Effects of the Gut Microbiota and Barrier Function on Melatonin Efficacy in Alleviating Liver Injury

Abstract

Environmental cadmium (Cd) exposure has been associated with severe liver injury. In contrast, melatonin (Mel) is a candidate drug therapy for Cd-induced liver injury due to its diverse hepatoprotective activities. However, the precise molecular mechanism by which Mel alleviates the Cd-induced liver injury, as well as the Mel–gut microbiota interaction in liver health, remains unknown. In this study, mice were given oral gavage CdCl2 and Mel for 10 weeks before the collection of liver tissues and colonic contents. The role of the gut microbiota in Mel’s efficacy in alleviating the Cd-induced liver injury was evaluated by the gut microbiota depletion technique in the presence of antibiotic treatment and gut microbiota transplantation (GMT). Our results revealed that the oral administration of Mel supplementation mitigated liver inflammation, endoplasmic reticulum (ER) stress and mitophagy, improved the oxidation of fatty acids, and counteracted intestinal microbial dysbiosis in mice suffering from liver injury. It was interesting to find that neither Mel nor Cd administration induced any changes in the liver of antibiotic-treated mice. By adopting the GMT approach where gut microbiota collected from mice in the control (CON), Cd, or Mel + Cd treatment groups was colonized in mice, it was found that gut microbiota was involved in Cd-induced liver injury. Therefore, the gut microbiota is involved in the Mel-mediated mitigation of ER stress, liver inflammation and mitophagy, and the improved oxidation of fatty acids in mice suffering from Cd-induced liver injury.

Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis

“…Upon cadmium-induced liver injury, melatonin supplementation alters the gut microbiota profile, leading to an increased production of gut-derived LPS. The involvement of gut microbiota mediates melatonin efficacy in mitigating mitophagy, ER stress, and liver inflammation, and improving the oxidation of fatty acids [ 146 ]. Melatonin also mitigates liver mitophagy and inflammation induced by ochratoxin A, a widespread contaminant, via reversing gut microbiota dysbiosis and restoring intestinal barrier function [ 147 ].…”

Gut Microbiome Interactions with Oxidative Stress: Mechanisms and Consequences for Health

“…The abnormalities in gut microbiome and OS development are identified in a variety of disease studies [ 27 , 28 , 29 ]. These two system changes are being evaluated in inflammatory disorders such as inflammatory bowel disease (IBD), liver inflammation, acute pancreatitis, and osteoarthritis [ 13 , 30 , 31 ]. A large number of results have been obtained from intestine inflammation models [ 13 , 32 , 33 , 34 , 35 , 36 ].…”

“…Interestingly, similar OS parameters results were observed in a Cd-induced liver inflammation model: GSH-Px and SOD activities decreased, whereas MDA and ROS production increased in the disease group compared with the control group in first-stage experiments and fecal transplantation tests. However, there were no significant changes in the antibiotic-treated groups [ 31 ]. This demonstrates a possible link between OS and alterations in the gut microbiome.…”

Oral Microbiome and CPT1A Function in Fatty Acid Metabolism in Oral Cancer

“…Some oral bacteria, e.g., Streptococcus and Fusobacterium may limit SCFAs and raise tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 levels, possibly facilitating cancer cell growth 12 . Previous data suggested that some gut bacteria severely impact the production of carnitine palmitoyltransferase 1 (CPT1), a crucial enzyme in mitochondrial fatty acid oxidation (FAO), which promotes the production of adenosine triphosphate (ATP), the primary energy source of cells 13 . Imbalanced FAO may facilitate oral cancer progression 14,15 .…”