Posted April 22, 2015
Joel Bornstein, Ph.D., Elisa Hill, Ph.D., and Heather Young, Ph.D., University of Melbourne;
Emma Allen-Vercoe, Ph.D., University of Guelph;
Sarkis Mazmanian, Ph.D., California Institute of Technology
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, affecting over 1% of children in the United States. In addition to the social, cognitive, and behavioral impairments that are characteristic of ASD, gastrointestinal (GI) abnormalities including constipation, diarrhea, and bloating affect a significant portion of individuals with ASD. The study of microbiota, which is defined as the community of commensal, symbiotic, and pathogenic microorganisms within the body, has emerged as an important field with various health implications. Microbial imbalance in the GI, or dysbiosis, has been found in many disorders including ASD, although much remains unknown about the connection between microbial dysbiosis, GI abnormalities, and ASD. Several Autism Research Program (ARP) awardees are currently pursuing research to answer these knowledge gaps.
Co-investigators Drs. Elisa Hill, Joel Bornstein, and Heather Young (1-4) of the University of Melbourne sought to understand why individuals with ASD experience GI co-morbidities. With support of a Fiscal Year 2011 ARP Idea Development Award, they are studying the "mini-brain"; the enteric neurons that control gut motility and secretion. They want to determine if the enteric neurons are altered in mice that express certain gene mutations. In particular, they are studying mice with a mutation in the neuroligin 3 (NL3) gene. NL3 has been shown to be important for brain function and cell adhesion. Mutations of this gene have been found in individuals with ASD. Using various imaging techniques, they have discovered that these mice also show altered colonic function, providing the first evidence that a gene mutation associated with ASD produces GI dysfunction.
Dr. Emma Allen-Vercoe and her research team at the University of Guelph in Ontario, Canada are interested in determining if GI-comorbidities of ASD correlate with differences in gut microbiota. With funding from a Fiscal Year 2012 ARP Pilot Award, she analyzed fecal samples from ASD children with concurrent GI co-morbidity, as well as samples from neurotypical controls, using a technique called nuclear magnetic resonance (NMR) to measure different metabolites from these samples. She found that microbes residing in the gut of the ASD children produced microbial metabolites that differed from the control samples. Specifically, she discovered differences in the levels of short chain fatty acids that many gut bacteria produce in response to ingested food. Furthermore, Dr. Allen-Vercoe developed a novel system called the "Robogut" to better study these microbes in the laboratory. This system allows for the study of the microbes in the context of the entire microbial community, rather than on an individual basis. Using this new system, Dr. Allen-Vercoe and her team hope to gain insight as to why the gut microbes in children with ASD behave differently from neurotypical children.
Dr. Sarkis Mazmanian (5-8) and his team at the California Institute of Technology are continuing the work of the late Paul Patterson, who was a pioneer in autism research. The team sought to examine whether treatment with a specific probiotic microbe may be able to improve behavioral symptoms and GI abnormalities in an ASD mouse model. Through support of a Fiscal Year 2010 ARP Idea Development Award, they studied the maternal immune activation (MIA) mouse model of ASD. They found that offspring of the MIA mothers exhibited increased intestinal permeability or "leaky gut," a phenomenon commonly seen in ASD individuals. These mice also displayed dysbiosis of the gut microbiota similar to what has been seen in humans. The Mazmanian laboratory showed that probiotic treatment of these mice with the human gut symbiont, Bacteroides fragilis (B. fragilis), corrected the intestinal permeability in the mice and restored imbalances in their microbiota. Remarkably, B. fragilis treatment also ameliorated ASD-related behavioral abnormalities in MIA mice. These findings suggest that microbiome-based therapies may be potential treatments for individuals with ASD.
Taken together, the work of these ARP-funded investigators helps answer gaps in knowledge about the growing link between the GI system and ASD. Ultimately, the researchers hope their work will translate into new treatments for both GI dysfunction and behavioral abnormalities associated with ASD.
Figure courtesy of Dr. Mazmanian's laboratory suggesting that the gut microbiota impacts ASD-like behaviors though modulation of brain activity.
Publications:
1) Argyropoulos A, Gilby KL, and Hill-Yardin EL. 2013. Studying autism in rodent models: Reconciling endophenotypes with comorbidities. Front Hum Neurosci 7:417.
2) Hao MM, Bornstein JC, Vanden BP, et al. 2013. The emergence of neural activity and its role in the development of the enteric nervous system. Dev Biol 382(1):365-374.
3) Hao MM, Bornstein JC, and Young HM. 2013. Development of myenteric cholinergic neurons in ChAT-Cre;R26R-YFP mice. J Comp Neurol 521(14):3358-3370. doi: 10.1002/cne.23354. PMID:23649862.
4) Hill-Yardin EL and Hannan AJ. 2013. Translating preclinical environmental enrichment studies for the treatment of autism and other brain disorders: Behav Neurosci 127(4):606-609.
5) Bauman MD, Losif AM, Smith SEP, et al. 2013. Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Bio Psychiat 15:75(4):332-341.
6) Garay PA, Hsiao EY, Patterson PH, et al. 2013. Maternal immune activation causes age- and region-specific changes in brain cytokines in the off-spring throughout development. Brain Behav Immun 31:54-68.
7) Hsiao EY, McBride SW, Hsien S, et al. 2013. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155(7):1451-1463.
8) Hsiao EY, McBride S, Chow J, et al. 2012. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci USA 109:12776-12781.