CROSSTALK AT THE LIVER-CNS AXIS

Letter to the Editor

C-U. Kutemeyer^*

Private Practice, von Eichendorffstr. 50, 33428 Harsewinkel, Germany.

*Correspondence to:
Cord-Urlich Kutemeyer, MD,
Private Practice,
von Eichendorffstr. 50,
33428 Harsewinkel, Germany.
e-mail: webmaster@dr-kuetemeyer.de

KEYWORDS: CNS, liver, liver-brain axis, neuroendocrine pathway, brain

INTRODUCTION

It is known that the central nervous system (CNS) communicates bidirectionally with the liver, influencing various biological reactions such as cognitive and behavioral functions, cellular metabolism, regulation of hormones and the immune system, and the inflammatory response (1). The liver-brain axis is a set of physiological processes that connect liver metabolism to brain function without affecting individual chemical reactions (2). The main reactions described concern the regulation of energy and metabolism, such as glycogen synthesis and glycogenolysis, which control blood sugar levels. The liver is an immunological organ: it produces cytokines and acute-phase reactants. It also regulates glucose, lipids, and amino acids, and produces ketone bodies (3). Alterations such as steatosis and insulin resistance modify the brain’s energy supply.

DISCUSSION

Gluconeogenesis is a reaction by which the liver synthesizes glucose from non-carbohydrate precursors. The main substrates for these reactions are lactate, alanine, glycerol, and glucogenic amino acids, which are involved in the Krebs cycle. The sites where these reactions occur are mitochondria, the cytosol, and the endoplasmic reticulum. The important reactions of glycolysis involve pyruvate, which is converted to oxaloacetate through the reaction: pyruvate + CO₂ + ATP = oxaloacetate, which is a fundamental metabolic intermediate in cellular metabolism, especially in the Krebs cycle (4).  Insulin and glucagon affect hunger, satiety, and energy expenditure. The liver regulates the availability of tryptophan, (a precursor to serotonin), dopamine, and norepinephrine (a precursor to tyrosine), and GABA and glutamate, which affect mood, attention, and behavior (5).

The liver is also involved in detoxifying urea by eliminating ammonia (6). If this organ is malfunctioning, ammonia accumulation can occur, leading to encephalopathy and other symptoms. The activation of neuroinflammation is due to the production of inflammatory cytokines that are implicated in stress, mental fatigue, and cognitive decline, such as IL-1, TNF, and IL-6 (7).  The liver-CNS axis influences the neuroendocrine metabolism of thyroid hormones, modulating the hypothalamic-pituitary-adrenal (HPA) axis, which has effects on stress and the sleep-wake cycle.

The liver-brain interaction regulates lipid metabolism and myelin. The synthesis of cholesterol and lipoproteins is important for the formation and maintenance of neuronal membranes and myelin. Additionally, the liver influences processes of the CNS such as learning and memory, alertness, and appetite control, and dysregulation can cause confusion, apathy, and irritability. Liver inflammation can become systemic and cross or modulate the blood-brain barrier (BBB), affecting mood and cognition. In these cases, the HPA axis is involved and could implicate immune cells and mediators such as inflammatory cytokines, prostaglandins, and chemokines (8). The mechanism driving these effects is linked to the release of corticotropin-releasing hormone (CRH) generated by mast cells and other cells, adrenocorticotropic hormone (ACTH) from the pituitary gland, and cortisol from the adrenal glands. Gut microbiota produce metabolites such as ammonia, short-chain fatty acids, and endotoxins that pass from the liver to the brain (8).

CONCLUSIONS

There is interesting bidirectional communication between the CNS and the liver. This crosstalk influences metabolism, cognitive and behavioral systems, hormone production, immune responses, and inflammation. Dysbiosis induces liver inflammation with neurological effects such as hepatic encephalopathy, where ammonia and neurotoxin accumulation occurs, leading to confusion, cognitive impairment, depression, sleep disturbances, and impaired consciousness. Ultimately, the liver communicates with the CNS through metabolic, immune, and inflammatory signals, and when this communication is disrupted, both neurological and psychological effects can occur.

Conflict of interest

The author declares that they have no conflict of interest.

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