Intestinal Microbiome & Autism: exploring the contribution of specific microbiome differences (like Clostridium, Bacteroides, Prevotella, and Sutterella species) in autism-spectrum disorder children on symptomology
Introduction. Compared to neurotypical controls, autism spectrum disorders (ASD) children more commonly experience hospitalizations with complaints of diarrhea, chronic constipation, and abdominal pain1. Several studies have shown abnormal gut microbiota in children with ASD. Studies using the maternal immune activation (MIA) model look at the offspring of MIA mice. The offspring, which exhibit ASD symptoms, had defects in their intestinal wall and altered microbiota that were similar to the microbiome defects reported in human ASD2. Other studies using rat models have shown potential links between the increased amounts of Clostridium in ASD children and severe neurological and behavioral effects3. Although many studies have explored the genetic and environmental risk factors for ASD, further research is needed to explore the role of GI abnormalities in ASD gut microbiomes. Here, we ask how abnormalities in the levels of certain organisms in the microbiota of children with ASD contribute to ASD symptomology. Methods. The MIA mouse model was used. Modeling MIA in mice by injecting pregnant female mice with the viral mimic poly(I:C) yields ASD offspring that also exhibit key microbiome changes4. Mice were selected at random and injected with B. fragilis. Intraventricular infusions of propionic acid in adult rats was used to model the effects of abundant Clostridium found in ASD microbiomes. 16S rRNA gene sequencing was utilized to study the bacterial communities in ASD models. ANOVA testing was used. Results. The MIA offspring that were treated with human Bacteroides showed improvements in the defects of their GI barrier, alterations in tight junctions, and specific microbiota changes were restored to a more typical presentation. MIA mice had significant increases in one particular serum metabolite, 4-ethylphenylsulfate (4EPS), that’s been shown to induce anxiety-like behaviors. 4EPS was massively increased in the MIA mice (46-fold), and treatment with B. fragilis restored 4EPS levels to normal and greatly improved behaviors5. Propionic acid infusions produced reversible ASD-like repetitive behaviors6. Conclusions. Studies have found microbiota of children with ASD have much lower levels of short fatty acid chains, over-representation of Clostridium and Sutterella species, atypical Bacteroides, Lactobacillus and Bifidobacterium organisms, and lowered abundance of fermenting species like Prevotella with overall decreased activity of digestive enzymes7,8. Discussion has opened into the applications of probiotics, special diets, helminthes, and microbiome transplants as potentially long-term treatments for ASD. Varied levels of specific organisms of the gut microbiome like Bacteroides or Clostridium may contribute to the pathogenesis of ASD and severity of symptoms.
- Kang D, Adams J, Gregory A et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017;5(1). doi:10.1186/s40168-016-0225-7
- Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism.Malkova, N.V., Yu, C.Z., Hsiao, E.Y., Moore, M.J., and Patterson, P.H.Brain Behav. Immun. 2012; 26: 607–616
- Macfabe D, Cain D, Rodriguezcapote K, et al. Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behavioural Brain Research. 2007;176(1):149-169. doi:10.1016/j.bbr.2006.07.025.
- Maternal immune activation alters fetal brain development through interleukin-6.Smith, S.E., Li, J., Garbett, K., Mirnics, K., and Patterson, P.H.J. Neurosci. 2007; 27: 10695–10702
- Hsiao EY, McBride SW, Hsien S, et al. The microbiota modulates gut physiology and behavioral abnormalities associated with autism. Cell. 2013;155(7):1451-1463. doi:10.1016/j.cell.2013.11.024
- Shultz SR, Macfabe DF, Ossenkopp K-P, et al. Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: Implications for an animal model of autism. Neuropharmacology. 2008;54(6):901-911. doi:10.1016/j.neuropharm.2008.01.013.
- Kang D-W, Park JG, Ilhan ZE, et al. Reduced Incidence of Prevotella and Other Fermenters in Intestinal Microflora of Autistic Children. Gilbert JA, ed. PLoS ONE. 2013;8(7):e68322. doi:10.1371/journal.pone.0068322.
- Williams BL, Hornig M, Parekh T, Lipkin WI. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio. 2012;3(1). doi:10.1128/mBio.00261-11.