Truce Pham

Introduction: Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder that affects an individual’s communication and interaction skills with an incidence of 1 in 59 in 2014^1,2. Because many causative factors have been attributed to ASD and none being a leading cause, there is no agreed upon treatment³. Instead, research has focused on gastrointestinal disturbances, a common comorbidity of ASD that affects 12% of ASD children⁴. The gut-brain axis is an extensive two-way communication pathway and is attributed to the connection between ASD and gastrointestinal disturbances⁵. Studies show dysbiosis in the microbiome of ASD patients compared to controls^3,5. Elevated levels of the anaerobe Clostridium in ASD contributes to an increase in propionic acid, a neurotoxin that travels to the brain at elevated levels^6,7. Studies also demonstrated that an increase in propionic acid and decreases in tryptophan and serotonin lead to decreased intestinal mobility^7,8. Researchers looked at how correcting the microbiome in the gut through probiotic treatment would affect behavior and intestinal symptoms⁵. Methods: Offspring of maternal immune activated (MIA) mice were used as an accepted model of autism. Pregnant mice were injected with a viral mimic poly(I:C) and pregnant controls were injected with saline. The MIA offspring were treated with oral Bacteroides fragilis to determine if there were corrections of ASD-related behavioral abnormalities and GI changes. Intestinal permeability was measured using a FITC-assay. Anxiety-like behaviors were determined through time spent in open-field exploration and communication was measured through ultrasonic vocalizations. Sociability was measured by interactions with familiar and unfamiliar mice. Statistical analysis was done using a two-tailed, unpaired Student t test. Results: B. fragilis restored epithelial barrier integrity compared to controls through decreased intensity of the FITC dextran solution in serum samples⁵. Mice improved their communication with longer ultrasonic vocalizations and decreased anxiety-like behaviors by spending more time in the open-field. However, mice did not show differences in sociability. Results were not just limited to B. fragilis but were relieved by other commensal bacteria as well. Conclusions: In ASD, the microbiomes of patients lead to symptoms associated with behavior and GI disturbances. B. fragilis treatment corrects most ASD behavior symptoms like communication and anxiety. Increased intestinal integrity can lead to protective effects by decreasing toxins produced in the gut from reaching the brain. Probiotic supplements are cheap and cost-effective and can be used as treatment.

References:

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. Washington, DC: American Psychiatric Association, 2013.
2. CDC – Autism Spectrum Disorder Facts and Statistics. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/ncbddd/autism/data.html. Published 2018. Accessed April 22, 2018.
3. Masi A, DeMayo MM, Glozier N, Guastella AJ. An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options. Neuroscience Bulletin. 2017;33(2):183-193.
4. Kohane IS, McMurry A, Weber G, et al. The Co-Morbidity Burden of Children and Young Adults with Autism Spectrum Disorders. Smalheiser NR, ed. PLoS ONE. 2012; 7(4).
5. 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.
6. Kesli R, Gokcen R, Bulug U, Terzi Y. Investigation of the Relation Between Anaerobic Bacteria Genus Clostridiumand Late-Onset Autism Etiology in Children. Journal of Immunoassay and Immunochemistry. 2013; 35(1): 101-109.
7. Frye RE, Rose S, Chacko J, et al. Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. Translational Psychiatry. 2016; 6 (10).
8. Golubeva AV, Joyce SA, Moloney G, et al. Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism. EBioMedicine. 2017; 24: 166-178.