01 September 2017

The Autism project is first of its kind, where in, hybrid modeling technique has been incorporated, integrating steady-state modeling (i.e., COBRA) and semi-detailed kinetic modeling methods (i.e., physiology based pharmacokinetic model, PBPK). Genome-scale metabolic models of five important gut-microbes [1, 2] (implicated in Autism) were combined with the enterocyte model [3] to represent the human gut. Further this gut model was coupled with brain model [4] and integrated with PBPK model. The PBPK model accounts for six tissue types that are actively involved in metabolism and excretion of gut bacteria-derived metabolites. With such an exhaustive modeling system, the effect of bacteria-derived toxins (i.e., superoxide and hydrogen peroxide) was analyzed on brain and gut, and effective dietary treatment options (i.e., antioxidants) were predicted that could improve autistic symptoms. Further, this study computationally re-confirmed that a dysfunctional mitochondrial metabolism in the brain along with disturbed neurotransmitter synthesis, mainly drives Autism. This is the first ever study that truly integrates steady-state and dynamic modeling approaches, which not only aids in identification of the precise biochemical factors contributing to a clinical condition (i.e., Autism), but also, quantified host-microbe interactions in a complex system.