An Integrated COBRA-PBPK Model to Study Interactions between the Gut Microbiome and the Brain in Autism

Autism, also ASD (Autism Spectrum Disorder) is a complex neurological condition characterized by social, behavioural and developmental issues such as impaired communication and repetitive actions. Gastro-intestinal disturbances in autistic patients have motivated experiments that identified abnormal concentrations of certain bacteria in the gut. To understand the role played by the most reported gut bacteria associated with autism, namely Bacteroides vulgatus, Clostridium perfringens, Desulfovibrio desulfuricans, Bifidobacterium longum and Lactobacillus acidophilus, a hybrid modeling approach was adopted. Genome-scale metabolic models of these bacteria were integrated with the human small intestinal enterocyte model. Simultaneously, a permeability-limited, two sub-compartment, whole body PBPK transport model was incorporated to determine the distribution of gut-bacteria derived toxins throughout organs. A novel framework was formulated for the development and analysis of an integrated gut-PBPK-brain model and was applied to the study of autism for the first time. The integrated model predicted that intake of probiotics (L. acidophilus and B. longum) leads to reduced oxidative stress in the brain, resulting in relief from autistic symptoms. Further, investigating the effect of various dietary schemes indicated that a typical western diet worsens symptoms in autistic individuals. Importantly, potential biomarkers for autism were predicted in terms of bacterial secretion products and affected pathways in the genome-scale metabolic model of the brain. Thus, the integrated model breaks new ground in developing a quantitative model for studying gut-brain interactions, with the potential to understand and remedy several neurological problems with links to the gut, such as autism, depression and anxiety. More generally, the framework for integration and analysis of constraint-based and PBPK models can be applied to study dynamically, the interactions between systems in various fields. Its applications are demonstrated by providing a mechanistic basis for autism pathogenesis and by proposing dietary changes and intake of probiotics for the alleviation of autistic symptoms.