A hierarchical gating hypothesis for GABA-Mediated gut-liver communication: a mechanistic framework
Year: 2026
Type: article
Abstract: γ -Aminobutyric acid (GABA) can produce divergent outcomes in colitis and liver injury, but the conditions linking exposure to organ responses remain unresolved. We propose a hierarchical gating hypothesis in which compartment-specific GABA exposure is an upstream prerequisite. JAK3-associated immune status and CDK2-associated proliferative status are proposed as parallel effect modifiers, not a fixed linear signaling cascade. Their possible roles as direct intracellular GABA targets represent a separate, unverified mechanistic extension. GABA-producing probiotic strains are considered potential delivery systems that may modify local exposure, while other metabolites and microbiome changes may also contribute to their effects. Exploratory evidence comprises DiffDock-generated poses, 200 ns molecular dynamics simulations of five candidate complexes, and biolayer interferometry (BLI) measurements at GABA concentrations of 25–200 μ M . The simulations describe conformational behavior but do not establish a ranking of binding affinities. BLI responses increased with GABA concentration and declined during dissociation. The reported fits yielded provisional apparent dissociation constants of 54.6 and 64.1 μ M for JAK3 and CDK2, respectively. Binding specificity and parameter uncertainty remain unresolved, and these observations do not establish intracellular engagement, kinase regulation, or efficacy in liver disease. We outline disease-specific tests combining exposure measurements, state-dependent response analysis, and independent evaluation of direct target engagement. Discriminating experiments must separate kinase-specific interactions from classical GABA receptor signaling, hepatic GABA production, and microbial cometabolite effects. The framework organizes testable predictions rather than establishing a validated therapeutic mechanism.
Source: Frontiers in Pharmacology
Institution: Nanjing University of Chinese Medicine
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225817687