Understanding the attention deficit hyperactivity disorder-gut axis by metabolic network analysis

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder diagnosed with hyperactivity, impulsivity, and a lack of attention inconsistent with the patient's development level. People with ADHD frequently experience gastrointestinal (GI) dysfunction, suggesting a possible role of the gut microbiome. The present research aims to determine a set of biomarkers for ADHD by reconstructing a model of the gut-microbial community and understanding the effects of metabolites produced by gut microbiota on the human brain. Genome-scale metabolic models (GEM), considering the relationship between gene-protein-reaction associations, are used to simulate metabolic activities in gut organisms. The production rates of dopamine and serotonin precursors and the key short-chain fatty acids which affect the health status are determined under three diets (Western, Atkins', Vegan) and compared with healthy subjects. Elasticities are calculated to understand the sensitivity of exchange fluxes to changes in diet and bacterial abundance at the species level. A pre-prepared human brain model with 812 metabolites, 994 reactions, 671 genes, and 71 metabolic pathways is used as the healthy brain model. Genes NOS1 and SLC6A3 are deleted from the healthy model to simulate an ADHD brain. In order to achieve an integrated gut-brain model, a three-compartment model (gut, blood, and brain) is curated. The presence of Bacillota, Actinobacteria, Bacteroidetes, and Bacteroidota may be possible gut microbiota indicators of ADHD. This type of modeling approach, taking microbial genome-environment interactions into account and how the metabolites they produced interact with other organs in the human body, aids in understanding gastrointestinal mechanisms behind ADHD and improving the quality of life for patients.