Excessive alcohol consumption is a leading contributor to chronic liver disease worldwide, leading to poor health and in many cases, premature death. Abstinence from drinking is the undisputed cornerstone of treatment, supplemented by medication, behavioral interventions, and support networks. However, the high frequency of relapses from alcohol cessation calls for new strategies to enhance management approaches.
Amassing evidence confirms that the gut microbiome is involved in the complex development of alcoholic liver disease (ALD). This blog will broadly explain the evidence as well as explore the potential for disease management with probiotics and other methods of gut microbiota modification.
ALD, in brief
There is a clear dose-dependent connection between alcohol intake and the risk of ALD. A large-scale study revealed that even minimal alcohol consumption raises the risk of cirrhosis-related mortality. (Other types of liver injury are not predicated on alcohol use, such as viral hepatitis and non-alcoholic fatty liver disease.)
Disturbingly, the COVID-19 pandemic saw a substantial increase in alcohol consumption, with monthly sales spiking up to 40% compared to pre-COVID times. Lockdowns and restrictions fueled online alcohol ordering, correlating with elevated rates of alcohol-related mortality, of which ALD played a role.
The liver serves as the main organ for the metabolism of ethanol (alcohol in beverages) and undergoes heightened tissue damage due to oxidative stress, and accumulation of acetaldehyde and lipopolysaccharide (LPS) following prolonged alcohol consumption. Early liver damage can lead to the development of a fatty liver and inflammation.
The clinical course of ALD ranges from steatosis (fatty liver) to alcoholic hepatitis, progressing to fibrosis, cirrhosis, and even cancer in some cases. The process begins with asymptomatic liver steatosis, the accumulation of triglycerides, phospholipids, and cholesterol esters within liver cells. If alcohol use persists, hepatic inflammation—alcohol-associated steatohepatitis (ASH) —can result and then lead to fibrosis and cirrhosis. Even in the absence of cirrhosis, severe ASH can lead to alcoholic hepatitis, which is linked to high mortality. Furthermore, there is a higher risk of liver cancer, thought to be attributed to “acetaldehyde-related hepatotoxicity, oxidative stress, activation of the innate immune system, and alterations of the host microbiome.”
Multiple risk factors, including sex, race, hepatitis virus infection, and smoking, influence the entire progression. The pathogenesis of ALD is intricate, involving environmental factors, genetic predisposition, and immune response. Increasingly, evidence points to interactions of the gut microbiome as a key factor.
ALD & gut microbiota
About 70% of the liver’s blood supply comes from the gut through the portal vein, together with the biliary system establishing a robust bidirectional connection between the liver and intestine. This “gut-liver axis” plays an important role in the pathogenesis of chronic liver diseases.
Alcohol disturbs the gut-liver axis across a range of areas, affecting the gut microbiome, mucus barrier, epithelial barrier, and antimicrobial peptide production. This disruption leads to heightened microbial exposure and a proinflammatory environment within the liver.
According to a recent review, chronic alcohol consumption induces changes in gut microbiota in patients with various stages of ALD. Some of the key findings:
- Alcohol use even without liver disease alters gut microbiota, with reduced Bacteroidaceae and increased Proteobacteria observed.
- Bacterial diversity was reduced in the microbiota of patients at all stages of ALD.
- A reduction in SCFA-producing bacteria was observed in alcohol-related cirrhosis and hepatitis.
- Both diseases showed increases in Enterobacteriaceae, Streptococcaceae, and Enterococcus (commonly pathogenic taxa). Reductions in Clostridiales and Blautia occur in cirrhosis, while a decrease in Akkermansia is observed in alcoholic hepatitis.
ALD not only impacts bacteria but also affects gut fungi. Reduced mycobial diversity, with an overgrowth of Candida, is linked to higher mortality in alcoholic hepatitis. Studies with mice, colonized with fecal microbes from ALD patients, reveal that Candida albicans secretes hemolysin, contributing to ALD and correlating with the severity of liver disease and mortality.
Effects of dysbiosis in ALD
Alcohol-induced gut dysbiosis leads to increased intestinal permeability, which allows transit of microbial products into the bloodstream (endotoxemia). The liver is the first organ to encounter endotoxins originating from the gut.
For example, lipopolysaccharide (LPS) passage through the leaky gut results in circulating endotoxemia and aggravates alcohol-induced liver inflammation through activation of receptors in the liver. Increased exposure to bacterial exotoxins and reduced toxin clearance in the liver also exacerbate alcohol-related liver injury and inflammation.
Increasing evidence indicates that microbe-derived metabolites, such as short-chain fatty acids (SCFAs) and bile acids (BAs) are significantly altered in in ALD pathology and play a role in its development.
Moreover, alcohol metabolites such as acetaldehyde are hepatotoxins that can spur systemic inflammation and disrupt epithelial barrier function. Thus, with continued alcohol consumption, liver damage and progression of disease ensue.
Restoring the gut microbiota in ALD
As described above, ALD is intricately linked to adverse changes in the gut microbiota, metabolites, and intestinal permeability. Dysbiosis — disruption of homeostasis— and pathogenic microorganisms lead to liver and gut inflammation that drives further liver injury. Therefore, restoring the gut microbiota of ALD patients is seen as a potential and promising therapy to help reverse alcohol-induced changes in microbiota and prevent the progression of AFLD.
Strategies targeting the gut microbiota, including probiotics, prebiotics, and fecal microbiota transplantation FMT) have been evaluated in ALD.
Probiotics
Animal studies
Numerous probiotic treatments in experimental ALD murine (rodents) models have yielded positive outcomes.
- Lactobacilli species such as Lactiplantibacillus plantarum), Lactobacillus acidophilus, Limosilactobacillus fermentum, and Lacticaseibacillus rhamnosus have been observed to safeguard against alcohol-induced liver injury in rodents by altering gut bacteria, enhancing intestinal barrier function, and regulating inflammatory cells in the blood.
- Akkermansia muciniphila supplementation decreased ethanol-induced gut leakiness and hepatic injury in mice.
- Specific strains of L. plantarum, Bifidobacterium longum, and a combination of the two were all able to alleviate alcohol-induced fatty liver in mice through restoration of the disturbed gut microbiota.
- An eight-strain probiotic mixture (mostly lactobacilli and bifidobacteria) prevented endotoxins and their products from spreading to portal circulation and downregulated liver inflammation in a rat model.
- A newly isolated strain of Pediococcus pentosaceus reduced ethanol-induced liver damage in mice by restoring gut microbiota balance, increasing SCFA-producing bacteria, enhancing intestinal barrier function, and lowering circulating levels of inflammatory mediators.
- A probiotic mixture (L. plantarum, L. fermentum, and L. reuteri) reduced oxidative stress and inflammatory responses in mice, protecting them from alcohol-induced liver injury.
Human studies
While evidence of therapeutic potential is established in animal models, trials in humans are limited likely due to challenges such as differences between mouse models and human patients, individual variations in treatment response, and other factors.
Despite these limitations, several studies in humans suggest that probiotics may be potentially beneficial in ALD.
- One study reported that oral supplementation with Bifidobacterium bifidum and L. plantaruminpatients with ALD restored the gut microbiota and resulted in more improvement in liver injury than standard treatment alone.
- Alcohol exposure diminished intestinal A. muciniphila abundance in humans and was recovered in experimental ALD by oral supplementation. A. muciniphila promotes intestinal barrier integrity partly by enhancing mucus production.
- Oral supplementation with Lactobacillus subtilis and Streptococcus faeciumwas associated with restoration of gut flora and enhancement of LPS levels in a group of patients with alcoholic hepatitis.
- In a trial with cirrhotic patients, a specific strain of L. rhamnosus was associated with a decrease in endotoxemia and dysbiosis.
Diverse studies in animals and humans indicate a potential beneficial impact of probiotics on ALD. Various mechanisms are at play: restoration of microbiota balance with reduction of dysbiosis, intestinal permeability, inflammation, and endotoxin translocation.
A recent review summarized some of the studies that have explored the use of probiotics in modulating gut microbiota in ALD.
Prebiotics
Prebiotics have also been considered as a potential therapy for ALD.
Prebiotics —“a substrate selectively utilized by host microorganisms conferring a health benefit”— show promise in ALD. Prebiotics are known to enrich probiotic bacteria, potentially mediating the complex interactions between the microbiome and liver disease.
- In a mouse model of ALD, fructo-oligosaccharides (FOS) improved alcohol-induced liver damage by reducing intestinal bacterial overgrowth and ameliorating alcoholic steatohepatitis.
- Inulin, a natural prebiotic found in plants, was observed to restore gut dysbiosis in a mouse model of ALD.
- Another study found that pectin treatment in alcohol-fed mice restored Bacteroides levels and also prevented the development of liver injury in the context of ALD.
Fecal microbiota transplantation
Fecal microbiota transplantation (FMT) — transferring gut microbiota from a healthy donor to a damaged recipient — is emerging as a potentially effective and complementary treatment for chronic liver diseases specifically for liver cirrhosis.
In mouse models, transferring fecal microbiota from alcohol-tolerant donors to alcohol-sensitive recipients can rectify alcohol-induced dysbiosis and prevent alcohol-induced liver injury.
In a pilot study in steroid-ineligible patients with severe alcoholic hepatitis, FMT from health donors improved survival rate.
A small study in alcohol-associated cirrhosis patients found that FMT led to positive microbial changes as well as a short-term decrease in alcohol craving and consumption, as compared to a placebo.
FMT has been reported to be safe in several types of liver disease including severe alcoholic hepatitis and cirrhosis. Nevertheless, the general acceptance of FMT in liver disease will require additional research.
Takeaway
Excessive alcohol intake is a leading cause of chronic liver disease, with abstinence as the primary treatment. The gut microbiome’s role in alcoholic liver disease (ALD) is gaining attention as a platform for novel treatments.
Research shows that alcohol consumption can lead to gut dysbiosis, inflammation, increased intestinal permeability, and pathogen translocation that disturbs the gut-liver axis and drives the progression of ALD.
Probiotics, prebiotics, and fecal microbiota transplantation are a few of the therapies being explored for ALD management.
Animal studies demonstrate positive outcomes with probiotic interventions, showcasing benefits in mitigating alcohol-induced liver injury. Human trials, although limited, suggest potential therapeutic benefits of probiotics in ALD, with improvements observed in gut flora and liver injury. Additionally, prebiotics show promise, enriching probiotic bacteria and ameliorating alcohol-induced liver damage in experimental models. FMT also shows potential benefits, improving survival rates in severe alcoholic hepatitis.
Despite challenges, these interventions offer hope for effective ALD management.
Image by Gerd Altmann from Pixabay
Key references
Albillos, Agustín et al. “The gut-liver axis in liver disease: Pathophysiological basis for therapy.” Journal of hepatology vol. 72,3 (2020): 558-577. doi:10.1016/j.jhep.2019.10.003
An, Lingxuan et al. “The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases.” Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract vol. 26,3 (2022): 671-683. doi:10.1007/s11605-021-05188-7
Bajaj, J S et al. “Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.” Alimentary pharmacology & therapeutics vol. 39,10 (2014): 1113-25. doi:10.1111/apt.12695
Bajaj, Jasmohan S et al. “A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder.” Hepatology (Baltimore, Md.) vol. 73,5 (2021): 1688-1700. doi:10.1002/hep.31496
Bjørkhaug, Steinar Traae et al. “Characterization of gut microbiota composition and functions in patients with chronic alcohol overconsumption.” Gut microbes vol. 10,6 (2019): 663-675. doi:10.1080/19490976.2019.1580097
Boicean, Adrian et al. “Fecal Microbiota Transplantation in Liver Cirrhosis.” Biomedicines vol. 11,11 2930. 30 Oct. 2023, doi:10.3390/biomedicines11112930
Brandl, Katharina et al. “Gut-liver axis at the frontier of host-microbial interactions.” American journal of physiology. Gastrointestinal and liver physiology vol. 312,5 (2017): G413-G419. doi:10.1152/ajpgi.00361.2016
Cassard, Anne-Marie, and Dragos Ciocan. “Microbiota, a key player in alcoholic liver disease.” Clinical and molecular hepatology vol. 24,2 (2018): 100-107. doi:10.3350/cmh.2017.0067
Chang, Bing et al. “The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury.” BMC gastroenterology vol. 13 151. 20 Oct. 2013, doi:10.1186/1471-230X-13-151
Chen, Rui-Cong et al. “Lactobacillus rhamnosus GG supernatant promotes intestinal barrier function, balances Treg and TH17 cells and ameliorates hepatic injury in a mouse model of chronic-binge alcohol feeding.” Toxicology letters vol. 241 (2016): 103-10. doi:10.1016/j.toxlet.2015.11.019
Fairfield, Bradley, and Bernd Schnabl. “Gut dysbiosis as a driver in alcohol-induced liver injury.” JHEP reports : innovation in hepatology vol. 3,2 100220. 10 Dec. 2020, doi:10.1016/j.jhepr.2020.100220
Fang, Tony J et al. “Protective effects of Lactobacillus plantarum against chronic alcohol-induced liver injury in the murine model.” Applied microbiology and biotechnology vol. 103,20 (2019): 8597-8608. doi:10.1007/s00253-019-10122-8
Ferrere, Gladys et al. “Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice.” Journal of hepatology vol. 66,4 (2017): 806-815. doi:10.1016/j.jhep.2016.11.008
Fuenzalida, Catalina et al. “Probiotics-Based Treatment as an Integral Approach for Alcohol Use Disorder in Alcoholic Liver Disease.” Frontiers in pharmacology vol. 12 729950. 24 Sep. 2021, doi:10.3389/fphar.2021.729950
Grander, Christoph et al. “Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease.” Gut vol. 67,5 (2018): 891-901. doi:10.1136/gutjnl-2016-313432
Han, Sang Hak et al. “Effects of probiotics (cultured Lactobacillus subtilis/Streptococcus faecium) in the treatment of alcoholic hepatitis: randomized-controlled multicenter study.” European journal of gastroenterology & hepatology vol. 27,11 (2015): 1300-6. doi:10.1097/MEG.0000000000000458
Hsieh, Pei-Shan et al. “Lactobacillus spp. reduces ethanol-induced liver oxidative stress and inflammation in a mouse model of alcoholic steatohepatitis.” Experimental and therapeutic medicine vol. 21,3 (2021): 188. doi:10.3892/etm.2021.9619
Jacob, Rachael et al. “Alcohol and its associated liver carcinogenesis.” Journal of gastroenterology and hepatology vol. 38,8 (2023): 1211-1217. doi:10.1111/jgh.16248
Jiang, Xian-Wan et al. “New strain of Pediococcus pentosaceus alleviates ethanol-induced liver injury by modulating the gut microbiota and short-chain fatty acid metabolism.” World journal of gastroenterology vol. 26,40 (2020): 6224-6240. doi:10.3748/wjg.v26.i40.6224
Kalinowski, Agnieszka, and Keith Humphreys. “Governmental standard drink definitions and low-risk alcohol consumption guidelines in 37 countries.” Addiction (Abingdon, England) vol. 111,7 (2016): 1293-8. doi:10.1111/add.13341
Kim, Byoung-Kook et al. “Protective Effect of Lactobacillus fermentum LA12 in an Alcohol-Induced Rat Model of Alcoholic Steatohepatitis.” Korean journal for food science of animal resources vol. 37,6 (2017): 931-939. doi:10.5851/kosfa.2017.37.6.931
Kim, Won-Gyeong et al. “Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 mitigate alcoholic steatosis in mice by inhibiting LPS-mediated NF-κB activation through restoration of the disturbed gut microbiota.” Food & function vol. 9,8 (2018): 4255-4265. doi:10.1039/c8fo00252e
Kirpich, Irina A et al. “Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study.” Alcohol (Fayetteville, N.Y.) vol. 42,8 (2008): 675-82. doi:10.1016/j.alcohol.2008.08.006
Kong, Ling-Zu et al. “Pathogenesis, Early Diagnosis, and Therapeutic Management of Alcoholic Liver Disease.” International journal of molecular sciences vol. 20,11 2712. 2 Jun. 2019, doi:10.3390/ijms20112712
Li, Huizhen et al. “Lactobacillus plantarum KLDS1.0344 and Lactobacillus acidophilus KLDS1.0901 Mixture Prevents Chronic Alcoholic Liver Injury in Mice by Protecting the Intestinal Barrier and Regulating Gut Microbiota and Liver-Related Pathways.” Journal of agricultural and food chemistry vol. 69,1 (2021): 183-197. doi:10.1021/acs.jafc.0c06346
Philips, Cyriac Abby et al. “Healthy Donor Fecal Microbiota Transplantation in Steroid-Ineligible Severe Alcoholic Hepatitis: A Pilot Study.” Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association vol. 15,4 (2017): 600-602. doi:10.1016/j.cgh.2016.10.029
Prince, David Stephen et al. “Alcohol-Associated Liver Disease: Evolving Concepts and Treatments.” Drugs vol. 83,16 (2023): 1459-1474. doi:10.1007/s40265-023-01939-9
Rocco, Alba et al. “Alcoholic disease: liver and beyond.” World journal of gastroenterology vol. 20,40 (2014): 14652-9. doi:10.3748/wjg.v20.i40.14652
Seitz, Helmut K et al. “Alcoholic liver disease.” Nature reviews. Disease primers vol. 4,1 16. 16 Aug. 2018, doi:10.1038/s41572-018-0014-7
Shalaby, Nicholas et al. “The Role of the Gastrointestinal Microbiome in Liver Disease.” Pathogens (Basel, Switzerland) vol. 12,9 1087. 27 Aug. 2023, doi:10.3390/pathogens12091087
Singal, Ashwani K et al. “Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review.” Alcoholism, clinical and experimental research vol. 40,7 (2016): 1390-402. doi:10.1111/acer.13108
Walter, Jens et al. “Establishing or Exaggerating Causality for the Gut Microbiome: Lessons from Human Microbiota-Associated Rodents.” Cell vol. 180,2 (2020): 221-232. doi:10.1016/j.cell.2019.12.025
White, Aaron M et al. “Alcohol-Related Deaths During the COVID-19 Pandemic.” JAMA vol. 327,17 (2022): 1704-1706. doi:10.1001/jama.2022.4308
Xu, Mengyi et al. “Role of Intestinal Microbes in Chronic Liver Diseases.” International journal of molecular sciences vol. 23,20 12661. 21 Oct. 2022, doi:10.3390/ijms232012661
Yan, Arthur W et al. “Enteric dysbiosis associated with a mouse model of alcoholic liver disease.” Hepatology (Baltimore, Md.) vol. 53,1 (2011): 96-105. doi:10.1002/hep.24018
Yang, An-Ming et al. “Intestinal fungi contribute to development of alcoholic liver disease.” The Journal of clinical investigation vol. 127,7 (2017): 2829-2841. doi:10.1172/JCI90562
Yang, Xiaoli et al. “Inulin Ameliorates Alcoholic Liver Disease via Suppressing LPS-TLR4-Mψ Axis and Modulating Gut Microbiota in Mice.” Alcoholism, clinical and experimental research vol. 43,3 (2019): 411-424. doi:10.1111/acer.13950
Zheng, Jiazhen et al. “Intestinal Microbiotas and Alcoholic Hepatitis: Pathogenesis and Therapeutic Value.” International journal of molecular sciences vol. 24,19 14809. 30 Sep. 2023, doi:10.3390/ijms241914809
Zipursky, Jonathan S et al. “Alcohol Sales and Alcohol-Related Emergencies During the COVID-19 Pandemic.” Annals of internal medicine vol. 174,7 (2021): 1029-1032. doi:10.7326/M20-7466