were significantly decreased in the feces of individuals with ASD”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Liu S, Li E, Sun Z, Fu D, Duan G, Jiang M, Yu Y, Mei L, Yang P, Tang Y, Zheng P. 2019. Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder. Sci Rep 9: 287. doi: 10.1038/s41598-018-36430-z. 30670726 PMC6342986 source
Not checked in the free run.
- Interpretationown data
Some specific bacteria may be associated with tryptophan and serotonin metabolism, including some genera belonging to o_Clostridiales, o_Bacteroidetes, and f_Erysipelotrichaceae.
“These results further confirmed that some specific bacteria may be associated with tryptophan and serotonin metabolism, including some genera belonging to the o_Clostridiales, o_Bacteroidetes, and f_Erysipelotrichaceae.”
Quote in the paperSubstantial claim - Premisecitation
A correlation between altered concentrations of tryptophan and serotonin and gut dysbiosis was observed in ASD patients.
“a correlation between altered concentrations of tryptophan and serotonin and gut dysbiosis was observed in ASD patients”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Gao K, Mu C, Farzi A, Zhu W. 2020. Tryptophan metabolism: a link between the gut microbiota and brain. Adv Nutr 11: 709– 715. doi: 10.1093/advances/nmz127. 31825083 PMC7231603 source
Not checked in the free run.
- Premisecitation
Tryptophan and serotonin metabolism is regulated by gut microbes.
“Animal studies have confirmed that tryptophan and serotonin metabolism is regulated by gut microbes”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF. 2013. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18: 666– 673. doi: 10.1038/mp.2012.77. 22688187 source
Not checked in the free run.
- Interpretationown data
The results provide preliminary clues about possible molecular mechanisms by which intestinal microorganisms influence tryptophan and serotonin metabolism.
“Overall, the above-described results provide preliminary clues about the possible molecular mechanisms by which intestinal microorganisms influence tryptophan and serotonin metabolism.”
Quote in the paperSubstantial claim - Interpretationreasoning
The colonic changes in TPH1, SERT, and 5-HT1AR in ASD-FMT mice may be attributable to self-regulation caused by decreased serotonin metabolites.
“These results may be attributable to self-regulation caused by decreased serotonin metabolites in ASD-FMT mice.”
Quote in the paperNot a substantial claim - Interpretationown data
The gut microbiota of children with ASD induced some core symptoms of ASD in mice.
“Taken together, these data suggest that the gut microbiota of children with ASD induced some core symptoms of ASD in the mice.”
Quote in the paperSubstantial claim - Premisecitation
Abnormal tryptophan metabolism has been reported in plasma and feces of children with ASD.
“in both plasma (17) and feces (18), abnormal tryptophan metabolism has been reported in children with ASD”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17] Gao K, Mu C, Farzi A, Zhu W. 2020. Tryptophan metabolism: a link between the gut microbiota and brain. Adv Nutr 11: 709– 715. doi: 10.1093/advances/nmz127. 31825083 PMC7231603 source
Not checked in the free run.
- cites [18] De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, Cristofori F, Guerzoni ME, Gobbetti M, Francavilla R. 2013. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One 8: e76993. doi: 10.1371/journal.pone.0076993. 24130822 PMC3793965 source
Not checked in the free run.
- Interpretationreasoning
ASD-related intestinal microorganisms may alter the expressions of related proteins involved in serotonin synthesis and transport in germ-free mice.
“In addition, ASD-related intestinal microorganisms may alter the expressions of related proteins involved in serotonin synthesis and transport in GF mice, which may be the molecular basis for the changes in tryptophan and serotonin metabolism.”
Quote in the paperNot a substantial claim- Rests on an assumption: The 5 ASD donors are representative of children with ASD.
- Study design and conductnone given
The TD children in the validation cohort were age, gender, region, height, weight, and socioeconomic status matched with the ASD group.
“The TD children were age (2 to 6 years), gender, region, height, weight, and socioeconomic status matched with the ASD group.”
Quote in the paperSubstantial claim
- May combine two claims. 19
- Classified as probably not a substantial claim. 23
May combine two claims.
Findingown dataThe three upregulated metabolites Trp-Trp, kynurenic acid, and indole-3-acetic acid were positively correlated with some genera in o_Bacteroidetes (but not Butyricimonas) and negatively correlated with o_Erysipelotrichales and f_Erysipelotrichaceae.
“these three significantly upregulated metabolites in the ASD-FMT group were positively correlated with some genera in the order_Bacteroidetes (o_Bacteroidetes) (but not Butyricimonas) and negatively correlated with the order_Erysipelotrichales (o_Erysipelotrichales), family_Erysipelotrichaceae (f_Erysipelotrichaceae).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLEfSe identified Verrucomicrobia and unidentified_Bacteria as key phyla and Helicobacter, Lachnoclostridium, and Akkermansia as key genera differing between TD-FMT and ASD-FMT mice.
“Verrucomicrobia and unidentified_Bacteria showed statistically significant differences between the two groups and were identified as key phyla. At the genus level, Helicobacter, Lachnoclostridium, and Akkermansia showed significant between-group differences and were identified as key genera”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data65 differentially expressed metabolites were identified in prefrontal cortex samples, of which 36 were downregulated and 29 were upregulated in ASD-FMT mice.
“In the prefrontal cortex samples, 65 differentially expressed metabolites were identified, of which 36 were downregulated and 29 were upregulated in the ASD-FMT group”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataThe sequencing depth was enough to cover the whole bacterial diversity and was suitable for the present study.
“The rarefaction curves for all the cecal samples collected from the TD-FMT and ASD-FMT mice tended to approach the saturation plateau (Fig. 2A), suggesting that the sequencing depth was enough to cover the whole bacterial diversity and was suitable for the present study.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPatients with ASD exhibit altered tryptophan metabolism, with reduced levels of tryptophan and an increased kynurenine-to-tryptophan ratio in the plasma.
“Patients with ASD exhibit altered tryptophan metabolism, with reduced levels of tryptophan and an increased kynurenine-to-tryptophan ratio in the plasma”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Kałużna-Czaplińska J, Gątarek P, Chirumbolo S, Chartrand MS, Bjørklund G. 2019. How important is tryptophan in human health? Crit Rev Food Sci Nutr 59: 72– 88. doi: 10.1080/10408398.2017.1357534. 28799778
Not checked in the free run.
May combine two claims.
PremisecitationIn autistic children, the serotonin level is increased in the serum and decreased in the brain.
“in autistic children, the serotonin level is increased in the serum and decreased in the brain”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] De Theije CGM, Wu J, Da Silva SL, Kamphuis PJ, Garssen J, Korte SM, Kraneveld AD. 2011. Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol 668: S70– S80. doi: 10.1016/j.ejphar.2011.07.013. 21810417
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSome bacteria belonging to the genera Clostridium, Ruminococcus, Blautia, and Lactobacillus can convert tryptophan to tryptamine.
“some bacteria belonging to the genera Clostridium, Ruminococcus, Blautia, and Lactobacillus have been identified as being able to convert tryptophan to tryptamine”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Williams BB, Van Benschoten AH, Cimermancic P, Donia MS, Zimmermann M, Taketani M, Ishihara A, Kashyap PC, Fraser JS, Fischbach MA. 2014. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16: 495– 503. doi: 10.1016/j.chom.2014.09.001. 25263219 PMC4260654
Not checked in the free run.
May combine two claims.
PremisecitationMicrobiota transfer therapy has improved behavioral problems and gastrointestinal symptoms in children with ASD.
“microbiota transfer therapy, which changes the intestinal microenvironment, has improved behavioral problems and gastrointestinal symptoms in children with ASD”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Kang D-W, Adams JB, Coleman DM, Pollard EL, Maldonado J, McDonough-Means S, Caporaso JG, Krajmalnik-Brown R. 2019. Long-term benefit of microbiota transfer therapy on autism symptoms and gut microbiota. Sci Rep 9: 5821. doi: 10.1038/s41598-019-42183-0. 30967657 PMC6456593 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTPH1 is present mainly in peripheral organs such as the intestines and spleen, while TPH2 predominates in the brain stem.
“TPH1 is present mainly in peripheral organs such as the intestines and spleen, while TPH2 predominates in the brain stem”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Walther DJ, Peter J-U, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M. 2003. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299: 76. doi: 10.1126/science.1078197. 12511643
Not checked in the free run.
May combine two claims.
Interpretationown dataASD-related intestinal microbes induced abnormal tryptophan and serotonin metabolism in both ASD-FMT mice and children with ASD.
“our findings show that ASD-related intestinal microbes induced abnormal tryptophan and serotonin metabolism in both ASD-FMT mice and children with ASD”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationClostridia and Bacteroides can produce propionic acid.
“Clostridia and Bacteroides can produce propionic acid”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] MacFabe DF, Cain NE, Boon F, Ossenkopp KP, Cain DP. 2011. Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: relevance to autism spectrum disorder. Behav Brain Res 217: 47– 54. doi: 10.1016/j.bbr.2010.10.005. 20937326
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIt is difficult to distinguish whether metabolites in the mouse cecum were derived from the host or from the gut microbiota.
“it is difficult to distinguish whether the metabolites in the mouse cecum were derived from the host or from the gut microbiota.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTPH catalyzes the rate-limiting step in serotonin synthesis.
“TPH catalyzes the rate-limiting step in serotonin synthesis”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Khan WI, Ghia JE. 2010. Gut hormones: emerging role in immune activation and inflammation. Clin Exp Immunol 161: 19– 27. doi: 10.1111/j.1365-2249.2010.04150.x. 20408856 PMC2940144
Not checked in the free run.
May combine two claims.
PremisecitationBifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter are decreased and Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium are increased in the gut microbiota of children with ASD relative to TD children.
“It has been found that Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter are decreased and that Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium are increased in the gut microbiota of children with ASD relative to TD children”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Liu F, Li J, Wu F, Zheng H, Peng Q, Zhou H. 2019. Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review. Transl Psychiatry 9: 43. doi: 10.1038/s41398-019-0389-6. 30696816 PMC6351640
Not checked in the free run.
May combine two claims.
Interpretationown dataASD-FMT mice showed increased repetitive behaviors and decreased sociability compared with TD-FMT mice.
“the mice in the ASD-FMT group showed increased repetitive behaviors and decreased sociability compared to the mice in the TD-FMT group.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe gut microbiota from donors with ASD resulted in abnormalities in tryptophan and serotonin metabolism and altered key proteins involved in the synthesis and transport of serotonin in mice.
“we hypothesized that the gut microbiota from donors with ASD resulted in abnormalities in tryptophan and serotonin metabolism and altered the key proteins involved in the synthesis and transport of serotonin in mice.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationCompared with specific-pathogen-free mice, germ-free mice show social communication disorders and increased anxiety behaviors, and these abnormal social behaviors are corrected after colonization with normal microbiota.
“compared with specific-pathogen-free (SPF) mice, germ-free (GF) mice show social communication disorders and increased anxiety behaviors, and these abnormal social behaviors are corrected after the mice are colonized with normal microbiota”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Winek K, Dirnagl U, Meisel A. 2016. The gut microbiome as therapeutic target in central nervous system diseases: implications for stroke. Neurotherapeutics 13: 762– 774. doi: 10.1007/s13311-016-0475-x. 27714645 PMC5081128 source
Not checked in the free run.
- cites [9] Crumeyrolle-Arias M, Jaglin M, Bruneau A, Vancassel S, Cardona A, Daugé V, Naudon L, Rabot S. 2014. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 42: 207– 217. doi: 10.1016/j.psyneuen.2014.01.014. 24636517
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSerotonin may be associated with the symptoms of ASD.
“it has been reported that serotonin may be associated with the symptoms of ASD”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Golubeva AV, Joyce SA, Moloney G, Burokas A, Sherwin E, Arboleya S, Flynn I, Khochanskiy D, Moya-Pérez A, Peterson V, Rea K, Murphy K, Makarova O, Buravkov S, Hyland NP, Stanton C, Clarke G, Gahan CGM, Dinan TG, Cryan JF. 2017. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine 24: 166– 178. doi: 10.1016/j.ebiom.2017.09.020. 28965876 PMC5652137
Not checked in the free run.
May combine two claims.
Study design and conductown dataTD children were age, gender, region, height, weight, and socioeconomic status matched with the ASD group, except picky eating behavior was more common in ASD children (66.7% vs 43.3%, P < 0.001).
“Except for picky eating behavior (TD, 26/60 [43.3%]; ASD, 80/120 [66.7%] [P < 0.001]), the TD children were age, gender, region, height, weight, and socioeconomic status matched with the ASD group”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe causal relationship between gut microbes, metabolites, and key metabolic proteins involved remains unclear.
“the causal relationship between gut microbes, metabolites, and key metabolic proteins involved remains unclear.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPropionic acid may induce ASD-like behaviors upon intraventricular administration, and the underlying mechanism may be related to regulation of neurotransmitters.
“Propionic acid may induce ASD-like behaviors upon intraventricular administration, and the underlying mechanism may be related to the regulation of neurotransmitters”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [42] MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE, Boon F, Taylor AR, Kavaliers M, Ossenkopp KP. 2007. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav Brain Res 176: 149– 169. doi: 10.1016/j.bbr.2006.07.025. 16950524 source
Not checked in the free run.
- cites [43] Mitsui R, Ono S, Karaki S, Kuwahara A. 2005. Neural and non-neural mediation of propionate-induced contractile responses in the rat distal colon. Neurogastroenterol Motil 17: 585– 594. doi: 10.1111/j.1365-2982.2005.00669.x. 16078948
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.
Study design and conductnone givenMultiple factors can affect the gut microbiome and metabolomics, and potential impacting factors cannot be fully controlled.
“multiple factors can affect the gut microbiome and metabolomics, and we cannot fully control the potential impacting factors.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe clinical trial was registered in the Chinese Clinical Trial Registry (registration number ChiCTR-ROC-14005442).
“This clinical trial was registered in the Chinese Clinical Trial Registry (registration number ChiCTR-ROC-14005442).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe TD children in the validation cohort received health examinations and were proven free from any signs of developmental disorders or mental illness.
“They also received health examinations and were proven to be free from any signs of developmental disorders or mental illness.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenThe exclusion criteria for the validation cohort included a history of other developmental disorders, neurological or psychiatric diseases, genetic metabolic disease, major physical illness, recent infections, and use of medications, antibiotics, antifungals, probiotics, or prebiotics within 3 months before sampling.
“The exclusion criteria included a history of other developmental disorders, neurological or psychiatric diseases, genetic metabolic disease, major physical illness, recent infections, and the use of medications, antibiotics, antifungals, probiotics, or prebiotics within 3 months before the sampling.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenThe 2 groups of mice were raised in 2 separate, gnotobiotic environments.
“The 2 groups of mice were raised in 2 separate, gnotobiotic environments.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenNone of the donors had received any medications, antibiotics, antifungals, probiotics, or prebiotics in the past 3 months.
“In addition, none of the donors had received any medications, antibiotics, antifungals, probiotics, or prebiotics in the past 3 months.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataTD donors were confirmed by health examinations to have no signs of developmental disorders or psychiatric diseases.
“Health examinations were also conducted for the TD donors to confirm that they did not have any signs of developmental disorders or psychiatric diseases.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe number of postsynaptic 5-HT1A receptors is decreased in the brains of patients with anxiety and depression.
“the number of postsynaptic 5-HT1A receptors is decreased in the brains of patients with anxiety and depression”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Meunier CNJ, Chameau P, Fossier PM. 2017. Modulation of synaptic plasticity in the cortex needs to understand all the players. Front Synaptic Neurosci 9: 2. doi: 10.3389/fnsyn.2017.00002. 28203201 PMC5285384
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
InterpretationreasoningThe altered expressions of related proteins involved in serotonin synthesis and transport may be the molecular basis for the changes in tryptophan and serotonin metabolism.
“In addition, ASD-related intestinal microorganisms may alter the expressions of related proteins involved in serotonin synthesis and transport in GF mice, which may be the molecular basis for the changes in tryptophan and serotonin metabolism.”
Quote in the paperNot a substantial claim- Rests on an assumption: The 5 ASD donors are representative of children with ASD.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigh peripheral serotonin levels are associated with changes in SERTs and serotonin receptors in children with ASD.
“High peripheral serotonin levels are associated with changes in SERTs and serotonin receptors in children with ASD”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Maes M, Anderson G, Betancort Medina SR, Seo M, Ojala JO. 2019. Integrating autism spectrum disorder pathophysiology: mitochondria, vitamin A, CD38, oxytocin, serotonin and melatonergic alterations in the placenta and gut. Curr Pharm Des 25: 4405– 4420. doi: 10.2174/1381612825666191102165459. 31682209
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAlterations in SERT levels can lead to physiological dysfunction.
“alterations in SERT levels can lead to physiological dysfunction”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Baganz NL, Blakely RD. 2013. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci 4: 48– 63. doi: 10.1021/cn300186b. 23336044 PMC3547518
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenASD diagnosis was made by a developmental pediatrician or psychologist through structured interviews according to DSM-5 criteria.
“The diagnosis of ASD was made by a developmental pediatrician or psychologist through a series of structured interviews, according to DSM-5 criteria.”
- Also stated in: § Subjects. · plain
“ASD was diagnosed by a developmental pediatrician or psychologist through a series of structured interviews according to DSM-5 criteria.”
Quote in the paperSubstantial claim- Also stated in: § Subjects. · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll 10 donors were boys aged 2 to 6 years with no history of other developmental disorders, neurological or psychiatric diseases, genetic metabolic diseases, or major physical illness.
“All 10 donors were boys aged 2 to 6 years with no history of other developmental disorders, neurological or psychiatric diseases, genetic metabolic diseases, or major physical illness.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataIn the three-chamber sociability test, each animal had no bias for any of the chambers.
“The mice could freely move through a small opening (6 by 6 cm) in each divider and were observed for 5 min in the empty box to confirm that each animal had no bias for any of the chambers.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenGF mice aged 4 weeks were randomly divided into 2 groups (TD-FMT and ASD-FMT).
“GF mice aged 4 weeks were randomly divided into 2 groups: the mice in the TD-FMT group were gavaged with 200 μl of the fecal suspension obtained from the TD children, and the mice in the ASD-FMT group were gavaged with the same volume of the fecal suspension obtained from the children with ASD.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSERTs are located on presynaptic serotonin nerve terminals as well as on axons and serotonin cell bodies in the raphe.
“SERTs are located on presynaptic serotonin nerve terminals as well as on axons and serotonin cell bodies in the raphe”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Daws LC, Gould GG. 2011. Ontogeny and regulation of the serotonin transporter: providing insights into human disorders. Pharmacol Ther 131: 61– 79. doi: 10.1016/j.pharmthera.2011.03.013. 21447358 PMC3131109
Not checked in the free run.
The paper relies on this without support.
The causal relationship between gut microbes and metabolites and ASD symptoms is not yet established.
“The relationship between the gut microbiota and ASD is not yet fully understood.”
“However, it is still not clear if these microbes and metabolites cause the development of ASD symptoms.”
The paper relies on this without support.
The 5 ASD donors are representative of children with ASD.
“In this study, 5 TD children and 5 ASD children were recruited, and their fecal samples were collected as donor samples.”
The paper relies on this without support.
The 5 TD donors are representative of typically developing children.
“In this study, 5 TD children and 5 ASD children were recruited, and their fecal samples were collected as donor samples.”
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?
Mice seeded with ASD microbiota presented more autistic-like behaviors in a similar experiment by Xiao et al.
“This is further confirmed by Xiao et al. [151], who performed a similar experiment, where mice seeded with ASD microbiota presented more autistic-like behaviors.”
From Unraveling the Connections: Eating Issues, Microbiome, and Gastrointestinal Symptoms in Autism Spectrum Disorder (2025) · cites this paper as [151]
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- Authors
- Xiao, L., Yan, J., Yang, T., Zhu, J., Li, T., Wei, H., & Chen, J.
- Affiliations
- Children's Hospital of Chongqing Medical University (CN)
- Army Medical University (CN)
- Corresponding author
- Wei, Hong
- Chen, Jie
- Venue
- mSystems
- Publisher
- American Society for Microbiology
- Published
- 2021-04-27
- Volume
- 6
- Issue
- 2
- ISSN
- 2379-5077 (ISSN-L)
- PMC
- PMC8547010
- OpenAlex
- W3144114196
- Semantic Scholar
- 596a405f3452caa2386fa6290c0680dabbf7a2d5
- Cited by
- 141
- References
- 64
- Citations by year
- 2026: 30 · 2025: 32 · 2024: 27 · 2023: 25 · 2022: 19 · 2021: 8
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mSystems (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81470799, 31971089, 81770526)
- 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 › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- autism spectrum disorder, gut microbiota, germ-free mice, tryptophan metabolism, serotonin metabolism, microbial metabolites
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 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
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