The Role of Short-Chain Fatty Acids and Altered Microbiota Composition in Autism Spectrum Disorder: A Comprehensive Literature Review
Abstract
:1. Introduction
2. Short-Chain Fatty Acids
2.1. Classification and Sources
2.2. Metabolism and Distribution
2.3. SCFA Levels in ASD
3. Microbiota
3.1. Overview
3.2. Microbiota Shift in Children with ASD
Author Year | Study Design | Change in ASD vs. Control | Other Findings | ||||
---|---|---|---|---|---|---|---|
Number of Participants | Age (Years) | Sample Source | Assessment Type | Increase | Decrease | ||
P: Phylum O: Order F: Family G: Genus S: Species | |||||||
Coretti et al., 2018 [41] | ASD: 11 CON: 14 | 2–4 | Stool | V3–V4 16S rRNA Illumina Miseq System | P: Bacteroidetes, Parabacteroidetes G: Bacteroides, Faecalibacterium Oscillospira, Ruminococcus | P: Actinobacteria G: Actinomyces, Corynebacterium, Bifidobacterium | Increased BA and PPA in ASD |
Finegold et al., 2010 [44] | ASD: 33 CON: 15 (including 7 siblings of ASD and 8 nonrelated subjects) | 2–14 | Stool | bTEFAP FLX sequencer | P: Bacteroidetes, Proteobacteria G: Desulfovibrio, Turicibacter Bacteroides Parabacteroides S: Desulfovibrio piger, Desulfovibrio Desulfovibrio intestinalis, Bacteroides vulgatus | P: Firmicutes Actinobacteria G: Weissella, Costridium, Actinomyces, Corynebacterium, Bifidobacterium, Ruminococcus Streptococcus, Dialister S: Dialister invisus, Bifidobacterium longum, Clostridium leptum | Very high level of Bacteroides in severe cases of ASD |
Parracho et al., 2005 [58] | ASD: 58 CON: 22 (12 siblings of ASD and 10 not related) | ASD: 3–16 CON: 2–13 | Stool | FISH 16S rRNA oligonucleotide probes | S: Clostridium histolyticum | A high portion of the ASD group had GI issues | |
Strati et al., 2017 [20] | ASD: 40 CON: 40 | 4–17 | Stool | V3–V5 16S rRNA. GS FLX + system | G: Collinsella, Corynebacterium, Dorea, Lactobacillus | G: Alistipes, Bilophila, Dialister, Parabacteroides, and Veillonella | ASD altered microbiota, constipation is an important factor |
De Angelis et al., 2013 [42] | ASD: 10 CON: 10 siblings | 4–10 | Stool | bTEFAP 454 FLX Sequencer | P: Bacteroidetes, G: Bacteroides Clostridium Roseburia Enterobacter Akkermansia | P: Fusobacteria, Verrucomicrobia G: Eubacterium, Fusobacterium, Lachnospira, Turicibacter, Bifidobacterium | Increase in PPA and AA |
Wang et al., 2020 [65] | ASD: 26 CON: 24 | 3–9 | Stool | V1-V2 16S rRNA Illumina HiSeq sequencer | F: Rikenellaceae, G: Ruminococcus, Victivallales Oscillospira, Odoribacter, Cetobacterium, | P: Actinobacteria O: Bifidobacteriales, F: Bifidobacteriaceae Veillonellaceae, G: Bifidobacterium, S: B. adolescentis, B. longum | Decrease in PPA in ASD Odoribacter: common SCFA producer |
Li et al., 2019 [55] | ASD: 59 children and their mothers CON: 30 children and their mothers | Children: 2–10 Mothers: 26–42 | Stool | V1-V2 16S rRNA Illumina HiSeq sequencer | Children- G: Enhydrobacter, Chryseobacterium, Streptococcus, Acinetobacter, Clostridium S: Acinetobacter rhizosphaerae, Acinetobacter johnsonii Mothers-F: Moraxellaceae Enterobacteriaceae G: Acinetobacter | Children-S: Prevotella melaninogenica Mothers- G: Faecalibacterium | Assessment of mother–child gut microbiome profile. There is a clear correlation; however, a unique bacteria profile is still present in ASD children. |
Kushak et al., 2017 [69] | ASD: 21 CON: 19 Both ASD and CON with GI symptoms | ASD: 14.43 ± 1.07 CON: 16.05 ± 1.25 | Duodenum, endoscopic biopsy | 16S rRNA 454 FLX Sequencer | G: Burkholderia, Oscillospira, Actinomyces, Neisseria, Peptostreptococcus, Ralstonia, | G: Neisseria, Devosia, Prevotella, Bacteroides, Streptococcus | Differences in bacteria associated with disaccharidase activity |
Williams et al., 2011 [71] | ASD: 15 CON: 7 Both ASD and CON children had GI issues | 3–6 | Biopsy of ileal and cecal tissues | V2 16S rRNA 454 FLX Sequencer | O: Clostridiale F: Lachnospiraceae, Ruminococcaceae, Alcaligenaceae, Methylobacteriaceae | P: Bacteroidetes | Deficits in gene expression involved in carbohydrate digestion and transport |
Williams et al., 2012 [70] | ASD: 15 CON: 7 | 3–5 | Biopsy of ilium and cecum | V2 16S rRNA GS FLX sequencer | High level of species from Sutterella genus | Sutterella 16S rRNA in ASD group and absent in control | |
Adams et al., 2011 [66] | ASD: 58 CON: 39 | ASD: 6.91 ± 3.4 CON: 7.7 ± 4.4 | Stool | The Vitek®2 identification cards and Vitek 2 system | G: Lactobacillus, Bacillus spp. | G: Bifidobacterium, Enterococcus Species: Enterobacter cloacae | Decrease in SCFAs (lower SCFAs due to higher absortion/lower intake of fibers) |
Tomova et al., 2015 [73] | ASD: 10 CON: 10 Siblings of ASD: 9 | ASD: 2–9 CON:2–11 Sib.: 5–17 | Stool | RT-PCR | Clostridia cluster l, Desulfovibrio | P: Bacteroidetes | Fecal TNFα increased in stool. Correlation between the amount of Desulfovibrio present and autism severity |
Wang et al., [74] | ASD: 23 ASD siblings: 22 CON (unrelated): 9 | ASD: 10.2 ± 0.75 CON: 9.5± 1.25 Sib.: 12 ± 1 | Stool | RT-PCR | S: Clostridium difficile | S: Akkermansia muciniphila, Bifidobacterium spp. | Lower abundance of Akkermansia muciniphila is suggestive of changes in the mucosal barrier |
David et al., 2021 [56] | ASD: 60 CON: 57 (siblings) | 2–11 | Stool | 16S rRNA V4 Illumina MiSeq | G: Bacteroides, Ruminococcus, Anaerococcus | F: Lachnospiraceae G: Desulfovibrio, Bifidobacterium | Unique crowdsourcing recruitment of subjects. |
Kang et al., 2013 [75] | ASD: 20 CON: 20 | 2–16 | Stool | V2/V3 16S bTEFAP FLX Sequencer | G: Akkermansia present at very high level | P: Proteobacteria, Verrucomicrobi, G: Veillonellaceae, Prevotella, Coprococcus | Less diverse gut microbial composition in ASD |
Finegold et al., 2017 [18] | ASD: 33 CON: 13 | 2–9 | Stool | Anerobic bacteria culture. ABI 3130 | Increase in Clostridium | Increase in C. perfringens beta2-toxin gene in ASD vs. control | |
Song et al., 2004 [76] | ASD: 15 CON: 8 | Not specified | Stool | TaqMan RT-PCR 16S rRNA | Increases in Clostridium 46-fold: C. bolteae 9.0-fold: cluster I 3.5-fold: cluster XI | Study focused on Clostridium | |
Zhang et al., 2018 [77] | ASD: 35 CON: 6 | ASD: 4.9 ± 1.5 CON: 4.6 ± 1.1 | Stool | 16S rRNA (V3–V4) Illumina HiSeq | P: Bacteroidetes G: Sutterella, Odoribacter, Butyricimona | P: Firmicutes Genus: Veillonella, Streptococcus | ASD group was characterized by increase in constipation |
Son et al., 2015 [78] | ASD: 59 CON: 44 (siblings of ASD) | ASD:4–18 CON:7–14 | Stool | V1V2 and V1V3 of 16S rRNA Illumina HiSeq | No difference found | No difference found | ASD group was characterized by increase in constipation |
Wang et al., 2013 [79] | ASD: 23 CON: 31 | Not specified | Stool | RT-PCR | G: Sutterella S: Ruminococcus torques | Focused on Sutterella | |
Jendraszak et al., 2021 [67] | ASD: 33 CON: 16 Allergies: 24 | ASD: 4–6 CON: 3–9 ALG: 4–9 | Stool | Microbial culture and RT-PCR | G: Klebsiella, Bifidobacterium | Probiotic use helps stabilize microbial composition | |
He et al., 2023 [40] | ASD: 40 CON: 40 | ASD: 5.3 ± 1.34 CON: 5.83 ± 1.28 | Stool | V3-V4 of the 16S rRNA Illumina HiSeq 2500 | Ruminococcaceae_UCG_002, Erysipelotrichaceae_UCG_003, Phascolarctobacterium, Megamonas, Ruminiclostridium_5, Parabacteroides, Prevotella_2, Fusobacterium, Prevotella 9 | Anaerostipes, Lactobacillus, Ruminococcus_gnavus_group, Lachnospiraceae_NK4A136_group, Ralstonia, Eubacterium_eligens_ group, and Ruminococcus_1 | Children enrolled in this study suffered from constipation. Significant increase in SCFAs in the ASD group |
3.3. Gut–Brain Axis
3.4. In Vivo Effect of SCFAs in Adult ASD-Animal Model
Author Year | Study Design | Outcomes | ||
---|---|---|---|---|
Animal | Sample Size | Treatment | ||
Sharon et al., 2019 [102] | Mice: Germ-free C57BL/6J weanlings (3–4 weeks of age) | 16 donor fecal samples 9 animals colonized by bacteria from each donor sample | GF mice grafted with gut microbiota from ASD and TD control subjects | Microbiota from ASD altered the behavior of mice: increased repetitive behavior, decreased locomotion, and decreased communication. It also induced alternative splicing of genes in the mice brain in ASD vs. TD control. Differences in the metabolome profile. |
MacFabe et al., 2007 [105] | Adult male Long–Evans rats (~75 days old) | Total of 74 rats across groups Group sizes 6–9 animals | Infusion with PPA. Low: 4.0 μL of a 0.052 M solution; high: PPA (4.0 μL of a 0.26 M solution. Controls: PBS or propanol | PPA treatment: increase in oxidative stress markers. Altered behavior (repetitive dystonic behaviors, hyperactivity, and turning behavior). Increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD68 immunoreactivity). |
Meeking et al., 2020 [112] | Adult male Long–Evans | Total of 35 rats across groups | 7 days, twice a day, 4 h apart, infusion of buffered PPA (low dose 0.052 M or high dose 0.26 M, pH 7.5, 4 μL/infusion) control: phosphate buffered saline (PBS, 0.1 M) | PPA-treated rats exhibited more locomotive activity, stereotypic behavior, and nose pokes versus control, which are associated with a rat model of ASD. The symptoms were dose-dependent and increased with consecutive treatments. |
De Theije et al., 2014 [113] | BALB/C mice from Charles River laboratories | 8 pups in treatment group and 11 in control | Dams treated at gestational day 11 with 600 mg/kg of valproic acid (VPA). Pups weaned at P21. Behavioral experiments performed at P28, after which they were sacrificed. VPA treatment during gestation is well established in the animal model of ASD. | An increase in cecal levels of BA in in utero VPA-treated pups vs. control. A decrease in Bacteroidales (order) and increase in Clostridiales (order) in VPA vs. control. Increased neutrophil infiltration in the intestine. |
MacFabe et al., 2011 [106] | Adolescent (41 ± 4 days) Long–Evans male | 20 and 17 animals in PPA and control groups, respectively | Intracerebroventricular injection of 4 μl of 0.26 M buffered PPA prior to each test session | PPA vs. control group characterized by activation of microglia and astrocytes, lesser sociability, and a focus on particular objects in a group of objects. |
El-Ansary et al., 2015 [107] | Male Western albino rats | 6 animals in each group | PPA: 250 mg/kg body weight/day (orally) Ampicillin: 50 mg/kg for three weeks | Treatment with PPA and ampicillin led to an increase in catalase activity and lipid peroxidation, while glutathione and potassium levels were decreased in comparison to the control group. |
El-Ansary et al., 2018 [108] | Young male golden Syrian hamsters | 10 animals in each group | PPA: 250 mg per kg of body weight (BW) (oroigastric) Clindamycin: 30 mg single dose | An increase in Candida albicans and Clostridia in PPA and clindamycin groups. An increase in Na+/Mg2+ and glutamate/GABA ratios. |
Lobzhanidze et al., 2019 [109] | Adolescent male Wistar rats (P30–35) | 15 animals in each group | Single injection of buffered PPA with a dose of 175 mg/kg | In the PPA vs. control groups, the number of neurons was decreased, while the number of glial cells was increased in the amygdala. Also, both microglia and astrocytes were activated, and neurons exhibited signs of apoptosis. The behavioral changes include decreased sociability (a decrease in the amount of time and number of encounters with unfamiliar rats). |
Foley et al., 2014 [110] | Long–Evans rats, offspring treated in utero and postnatal | 8 to 11 animals in each group | Prenatal administration of PPA (500 mg/kg,) and LPS (50 μg/kg). Postnatal PPA administered at PPA (500 mg/kg) | Treatments (both prenatal and postnatal) altered the behavior of rodents to autism-like behavior. PPA-treated rats spend less time in the center of the open field and exhibited increased anxiety. Treatment induced delays in eye opening. |
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Lagod, P.P.; Naser, S.A. The Role of Short-Chain Fatty Acids and Altered Microbiota Composition in Autism Spectrum Disorder: A Comprehensive Literature Review. Int. J. Mol. Sci. 2023, 24, 17432. https://doi.org/10.3390/ijms242417432
Lagod PP, Naser SA. The Role of Short-Chain Fatty Acids and Altered Microbiota Composition in Autism Spectrum Disorder: A Comprehensive Literature Review. International Journal of Molecular Sciences. 2023; 24(24):17432. https://doi.org/10.3390/ijms242417432
Chicago/Turabian StyleLagod, Piotr P., and Saleh A. Naser. 2023. "The Role of Short-Chain Fatty Acids and Altered Microbiota Composition in Autism Spectrum Disorder: A Comprehensive Literature Review" International Journal of Molecular Sciences 24, no. 24: 17432. https://doi.org/10.3390/ijms242417432