title: Model-based hypothesis of gut microbe populations and gut/brain barrier permeabilities in the development of regressive autism.
abstract: Regressive autism is a devastating disorder affecting children between the ages of 15-30 months. The disorder is characterized by the loss of social interaction and communication ability following otherwise healthy development. In spite of rising autism prevalence, current detection methods and treatment options for this disease are lacking. Therefore, this study introduces a systems-level model, which suggests that gut microbes and intestinal inflammation influence the onset of regressive autism through increasing gut permeability. This computational model provides a framework for quantitative understanding of how imbalances in populations of gut microbes alters the whole-body and brain distributions of neurotoxins produced by GI tract bacteria. Our results indicate that increased levels of the bacteria Bacteroides vulgatus lead to increased brain levels of propionic acid, a neurotoxin which has been known to cause symptoms characteristic of autism when injected into the brain of rats. Our results further indicate that immune response to virulence factors produced by bacteria in the gut leads to increased systemic levels of inflammatory cytokines, such as IL-1β, which significantly alter the permeability of the gut epithelial layer and the blood-brain barrier. Due to the large size of cytokines, however, we predict the time required for concentrations in the brain to stabilize to be on the order of years. This suggests that treatments preventing autism development could be administered after identifying microbial biomarkers of disease but before debilitating brain inflammation leads to regressive autism progression. Future research extending this work could provide new treatment options and diagnostic techniques to help combat regressive autism.
authors.affiliation: University of Delaware, Department of Chemical and Biomolecular Engineering, 150 Academy Street, Newark, DE 19716, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Downs
authors.affiliation: University of Delaware, Department of Chemical and Biomolecular Engineering, 150 Academy Street, Newark, DE 19716, USA.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Perna
authors.affiliation: University of Delaware, Department of Chemical and Biomolecular Engineering, 150 Academy Street, Newark, DE 19716, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Vitelli
authors.affiliation: University of Delaware, Department of Chemical and Biomolecular Engineering, 150 Academy Street, Newark, DE 19716, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cook
authors.affiliation: University of Delaware, Department of Chemical and Biomolecular Engineering, 150 Academy Street, Newark, DE 19716, USA. Electronic address: dhurjati@udel.edu.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dhurjati
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000209:etiology* / Q000382:microbiology*; D001439:Bacteroides; D001812:Blood-Brain Barrier; D002675:Child, Preschool; D003198:Computer Simulation; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007223:Infant; D007249:Inflammation; D007422:Intestines / Q000382:microbiology*; D008954:Models, Biological; D009498:Neurotoxins / Q000737:chemistry; D010539:Permeability; D011422:Propionates / Q000737:chemistry; D051381:Rats; D013997:Time Factors; D014774:Virulence
chemical_list: D016207:Cytokines; D009498:Neurotoxins; D011422:Propionates; C029658:propionic acid