Ellagic Acid Prevents Binge Alcohol-Induced Leaky Gut and Liver Injury through Inhibiting Gut Dysbiosis and Oxidative Stress

Abstract

Alcoholic liver disease (ALD) is a major liver disease worldwide and can range from simple steatosis or inflammation to fibrosis/cirrhosis, possibly through leaky gut and systemic endotoxemia. Many patients with alcoholic steatohepatitis (ASH) die within 60 days after clinical diagnosis due to the lack of an approved drug, and thus, synthetic and/or dietary agents to prevent ASH and premature deaths are urgently needed. We recently reported that a pharmacologically high dose of pomegranate extract prevented binge alcohol-induced gut leakiness and hepatic inflammation by suppressing oxidative and nitrative stress. Herein, we investigate whether a dietary antioxidant ellagic acid (EA) contained in many fruits, including pomegranate and vegetables, can protect against binge alcohol-induced leaky gut, endotoxemia, and liver inflammation. Pretreatment with a physiologically-relevant dose of EA for 14 days significantly reduced the binge alcohol-induced gut barrier dysfunction, endotoxemia, and inflammatory liver injury in mice by inhibiting gut dysbiosis and the elevated oxidative stress and apoptosis marker proteins. Pretreatment with EA significantly prevented the decreased amounts of gut tight junction/adherent junction proteins and the elevated gut leakiness in alcohol-exposed mice. Taken together, our results suggest that EA could be used as a dietary supplement for alcoholic hepatitis patients.

Effects of Ellagic Acid Supplementation on Jejunal Morphology, Digestive Enzyme Activities, Antioxidant Capacity, and Microbiota in Mice

“…The intestinal microflora plays an important role in maintaining intestinal microenvironment homeostasis ( Liu et al, 2019 ). Previous studies have revealed an increase in the abundance of Firmicutes and Lactobacillus species and a decrease in the abundance of Verrucomicrobia and Bacteroidetes species in mice after polyphenols supplementation ( Kim et al, 2021 ; Lu et al, 2021 ). Our results demonstrated that EA supplementation decreased the count of E. coli but increased the count of Lactobacillus species.…”

“…The intestinal antioxidant capacity is also crucial for maintaining intestinal health ( Kim et al, 2021 ). The body has a series of defense mechanisms for controlling oxidative stress; one of these is the enzymatic antioxidant system ( Pari and Sivasankari, 2008 ).…”

Ellagic acid Alleviates hepatic ischemia–reperfusion injury in C57 mice via the Caspase-1-GSDMD pathway

“…Mice in the treatment group were subjected to oral administration of a daily dose of 60 mg/kg EA (Solarbio, Beijing, China) (add 0.6 g of EA to 100 mL normal saline. )for 14 days before performing surgery to model liver ischemia [ 20 ]. The experiment design is illustrated in Fig.…”

“…The research from Elyamany M. shows that EA treatment can significantly reduce the liver damage caused by valproic acid in rats [ 18 ], and L. Gu et al demonstrated that EA protected against LPS/GalN-induced liver injury in SD rats by enhancing the antioxidative defense system and reducing the inflammatory response [ 19 ]. Kim, D described a significant reduction in endotoxemia and inflammatory liver damage with EA treatment by inhibiting the imbalance of the intestinal flora in c57 mice, elevated oxidative stress and apoptosis marker proteins [ 20 ]. However, the effect and underlying specific molecular mechanisms of EA on hepatic IRI remain unclear.…”

The intestinal and biliary microbiome in autoimmune liver disease—current evidence and concepts

“…Various mechanisms are causing a leaky intestine; they are still incompletely understood and subject to vibrant research. Such mechanisms include physical trauma and toxins such as alcohol, TJ severance, altered epithelial stem cell turnover, and alterations to the mucus layer texture [ 48 , 49 ]. Emerging research points towards a close relationship between gut microbiome alterations, intestinal leakiness, and autoimmunity [ 50 ].…”