Probiotics Applications in Liver Diseases Treatment

Liver diseases account for approximately 2 million deaths worldwide each year, with 1 million due to complications from cirrhosis and 1 million attributed to liver cancer from hepatocellular cells, representing 3.5% of global deaths [1,2]. Cirrhosis currently stands as the 11th most common cause of death worldwide, and liver cancer ranks 16th [1,2]. Cirrhosis is among the top 20 causes of decreased life expectancy globally, constituting 2.1% of the worldwide burden. Around 2 billion people consume alcohol worldwide, with over 75 million diagnosed with alcohol use disorders and at risk of alcohol-related liver disease. Chronic hepatitis B affects 0.5–0.7% of the population in Europe. Over the past decade, the prevalence of chronic hepatitis C has ranged from 0.13% to 3.26%. Of concern, approximately 90% of individuals in Europe with chronic hepatitis B are unaware of their status [2-4].

Currently, the global organ transplant demand is not being met, even though liver transplantation is the second most common method. Moreover, transplantation is costly and carries numerous unwanted risks. Despite these alarming statistics, they highlight a significant opportunity to improve community health, as most causes of liver disease are preventable. The use of probiotics presents an effective method to participate in the treatment and support of liver diseases.

Probiotics are beneficial microorganisms defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.” Due to their advantageous characteristics, extensive research has been conducted to explore their effects on various illnesses [5]. Probiotics have been used to treat or prevent diseases, conditions, and syndromes in humans. They have also demonstrated positive effects on neuroinflammation, pain symptoms, and seasonal infections. The mechanisms and impacts of probiotics depend on the specific nature of each beneficial strain. Products derived from Lactobacillus bacteria are a type of probiotics with a long history of use in food. These bacteria produce lactic acid and are “generally recognized as safe” [6]. Presently, there is increasing interest in using them as a dietary supplement.

The microbiota composition varies and is individualized, influenced by diet, gut health, and host factors in temporarily harboring certain bacteria. Surprisingly, the health-promoting effects of probiotics are not limited to strain levels but extend to their metabolic interactions. Lactobacillus bacteria found in the oral cavity can improve conditions related to gastrointestinal diseases, allergies, and liver diseases through various mechanisms, such as producing metabolites that can directly inhibit pathogens, exhibiting immune-modulating effects, and altering the gut microbiota [7].

Intestinal microbiota also has a known impact on liver diseases due to the close functional interaction between the digestive tract and the hepatic portal system. The disease-improving effects of various probiotic strains have been confirmed for both alcohol-related and non-alcohol-related liver diseases.

Using Probiotics for Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is often a common cause of chronic liver disease, yet there hasn’t been a definitive treatment method to date. Probiotics have been proven in numerous studies to have anti-obesity effects. In fact, many NAFLD patients are obese or overweight, and there’s a suggestion that probiotics might be a new treatment approach for NAFLD. The use of Lactobacillus, the most common probiotic, not only prevents obesity caused by fat but also improves inflammation, regulates the gut microbiota, and enhances intestinal barrier protection [8]. NAFLD is related to metabolic disturbances in the liver. Changes in liver lipid metabolism primarily lead to fatty acid accumulation and increased triglyceride storage in the liver. Treatment with L.plantarum has restored liver function and oxidative stress in animal models, reducing fat accumulation in the liver. Besides regulating liver lipid metabolism, it also reduces inflammation by increasing interleukin concentrations while decreasing pro-inflammatory factors, including IL-, IL-β, TNF-α, and IFN-γ [9].

Furthermore, the levels of endotoxins and pro-inflammatory cytokines have significantly decreased, and the gut microbiota has been regulated. Studies have also shown that increased cholesterol accumulation contributes to more severe NAFLD. Over the past few decades, clinical trials have been conducted to investigate the therapeutic effects of probiotics on NAFLD patients. When Lactobacillus rhamnosus GG was used for several weeks in obese children with NAFLD, significant reductions were observed in BMI, alanine transaminase, TNF-α, and anti peptidoglycan-polysaccharide antibodies [10]. In another study, when L. acidophilus was administered three times daily to adult NAFLD patients, aminotransferase and alanine transaminase levels were significantly reduced, indicating an improvement in the patient’s liver inflammation [11]. Research using L.reuteri and inulin for several months in NAFLD patients showed reduced body weight, waist circumference, BMI, and improved liver inflammation. Overall results indicate that Lactobacillus could be a promising treatment strategy for NAFLD.

Using Probiotics for Alcoholic Liver Disease

Alcoholic liver disease (ALD) occurs due to the migration of bacteria and release of LPS (lipopolysaccharide) from gut dysfunction, where LPS originating from the gut plays a role in increasing liver inflammation and fatty liver. Probiotics alter the gut microbiota composition, reducing endotoxins, migration, and gut bacterial disorders, resulting in decreased ALD. In a chronic alcoholic liver disease animal model, a combination of Lactobacillus reduced serum LPS, and inhibited inflammation, lipid accumulation, and oxidative stress through gut-liver regulation by adjusting TLR/NF-kB. Thus, Lactobacillus modulates the excessive expression of alcohol-induced TLR, reducing pro-inflammatory cytokines and alanine transaminase levels. Treating with LGG reduces alcohol-induced liver inflammation by reducing TNF-α production through TLR and endotoxin inhibition. In human studies, supplementing Lactobacillus to alcohol-injured liver patients significantly improved lipid metabolism [12].

Using Probiotics for Cirrhosis and Liver Cancer

Liver tissue damage or inflammation causes cirrhosis, which affects its function. Several causes of cirrhosis include viruses, alcohol consumption, and bile acid accumulation. After the fibrosis process, it develops into cirrhosis. Bile acid accumulation in the liver plays a significant role in the pathogenesis of liver injury, and excess bile acids can cause liver damage and lead to cirrhosis. Probiotic supplementation increases bile acid synthesis inhibition. Additionally, Lactobacillus probiotics reduce gene expression related to fibrosis. In cirrhosis patients, probiotic capsules administered resulted in reduced endotoxins and gut bacterial disorders [13]. 

Hepatocellular carcinoma primarily occurs in patients infected with viruses, alcohol-induced cirrhosis, or non-alcoholic fatty liver disease. Probiotics, bacterial supplements for humans, are used as biological therapeutic agents because they bring about beneficial effects on gut microbiota changes. While other treatments have side effects, biological treatment like probiotic supplementation has none. In animal models of hepatocellular carcinoma, using probiotics has been shown to slow tumor progression [14]. Thus, it has controlled the progression of L.acidophillus – induced liver damage.

The Potential Applications of Probiotics in Future Liver Disease Treatments

Although a definitive treatment method for liver diseases has yet to be established, numerous studies are underway to improve liver health using probiotics in general and Lactobacillus bacteria in particular. These efforts aim to reduce fat accumulation and inflammation and regulate the microbiota. Biological treatment methods such as probiotics currently show no adverse effects and are increasingly being researched due to their potential and advantages. However, as each gut microbiota is unique, it’s crucial to elucidate the mechanisms by which probiotics influence liver diseases, necessitating further studies. Probiotics can be applied as a biological therapy due to their beneficial effects on health through microbiota balance. Among probiotics, lactic acid bacteria like Bifidobacterium and Lactobacillus are widely used. Particularly, Lactobacillus has shown improved efficacy across various diseases, notably in liver diseases. Thus, biological products are emerging as medical microbiota candidates. They might prove more beneficial, especially in research areas where specific drugs have not been developed, such as liver diseases.

References:

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