The DOI matches its Crossref record; 96 of the 96 references it cites were found in a registry or an index.
Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances
Open accessAbstract
Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism.
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![Figure 6 Levels of Clostridiales members in AUT-GI patients stratified by timing of GI onset. (A–B) Abundance of Clostridiales from ileal (A) and cecal (B) biopsies from AUT-GI and Control-GI patients (n = 7), with AUT-GI stratified by whether the onset of GI symptoms occurred after (n = 5) the onset of autism symptoms (GI-After) or before and at the same time (n = 10) as autism symptoms (GI-Before/Same). [A: AUT (GI-After) vs. AUT (GI-Before/Same), Mann-Whitney, p = 0.028; AUT (GI-Before/Same) vs. Control-GI, Mann-Whitney, p = 0.015; AUT (GI-After) vs. Control-GI, Mann-Whitney, p = 0.935] [B: AUT (GI-After) vs. AUT (GI-Before/Same), Mann-Whitney, p = 0.037; AUT (GI-Before/Same) vs. Control-GI, Mann-Whitney, p = 0.019; AUT (GI-After) vs. Control-GI, Mann-Whitney, p = 0.935]. (C–D) Cumulative abundance of Lachnospiraceae and Ruminococcaceae from ileal (C) and cecal (D) biopsies from AUT-GI and Control-GI patients (n = 7), with AUT-GI stratified by whether the onset of GI symptoms occurred after (n = 5) the onset of autism symptoms or before and at the same time (n = 10) as autism symptoms [C: AUT (GI-After) vs. AUT (GI-Before/Same), Mann-Whitney, p = 0.028; AUT (GI-Before/Same) vs. Control-GI, Mann-Whitney, p = 0.015; AUT (GI-After) vs. Control-GI, Mann-Whitney, p = 0.808] [D: AUT (GI-After) vs. AUT (GI-Before/Same), Mann-Whitney, p = 0.020; AUT (GI-Before/Same) vs. Control-GI, Mann-Whitney, p = 0.011; AUT (GI-After) vs. Control-GI, Mann-Whitney, p = 0.685]. (E) Age at GI onset (in months) for AUT-GI and Control-GI patients, with AUT-GI stratified by whether GI onset occurred after (n = 5) the onset of autism symptoms or before and at the same time (n = 10) as autism symptoms [E: AUT (GI-After) vs. AUT (GI-Before/Same), Mann-Whitney, tied p = 0.007; AUT (GI-Before/Same) vs. Control-GI, Mann-Whitney, tied p = 0.757; AUT (GI-After) vs. Control-GI, Mann-Whitney, tied p = 0.027]. *, p<0.05; **, p<0.01; n.s., not significant.](/paper-figures/c4c3934aca7842758c8bc37ef71cecb6/impaired-carbohydrate-digestion-and-transport-and-mucosal-dysbiosis-in-the-figure-6.jpg)
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In the citing paper
“At the phylum level, none of the six studies showed an increase in absolute or relative abundance [31, 33, 36, 48, 51, 54].”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [54]
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In the citing paper
“Interestingly, from a Clostridiales cluster standpoint, the studies on Cluster I and Cluster II, as well as Cluster XI, while few, collectively suggested an increase in children with ASD [45, 49, 51, 52, 54].”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [54]
In the citing paper
“Ileal and cecal biopsies from children with ASD and GI dysfunction showed increased Firmicutes and decreased Bacteroidetes [51].”
From The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders (2018) · cites this paper as [51]
In the citing paper
“Two studies showed increases [31, 33] and six studies showed no significant changes in alpha diversity [36, 42, 43, 48, 50, 54].”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [54]
In the citing paper
“The rest of the studies observed either a decrease in Bacteroidetes percentage [50, 54] or no significant differences between cases and controls [31, 36, 48].”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [54]
In the citing paper
“For relative abundance in both total and metabolically active Firmicutes, the studies demonstrated either a decrease [31, 33, 36] or no significant differences between children with ASD, SIB, and HC [48, 51, 54].”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [54]
In the citing paper
“Although focusing mainly on phylum level changes, the key differences associated with the ASD group with FGID were seen as an increase in Clostridiales, particularly in Lachnospiraceae and Ruminococcaceae.”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [23]
In the citing paper
“A single study, with a follow-up report, remains the only characterization of the mucosal microbiome in pediatric ASD.23, 34”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [23]
In the citing paper
“Differences in the types and composition of various bacterial species in children with ASD have been reported.22, 23, 24, 25, 26, 27”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [23]
In the citing paper
“Although the analysis focused mainly on higher taxonomic levels, an increase in Clostridiales, especially Lachnospiraceaea and Ruminococcaceae, was observed.23”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [23]
In the citing paper
“A single tissue-based study in pediatric ASD has been published with a total sample size of 22 subjects (ASD, n = 15; NT, n = 7) and a limited age range of 3–5 years.”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [23]
In the citing paper
“A significantly higher prevalence of Sutterella species in biopsies taken from the GI tract of ASD children with GI disturbances compared to controls with GI disturbances has been found [146].”
From Autism, Gastrointestinal Symptoms and Modulation of Gut Microbiota by Nutritional Interventions (2019) · cites this paper as [146]
In the citing paper
“Interestingly, some of the microbial differences seen in children with ASD have been associated with impaired transcription of genes involved in carbohydrate metabolism 52.”
From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [52]
In the citing paper
“In terms of gender, Luna et al.17 and William et al.24 only included male individuals, the remaining studies included both male and female.”
From Altered composition and function of intestinal microbiota in autism spectrum disorders: A systematic review (2019) · cites this paper as [24]
In the citing paper
“Consistently, William et al.24 and Finegold et al.27 both reported that the Proteobacteria was elevated in ASD patients rather than HCs.”
From Altered composition and function of intestinal microbiota in autism spectrum disorders: A systematic review (2019) · cites this paper as [24]
In the citing paper
“Three studies indicated a clear alteration of the gut bacterial community in ASD patients characterized by a higher Firmicutes/Bacteroidetes ratio in ASD than that in HCs due to a significant increase of Firmicutes and/or a reduction of Bacteroidetes18,24,28.”
From Altered composition and function of intestinal microbiota in autism spectrum disorders: A systematic review (2019) · cites this paper as [24]
In the citing paper
“As for comparability, Luna et al.17, Inoue et al.20, De Angelis et al.23 and William et al.24,25 included case and control with better design, such as all participants has consistent GI symptoms at baseline, thus these studies achieved 2 points in the comparability assessment.”
From Altered composition and function of intestinal microbiota in autism spectrum disorders: A systematic review (2019) · cites this paper as [24]
In the citing paper
“Clostridium has been extensively studied in ASD51,52 due to its characteristic of producing exotoxins and propionate, which may aggravate the symptoms of ASD53.”
From Altered composition and function of intestinal microbiota in autism spectrum disorders: A systematic review (2019) · cites this paper as [52]
In the citing paper
“Faecalibacterium20,23,24 and Ruminococcus23,24,29 were reported increased in ASD patients by three studies, but they were reported reduced in another study27.”
From Altered composition and function of intestinal microbiota in autism spectrum disorders: A systematic review (2019) · cites this paper as [24]
In the citing paper
“In addition, GI microbial dysbiosis, an imbalance in the organisms that make up the gut microbiota, has been documented in multiple studies of children with ASD [5, 7–14].”
From Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms (2019) · cites this paper as [12]
In the citing paper
“Further, an abnormal ratio of Firmicutes to Bacteroidetes [12] has been observed as well as increased levels of certain detrimental taxa, such as Proteobacteria [10, 12].”
From Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms (2019) · cites this paper as [12]
In the citing paper
“Many reports show that children with ASD have higher counts of potentially pathogenic Clostridia than typically developing children [7–10, 12], although this is not universally true [13].”
From Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms (2019) · cites this paper as [12]
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Citations
Cites
1 retracted
Enterocolitis in children with developmental disorders
Wakefield, A. J., Anthony, A., MURCH, S. H., Thomson, M. A., Montgomery, S., Davies, S. E., O’Leary, J. J., Berelowitz, M., & Walker-Smith, J. A. (2000) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2000.03248.x · Cited by 244
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An obesity-associated gut microbiome with increased capacity for energy harvest
Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., & Gordon, J. I. (2006) · Nature · doi:10.1038/nature05414 · Cited by 12,444
Human gut microbes associated with obesity
Ley, R. E., Turnbaugh, P. J., Klein, S., & Gordon, J. I. (2006) · Nature · doi:10.1038/4441022a · Cited by 8,785
Obesity alters gut microbial ecology
Ley, R. E., Bäckhed, F., Turnbaugh, P., Lozupone, C. A., Knight, R. D., & Gordon, J. I. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504978102 · Cited by 6,176
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Normal gut microbiota modulates brain development and behavior
Heijtz, R. D., Wang, S., Anuar, F., Qian, Y., Björkholm, B., Samuelsson, A., Hibberd, M. L., Forssberg, H., & Pettersson, S. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010529108 · Cited by 3,228
The gut flora as a forgotten organ
O'Hara, A. M., & Shanahan, F. (2006) · The EMBO Reports · doi:10.1038/sj.embor.7400731 · Cited by 2,791
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Cited by
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Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R., McCue, T., Codelli, J. A., Chow, J., Reisman, S. E., Petrosino, J. F., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.024 · Cited by 3,283
Gut–brain axis: How the microbiome influences anxiety and depression
Foster, J. A., & McVey Neufeld, K.-A. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.01.005 · Cited by 2,460
Interactions between the microbiota, immune and nervous systems in health and disease
Fung, T. C., Olson, C. A., & Hsiao, E. Y. (2017) · Nature Neuroscience · doi:10.1038/nn.4476 · Cited by 1,900
The interplay between the intestinal microbiota and the brain
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Sharon, G., Sampson, T. R., Geschwind, D. H., & Mazmanian, S. K. (2016) · Cell · doi:10.1016/j.cell.2016.10.027 · Cited by 1,513
Metadata
- Authors
- Williams, B. L., Hornig, M., Buie, T., Bauman, M. L., Cho Paik, M., Wick, I., Bennett, A., Jabado, O., Hirschberg, D. L., & Lipkin, W. I.
- Affiliations
- Columbia University (US)
- Massachusetts General Hospital (US)
- Harvard University (US)
- Corresponding author
- Lipkin, W. Ian
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-09-16
- Volume
- 6
- Issue
- 9
- Pages
- e24585
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3174969
- OpenAlex
- W2005365566
- Cited by
- 492
- References
- 96
- Citations by year
- 2026: 10 · 2025: 34 · 2024: 25 · 2023: 31 · 2022: 41 · 2021: 46 · 2020: 38 · 2019: 52 · 2018: 45 · 2017: 21 · 2016: 31 · 2015: 37 · 2014: 32 · 2013: 28 · 2012: 19
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS 047537, U01NS047537)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- autism spectrum disorder, gastrointestinal diseases, carbohydrate digestion, disaccharidases, hexose transporters, intestinal gene expression, CDX2, Firmicutes/Bacteroidetes ratio, Betaproteobacteria, Bacteroidetes, enterocytes
- MeSH terms
- Autistic Disorder, Biological Transport, Child, Preschool, Clostridium, Digestion, Female, Food Hypersensitivity, Gastrointestinal Diseases, Humans, Ileum, Infant, Intestinal Mucosa, Male, RNA, Bacterial, RNA, Messenger, RNA, Ribosomal, 16S, Time Factors, Comorbidity, Membrane Transport Proteins, Carbohydrate Metabolism, Metagenomics, Transcriptome
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