Serotonin Modulation in Liver Disease Mechanisms

Serotonin, traditionally recognised as a central neurotransmitter, exerts a critical influence on liver physiology through peripheral routes. Synthesised predominantly in the gut by the enzyme tryptophan hydroxylase 1, circulating serotonin engages specific receptors on hepatocytes and non-parenchymal cells. This modulation affects lipid accumulation (steatosis), inflammatory signalling and activation of hepatic stellate cells, which are central to fibrogenesis. Aberrant serotonin signalling is implicated in the progression from simple fatty liver to non-alcoholic steatohepatitis and advanced fibrosis. Emerging research has delineated a gut-liver axis in which inhibition of serotonin synthesis or blockade of key receptor subtypes attenuates steatosis and stellate-cell-driven scarring, offering new avenues for targeted therapeutics in chronic liver disease.

Research from Nature Portfolio

In preclinical models of metabolic dysfunction-associated steatohepatitis, a first-in-class peripheral antagonist of the 5-HT2A receptor demonstrated potent reduction of hepatic steatosis and fibrosis markers. Rodent studies showed improved histological features and downregulation of fibrogenic gene expression, reinforcing the therapeutic promise of selective receptor blockade. Complementary work using three-dimensional human liver spheroids has confirmed that antagonists of multiple 5-HT receptors, particularly 5-HT2A, inhibit free-fatty-acid-induced stellate cell activation and collagen deposition. Moreover, foundational studies have revealed that suppression of gut-derived serotonin synthesis mitigates diet-induced hepatic lipid accumulation by attenuating HTR2A signalling, thereby establishing the gut-liver serotonin axis as a critical target in non-alcoholic fatty liver disease.

Serotonin Modulation in Liver Disease Mechanisms publication trend

The graph below shows the total number of articles in serotonin modulation in liver disease mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Serotonin (5-HT): A biogenic monoamine synthesised in enterochromaffin cells, acting on multiple receptor subtypes to regulate vascular tone, metabolism and cell proliferation.

Non-alcoholic steatohepatitis (NASH): An inflammatory liver condition characterised by steatosis, hepatocyte injury and fibrosis, arising in the absence of significant alcohol consumption.

Steatosis: Intracellular accumulation of triglycerides within hepatocytes, often the initial stage of metabolic liver disease.

Fibrosis: Excessive deposition of extracellular matrix proteins, chiefly collagen, leading to architectural distortion and impaired liver function.

Hepatic stellate cell: A perisinusoidal cell type that, upon activation by injury signals, transdifferentiates into a collagen-producing myofibroblast.

5-HT2A receptor: A G-protein-coupled receptor subtype mediating many of serotonin’s peripheral effects on lipid metabolism and fibrogenesis.

Gut-liver axis: The bidirectional communication network between intestinal and hepatic systems involving neural, metabolic and immunological pathways.

References

1. Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis. Nature Communications (2024).
2. Mechanisms of 5-HT receptor antagonists in the regulation of fibrosis in a 3D human liver spheroid model. Scientific Reports (2024).
3. Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nature Communications (2018).
4. Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver. Disease Models & Mechanisms (2021).
5. Involvement of the liver-gut peripheral neural axis in nonalcoholic fatty liver disease pathologies via hepatic HTR2A. Disease Models & Mechanisms (2022).