Lactoferrin alleviates non-alcoholic steatohepatitis via remodeling gut microbiota to regulate serotonin-related...

Lactoferrin (LF), a multifunctional glycoprotein, has been implicated in the regulation of glucose and lipid metabolism.

This study employed in vivo and in vitro models to investigate the direct effects of LF on non-alcoholic steatohepatitis (NASH) and to elucidate its underlying mechanisms.

LF intervention alleviated hepatic lipid metabolic disorders and liver injury in high-fat, high-cholesterol cholate-containing diet (HFCCD)-fed mice by mitigating oxidative stress, suppressing the inflammatory cGAS/STING pathway, and reducing M1 proinflammatory macrophage polarization. These effects were validated in free fatty acid (FFA)-treated HepG2 cells and AML12 cells. Furthermore, LF ameliorated HFCCD-induced gut microbiota dysbiosis and increased short-chain fatty acid levels. The critical role of gut microbiota in mediating the hepatoprotective effects of LF was confirmed through antibiotic-induced microbiome depletion and fecal microbiota transplantation. Mechanistically, LF modulated gut-liver serotonin signaling and promoted fatty acid β-oxidation through the HTR2A-PPARα-CPT-1A pathway, an effect abolished by the HTR2A agonist DOI. In a co-culture system, LF treatment of the Caco-2/HT29 monolayer alleviated lipid accumulation and regulated the HTR2A-PPARα-CPT-1A pathway in FFA-treated HepG2 cells.

These findings indicate that LF attenuates NASH by remodeling gut microbiota to modulate microbiota-derived serotonin signaling and enhance fatty acid oxidation.