Alcohol or Gut Microbiota: Who Is the Guilty? - PubMed (original) (raw)

Review

Alcohol or Gut Microbiota: Who Is the Guilty?

Marica Meroni et al. Int J Mol Sci. 2019.

Abstract

Alcoholic liver disease (ALD), a disorder caused by excessive alcohol intake represents a global health care burden. ALD encompasses a broad spectrum of hepatic injuries including asymptomatic steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The susceptibility of alcoholic patients to develop ALD is highly variable and its progression to more advanced stages is strongly influenced by several hits (i.e., amount and duration of alcohol abuse). Among them, the intestinal microbiota and its metabolites have been recently identified as paramount in ALD pathophysiology. Ethanol abuse triggers qualitative and quantitative modifications in intestinal flora taxonomic composition, mucosal inflammation, and intestinal barrier derangement. Intestinal hypermeability results in the translocation of viable pathogenic bacteria, Gram-negative microbial products, and pro-inflammatory luminal metabolites into the bloodstream, further corroborating the alcohol-induced liver damage. Thus, the premise of this review is to discuss the beneficial effect of gut microbiota modulation as a novel therapeutic approach in ALD management.

Keywords: alcoholic liver disease; fecal microbiota transplantation; gut microbiota; gut-liver axis; intestinal permeability; leaky gut; target therapy; tight junctions.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Role of ‘leaky gut’ in progressive ALD. In this figure, we reported a schematic illustration of the main alterations that contribute to alcohol-induced liver injury. Excessive alcohol abuse (Et-OH) exerts a direct detrimental effect on the intestinal barrier integrity by affecting the tight junction protein (i.e., zonula occludens 1 (ZO-1)) expression and mucus layer. Physiologically, mucus (Muc2) is produced by the goblet cells, instead, the Paneth cells (immune cells) secrete antimicrobial peptides (i.e., c-lectin Reg3b/g), that contribute to maintain the inter-species bacterial balance. Alteration in quality/quantity of microflora taxonomic composition (referred to as ‘dysbiosis’) may trigger the dysfunction of barrier properties and enhance intestinal permeability. The hyperpermeability facilitates the translocation into the enterohepatic circulation of viable pathogenic bacteria, Gram-negative microbial products, mainly lipopolysaccharides (LPS). LPS, peptidoglycans, and β-glucans bind Toll-like receptor 4 (TLR4)/CD14 complex, TRL2, and C-type lectin-like receptor (CLEC7A), respectively, and mediate the activation of hepatic Kupffer cells and peripheral blood mononuclear cells (PBMCs), via NF-κB and IL6/STAT3 signaling. Activated Kupffer cells and PBMCs, in turn, release a large amount of pro-inflammatory cytokines and chemokines (such as TNFα and IL1β), further perpetuating the hepatic inflammation and oxidative stress in the context of already damaged hepatocytes. These events can even contribute to the worsening of hepatic injury to advance stages, favoring also the activation of hepatic stellate cells (HSCs), involved in fibrogenic processes.

Similar articles

Cited by

References

    1. Rehm J., Samokhvalov A., Shield K. Global burden of alcoholic liver diseases. J. Hepatol. 2013;59:160–168. doi: 10.1016/j.jhep.2013.03.007. - DOI - PubMed
    1. World Health Organisation . Global Status Report on Alcohol and Health 2014. World Health Organisation; Geneva, Switzerland: 2014.
    1. Mathurin P., Bataller R. Trends in the management and burden of alcoholic liver disease. J. Hepatol. 2015;62:S38–S46. doi: 10.1016/j.jhep.2015.03.006. - DOI - PMC - PubMed
    1. Teli M., James O., Burt A., Bennett M., Day C. The natural history of nonalcoholic fatty liver: A follow-up study. Hepatology. 1995;22:1714–1719. doi: 10.1002/hep.1840220616. - DOI - PubMed
    1. Stickel F. Alcoholic cirrhosis and hepatocellular carcinoma. Adv. Exp. Med. Biol. 2015;815:113–130. doi: 10.1007/978-3-319-09614-8_7. - DOI - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources