Gut-derived lipopolysaccharide promotes alcoholic hepatosteatosis and subsequent hepatocellular carcinoma by stimulating neutrophil extracellular traps through toll-like receptor 4

Abstract

Background/Aims: Binge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and the activation of neutrophil extracellular traps (NETs).Methods: Serum samples from both binge drinking and alcohol-avoiding patients were analyzed. Mouse models of chronic plus binge alcohol-induced hepatosteatosis and HCC models were used.Results: A marker of NETs formation, lipopolysaccharide (LPS), was significantly higher in alcoholic hepatosteatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE knockout mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and development of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product LPS. When mice lacking toll-like receptor 4 (TLR4) received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated.Conclusions: Formation of NETs following LPS stimulation of TLR4 upon chronic alcohol use leads to increased alcoholic steatosis and subsequent HCC.

The causal correlation between gut microbiota abundance and pathogenesis of cervical cancer: a bidirectional mendelian randomization study

“…Indeed, in vivo and in vitro studies have shown that TLRs are key mediators in bacteria-triggered cancer. Lipopolysaccharide (LPS) derived from GM could induce hepatocellular carcinoma by activating TLR4 in immune cells ( Liu et al, 2022 ). Similarly, Ochi et al (2012) found that TLR4 was a key factor mediating carcinogenesis from pancreatic inflammatory disease to pancreatic cancer.…”

Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor–deficient mice

“… 42 – 44 However, our study suggests that flagellin-mediated activation of TLR5 may be tumor suppressive, similar to accounts of TLR2 signaling 45 , 46 when compared with the many studies that demonstrate LPS-TLR4 signaling to promote HCC. 42 , 47 , 48 Notably, a single-nucleotide polymorphism of the TLR5 gene in humans was recently uncovered that affected immune responses to flagellin and was associated with steatohepatitis-dependent HCC. 49 Considering that regulation of the gut microbiota is predominately mediated by basolateral expression of TLR5 on intestinal epithelia, 26 , 50 future studies should explore how tissue-specific disruption of Tlr5 (ie, liver vs. intestine) impacts the gut microbiota and HCC progression in Fxr KO mice.…”

Advancements in the Alcohol-Associated Liver Disease Model

“…Furthermore, although most alcohol-associated liver disease can be achieved in animals by altering stimulating factors and experimental animals, it is currently difficult to establish animal models of alcohol-triggered HCC that can reproduce pathophysiological processes similar to those of human HCC [ 206 , 207 ]. As a precarcinogen, alcohol-induced liver inflammation and the related oxidative stress can cause DNA damage in liver cells [ 208 ].…”