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Review
. 2021 Sep 24:12:729950.
doi: 10.3389/fphar.2021.729950. eCollection 2021.

Probiotics-Based Treatment as an Integral Approach for Alcohol Use Disorder in Alcoholic Liver Disease

Catalina Fuenzalida  1   2 , María Soledad Dufeu  1   2 , Jaime Poniachik  3 , Juan Pablo Roblero  3 , Lucía Valenzuela-Pérez  1   2   4 , Caroll Jenny Beltrán  1   2
Affiliations
Review

Probiotics-Based Treatment as an Integral Approach for Alcohol Use Disorder in Alcoholic Liver Disease

Catalina Fuenzalida et al. Front Pharmacol. .

Abstract

Alcoholic liver disease (ALD) is one of the leading causes of morbidity among adults with alcohol use disorder (AUD) worldwide. Its clinical course ranges from steatosis to alcoholic hepatitis, progressing to more severe forms of liver damage, such as cirrhosis and hepatocellular carcinoma. The pathogenesis of ALD is complex and diverse elements are involved in its development, including environmental factors, genetic predisposition, the immune response, and the gut-liver axis interaction. Chronic alcohol consumption induces changes in gut microbiota that are associated with a loss of intestinal barrier function and inflammatory responses which reinforce a liver damage progression triggered by alcohol. Alcohol metabolites such as acetaldehyde, lipid peroxidation-derived aldehyde malondialdehyde (MDA), and protein-adducts act as liver-damaging hepatotoxins and potentiate systemic inflammation. Additionally, ethanol causes direct damage to the central nervous system (CNS) by crossing the blood-brain barrier (BBB), provoking oxidative stress contributing to neuroinflammation. Overall, these processes have been associated with susceptibility to depression, anxiety, and alcohol craving in ALD. Recent evidence has shown that probiotics can reverse alcohol-induced changes of the microbiota and prevent ALD progression by restoring gut microbial composition. However, the impact of probiotics on alcohol consumption behavior has been less explored. Probiotics have been used to treat various conditions by restoring microbiota and decreasing systemic and CNS inflammation. The results of some studies suggest that probiotics might improve mental function in Alzheimer's, autism spectrum disorder, and attenuated morphine analgesic tolerance. In this sense, it has been observed that gut microbiota composition alterations, as well as its modulation using probiotics, elicit changes in neurotransmitter signals in the brain, especially in the dopamine reward circuit. Consequently, it is not difficult to imagine that a probiotics-based complementary treatment to ALD might reduce disease progression mediated by lower alcohol consumption. This review aims to present an update of the pathophysiologic mechanism underlying the microbiota-gut-liver-brain axis in ALD, as well as to provide evidence supporting probiotic use as a complementary therapy to address alcohol consumption disorder and its consequences on liver damage.

Keywords: alcohol addiction; alcohol craving; alcoholic liver disease; gut-liver-brain axis; microbiota; neuroinflammation; probiotics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Gut-microbiota-liver-brain axis in ALD. Interaction diagram of the different mechanisms participating in the gut-microbiota-liver-brain axis involved in the pathophysiology of ALD. (A) Alcohol consumption has adverse effects on the gut; it disrupts the gut barrier leading to high permeability and translocation of bacterial products. These effects create a proinflammatory environment which affects microbiota. (B) ALD has a specific microbiota dysbiosis favoring an overgrowth of nonbeneficial bacteria. The decrease of SCFA due to alcohol consumption influences these alterations because SCFA is food for helpful bacteria. This context produces a translocation of different substances called PAMPs, such as LPS or peptidoglycan, to the liver and circulation, increasing endotoxemia. (C) The liver is a vital organ in ethanol metabolization and suffers many changes in chronic consumption; activation of Küpffer cells and proinflammatory TLR4 pathway, causing hepatitis, increased reactive oxygen species, and cytokines, such as IL-18, IL-8, and IL-1β. In advanced stages, the liver fails in its detox task, and organisms accumulate ammonia. (D) All the aforementioned inflammatory processes lead to a systemic inflammation that affects the brain, contributing to ethanol-triggered neuroinflammation. PAMPs and alcohol also produce disruption of the blood-brain barrier, astrocyte senescence, and more significant changes in the brain; alteration of the DR1 and 2, increased levels of anxiety, depression, and alcohol craving. Finally, the gut and the microbiota are influenced by the brain and vice-versa through nerve and GABA signaling modulation. ALD: Alcoholic liver disease; SCFA: Short-chain fatty acids; PAMPs: Pathogen-associated molecular patterns; LPS: Lipopolysaccharide: PGN: Peptidoglycan; ROS: Reactive oxygen species; BBB: Blood-brain barrier; DR1/DR2: Dopamine receptor 1/2; GABA: γ-aminobutyric acid; TLR4: Toll-like receptor 4.
FIGURE 2
FIGURE 2
Probiotics’ effect on the gut-microbiota-liver-brain axis in ALD. Probiotics exert their actions at different levels of the gut-microbiota-liver-brain axis, acting directly on each of these organs and indirectly due to the axis component's interplay. (A) At the intestinal level, probiotics improve digestion and tight junction’s expression and are a protective factor for the crypts and mucous layer. (B) The change enhances the effects that probiotics produce in the microbiota, restoring it and decreasing dysbiosis triggered by alcohol abuse, which will lead to a decrease in harmful bacteria and an increase in beneficial ones, therefore reducing the high permeability of the gut and the translocation of PAMPs to the liver. (C) Probiotics’ effect in the brain causes a decrease in proinflammatory cytokines at the systemic level; consequently, the system and neuroinflammation are attenuated by a probiotic-based therapy. Inflammation control is one of the mechanisms behind controlling alcohol consumption and psychological symptoms, such as anxiety and depression. Furthermore, the control of high permeability and the translocation of substances contributes to controlling the disruption of the blood-brain barrier and neuroinflammation. Finally, FGF21 has an important effect on the brain since it produces dopamine transporter transcription in the nucleus accumbens, allowing less dopamine to access the postsynaptic receptor. (D) Probiotics have demonstrated multiple benefits at the liver level since the decrease of steatosis to encephalopathy and cirrhosis. These liver effects are explained by the decrease of PAMPs in the systemic circulation, especially LPS, that induce the normalization of the inflammatory processes that are associated, among others, with the TLR4 pathway. Consequently, the adverse effects of alcohol on the liver are decreased; less activation of Küpffer cells, decreased liver enzymes, proinflammatory cytokines, and less fibrosis. Some probiotics cause increased formation of FGF21 in the liver, which has effects on the brain. ALD: Alcoholic liver disease; SCFA: Short-chain fatty acids; PAMPs: Pathogen-associated molecular patterns; BBB: Blood-brain barrier; TLR4: Toll-like receptor 4; FGF21: fibroblast activation protein 21.
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