Multisystem pathology in chronic variable stress: gut-liver-brain axis disruption and the therapeutic promise of magnesium-L-theanine.

Abstract

Chronic variable stress (CVS) is a well-established translational model that captures the unpredictability, persistence, and cumulative burden of long-term stress exposure. Through repeated application of heterogeneous mild-to-moderate stressors in a non-habituating manner, CVS induces sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis, chronic glucocorticoid excess, oxidative stress, and neuroinflammatory signaling. These processes collectively drive coordinated dysfunction across multiple organ systems. Accumulating evidence now indicates that CVS pathology extends beyond the central nervous system (CNS), engaging the gut-liver-brain axis as a key integrative network linking stress to systemic metabolic and inflammatory outcomes. Stress-induced impairment of intestinal barrier integrity, dysregulation of nutrient transporters, hepatic lipid accumulation, iron dyshomeostasis, and cardiometabolic disturbances synergistically amplify both peripheral and neural vulnerability. Magnesium-L-theanine (MgT), a novel complex combining magnesium with the green tea-derived amino acid L-theanine, has emerged as a promising multi-target intervention against CVS-induced multisystem injury. Preclinical studies demonstrate that MgT preserves epithelial barrier architecture, restores tight junction and mucus-associated proteins, normalizes intestinal nutrient transporter expression, and attenuates hepatic steatosis, oxidative stress, and iron-driven metabolic damage under CVS conditions. These protective effects converge on the reactivation of key metabolic regulators, including nicotinamide adenine dinucleotide (NAD⁺)/sirtuin 1 (SIRT1) and PPARγ signaling pathways, positioning MgT as a modulator of metabolic flexibility and redox resilience. Co-administration with the NAD⁺ precursor nicotinamide riboside further potentiates these responses by reinforcing NAD⁺ availability and downstream metabolic control. In parallel, human studies of magnesium and L-theanine supplementation report anxiolytic, antidepressant, sleep-promoting, and anti-inflammatory benefits, supporting the translational relevance of this combined approach. This review integrates current evidence on CVS-induced multisystem pathology, with a focus on the gut-liver-brain axis, and proposes MgT as a trace-element-based, systems-oriented strategy to mitigate chronic stress-related gastrointestinal, metabolic, and neuropsychiatric complications, while highlighting key mechanistic gaps and translational priorities for clinical advancement.