Targeting the Gut Dysbiosis as a Treatment for Alcoholic Liver Disease

Review Article

Austin J Pharmacol Ther. 2021; 9(3).1136.

Targeting the Gut Dysbiosis as a Treatment for Alcoholic Liver Disease

Shaikh GM1 and Gupta GL1,2*

¹Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, Mumbai, India

²School of Pharmacy & Technology Management, SVKM'S NMIMS, Shirpur Campus, Shirpur, India

*Corresponding author: Girdhari Lal Gupta, Department of Pharmacology, School of Pharmacy & Technology Management, SVKM’S NMIMS, Shirpur Campus, Shirpur-425405, India

Received: May 03, 2021; Accepted: May 28, 2021; Published: June 04, 2021


Alcohol Use Disorders (AUD) originates due to heavy and uncontrolled drinking of alcohol. It is one of the most prevalent mental disorders, which predominantly affects men globally. In the review article alcohol use disorders and several risk factors like gender, drinking habit, genetic differences, and obesity Hepatitis C virus has been described for the provocation of intestinal dysbiosis. Alcoholic Liver Disease (ALD) is a spectrum of diseases from steatohepatitis to Hepatocellular Carcinoma (HCC). Due to dysbiosis, there are microbial changes also taking place in the liver and it further worsens the conditions. Treatment involves treating gut dysbiosis and altered balance of the micro-organism. The treatment strategy of ALD may also involve a non-dietary approach or dietary approach or by microbiota modulation.

Keywords: AUD; Alcohol; Microbial dysbiosis; ALD; Treatment


51Cr-EDTA: 51Cr-Ethylenediamine Tetraacetic Acid; ACC: Anterior Cingulate Cortex; ADH: Alcohol Dehydrogenase; ALD: Alcoholic Liver Disease; ALDH: Aldehyde Dehydrogenase; ALDH2: Aldehyde Dehydrogenase-2; ALT: Alanine Aminotransferase; AST: Aspartate Transaminase; AUD: Alcohol Use Disorders; BCAA: Branched-Chain Amino Acid; BMI: Body Mass Index; FMT: Fecal Matter Transfer; GIT: Gastro Intestinal Tract; HCC: Hepato-Cellular Carcinoma; HCV: Hepatitis C Virus; HE: Hepatic Encephalopathy; HSD17B13: Hydroxysteroid 17-Beta Dehydrogenase 13; IL- 17: Interleukin-17; IL-6: Interleukin-6; LOLA: L-Ornithine-LAspartate; LPS: Lipo-Polysaccharides; MBOAT7: Membrane-Bound O-Acyltransferase Domain- Containing 7; MDA: Malondialdehyde; MHE: Minimal Hepatic Encephalopathy; NAFLD: Non-Alcoholic Fatty Liver Disease; NASH: Non-Alcoholic Steatohepatitis; NF- κB: Nuclear Factor Kappa-light chain enhancer of activated B cells; NHANES III: The Third National Health and Nutrition Examination Survey; NIAAA: National Institute on Alcohol Abuse and Alcoholism; PEG: Polyethylene Glycol; PGN: Peptidoglycan; PNPLA-3: Patatin-Like Phospholipase Domain-Containing Protein 3; PPAR-a: Peroxisome Proliferator Activated Receptor-a; Reg3b: Regenerating Islet-Derived Protein 3-beta; Reg3g: Regenerating Islet- Derived Protein 3-gamma; ROS: Reactive Oxygen Species; SCFA: Short Chain Fatty Acids; TM6SF2: Transmembrane 6 Superfamily Member 2; TNFa: Tumor Necrosis Factor-a


Alcohol Use Disorders (AUD) is characterized by heavy alcohol use coupled with the loss of control over its intake. It is one of the most prevalent mental disorders, which predominantly affects men globally. A person suffering from AUD is unable to control the consumption of alcohol and thereby affects their health, family, friends, and social lives. Therefore, it results in compulsive use of alcohol [1,2]. AUD is also accompanied by liver cirrhosis and death [3]. AUD is also coupled with a high mortality rate and it was found that in the European Union, in 2004 AUD was accounted for 62% of alcohol use [4]. In Nordic Countries, it was found that people with AUD were having a shorter life span by 24-28 years than in the general population [5]. Due to the difference in socioeconomic status, individuals with low socioeconomic status are at a higher risk of AUD than high socioeconomic status [6].

Risk Factors for AUD

People with a heavy intake of alcohol are more likely to develop AUD which is associated with steatohepatitis, fibrosis, and cirrhosis. But, some patients do not develop cirrhosis even after chronic intake of alcohol [7]. These are dependent on various factors which are discussed below.


Women consume less alcohol than men and therefore have a lower chance of developing AUD [8]. Longitudinal studies have discovered that men have a higher prevalence of AUD than women [9]. Women are more likely than men to develop hepatotoxicity due to lower levels of gastric Alcohol Dehydrogenase (ADH). This is most likely due to higher levels of alcohol in the bloodstream increasing alcohol bioavailability. This has an impact on hormonal activity [10,11]. Estrogen receptors are found in both parenchymal and nonparenchymal cells. Huge amounts of alcohol can also increase the expression of estrogen receptors [12]. Alcohol levels are also affected by hormone levels in the body. It was discovered that oestrogen therapy raises the risk of alcoholic-induced steatohepatitis, while ovariectomy reduces it. Estrogen therapy also stimulates kupffer cells, which raises TNF levels. Its inflammatory properties aid in increased alcohol permeation via the intestine, resulting in apoptosis [13]. It is also reported that male mice have higher levels of hepatoprotective betaine-homocysteine methyltransferase [14,15]. The change in the ratios of anti-inflammatory ω-3 and pro-inflammatory ω-6 are also responsible for AUD development. A report stated that in female drinkers, levels of pro-inflammatory were increased, whereas, in male drinkers, levels of anti-inflammatory were increased [16]. All these above studies suggest that differences in the hormone, hepatoprotective agent, proinflammatory conditions may be a responsible difference in male and female Alcoholic Liver Disease (ALD) prevalence.

Drinking habit

A study conducted that there is a shift in the drinking pattern of heavy drinkers and binge drinkers [17]. According to several surveys, binge drinking refers to an episode where men tend to have five or more drinks or women tend to have four or more drinks. The Centers for Diseases Control in 2010 conducted a survey and estimated that one in every six adults is engaged in binge drinking. In this survey, it was also found that 50% of college students found themselves in binge drinking [18]. Binge drinking is an important risk factor for young adults for alcohol dependence and its abuse [19]. In the previous section, we have seen that women are prone to deleterious effects of heavy drinking. Therefore, younger women are likely to binge drinking. It is also supported by the study which suggests that hormone levels of female mice contribute to binge drinking [20].

Genetic differences

AUD is dependent on environmental as well as host factors. It was found that Hispanics are more prone to AUD whereas monozygotic twins have a high probability of cirrhosis as compared to dizygotic twins [21]. Aldehyde Dehydrogenase-2 (ALDH-2) is responsible for the conversion of Acetaldehyde to Acetic acid. A study reported that inactivate form of ALDH-2 (E487K) is responsible for the flush reaction, and it was expected that 40% of East Asian shows this effect [22]. The PNPLA-3 is a well-known risk factor of Non-Alcoholic Steatohepatitis (NASH) is associated with the development of AUD, which ultimately leads to cirrhosis [23]. A study from two cohorts from Europe found that TM6SF2 and MBOAT7 were responsible for cirrhosis [24]. Further, a study on hydroxysteroid 17-Beta Dehydrogenase (HSD17B13) found that it is capable of reducing alcohol-induced cirrhosis [25].


According to the World Health Organization, a person with a BMI of more than 25kg/m2 and 30kg/m2 is said to be overweight and obese. During the initial diagnosis of steatosis (an early stage of AUD), there are high levels of triglycerides present in hepatocytes and histologically it was found that 90% of alcoholics suffered from the fatty liver [26]. The reports from The Third National Health and Nutrition Examination Survey (NHANES III) found that patients with AUD that 44.5% obesity prevalence and high liver-related mortality [27]. Individuals who consume a lot of alcohol and are overweight have their liver enzymes elevated synergistically. This effect is responsible for an 8.9-fold increase in serum Alanine Aminotransferase (ALT) and a 21-fold increase in serum Aspartate Transaminase (AST) [28].

Hepatitis C virus

When compared to non-drinkers, 1574 Hepatitis C Virus (HCV) patients with chronic liver disease who consumed more than 50g of alcohol a day had a higher risk of developing fibrosis [29]. HCV patients who drink alcohol are found to be 2-3 times more likely than non-drinkers to develop AUD [30].

Gastrointestinal Flora and their Useful Functions

The Gastro-Intestinal Tract (GIT) has 1014 microorganisms, which is approximately said to be equal to the total number of cells present in the body [31]. This microbial colony resides in the outer layer of the gut lumen of mucus and it is expected to have a total mass of 2kg. The microbiome contains 150 times more genes than the human genome [32]. It has been proved that these gut microflorae act as beneficial factors. They supply essential nutrients like vitamins. They also help in metabolizing indigestible food. They also act as a protective shield against the colonization of pathogens. They also actively help in enhancing immunity. As a result, they are also in charge of converting various metabolites that are likely to be absorbed into the bloodstream and eventually enter the brain and liver through cellular pathways [33].

However, there is a presence of physical barriers between systemic circulation and lumen that prevents penetration of bacteria along with the nutrients. The intestinal barrier is made of enterocytes, which are held by tight junctions and adherens junction. The enterocytes are covered by mucus layers which act as a physical barrier and protect epithelium against harmful agents and bacteria. This mucus barrier has two separate layers. The inner mucus layer is in direct contact with the epithelial cell and contains no bacterial colonies, while the outer mucus layer is easily washable and contains bacterial colonies [34].

The mucus lining of the intestine is made up of secreted and membrane-bound mucins, which are formed by goblet cells and are responsible for protecting the mucus layer from pathogens and preserving its viscosity. Reg3b and Reg3g, which are produced by regenerating islets, are also secreted by Paneth cells in the mucus layer. They are responsible for maintaining the intestinal homeostasis balance and also exert anti-microbial activity [35]. The intestine also shows the presence of lamina propria which plays an important role in providing immunity against the invading bacteria [36].

Intestinal Dysbiosis due to Alcohol

Intestinal dysbiosis is a disorder in which the microbial equilibrium in the gut is disrupted. Excessive alcohol consumption is a significant underlying factor in dysbiosis. Microorganisms play a significant role in an individual's innate immunity. But due to excess alcohol, there are various changes taking place into the gut and thereby are responsible for tissue inflammation. The mucus lining holds different microbial colonies, however, due to excess intake of alcohol, the mucus lining decreases, and thereby the tight junctions began to lose their integrity. Owing to hampered gut permeability, the microbial colonies can easily permeate into the portal circulation with their metabolic by-products. Accompanied with microbes, Peptidoglycan (PGN) and Lipopolysaccharides (LPS) are also leaked out. They result in the activation of various inflammatory chemicals namely IL-1, IL-6, and TNF-a (Figure 1). These chemicals get concentrated into the nearby tissue especially in the liver and result in inflammation [37]. The altered permeability of the gut can be determined using permeability enhancers like mannitol, PEG, and 51Cr-EDTA. Keshavarzian et al. found that individuals that were consuming higher amounts of alcohol were subjected to higher levels of above permeability enhancers in urine [38].