The Role of Intestinal Microbiota, Bile Acids, and Th17/IL-17 Axis in Hepatitis B Virus-Related Liver Fibrosis
Hepatitis B virus (HBV) infection remains a significant public health issue, particularly in China, where it affects approximately 90 million people. Chronic HBV infection is a leading cause of liver cancer and cirrhosis, with hepatic fibrosis being the underlying pathological process that drives these conditions. Recent research has highlighted the potential roles of intestinal microbiota, bile acids, and the T helper (Th)17/interleukin (IL)-17 axis in the development and progression of HBV-related liver fibrosis. This article provides a comprehensive overview of the interplay between these factors and their contributions to liver fibrosis in the context of chronic HBV infection.
The Role of Intestinal Microbiota in HBV Infection and Liver Fibrosis
The intestinal microbiota, a complex community of microorganisms residing in the gut, plays a crucial role in maintaining immune homeostasis and influencing systemic health. In the context of HBV infection, the composition and maturity of the intestinal microbiota have been shown to significantly impact the immune response to the virus. Studies using HBV-transfected mouse models have demonstrated that the clearance of the virus is highly dependent on the establishment of a mature intestinal microbiota. Adult mice with a stable and mature gut microbiota were able to completely clear the virus within six weeks of HBV plasmid injection, whereas young mice with immature microbiota exhibited persistent viral infection. Furthermore, the administration of antibiotics delayed viral clearance in adult mice, underscoring the importance of a healthy gut microbiota in mounting an effective immune response against HBV.
Clinical studies have also provided evidence supporting the role of intestinal microbiota in HBV infection. In patients with chronic HBV infection, the combination of nucleoside antiviral drugs with fecal microbiota transplantation (FMT) significantly reduced viral load, increased HBV E antigen conversion, and improved liver function. These findings suggest that modulating the intestinal microbiota could be a potential therapeutic strategy for managing chronic HBV infection and preventing the progression to liver fibrosis.
The Th17/IL-17 Axis in Chronic Inflammation and Liver Fibrosis
Th17 cells, a subset of CD4+ T cells, are known to play a pivotal role in chronic inflammation and immune-related diseases. These cells secrete pro-inflammatory cytokines such as IL-17 and IL-22, which can activate hepatic stellate cells and Kupffer cells, leading to the overproduction and accumulation of extracellular matrix components. This process is a key driver of liver fibrosis, which underlies the development of cirrhosis and liver cancer.
In patients with chronic HBV infection, elevated levels of Th17 cells have been observed in both peripheral circulation and liver tissue. The number of Th17 cells in the peripheral blood of these patients is significantly higher than in healthy controls and is positively correlated with serum alanine aminotransferase (ALT) levels, a marker of liver injury. Similarly, the infiltration of Th17 cells into liver tissue is associated with the severity of liver inflammation and fibrosis. Antiviral therapy with nucleoside analogs has been shown to reduce the levels of Th17 cells and IL-17 in the peripheral blood of chronic HBV patients, suggesting that controlling viral replication can mitigate the Th17-mediated inflammatory response.
Migration of Th17 Cells to the Liver in HBV Infection
Th17 cells in the liver are thought to originate primarily from the intestinal lamina propria, which contains a high density of CD4+ T cells, including Th17 and regulatory T cells (Tregs). HBV infection induces the migration of Th17 cells from the periphery to the liver through the upregulation of chemokines such as CCL17, CCL20, and CCL22 in hepatocytes. In patients with chronic HBV infection, the mRNA levels of these chemokines are significantly elevated compared to uninfected controls. In vitro experiments have confirmed that HBV DNA can induce hepatocytes to express Th17 chemokines, further supporting the role of HBV in promoting the migration of Th17 cells to the liver.
The Influence of Intestinal Microbiota on Th17 Cell Differentiation
The differentiation of Th17 cells is influenced by the composition of the intestinal microbiota. Specific commensal bacteria, such as segmented filamentous bacteria, Citrobacter rodentium, and Escherichia coli O157, have been shown to directly stimulate the differentiation of Th17 cells. Additionally, a mixture of 20 bacterial strains isolated from fecal flora, including Clostridium, Bifidobacterium, Ruminococcus, and Bacteroides, has been found to promote Th17 cell differentiation. The intestinal microbiota also plays a role in maintaining the balance between Th17 and Treg cells, which is crucial for immune regulation.
Germ-free mice, which lack intestinal microbiota, have significantly fewer Th17 cells in the intestinal lamina propria compared to specific pathogen-free (SPF) mice. Transplantation of intestinal microbiota from normal mice to germ-free mice increases the number of Th17 cells, demonstrating the direct influence of gut bacteria on Th17 cell differentiation. Moreover, early-life exposure to low-dose penicillin alters the composition of the intestinal microbiota and affects the differentiation of Th17 cells and the expression of IL-17, highlighting the long-term impact of microbiota modulation on immune responses.
The Role of Bile Acids in Mediating the Microbiota-Th17 Interaction
Bile acids, which are synthesized in the liver and metabolized by the intestinal microbiota, play a critical role in mediating the interaction between gut bacteria and Th17 cells. Intestinal bacteria produce enzymes such as choline dehydrogenase and steroid dehydrogenase, which modify bile acids and contribute to the formation of secondary bile acids. These secondary bile acids can stimulate intestinal epithelial cells and immune cells in the lamina propria to produce inflammatory regulatory factors, thereby influencing the immune response.
Recent studies have identified specific bile acid metabolites, such as 3-oxo lithocholic acid (LCA) and isoallo LCA, that can reduce the differentiation of Th17 cells and promote the differentiation of Treg cells. The composition of the intestinal bile acid pool has also been shown to regulate the expression of the transcription factor RORγt on colonic Treg cells. Disruption of the bile acid metabolic pathway reduces the number of intestinal Treg cells, while restoration of the bile acid pool increases the number of RORγt+ Treg cells and ameliorates colonic inflammation. These findings suggest that bile acids play a key role in mediating the regulatory effects of intestinal microbiota on Th17 cell differentiation and immune homeostasis.
A Proposed Mechanism for HBV-Related Liver Fibrosis
Based on the evidence presented, a potential mechanism for the development of HBV-related liver fibrosis can be proposed. In chronic HBV infection, distinct alterations in the gut microbiota lead to changes in the composition of the intestinal bile acid pool. These changes stimulate naive T cells to differentiate into Th17 cells, which then enter the peripheral circulation and migrate to the liver via chemokines such as CCL20. Once in the liver, Th17 cells secrete IL-17 and IL-22, which activate hepatic stellate cells and Kupffer cells, leading to the overproduction of extracellular matrix components and the progression of liver fibrosis.
While this hypothesis provides a framework for understanding the role of intestinal microbiota, bile acids, and the Th17/IL-17 axis in HBV-related liver fibrosis, many aspects of the underlying mechanisms remain to be elucidated. Further research is needed to fully uncover the complex interactions between these factors and to explore the therapeutic potential of targeting the microbiota-bile acid-Th17/IL-17 axis in the treatment of HBV infection and its complications.
doi.org/10.1097/CM9.0000000000001199
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