Alcohol dependence and alcoholic liver disease represent a major public health problem with substantial morbidity and mortality. By yet incompletely understood mechanisms, chronic alcohol abuse is associated with increased intestinal permeability and alterations of the gut microbiota composition, allowing bacterial components, bacteria, and metabolites to reach the portal and the systemic circulation. These gut-derived bacterial products are recognized by immune cells circulating in the blood or residing in remote organs such as the liver leading to the release of pro-inflammatory cytokines which are considered important mediators of the liver–gut–brain communication. Although circulating cytokines are likely not the sole factors involved, they can induce liver inflammation/damage and reach the central nervous system where they favor neuroinflammation which is associated with change in mood, cognition, and drinking behavior. In this review, the authors focus on the current evidence describing the changes that occur in the intestinal microbiota with chronic alcohol consumption in conjunction with intestinal barrier breakdown and inflammatory changes sustaining the concept of a gut–liver–brain axis in the pathophysiology of alcohol dependence and alcoholic liver disease.

Introduction

Alcohol abuse is a major public health problem worldwide causing a wide range of preventable morbidity and mortality [13]. Subjects drinking up to two drinks/day (men) or one drink/day (women) do not disclose increased risk of organ damage compared with abstainers [4]. Daily consumption above these limits can induce psychological, social, and health problems. Estimates indicate that more than 11% of the European male population and more than 5% of females abuse alcohol (>60 g per day) with respectively 5.4 and 1.5% being alcohol dependent [5].

Alcohol is one of the leading causes of chronic liver disease and liver-related deaths worldwide. In particular, average level of alcohol consumption and heavy drinking occasions are important factors that seem to impact disease and injury. The risk of cirrhosis increases with the amount of alcohol consumed. A meta-analysis observed that consumption of more than 25 g/day already increases the relative risk of cirrhosis [6] and subjects who consumed more than 120 g/day had the highest risk of cirrhosis, with a prevalence of 13.5% [7]. The spectrum of alcoholic liver disease (ALD) comprises simple steatosis, alcoholic steatohepatitis (ASH), alcoholic hepatitis, progressive fibrosis, cirrhosis, and the development of hepatocellular carcinoma. Although up to 90% of heavy drinkers develop steatosis, only a minority of those with steatosis progress to ASH and 10–20% eventually develop cirrhosis [4,8,9] suggesting that alcohol is not the only factor that mediates disease progression. The natural history of ALD cannot be separated from the natural history of alcoholism. Although some progression has been made in the understanding of factors that may be involved in the development of alcohol dependence and ALD, many aspects of their pathophysiology and mechanisms implicated in disease progression still remain obscure. Recent evidence suggests the existence of a gut–liver, gut–brain, or even a gut–liver–brain axis not only playing a role in organ damage but also in alcohol dependence. This review will focus on pathophysiological aspects related to intestinal microbiota as a potential driver of alcohol dependence and remote organ damage, particularly in the liver.

The intestinal microbiome and the gut barrier

The human gastrointestinal tract is the natural habitat for 1014 microorganisms, which approximately represents an equal amount of cells in the human body [10]. This large and dynamic bacterial community residing in the gut lumen or in the outer layer of the mucus is called the ‘gut microbiota’ and has an approximate mass of 2 kg. The microbiome, that refers to the collective genomes of all members of the gut microbiota, contains 150 times more genes than the human genome [11]. Intestinal bacteria have long been appreciated for the benefits they provide to the host: they supply essential nutrients such as vitamins, metabolize indigestible compounds, defend against pathogen colonization, contribute to the development of intestinal architecture and to the functioning of the immune system. The colonic bacteria can ferment nutrients or endogenous host-derived substrates such as mucus and pancreatic enzymes, as well as dietary components that escape digestion in the upper part of the gastrointestinal tract. Thus, the intestinal microbiota produces or transforms a large variety of metabolites which are likely absorbed into blood where they can reach the brain and the liver and trigger or influence cellular pathways [12,13].

Certain aspects of health and disease may depend on the status of the microbiota [14] as intestinal bacteria have been shown to shape and modulate the immune system [15], to participate in the intestinal ‘barrier effect’ through several mechanisms [16], as well as to influence brain functions and behavior.

A physical barrier between the gut lumen and the systemic circulation allows nutrient absorption while preventing bacterial penetration. The intestinal barrier (Figure 1A) is mainly composed by enterocytes tightly bound to their neighboring cells by apical junctional proteins (claudins, occludin, and zonula occludens) known as tight junctions and adherens junctions [17]. The enterocytes are overlaid by a mucus layer that forms a physical barrier between the underlying epithelium and the lumen of the gastrointestinal tract, and protects the epithelium against noxious agents, viruses, and pathogenic bacteria. The mucus barrier consists of two separate sublayers: the inner layer is attached to the epithelial cell layer and is devoid of bacteria; the outer layer can be washed off easily and is colonized by bacteria [18,19]. The intestinal mucus layer is composed of secreted (Muc2, Muc5AC, and Muc6) and membrane-bound mucins (Muc1, Muc3–4, Muc12–13, and Muc17) that are produced by intestinal goblet cells [20] and contribute to the viscous properties of intestinal mucus layer [21] and protect against pathogens that penetrate the inner mucus layer [22], respectively. In addition, Regenerating islet derived (Reg)3b and Reg3g are secreted by the Paneth cells into the mucus layer. They are implicated in intestinal homeostasis and exhibit antimicrobial activity [23] which shape the composition of the intestinal microbiome [24]. The intestinal defense mechanisms are reinforced by numerous immune cells in the lamina propria which play an essential role in protecting the intestinal mucosa against invading bacteria [17].

Normal and alcohol-associated intestinal barrier (dys)function

Figure 1
Normal and alcohol-associated intestinal barrier (dys)function

(A) Normal intestinal barrier with a dense mucus layer containing secreted Reg antimicrobial proteins and a tight epithelium held together by tight junctions (TJs) that prevent bacterial epithelial invasion and translocation as well as stimulation of immune cells in the lamina propria. (B) Loose, thickened mucus layer, reduced Reg production, disrupted TJ leading to increased epithelial permeability. Bacterial overgrowth and dysbiosis together with a failing intestinal barrier allows translocation of bacterial products and eventually total bacteria to reach the lamina propria and the portal blood flow. Stimulation of immune cells (lymphocytes, macrophages, dendritic cells) by bacterial products initiates secretion of various pro-inflammatory cytokines as a first defense mechanism but also amplifies barrier dysfunction. Abbreviations: LPS, lipopolysaccharide; PGN, peptidoglycan.

Figure 1
Normal and alcohol-associated intestinal barrier (dys)function

(A) Normal intestinal barrier with a dense mucus layer containing secreted Reg antimicrobial proteins and a tight epithelium held together by tight junctions (TJs) that prevent bacterial epithelial invasion and translocation as well as stimulation of immune cells in the lamina propria. (B) Loose, thickened mucus layer, reduced Reg production, disrupted TJ leading to increased epithelial permeability. Bacterial overgrowth and dysbiosis together with a failing intestinal barrier allows translocation of bacterial products and eventually total bacteria to reach the lamina propria and the portal blood flow. Stimulation of immune cells (lymphocytes, macrophages, dendritic cells) by bacterial products initiates secretion of various pro-inflammatory cytokines as a first defense mechanism but also amplifies barrier dysfunction. Abbreviations: LPS, lipopolysaccharide; PGN, peptidoglycan.

Alcohol-induced changes in the intestinal micobiota

Chronic alcohol consumption is associated with quantitative and qualitative changes in the intestinal microbiota also called as intestinal dysbiosis. The first experimental study that investigated whether chronic ethanol consumption affects gut bacterial composition was conducted by Mutlu et al. in 2009 [25] who showed that chronic ethanol treatment induced alterations in the mucosa-associated colonic bacterial microbiota in rats. Thereafter, small intestinal bacterial overgrowth which occurred within 3 weeks of ethanol feeding was described in a murine model of alcoholic steatohepatitis (Tsukamoto-French model). More detailed analysis in these mice using deep sequencing has shown decreases in Firmicutes but increases in Bacteroidetes. Interestingly, beneficial bacteria, including Lactobacillus, Pediococcus, Leuconostoc, and Lactococcus, were strongly suppressed in alcohol-fed mice compared with controls [26]. Similar findings were reported in another study that examined the gut microbiota of chronic alcohol fed mice showing a reduction in Firmicutes (unclassified Lachnospiraceae and Ruminococcaceae), Bacteroidetes, and an increase in Proteobacteria, Actinobacteria, and in Lactobacillus [27].

A few studies tried to correlate changes in the gut microbiota with alcohol consumption in humans (Table 1). Culturing stool samples from alcoholic patients revealed decreased numbers of Bifidobacterium, Lactobacillus, and Enterococcus compared with healthy controls [28]. In 2012, Mutlu et al. [29] characterized the gut microbiota composition in alcoholics using non-cultured, next-generation sequencing technologies and showed that only a subgroup of alcoholics had altered colonic microbiota composition. Indeed, 31% of subjects were defined as ‘dysbiotic’ mainly consisting of lower abundance of Bacteroidetes and higher ones of Proteobacteria in the colonic mucosa. Studies of our own group confirmed the presence of intestinal dysbiosis in stool samples of alcohol-dependent patients. We further demonstrated that alcoholics exhibit reduced numbers of the beneficial bacteria including Lactobacillus spp. and Bifidobacterium spp. Intriguingly, alcohol abstinence alone resulted in a restoration of suppressed levels of Bifidobacterium spp. and Lactobacillus spp [30]. Very recently, it has also been shown that alcohol depletes another potentially good bug, Akkermansia muciniphila, in mice and in humans [31].

Table 1
Studies exploring the micro/mycobiome in patients with AD and ALD and mild (m) to severe (s) AH
Author Patients Methods Principal findings associated with alcohol 
Bode (1984) [136AD Jejunum aspirates Dysbiosis in AD 
 Controls Bacterial culture ↑ Gram – anaerobic bacteria 
   ↑coliform bacteria 
Chen (2011) [135Cirrhosis1 Fecal samples ↓ Bacteroidetes 
 ALD cirrhosis1 16S rRNA ↑Proteobacteria 
 Controls pyrosequencing ↑Fusobacteria 
Mutlu (2012) [29ALD cirrhosis2 Sigmoid biopsies Dysbiosis in 27% with ALD/AD 
 AD3 16S rRNA ↓ Bacteroidetes 
 Controls Length heterogeneity PCR ↑Proteobacteria 
  Multitag pyrosequencing Clostridium 
Leclercq (2014) [30AD4 Fecal samples Dysbiosis in 45% with AD 
 Controls 16S rRNA ↓ Ruminococcacae 
  454 pyrosequencing ↑Lachnospiraceae 
   Bifidobacterium 
   Lactobacillus 
   Clostridium 
Llopis (2016) [76noAH Fecal samples Dysbiosis in sAH 
 mAH 16S rRNA Bifidobacteria 
 sAH 454 pyrosequencig Streptococci 
   Enterobacteria 
Yang (2017) [34ALD cirrhosis2 ITS amplicon sequencing Fungal dysbiosis 
 AD4  ↑↑ Candida 
 sAH  Epicoccum 
 Controls  Galactomyces 
   Debaryomyces 
Author Patients Methods Principal findings associated with alcohol 
Bode (1984) [136AD Jejunum aspirates Dysbiosis in AD 
 Controls Bacterial culture ↑ Gram – anaerobic bacteria 
   ↑coliform bacteria 
Chen (2011) [135Cirrhosis1 Fecal samples ↓ Bacteroidetes 
 ALD cirrhosis1 16S rRNA ↑Proteobacteria 
 Controls pyrosequencing ↑Fusobacteria 
Mutlu (2012) [29ALD cirrhosis2 Sigmoid biopsies Dysbiosis in 27% with ALD/AD 
 AD3 16S rRNA ↓ Bacteroidetes 
 Controls Length heterogeneity PCR ↑Proteobacteria 
  Multitag pyrosequencing Clostridium 
Leclercq (2014) [30AD4 Fecal samples Dysbiosis in 45% with AD 
 Controls 16S rRNA ↓ Ruminococcacae 
  454 pyrosequencing ↑Lachnospiraceae 
   Bifidobacterium 
   Lactobacillus 
   Clostridium 
Llopis (2016) [76noAH Fecal samples Dysbiosis in sAH 
 mAH 16S rRNA Bifidobacteria 
 sAH 454 pyrosequencig Streptococci 
   Enterobacteria 
Yang (2017) [34ALD cirrhosis2 ITS amplicon sequencing Fungal dysbiosis 
 AD4  ↑↑ Candida 
 sAH  Epicoccum 
 Controls  Galactomyces 
   Debaryomyces 

Abbreviations: AD, alcohol dependence; AH, alcoholic hepatitis.

1, compensated and decompensated;

2, mainly compensated;

3, without liver disease;

4, without or with mild liver disease.

The gut microbiota also contains commensal fungi, also called the intestinal mycobiome. Predominant commensal fungal species are Candida spp., Saccharomyces cerevisiae, and Malassezia spp. in the human intestine [32]. Similar to commensal bacteria in the intestine, fungi interact with the host. While the host immune system develops tolerance to colonization with commensal fungi, it must contain the spread and in particular invasion of fungi [33]. In a very recent study, we observed fungal overgrowth in feces of mice after chronic alcohol administration. Subsequently, we also found changes in the abundance and composition of the fecal mycobiome with dramatically decreased fungal diversity in a small number of alcohol-dependent patients compared with healthy controls [34]. However, these changes need to be confirmed in a larger population of alcohol-dependent patients. Even though our recent experimental data suggest that fungi might contribute to organ damage [34], it is not known if and how fungi cause progression of alcoholic liver disease in humans.

Alcohol-associated alterations in the gut barrier function

Early studies in animals and patients already suggest that acute and chronic alcohol consumption can disrupt the intestinal epithelial barrier (Figure 1B) resulting in increased gut permeability [3540]. More recent studies in preclinical animal models and in patients with alcohol abuse confirm the early findings [4143]. In vitro and animals studies reveal that alcohol and its main oxidative metabolite acetaldehyde likely alter the intestinal ultrastructure by disrupting the epithelial tight junctions integrity, in particular occludin and zonula occludens thus contributing to increased intestinal leakage [4448]. The exact molecular mechanisms of increased intestinal permeability remain however largely unknown.

Amongst the numerous molecular mechanisms (for more detailed review, see reference [49]) that have been proposed to explain increased intestinal permeability after alcohol exposure, activation of the tumor necrosis factor (TNF)-NFκB pathway and its related pro-inflammatory cytokine response including interferon (IFN)γ, interleukin (IL)-1β, and IL-6 could play an important role. TNF-α, acting as an immune-mediated regulator, has been demonstrated to regulate tight junctions and cause disruption of the gut barrier [5052]. Interestingly, high levels of TNF [53] and IL-6 (own unpublished data) have been found in duodenal biopsies of alcohol-dependent subjects which tend to confirm data obtained in the animal models.

Whether a cause and effect relationship between increased intestinal permeability and gut dysbiosis does exist is still a matter of debate. Recently, we were able to link changes in the intestinal microbiota with barrier dysfunction. In the present study, intestinal decontamination with non-absorbable antibiotics reduced enteric TNF production, ameliorated intestinal inflammation and stabilized the gut barrier [53] in alcohol-fed mice. Other observations indirectly illustrate a potential interplay between dysbiosis and a leaky gut. Increased intestinal permeability allows pathogen-associated molecular patterns (PAMPs) to translocate from the intestinal lumen to extraintestinal space and finally to reach the blood steam. PAMPs are components of bacteria or other microorganisms, as for example bacterial cell wall components such as lipopolysaccharides (LPS) or peptidoglycan (PGN), bacterial DNA, viral RNA, fungi, or parasites that bind to pathogen-recognition receptors on immune cells where they trigger an inflammatory response. This rapid and co-ordinated response to a perceived threat is part of the normal surveillance activity of the innate immune system. By contrast, dysregulation of this response can lead to inappropriate inflammation and tissue damage. Translocation of bacteria-derived products from the intestinal lumen to the portal and systemic circulation is supported by increased blood LPS and PGN in alcohol-dependent subjects [43,5456]. Therefore, it is conceivable that translocated microbial products can reach other organs such as the liver and do contribute to local and/or systemic inflammatory responses ultimately amplifying remote organ damage.

Intriguingly, two independent studies have shown that only some, but not all subjects with heavy alcohol consumption presented with dysbiosis and higher intestinal permeability [29,30]. Even more surprisingly, after more than 2 weeks of abstinence sober alcoholics still exhibited gut dysbiosis despite a total restoration of intestinal permeability. The reasons for these differences remain unclear. It is possible that host genetic factors and/or differences in host immune responses to alcohol, e.g. in the intestinal mucosa, could explain those observations. Alternatively, dietary factors could also play a role in preventing or accelerating intestinal damage in alcoholic patients. Our own unpublished studies reveal profound changes/variations in dietary habits of and quality of food consumed by alcoholic patients. Maintenance of an adequate diet while consuming alcohol might confer some protection against the development of dysbiosis and increased intestinal permeability. Future studies should address these possibilities.

Taken together, alcohol-induced epithelial cell damage impairs the mucosal innate immune system and results in the intestinal homeostasis system to fail. Up to know we still do not exactly know how this phenomenon relates to dysbiosis which is observed in chronic alcohol (ab)use in rodents and humans and what exactly causes dysbiosis in alcohol-dependent subjects. Whether it is a consequence of chronic alcohol abuse itself or an eventually pre-existing dysbiosis could contribute to the development of more severe forms of remote organ damage in susceptible individuals remains a field of investigation. In addition, whether the direct toxic effect of ethanol on liver cells contributes to dysbiosis is also not known and deserves future investigation.

Is there a connection between the intestinal microbiota and alcoholic liver disease?

The gut and liver are intimately connected with each other via the portal vein and fortunately a ‘healthy’ microbiota likely contributes to maintaining hepatic homeostasis [57]. As a down-side of this close relationship, bacteria-derived products or toxins can take the route via the portal vein to get into the liver and disrupt homeostasis if the natural equilibrium or natural barriers are disrupted. These noxious products are recognized by specific receptors (toll-like receptors, TLR) on immune cells and elicit a change in the inflammatory response to cause direct hepatocyte death or to contribute to chronic liver injury [58,59] (Figure 2).

Relationship between alcohol, the microbiota, and remote organ damage

Figure 2
Relationship between alcohol, the microbiota, and remote organ damage

Potential direct and indirect ways by which the intestinal microbiota could influence alcoholic liver disease, drinking behavior, and alcohol dependence. Abbreviations: BBB, blood–brain barrier; PBMC, peripheral blood mononuclear cell; P/Damp, pathogen/danger associated molecular pattern.

Figure 2
Relationship between alcohol, the microbiota, and remote organ damage

Potential direct and indirect ways by which the intestinal microbiota could influence alcoholic liver disease, drinking behavior, and alcohol dependence. Abbreviations: BBB, blood–brain barrier; PBMC, peripheral blood mononuclear cell; P/Damp, pathogen/danger associated molecular pattern.

In line with this concept, it has been demonstrated that the complete absence of microbes in germ-free mice makes them more susceptible to acute binge ethanol-induced liver damage [60]. On the other hand, small intestinal bacterial overgrowth and dysbiosis (i.e. alteration of the gut microbiota) have been associated with alcoholic liver disease in rodents chronically exposed to ethanol [27,61]. Intestinal decontamination not only with a cocktail of non-absorbable antibiotics but also with amphotericin monotherapy ameliorates ethanol-induced liver disease in preclinical animal models [34,53,62,63]. However, no improvement of endotoxemia or liver function has been shown in alcoholics receiving the broad-spectrum antibiotic paromomycin for 4 weeks [64]. Treatment with probiotics as, for example Lactobacillus rhamnosus species or administration of their supernatants to mice improves the intestinal barrier function and protects them from alcohol-induced liver injury in various acute and chronic animal models of alcohol exposure [6569]. In animals, reversal of dysbiosis by supplementation of saturated long-chain fatty acids results in protection of the intestinal barrier and in amelioration of alcoholic liver disease [70]. Improvement of intestinal barrier integrity as well as liver injury can be also be achieved in rodents by using dietary fibers [71,72] that all modify the composition of the gut microbiota.

Evidence suggests that viable bacteria might also translocate to the mesenteric lymph nodes through yet not completely understood mechanisms. This translocation is not modulated by disrupted tight junctions and might occur through transcytosis. Chronic alcohol consumption suppresses mucosal antimicrobial molecules and alters the composition of the intestinal mucus layer in humans and mice which becomes thicker but more permeable [26,73,74]. Although these changes do not affect the composition of the luminal gut microbiome, they favor increased numbers of mucosa-associated and adherent bacteria in mice and humans [75]. Interventions such as overexpression of antimicrobial Reg3g [75] or knockdown of mucin 2 resulting in a reduced thickness of the mucus layer [74], are associated with lower bacterial translocation in rodents and reduction in liver injury. More evidence that gut bacteria are directly involved in modulating ALD comes from two recent studies. In one study, administration of the supposed good microbe A. muciniphila protected mice from acute and chronic experimental alcoholic liver damage and also showed benefits in already established ALD. This effect seemed to be mediated by a restored intestinal barrier function and protection against ethanol-induced gut leakiness [31]. In another study, researchers transplanted the intestinal microbiota derived from alcoholic patients with or without severe alcoholic hepatitis to germ-free mice and challenged them with alcohol. They found that mice harboring the gut microbiota from a patient with severe alcoholic hepatitis developed greater intestinal permeability, higher bacterial translocation, and more severe liver inflammation than mice harboring the gut microbiota from a patient without alcoholic hepatitis, despite the same amount of alcohol consumed. These observations support the hypothesis that the gut microbiota contains pro-inflammatory signals, which likely derive from pathobionts and might even be linked to specific gut microbes since the composition of the donor microbiota differed for several potentially deleterious species [76].

Studies in humans showing a benefit of modulating the intestinal microbiota in ALD are scarce. A 5-day supplementation with probiotics Bifidobacterium bifidum and Lactobacillus plantarum 8PA3 in patients undergoing alcohol detoxification had greater effect on the reduction in liver enzymes than abstinence alone [77] and a 4-week administration of Lactobacillus casei shirota to alcoholic cirrhosis patients improved the neutrophil phagocytic capacity [78].

More well-designed clinical studies are warranted to clearly show an additional benefit of interfering with the intestinal microbiota over abstinence alone.

How can the microbiota influence psychological factors implicated in alcohol dependence?

As already mentioned, ALD and alcohol dependence are interdependent and difficult to dissociate. Alcohol dependence is amongst the most frequent psychiatric disorders and currently represents the second cause of death and morbidity worldwide [79]. Besides genetic [80] and personality factors [81], the development of alcohol use disorder also results from an interaction of ethanol with the brain reward circuit [82], where different neurotransmitter pathways are dysregulated by chronic ethanol intake. A detailed description of the complex interaction of alcohol with the brain goes too far beyond the scope of this review and the interested reader is directed to other reviews in the field. The current paper will focus on those aspects of the network which might implicate or be influenced by the intestinal microbiota.

An important dimension of alcohol use disorders is the relation of compulsive drinking with emotional processes where drinking is often triggered by affective situations, most often negative emotions. In patients, a strong correlation has repeatedly been observed between alcohol craving and depression or anxiety [8385]. All those processes finally culminate in a negative reinforcement process which could explain a large proportion of relapses in abstinent alcohol-dependent subjects [86]. The possible role of the gut and of the gut microbiota in the development of psychiatric disorders mainly arises from animal studies showing that processes occurring at the level of the intestine may profoundly affect behaviors [87]. Studies of the impact of gut dysbiosis on psychiatric disorders have mainly focussed on two domains of psychiatry: the development of mood symptoms, for instance depression and anxiety (for review, see reference [88]) and the development of profound social impairments as observed in autistic spectrum disorders [89,90]. Alcoholic patients with a high intestinal permeability and dysbiosis show more severe scores for depression, anxiety, and craving than patients with normal intestinal permeability and without dysbiosis. In addition, the latter completely recover at the end of a detoxification period while alcohol-dependent subjects with high intestinal permeability and dysbiosis are still characterized by higher levels of depression, anxiety, and craving [30]. How can this observation be explained or in other words how can the microbiota influence behavioral changes (Figure 2)?

Systemic inflammation

Systemic low-grade inflammation has been observed in alcohol-dependent subjects even in the absence of actual bacterial or viral infection [43,91,92]. Elevated plasma levels of TNFα, IL-1β, IL-6, IL-8, IL-10, hsCRP, and increased blood LPS levels in alcohol-dependent subjects have been shown in numerous studies [43,9395]. Inflammation markers correlate with the severity of experimental liver disease [96] and pro-inflammatory circulating cytokines are also found to positively correlate with scores of depression, anxiety, and alcohol craving in active drinkers [43,92]. Although systemic inflammation and psychological symptoms decrease at the end of a 3-week detoxification period, their levels in recently sober patients are still higher than in healthy controls and both variables remain correlated [43]. Mechanistic analyses performed in naturalistic conditions in alcohol-dependent patients have revealed that LPS and to a higher extent PGN, derived respectively from Gram-negative and Gram-positive bacteria also present in the gut, can contribute to the activation of peripheral blood mononuclear cells (PBMCs). Indeed, the LPS–receptor complex TLR4–CD14 as well as the PGN–receptor, TLR2, expression and activation were found to be higher in PBMCs of alcoholics compared with healthy subjects in conjunction with up-regulation of markers suggesting inflammasome activation [92]. PBMCs are likely implicated in PGN-triggered release of IL-1β and IL-8 into the blood of alcohol-dependent subjects. In line with restoration of normal blood LPS levels [43], a 3-week period of alcohol detoxification was associated with a total recovery of LPS-associated receptors in PBMCs, while the expression of PGN-associated receptors remained increased in PBMCs of alcohol-dependent patients. This observation suggests that PGN might still be present in the blood after 3 weeks of alcohol withdrawal and could therefore contribute to the persistence of elevated plasma inflammatory cytokines observed in sober patients [30,43].

By contrast, TNFα and IL-6 are down-regulated in PBMCs suggesting that their elevated levels in the blood might originate from other sources, e.g. the liver or the gut wall itself.

Our own data revealed that the liver likely contributes to systemic TNFα and IL-1β in alcoholic patients whereas the expression of IL-6 was totally blunted in the liver [97]. On the other hand, IL-6 was up-regulated in duodenal biopsies of alcohol-dependent patients compared with healthy controls while the intestinal expression of IL-8 remained low (unpublished data). Overall, these results suggest that various sources contribute to systemic inflammation in alcohol dependence: PBMCs being the main source of IL-1β and IL-8, the intestinal tissue releases IL-6 in the blood, while circulating TNFα is likely coming from the liver.

Neuroinflammation

Ethanol, a lipophilic molecule, easily crosses the blood–brain barrier (BBB) to activate brain immune cells that results in neuroinflammation and epigenetic changes which could favor addictive behavior [98,99] in animals. The involvement of the brain immune system in the modulation of alcohol consumption and addictive behavior has also been shown by studies reporting up-regulation of TNFα, IL-1β, IL-6, and MCP-1 expression in several brain areas of rodents chronically exposed to ethanol [100106]. In humans, increased expression of innate immune genes (MCP-1, TLR2, TLR3, TLR4, and high-mobility group box 1 (HMGB1, a danger signal exerting cytokine-like effects) has been shown in the brain of alcoholics collected postmortem [107,108]. Although these studies do not directly implicate the gut microbiome in the observed modifications, it is thought the gut-derived microorganisms do play a role in controlling different aspects of behavior [87]. It is likely that the brain reacts to alcohol-induced systemic inflammation. Experimental evidence in animals suggests that the systemic, LPS-driven, inflammatory response might act as an amplifier of neuroinflammation [103]. Indeed, intragastric ethanol administration and systemic injection of LPS into mice increases cytokine levels, in particular TNFα, in the brain even though LPS itself does not cross the BBB [103]. Furthermore, peripheral injection of LPS induces long-lasting increase in ethanol drinking in mice [109]. Studies investigating the role of TLR4 in this process have led to conflicting results. Initial experiments using knockout mice and siRNA suggest that activation of TLR4 in the brain following ethanol exposure is crucial to induce neuroinflammation and BBB impairment [101,110,111]. However, a recent study across multiple laboratories, using different animal species and different models of drinking patterns, has called into question the role of TLR4 which was not a critical determinant of excessive drinking [112].

The mechanisms discussed above imply an indirect influence of ethanol on brain immune responses. An important question remains whether ethanol, a lipophilic molecule that crosses the BBB, directly induces an inflammatory response in the brain through its action on neurones, microglia, and astrocytes. Studies in rodents reveal the existence of a large number of alcohol-responsive genes in the brain which once activated by ethanol interact with and regulate many cell functions and biological processes [113,114]. Microglia and astrocytes are part of the brain innate immune system and repeated exposure to alcohol leads to their long-term activation and subsequent secretion of pro-inflammatory cytokines resulting in neuronal damage, cell death, and behavioral changes such as anxiety-like behavior and impaired cognitive function [98,100,102] in animals. In addition, as already mentioned earlier, activation of TLR4 in microglia and astrocytes following ethanol exposure contributes to the induction of neuroinflammation and BBB impairment [101,110,111]. It is therefore conceivable that alcohol first directly triggers brain inflammation which then differentially modulates local but also distant cell events and mechanisms.

Overall, the current evidence suggests that events occurring in the gut either directly or indirectly related to changes in the gut microbiota could shape behavioral patterns in alcohol-dependent patients and likely play a role in the complex pathophysiology of alcohol dependence together with yet non-identified factors and mechanisms.

The bacterial metabolome as a potential mediator of intestinal and remote organ damage

The intestinal microbiota is an additional organ with its own genome in our body. Bacterial genes enable changes in the metabolome. Bacteria can increase the synthesis of bacterial metabolites and can extend host metabolic capacity [115]. Those metabolites can act locally on the intestinal level or be absorbed into the blood and reach the liver via the portal vein. Once they have been taken up by the liver, they can be stored, metabolized, or released into the systemic circulation where they can then reach the brain.

Bacterial carbohydrate fermentation generates short-chain fatty acids (SCFAs) whereas protein fermentation produces branched-chain fatty acids (BCFAs), phenolic and indole compounds. It is important to note that BCFAs, phenolic and indole compounds are not produced by human enzymes and are therefore unique colonic bacterial metabolites. Several metabolomic studies highlighted differences in the metabolome in humans [30,116,117] or rodents [118,119] following chronic ethanol consumption. Butyrate and propionate concentrations decrease in the gastrointestinal tract following chronic ethanol administration in rats [118]. Analysis of the human fecal metabolome revealed a decrease in metabolites with antioxidant properties as well as a decrease in SCFAs [120] in alcoholics. Butyrate is an important energy source for enterocytes and its lower intestinal levels might contribute to dysfunction of the gut barrier. Other metabolites show different levels in alcohol-dependent patients [30]. Dramatic changes in secreted metabolites from bacteria were found in fecal samples from these patients [30] with increased phenolic compounds but blunted 3-methylindole levels. The toxic effect of phenol on intestinal epithelial cells has been demonstrated in two independent in vitro studies [121,122] suggesting that phenol is a potential driver of gut barrier alterations. By contrast, in in vitro studies, indolic compounds were shown to improve intestinal cell barrier function and to decrease pro-inflammatory IL-8 expression [123,124]. It is therefore conceivable that gut microbes that produce indolic compounds exert a protective role on the gut barrier and inflammation while those bacteria producing phenol have a detrimental impact. Animal studies also showed that modulation of the intestinal metabolome through dietary interventions (e.g. administration of saturated and unsaturated dietary fats or a butyrate derivate) can either exacerbate or reduce acute and/or chronic liver injury pointing at a potential link between intestinal bacterial metabolites and alcoholic liver disease [70,125128]. Whether and how these changes contribute to gut barrier dysfunction and/or directly affect liver disease deserves further investigation.

Alternative ways allowing the microbiota to influence distant targets

The gut and the liver engage into a complex interplay which might directly or indirectly impact the intestinal microbiota. In addition, afferent neurones (e.g. the vagus nerve) that mediate and co-ordinate responses between the gut, the liver, and the central nervous system may be influenced by the microbiota. The different ways of communication have been extensively reviewed elsewhere [129131].

Intestinal bacteria can synthesize neurotransmitters [132], such as GABA, serotonin, dopamine which are important regulators of the brain reward circuit. Gut bacteria can also release SCFAs following the fermentation of dietary fibers. These compounds have neuroactive properties that could directly influence brain function and behavior [133]. The tryptophan/kynurenine pathway is regulated by several enzymes tightly controlled by the immune system [134]. This pathway is activated and modulated by inflammatory conditions to which the microbiota likely contributes directly or indirectly. As a consequence, tryptophan, the precursor of serotonin, is converted into kynurenine, which in turn is converted into other neuroactive metabolites. Depletion of serotonin and production of kynurenine metabolites that could cross the BBB and exert neurotoxic actions is also one potential means of communication between the periphery and the brain.

Conclusion and perspectives

The intestinal microbiota is increasingly recognized as an important player in health and disease including alcohol dependence and the development of alcoholic liver disease. Changes in the microbial composition, also called dysbiosis, favoring the proliferation of harmful over good microbes is generally associated with gut barrier breakdown and increased intestinal permeability. A causal relationship of both the phenomena has not been clearly established by now. A leaky gut allows translocation of bacterial products or even total bacteria to the portal and systemic circulation where they can reach organs such as the liver and the brain and establish a gut–liver, gut–brain, or even a gut–liver–brain axis. Danger signals likely trigger local and systemic inflammation which might elicit, sustain, or amplify remote organ damage. However, many pathophysiological aspects of this complex interplay remain to be elucidated and future basic and translational research should concentrate on demonstrating a true relationship between dysbiosis and increased intestinal permeability as well as on identifying key components not only in the intestine itself but also in remote organs that might serve as potential therapeutic targets. From the clinical perspective, well-designed studies should explore whether modulating the microbiota with the aim of correcting the dysbiosis as a whole and/or restoring the deficit of good microbes could prevent the development of a full blown disease in high risk patients, modify the clinical course of the patients who have already engaged the vicious circle of alcohol addiction and alcoholic liver disease, or eventually reverse disease in those who are not at a too advanced stage of their disease.

S.L. is a postdoctoral researcher from the F.R.S.-FNRS (Fond National de la Recherche Scientifique, Belgium), and P.S. and P.d.T. are both clinical researchers from Fonds de Recherche Clinique of the university.

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Fonds de Recherche Scientifique Médicale [grant number 3.4614.12 (to P.d.T.)]; the Fondation Saint-Luc, Belgium ; the Fonds de Recherche Scientifique Médicale, Belgium [grant number J.0146.17 (to P.S.)]; and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health [grant number U01AA024726 (to P.S. and B.S.)].

Author contribution

P.S. conceived and wrote the paper. S.L. reviewed and contributed to the microbiota and psychological sections of the paper. P.d.T. critically reviewed the psychological and psychiatric aspects of the paper. B.S. reviewed and contributed to the microbiota and liver disease part of the paper. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Abbreviations

     
  • ALD

    alcoholic liver disease

  •  
  • ASH

    alcoholic steatohepatitis

  •  
  • BBB

    blood–brain barrier

  •  
  • BCFA

    branched-chain fatty acid

  •  
  • GABA

    γ-aminobutyric acid

  •  
  • hsCRP

    high sensitivity C-reactive protein

  •  
  • IL

    interleukin

  •  
  • LPS

    lipopolysaccharide

  •  
  • MCP-1

    monocyte chemoattractant protein 1

  •  
  • Muc

    membrane-bound mucin

  •  
  • NFκB

    nuclear factor kappa B

  •  
  • PAMP

    pathogen-associated molecular pattern

  •  
  • PBMC

    peripheral blood mononuclear cell

  •  
  • PGN

    peptidoglycan

  •  
  • Reg

    regenerating islet derived

  •  
  • SCFA

    short-chain fatty acid

  •  
  • TLR

    toll-like receptor

  •  
  • TNF

    tumor necrosis factor

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