Review Article

Alcohol and Gut Microbiota

The Possible Role of Gut Microbiota Modulation in the Treatment of Alcoholic Liver Disease

G. Vassallo; A. Mirijello; A. Ferrulli; M. Antonelli; R. Landolfi; A. Gasbarrini; G. Addolorato

Disclosures

Aliment Pharmacol Ther. 2015;41(10):917-927. 

In This Article

Role of Gut Microbiota in Alcoholic Liver Disease

ALD represents a wide-spectrum of liver injury, ranging from simple steatosis to steatohepatitis, cirrhosis and its complications (e.g. hepatocellular carcinoma), developing in patients with chronic alcohol abuse.[2]

Besides the effects of environmental and host factors on the pathogenesis of ALD, in the last years growing evidences suggested the importance of alcohol-induced changes on gut microbiota.[43,44] The dysbiosis related to alcohol abuse, in particular the increase in Proteobacteria,[34] may induce an intestinal mucosal inflammation.[8,45] Moreover, chronic alcohol abuse could result in intestinal bacterial overgrowth and increase gut permeability.[36,38] Both alterations could increase bacterial translocation from intestinal lumen to portal blood with a massive exposure of liver parenchyma to Lipopolysaccharides (LPS). LPS are able to stimulate innate immune receptors, such as Toll-like receptors and CD14, which activate hepatic stellate and Kupffer cells,[7] with the consequent release of pro-inflammatory mediators, such as ROS, leukotrienes, chemokines and cytokines (e.g. TNFα and IL-1β), that ultimately contribute to liver damage and prolong inflammation in patients affected by chronic alcohol abuse.[7] Microbiota quantitative and qualitative alterations leading to high LPS concentrations in the portal blood represent an injury for the hepatocytes, already damaged by the chronic alcohol exposure. In particular, according to some authors, the effect of gut microbiota seems to play a major role in the pathogenesis of ALD.[36]

First clinical data on the involvement of gut microbiota in the pathogenesis of ALD were showed by Fukui and colleagues, demonstrating a significantly higher blood endotoxin concentration in patients affected by alcoholic cirrhosis with respect to patients affected by non-alcoholic cirrhosis.[46] This evidence was supported by a pre-clinical study conducted by Adachi in alcohol feeding rats: antibiotic treatment was able to prevent the onset of alcohol-induced liver injury.[47] Moreover, Campos Canesso and co-workers showed that the administration of alcohol to germ-free mices is associated to the absence of liver inflammation and injury.[26] These preliminary results indicate that alcohol alone is not sufficient for the development of liver disease, and that the presence of microbiota alterations is also necessary. More recently, Parlesak and colleagues showed that chronic alcohol abuse impairs the function of the intestinal barrier, which might enhance the translocation of bacterial toxins, thereby contributing to inflammatory processes in ALD.[48] A significant increase in endotoxemia was also found after acute alcohol intoxication.[49] The endotoxemia seems to be correlated with haemodynamic derangement in cirrhotic portal hypertension, and with levels of soluble TNFα-receptors.[50]

These studies showed as the alteration of gut microbiota is involved in pathogenesis of ALD and may also influence the risk of development of severe complications (i.e. spontaneous bacterial peritonitis) that have poor prognosis.[8] Although further studies are needed to understand and clarify this relationship, these evidences suggest that gut microbiota could be a therapeutic target for the treatment of ALD.

Microbiota as Target for the Treatment of Alcoholic Liver Disease

Pre-clinical studies have shown that the pre-treatment with antibiotics to cleanse the gut flora, or with probiotics (lactobacilli) to repopulate gut flora, is able to reduce LPS endotoxin induced by alcohol and fat infusion and to prevent alcoholic liver injury.[24,47,51] In the clinical practice, the cornerstone of the treatment of ALD is to achieve and maintain long-term total alcohol abstinence.[52] However, there is a subgroup of ALD patients (about 5–15%) that shows progression to fibrosis and cirrhosis despite total alcohol abstinence.[3] Therapeutic modulation of gut microbiota in addition to total alcohol abstinence might be an adjunctive strategy for the treatment of ALD with the aim to prevent or delay hepatic damage.[53–55] At present, some preliminary human evidences indicate that antibiotics and probiotics are effective to reduce Gram-negative bacteria population and to prevent alcohol-induced liver injury and progression of liver disease.[36,54–56] Human studies have also shown that the prophylactic administration of antibiotics in patients with liver cirrhosis is effective in preventing infections in upper gastrointestinal haemorrhage,[57] in preventing first episode[58] and recurrence of spontaneous bacterial peritonitis[59] and in maintaining remission of hepatic encephalopathy.[60]

Despite these data, there are few human studies investigating the role of antibiotics in patients with ALD. A preliminary study on a small sample of patients, affected by ALD and treated with antibiotics (norfloxacin and neomycin), showed an improvement of Child–Pugh score of these patients after 3 and 6 months of treatment.[56]

The fear of complications related to long-term antibiotic administration (i.e. antibiotic resistance and hepatic side effects) are the main reasons of the lack of studies concerning antibiotic treatment in patients with ALD.[61,62] On this connection, rifaximin, a nonabsorbable oral antibiotic with broad-spectrum anti-microbial activity, has been used in ALD[63] and approved for the long-term treatment of hepatic encephalopathy in patients with liver cirrhosis.[60] Starting from this background, three studies conducted in patients with alcoholic cirrhosis showed that the treatment with rifaximin improves systemic haemodynamics and renal function,[64] cirrhosis-related thrombocytopenia[65] and survival, reducing risk of developing complications of portal hypertension.[66] According to the conclusions of these studies, considering the minimal intestinal absorption of rifaximin, it can be hypothesised that the effect of rifaximin in patients with ALD are related to intestinal decontamination. However to confirm these preliminary results, randomised clinical trials with large sample size are needed to clarify the role of antibiotics and, in particular, of rifaximin in the treatment of ALD.

Probiotics are nonpathogenic microorganisms, able to modify host gut microbiota. Some human studies have demonstrated that administration of probiotics can improve liver function by improving immune response to enteric pathogens,[67] decreasing oxidative damage/stress[55] and reducing endotoxin levels.[68] In a recent open-label study, Lactobacillus casei Shirota was administered three times daily for 4 weeks to a group of 12 patients affected by alcoholic cirrhosis (n = 12), compared to a control group who did not receive probiotics. Probiotics administration restored neutrophil phagocytic activity. Further studies are needed to better understand this effect.[67] Kirpich and colleagues randomised 66 alcoholic patients to receive standard therapy (abstinence plus vitamins) plus probiotics (Bifidobacterium bifidum and Lactobacillus plantarum 8PA3) vs. standard therapy alone for 5 days. The short-term oral supplementation with probiotics was associated to greater improvement in terms of liver function test than standard therapy alone and to the restoration of the bowel flora, although this data were evaluated by analysing bacterial culture of faecal samples.[54] In addition, the study conducted by Loguercio and colleagues, evaluating the effects of administration of probiotics for 3 months in patients with ALD, showed significantly reduced plasma levels of oxidative stress parameters, an improvement of liver function test and cytokine levels.[55] According to these preliminary studies, probiotics treatment may improve the prognosis of ALD. Moreover the effects of probiotics are strain-dependent, therefore, further clinical studies are warranted to determine which probiotic strain should be used and which patient population should be treated.[23] Finally, further studies are warranted to assess the safety of administration of probiotics, in particular in patients with gut barrier leakage for the possible higher risk of systemic infection.[69,70]

Another group of molecules able to modify gut microflora is represented by prebiotics. Prebiotics are complex carbohydrates that cannot be digested in the intestinal lumen and are metabolised by gut microflora, such as lactulose. The latter is used in patients with liver disease for the treatment and prevention of hepatic encephalopathy.[71] Some pre-clinical studies showed that the administration of prebiotics could attenuate liver damage in rats.[72] However, to date, there are no clinical studies in patients with ALD.

Finally, synbiotics are combinations of prebiotics and probiotics. Starting by a pre-clinical study showing that synbiotics could prevent liver damage during heavy alcohol consumption,[73] Riordan and colleagues randomised 30 cirrhotic patients to receive symbiotic preparations for 7 days. The study showed that modulation of gut flora with synbiotics could improve liver function in these patients.[74] However, further confirmatory studies are needed to speculate a possible role in the treatment of ALD.

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