Role of Gut Microbiota in the Pathogenesis of Liver Diseases: Insights and Implications

Sabinesasika Grob^*
*Correspondence: Sabinesasika Grob, Department of General Pathology and Pathological Anatomy, University Hospital Tübingen, 72076 Tübingen, Germany, Email:

Keywords

Fecal Microbiota Transplantation (FMT) • Chenodeoxycholic Acid (CDCA) • Apical Sodium-dependent Bile Acid Transporter (ASBT) • Organic Solute Transporter Alpha/Beta (OSTα/β) • Short-Chain Fatty Acids (SCFAs)

Introduction

Liver diseases encompass a wide range of conditions that affect the liver, a vital organ responsible for metabolic functions, detoxification, and bile production. Liver diseases can be broadly categorized into acute and chronic conditions, with varying causes and clinical manifestations. Acute liver diseases include hepatitis A, hepatitis B, and hepatitis C, which are primarily caused by viral infections. These infections can lead to inflammation of the liver and, in severe cases, progress to liver failure. Other acute liver conditions include drug-induced liver injury, autoimmune hepatitis, and acute alcoholic hepatitis. Chronic liver diseases are characterized by long-term inflammation and progressive damage to the liver. They include Non-Alcoholic Fatty Liver Disease (NAFLD), Alcoholic Liver Disease (ALD), Viral Hepatitis (Hepatitis B and C), Autoimmune Liver Diseases (such as primary biliary cholangitis and primary sclerosing cholangitis), and Liver cirrhosis. The gut microbiota, also known as the gut microbiome, refers to the vast and diverse community of microorganisms that reside in the gastrointestinal tract. It consists of bacteria, viruses, fungi, and other microbes that interact with each other and with the human host. The gut microbiota is highly complex and unique to each individual, influenced by factors such as genetics, diet, age, and environment. The gut microbiota plays a crucial role in maintaining overall health and well-being. It performs a wide array of functions that contribute to digestion, metabolism, and immune system regulation. The symbiotic relationship between the gut microbiota and the human host is characterized by mutual benefits.

Literature Review

Gut microbiota dysbiosis refers to an imbalance or disruption in the composition and function of the gut microbial community. Emerging evidence has shown that gut microbiota dysbiosis plays a significant role in the pathogenesis of liver diseases. The disruption of the gut microbial ecosystem can lead to alterations in microbial diversity, changes in the abundance of specific bacterial taxa, and functional imbalances, all of which can contribute to liver disease development and progression.

Non-Alcoholic Fatty Liver Disease (NAFLD) is strongly associated with gut microbiota dysbiosis. Studies have demonstrated alterations in the gut microbiota composition in individuals with NAFLD, characterized by a reduction in beneficial bacteria such as bifid bacterium and Lactobacillus, and an increase in potentially harmful bacteria like Escherichia coli. These microbial changes can affect host metabolism and promote liver inflammation, leading to the progression of NAFLD to Non-Alcoholic Steatohepatitis (NASH) and Liver fibrosis. Similarly, gut microbiota dysbiosis has been observed in Alcoholic Liver Disease (ALD). Chronic alcohol consumption disrupts the gut barrier function, allowing harmful bacterial products, such as LipoPolySaccharides (LPS), to enter the bloodstream and reach the liver [1]. LPS, along with other gut-derived microbial metabolites, triggers inflammation and promotes liver injury. Moreover, alcohol-induced dysbiosis alters bile acid metabolism, further exacerbating liver damage and impairing liver function. In liver cirrhosis, gut microbiota dysbiosis is characterized by a decrease in beneficial bacteria and an increase in potentially pathogenic species. These microbial changes contribute to intestinal barrier dysfunction and increased gut permeability, leading to the translocation of bacteria and microbial products into the liver, a condition known as bacterial translocation. Bacterial translocation triggers a cascade of events, including inflammation, immune activation, and fibrosis, which contribute to the progression of cirrhosis.

The mechanisms linking gut microbiota and liver diseases involve complex interactions between the gut microbial community, the gut barrier, the immune system, and the liver [2]. Disruption of these interactions can contribute to the pathogenesis and progression of various liver diseases. Several key mechanisms have been identified, shedding light on the intricate relationship between gut microbiota and liver health. Gut microbiota dysbiosis can impair the integrity of the intestinal barrier, allowing harmful microbial products, such as LipoPolySaccharides (LPS), to translocate from the gut into the bloodstream. This phenomenon, known as bacterial translocation, triggers an immune response and promotes liver inflammation and injury. Gut microbiota produces various metabolites that can directly influence liver health. For example, Short-Chain Fatty Acids (SCFAs), produced through the fermentation of dietary fibre by gut bacteria, have been shown to possess anti-inflammatory properties and protect against liver injury. On the other hand, toxic metabolites like ethanol and endotoxins can promote liver inflammation and damage.

The gut microbiota plays a crucial role in shaping the development and function of the immune system. Alterations in the gut microbial composition can lead to immune dysregulation, characterized by an imbalance between pro-inflammatory and anti-inflammatory responses [3]. This dysregulation can contribute to chronic liver inflammation and the progression of liver diseases. Gut microbiota plays a significant role in bile acid metabolism, influencing the composition and concentration of bile acids. Disruption of this balance can lead to the accumulation of toxic bile acids, which can promote liver injury and inflammation. Additionally, altered bile acid metabolism can impact lipid and glucose metabolism, contributing to metabolic liver diseases. The gut and liver are connected through a bidirectional communication pathway known as the gut-liver axis. This axis involves various signalling molecules, such as cytokines, Toll-Like Receptors (TLRs), and bile acids that mediate crosstalk between the gut microbiota and the liver. Dysregulation of gut-liver axis communication can lead to chronic inflammation and liver damage.

Discussion

The gut microbiota and bile acid metabolism are closely intertwined, with the gut microbiota playing a significant role in modulating bile acid composition and metabolism. Bile acids are synthesized in the liver and play a crucial role in the digestion and absorption of dietary fats. However, the gut microbiota also actively participates in bile acid metabolism through various mechanisms. Firstly, the gut microbiota cans bio transform primary bile acids, primarily Cholic Acid (CA) and Chenodeoxycholic Acid (CDCA), into secondary bile acids, such as Deoxycholic Acid (DCA) and Lithocholic Acid (LCA). Microbes in the gut possess enzymes, such as 7α-dehydroxylase, which can remove the hydroxyl group from the primary bile acids, leading to the production of secondary bile acids [4]. This microbial conversion expands the diversity of bile acid species in the gut. Furthermore, the gut microbiota can influence bile acid metabolism through bile acid deconjugation. Primary bile acids are conjugated with glycine or taurine in the liver, facilitating their solubility and transport. However, some gut bacteria possess bile salt hydrolase enzymes that can deconjugate these bile acids. Deconjugated bile acids are less efficiently reabsorbed in the ileum, leading to increased fecal bile acid excretion. The gut microbiota also impacts bile acid metabolism by regulating bile acid transporters. Bile acids are transported across the intestinal epithelium through various transporters, such as the Apical Sodium-dependent Bile Acid Transporter (ASBT) and the Organic Solute Transporter Alpha/Beta (OSTα/β). The gut microbiota can influence the expression and function of these transporters, thereby modulating the absorption and reabsorption of bile acids.

The emerging understanding of the role of gut microbiota in liver diseases has opened up new avenues for therapeutic interventions and holds promise for future directions in clinical management. Therapeutic strategies targeting the gut microbiota aim to restore microbial homeostasis, modulate microbial composition and function, and mitigate the progression and severity of liver diseases [5]. Some of the current and potential therapeutic implications include probiotics which are live microorganisms that, when administered in adequate amounts, confer health benefits to the host. Prebiotics are substances that selectively stimulate the growth or activity of beneficial gut bacteria. Both probiotics and prebiotics can modulate the gut microbiota, restore microbial diversity, and improve gut barrier function. Clinical studies have shown promising results in using probiotics and prebiotics to manage liver diseases, including NAFLD and liver cirrhosis.

Fecal Microbiota Transplantation (FMT) involves the transfer of fecal material from a healthy donor to a recipient with a dysbiotic gut microbiota. FMT has shown success in treating recurrent Clostridioides difficile infection and is being explored as a potential therapeutic approach for liver diseases. Clinical trials evaluating the efficacy of FMT in liver diseases are underway, with preliminary evidence suggesting its potential benefits in improving liver function and reducing inflammation.

Advancements in high-throughput sequencing technologies and bioinformatics have enabled the identification of specific microbial signatures associated with different liver diseases [6]. Precision medicine approaches aim to develop personalized interventions targeting the unique microbial composition and function of each individual. By analyzing an individual's gut microbiota profile, tailored interventions can be designed; including personalized dietary recommendations, targeted probiotic strains, or antimicrobial therapies. Understanding the specific microbial metabolites and molecular pathways involved in gut-liver crosstalk opens up the possibility of developing novel microbiota-derived therapeutics. For example, modulating the production or metabolism of specific microbial metabolites, such as shortchain fatty acids or secondary bile acids, may hold therapeutic potential in liver diseases.

Conclusion

The gut microbiota plays a crucial role in the pathogenesis of liver diseases through its influence on intestinal barrier integrity, immune modulation, metabolism, and bile acid metabolism. Understanding the mechanisms by which gut microbiota dysbiosis contributes to liver diseases provides valuable insights for the development of innovative therapeutic approaches. Further research and clinical trials are needed to elucidate the therapeutic potential of targeting the gut-liver axis, paving the way for precision medicine interventions in the management of liver diseases.

Acknowledgement

None.

Conflict of Interest

There are no conflicts of interest by author.

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