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

内容摘要

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. Chronic stress affects the whole body: The gut–liver–brain connection and the potential benefits of magnesium-L-theanine Chronic stress is not limited to psychological symptoms but affects multiple organs involved in metabolic and hormonal regulation. Long-term exposure to stress can disrupt stress hormone balance, increase inflammation, and impair communication between the gut, liver, and brain. This interconnected system plays a critical role in maintaining metabolic health, immune balance, and brain function. When it is disturbed, intestinal barrier function weakens, nutrient handling is altered, fat accumulates in the liver, iron balance becomes dysregulated, and the risk of metabolic and mood-related disorders increases. Magnesium-L-theanine is a nutritional compound that combines magnesium with L-theanine, a natural amino acid found in green tea. Experimental studies show that this combination helps protect the intestinal barrier, improves nutrient transport, reduces liver fat accumulation, and limits oxidative and inflammatory damage during chronic stress. These effects are linked to improved cellular energy balance and metabolic regulation. When combined with a supplement that supports cellular energy production, these protective actions appear to be further enhanced. Clinical studies of magnesium and L-theanine supplementation also report improvements in anxiety, sleep quality, and inflammatory markers. Together, these findings suggest that Magnesium-L-theanine may represent a promising supportive strategy for reducing the metabolic and endocrine consequences of chronic stress by targeting the gut–liver–brain axis.