The Role of Intestinal Microbiota, Bile Acids, and Th17/IL-17 Axis in HBV-Related Liver Fibrosis

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The Role of Intestinal Microbiota, Bile Acids, and Th17/IL-17 Axis in HBV-Related Liver Fibrosis

Did you know 90 million people in China live with chronic hepatitis B virus (HBV) infection? HBV is a leading cause of liver cirrhosis and cancer, but new research is uncovering a surprising link between gut health—specifically the trillions of bacteria in our intestines (gut microbiota)—and the progression of HBV-related liver damage. Here’s what we know about how gut bacteria, bile acids, and a key immune pathway (the Th17/IL-17 axis) work together to drive liver fibrosis.

Gut Microbiota: A Hidden Player in HBV Clearance

Your gut microbiota isn’t just for digestion—it’s a critical part of your immune system. Studies show mature gut bacteria help the body clear HBV. In mouse experiments, adult mice with stable gut communities cleared HBV within 6 weeks of infection, while young mice with immature microbiota kept the virus longer. Even adult mice given antibiotics (which disrupt gut bacteria) took longer to get rid of HBV.

In people, the evidence is equally compelling. A clinical trial found combining standard antiviral drugs with fecal microbiota transplantation (FMT)—transferring healthy gut bacteria from a donor—significantly reduced HBV levels, improved liver function, and helped clear a key viral marker (HBeAg) in chronic HBV patients. This tells us gut bacteria are essential to how the body fights HBV—though exactly how remains a mystery.

Th17 Cells: The Double-Edged Sword of Inflammation

Enter Th17 cells—a type of immune cell that secretes inflammatory molecules like IL-17 and IL-22. Normally, Th17 cells protect against infections, but too many can cause harm. In HBV-related liver fibrosis, Th17 cells overactivate two types of liver cells:

  • Hepatic stellate cells: Cells that produce scar tissue (fibrosis).
  • Kupffer cells: The liver’s resident immune cells that drive inflammation.

For HBV patients, more Th17 cells in the blood and liver correlate with higher liver enzyme levels (a sign of damage) and more severe fibrosis. The good news? Antiviral therapy lowers Th17 levels as viral load drops—linking HBV activity directly to this immune pathway.

Where Do Th17 Cells Come From? The Gut

Most Th17 cells start in the intestinal lamina propria—the gut’s inner lining, which is packed with immune cells. Gut microbiota balances Th17 cells with regulatory T cells (Tregs)—cells that calm inflammation. Here’s the proof:

  • Mice with no gut bacteria (germ-free) have far fewer Th17 cells than mice with normal bacteria.
  • Transferring healthy gut bacteria to germ-free mice restores Th17 levels.
  • Early-life antibiotic use (like low-dose penicillin) changes gut bacteria and reduces Th17 cells, while vancomycin (another antibiotic) lowers Th17 cells in the lungs—showing how gut health affects immune cells elsewhere in the body.

Bile Acids: The Middlemen Between Gut Bacteria and Th17

Gut bacteria don’t act alone—they change how our bodies process bile acids, digestive fluids made by the liver. Bacteria turn “primary” bile acids (made by the liver) into “secondary” bile acids, which signal immune cells. A 2019 study identified two secondary bile acids (3-oxo lithocholic acid and isoallo lithocholic acid) that reduce Th17 cells and increase Tregs—directly balancing inflammation.

Another study found bile acids regulate a protein (RORγ) that controls Treg cells. Without bile acids, Tregs drop, and inflammation rises. This suggests bile acids are the “middlemen” between gut bacteria and Th17 cell growth—translating microbial changes into immune responses.

Putting It All Together: A New Hypothesis for HBV-Related Fibrosis

Researchers propose this chain reaction:

  1. HBV changes gut microbiota: Chronic HBV infection alters the balance of bacteria in the gut.
  2. Bile acid pool shifts: These bacterial changes rewrite the “menu” of bile acids in the gut.
  3. More Th17 cells: The new bile acids push naive T cells to become Th17 cells.
  4. Th17 cells migrate to the liver: Chemical signals (like CCL20) draw Th17 cells from the gut to the liver.
  5. Fibrosis starts: In the liver, Th17 cells secrete IL-17 and IL-22, activating scar-producing cells and driving inflammation.

What’s Next?

While many questions remain—like which specific bacteria or bile acids are most important—targeting this axis (gut microbiota → bile acids → Th17/IL-17) could revolutionize HBV treatment. Imagine therapies that restore healthy gut bacteria, balance bile acids, or calm overactive Th17 cells—all to stop fibrosis before it becomes cirrhosis or cancer.

This article summarizes research by Yan-Fei Chen, Jiu Chen, and Lan-Juan Li from the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases at Zhejiang University, China. The original study was published in the Chinese Medical Journal in 2020.

doi.org/10.1097/CM9.0000000000001199

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