Taylor Newman

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication, repetitive behavioral patterns, highly restricted interests and/or sensory behaviors early in life. ^1,3 Children with ASD are 3.5 times more likely to suffer from GI disorders, such as diarrhea and constipation, than children without developmental disorders.⁴ Individuals with ASD often have highly self-restrictive diets and GI motility issues, like constipation and diarrhea, which can affect their gut microbiome. Also, the extensive genetic and medical heterogeneity found in the Autistic population can impact the microbial composition.²  It is hypothesized that the gut-brain axis can potentially play a large role in the reduction of GI symptoms as well as reduced social deficits in autism spectrum disorder individuals.

Objective: In this narrative review, we explored the mechanisms by which alteration of the gut microbiome and addition of probiotics can reduce the behavioral symptoms associated with ASD via the gut-brain axis.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2023 using the following keywords: “Autism”, “autism spectrum disorder”, “gut microbiome”, “probiotic”, and “gut-brain axis”.

Results: Results showed that the ASD population had a significantly different composition of their gut microbiome when compared to the neurotypical population.⁵ They specifically had a significantly higher incidence of C. perfringens and the C. perfringens isolated from the ASD group (54.5%) were significantly more resistant to clindamycin.⁵ This suggests that the high incidence of C. perfringens and its toxin gene (Cpb2) may be linked to the autism spectrum disorder-related GI complications and other associated symptoms. Several studies, performed on Shank-3 deficient mice, then showed that the intervention with a Clostridium probiotic, Lactobacillus reuteri, reduced unsocial and repetitive behaviors while significantly reducing the incidence of Clostridium.^6,7,8 Further investigation examined the effect of the probiotic on the gut-brain axis specifically. One study looked at the role of the Vagus Nerve (CN X) by performing a bilateral sub diaphragmatic vagotomy on Shank-3 deficient mice. The control group underwent the same procedure, but their vagal branches were not transected. They were then treated with the probiotic, and the L. reuteri enhanced social behaviors in sham-operated, but not in vagotomized Shank3B^−/− mice.⁷ A separate study investigated the role of oxytocin by revealing that an abundance of L. reuteri correlated with increases hypothalamic expression of oxytocin and increases in the gene expression and protein levels of three GABA receptor subunits in the hippocampus and frontal cortex of Shank3 KO mice.⁸

Conclusions:  This narrative review showcases the therapies that can be centered on the gut microbiome, specifically targeting L. reuteri, in children with ASD. L. reuteri was able to play a role in the significant reduction of negative behavioral and unsocial symptoms. This review also illustrates the possible links between and gut and brain though CN X and its associated oxytocinergic and GABA pathways. Researchers are now likely to further explore the gut-brain axis with focus on long-term probiotic or preventative probiotic treatments in children with autism spectrum disorder.

Works Cited:

1. Lord C, Brugha TS, Charman T, et al. Autism spectrum disorder. Nature Reviews Disease Primers. 2020;6(1):1-23. doi:https://doi.org/10.1038/s41572-019-0138-4
2. Saurman V, Margolis KG, Luna RA. Autism Spectrum Disorder as a Brain-Gut-Microbiome Axis Disorder. Digestive Diseases and Sciences. 2020;65(3):818-828. doi:https://doi.org/10.1007/s10620-020-06133-5
3. Sharma SR, Gonda X, Tarazi FI. Autism Spectrum Disorder: Classification, diagnosis and therapy. Pharmacology & Therapeutics. 2018;190(1):91-104. doi:https://doi.org/10.1016/j.pharmthera.2018.05.007
4. Srikantha P, Mohajeri MH. The Possible Role of the Microbiota-Gut-Brain-Axis in Autism Spectrum Disorder. International Journal of Molecular Sciences. 2019;20(9):2115. doi:https://doi.org/10.3390/ijms20092115
5. Alshammari MK, AlKhulaifi MM, Al Farraj DA, Somily AM, Albarrag AM. Incidence of Clostridium perfringens and its toxin genes in the gut of children with autism spectrum disorder. Anaerobe. 2020;61:102114. doi:10.1016/j.anaerobe.2019.102114
6. Li YQ, Sun YH, Liang YP, Zhou F, Yang J, Jin SL. Effect of probiotics combined with applied behavior analysis in the treatment of children with autism spectrum disorder: a prospective randomized controlled trial. Zhongguo Dang Dai Er Ke Za Zhi. 2021 Nov 15;23(11):1103-1110. English, Chinese. doi: 10.7499/j.issn.1008-8830.2108085. PMID: 34753541; PMCID: PMC8580031.
7. Sgritta M, Dooling SW, Buffington SA, et al. Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. Neuron. 2019;101(2):246-259.e6. doi:https://doi.org/10.1016/j.neuron.2018.11.018
8. Tabouy L, Getselter D, Ziv O, et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav Immun. 2018;73:310-319. doi:10.1016/j.bbi.2018.05.015
9. Harony-Nicolas H, Kay M, du Hoffmann J, et al. Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. Elife. 2017;6:e18904. Published 2017 Jan 31. doi:10.7554/eLife.18904