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.
Highlights
Alcohol-associated medical and socioeconomic burdens still pose serious problems in many countries, these stigmas can be prevented by simple behavioral modification and abstinence
E. coli abundance was markedly elevated in binge alcohol-exposed mice, while its amounts were significantly reduced in ellagic acid (EA) pretreated mice (Figure 1E). These results demonstrate that EA pretreatment was likely to block or retard the gut dysbiosis caused by binge alcohol-exposure, leading to the significant prevention of leaky gut and endotoxemia observed in binge alcohol-exposed rodents [13,14]
There is no FDAapproved drug for treating patients with alcoholic hepatitis or fibrosis/cirrhosis at this moment, many agents are being evaluated in randomized clinical tests [30,31]
Summary
Alcohol-associated medical and socioeconomic burdens still pose serious problems in many countries, these stigmas can be prevented by simple behavioral modification and abstinence. Alcohol-induced gut leakiness is critically important in the progression of ALD to more severe disease stages, including fibrosis/cirrhosis since the elevated levels of endotoxin are positively correlated with the development of liver cirrhosis [10]. Many patients with alcoholic hepatitis are known to die within 30~60 days after their diagnoses and high serum LPS levels are critical determinants of alcohol-mediated inflammatory multi-organ failure and deaths [11]. This clinically challenging condition suggests an urgent need for the development of safe and effective therapeutics and/or preventive agents against ASH. One potential approach to help in managing the severity of ASH can be achieved by preventing gut barrier dysfunction and elevated endotoxemia with dietary supplements and/or the potential repurposing of the existing drugs that were already approved by the Food and Drug Administration (FDA)
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