Melatonin may protect the liver from cholestasis-related injury
Mouse study shows daily therapy lowered liver injury markers, inflammation
Treatment with melatonin, a naturally occurring hormone best known for regulating sleep, may help reduce liver injury caused by cholestasis, according to a study in a mouse model of the disease.
Animals treated daily with melatonin showed significantly lower levels of liver-injury markers in the blood, along with less liver inflammation and scarring (fibrosis), data showed.
Although more studies are needed to test whether melatonin is safe and effective for treating cholestasis in people, this preclinical study “will lay the foundation for the clinical use of melatonin on cholestatic liver injury,” the researchers wrote.
The study, “Melatonin alleviates cholestatic liver injury through modulating gut microbiota and activating the NRF2/HO-1 antioxidant pathway,” was published in Tissue and Cell by a team of researchers in China.
What cholestasis is and why it harms the liver
One of the liver’s main jobs is to make bile, a digestive fluid that normally travels to the intestines through a series of tubes called bile ducts. Cholestasis occurs when this bile flow slows or stops, causing bile to build up in the liver to toxic levels. That buildup can lead to liver damage, including inflammation and fibrosis.
“The ecological imbalance of gut microbiota is inextricably associated with the [development] of cholestasis, while the potential mechanism is not entirely clear,” the researchers wrote. “Emerging evidence demonstrated that gut dysbiosis, characterized by the imbalance of intestinal microbes, could trigger [liver] inflammation and lead to liver fibrosis in cholestatic liver diseases.”
Gut microbiota refers to the community of microorganisms that live throughout the digestive tract.
While best known for helping regulate sleep, melatonin is involved in several body processes. The hormone has “antioxidant, anti-inflammatory, anti-fibrosis, … and immunomodulatory properties,” and has been shown to influence gut microbiota composition, the researchers wrote.
“Whether melatonin could alleviate cholestatic liver diseases and the underlying mechanisms remain to be further determined,” they added.
To learn more, the team conducted experiments in a mouse model of induced cholestasis. The mice were fed a diet containing DDC, a chemical that causes bile flow to stall. Some received daily melatonin injections, while others were left untreated to serve as controls.
“We employed DDC-feeding mice to investigate the [liver-protecting] potential of melatonin on cholestatic liver injury,” the researchers wrote, noting this lab model “reliably recapitulated hallmark [disease] features in the liver.”
Melatonin treatment eased multiple signs of liver injury
Results showed that mice treated with melatonin had significantly lower blood levels of several markers of liver damage, including bile acids (bile’s main component) and the liver enzymes alanine transaminase, alkaline phosphatase, and gamma-glutamyltransferase.
Examination of liver samples showed that melatonin treatment was also associated with fewer signs of liver damage, such as reduced inflammation, less fibrosis, and a milder ductular reaction — the growth of bile duct cells that occurs with liver injury.
These data “demonstrated that melatonin strongly improved liver [tissue] changes and biochemical parameters reflecting liver injury,” the researchers wrote.
Analyses of the mice’s gut bacteria broadly indicated the gut microbiota was healthier and that the intestinal barrier was improved in animals given melatonin.
An impaired intestinal barrier can allow gut bacteria to leak into the bloodstream and reach the liver, causing additional injury. The team found that mice with cholestasis had significantly increased levels of bacterial proteins in the liver, and these levels were significantly reduced with melatonin treatment.
Hormone appears to trigger key antioxidant defenses
Further tests indicated that melatonin interacted with the MT1 melatonin receptor protein at the surface of cholangiocytes, the cells lining the bile ducts, triggering the activation of an antioxidant pathway known as NRF2/HO-1.
The scientists said that rebuilding the intestinal barrier, normalizing gut microbiota, and activating antioxidant pathways may all contribute to melatonin’s liver-protecting effects in this mouse model.
“Overall, the present study confirms that melatonin possesses a therapeutic effect on cholestasis-induced liver injury, inflammation, and fibrosis, possibly acting by modulating gut microbiota and activating the cholangiocyte NRF2/HO-1 antioxidant pathway through MTNR1A,” the team wrote. “However, further investigations are needed to explore the complicated mechanisms of interactions between gut microbiota [and liver and bile duct cells].”
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