Abstract
IntroductionThe integrity of the intestinal epithelium is crucial for human health and is harmed in autism spectrum disorder (ASD). An aberrant gut microbial composition resulting in gut-derived metabolic toxins was found to damage the intestinal epithelium, jeopardizing tissue integrity. These toxins further reach the brain via the gut-brain axis, disrupting the normal function of the brain. A mechanistic understanding of metabolic disturbances in the brain and gut is essential to design effective therapeutics and early intervention to block disease progression. Herein, we present a novel computational framework integrating constraint based tissue specific metabolic (CBM) model and whole-body physiological pharmacokinetics (PBPK) modeling for ASD. Furthermore, the role of gut microbiota, diet, and oxidative stress is analyzed in ASD.MethodsA representative gut model capturing host-bacteria and bacteria-bacteria interaction was developed using CBM techniques and patient data. Simultaneously, a PBPK model of toxin metabolism was assembled, incorporating multi-scale metabolic information. Furthermore, dynamic flux balance analysis was performed to integrate CBM and PBPK. The effectiveness of a probiotic and dietary intervention to improve autism symptoms was tested on the integrated model.ResultsThe model accurately highlighted critical metabolic pathways of the gut and brain that are associated with ASD. These include central carbon, nucleotide, and vitamin metabolism in the host gut, and mitochondrial energy and amino acid metabolisms in the brain. The proposed dietary intervention revealed that a high-fiber diet is more effective than a western diet in reducing toxins produced inside the gut. The addition of probiotic bacteria Lactobacillus acidophilus, Bifidobacterium longum longum, Akkermansia muciniphila, and Prevotella ruminicola to the diet restores gut microbiota balance, thereby lowering oxidative stress in the gut and brain.ConclusionThe proposed computational framework is novel in its applicability, as demonstrated by the determination of the whole-body distribution of ROS toxins and metabolic association in ASD. In addition, it emphasized the potential for developing novel therapeutic strategies to alleviate autism symptoms. Notably, the presented integrated model validates the importance of combining PBPK modeling with COBRA -specific tissue details for understanding disease pathogenesis.
Highlights
The integrity of the intestinal epithelium is crucial for human health and is harmed in autism spectrum disorder (ASD)
An interesting observation shown in Supplementary Files/Additional File/Table S17 is that among the top three secretion products, the Bacteroides vulgatus model contributed the maximum amount to the total formate and acetate generated in the autistic gut (Supplementary Files/Additional File/Table S17)
The novel in silico approach used in this study demonstrates how toxins produced by gut dysbiosis alter the normal function of the brain in Autism spectrum disorder (ASD)
Summary
The integrity of the intestinal epithelium is crucial for human health and is harmed in autism spectrum disorder (ASD). Comorbidity patterns describe the pathogenesis of autism, most notably gastrointestinal defects and abnormal gut microbiome composition (Adams et al, 2011; Wang et al, 2011; Frye et al, 2013, 2015; Cheng et al, 2017) These factors can be transmitted to the brain via the gut-brain axis, resulting in neuronal dysfunction (Ding et al, 2017). Toxins produced by dysbiosis, such as propionic acid (Adamberg et al, 2014), lipopolysaccharides (Wang et al, 2019), and most importantly, reactive oxygen species (ROS; Frye et al, 2015), stimulate the production of inflammatory cytokines As a result, it increases permeability in the gut, allowing toxins into the bloodstream where they can cross the blood-brain barrier and cause symptoms of autism (de Theije et al, 2011; Li et al, 2017). It reinforces the concept that any intervention successfully treating gastrointestinal dysfunction may alleviate ASD-related brain symptoms
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