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Gut Microbes May Play a Role in Age-Related Hepatitis B Virus Clearance

Treating adult mice with antibiotics to wipe out their intestinal microbiota made them unable to naturally clear hepatitis B virus (HBV), so they became more like young mice that developed chronic infection, according to a report in the February 2 Proceedings of the National Academy of Sciences. The researchers also showed that mice lacking toll-like receptor 4 (TLR4) cleared HBV regardless of age.

Among people infected with HBV as adults, up to 95% will clear the virus spontaneously without treatment. In contrast, most exposed infants and young children develop immune tolerance and do not clear HBV, resulting in chronic infection; the likelihood of natural clearance rises with age.

Han-Hsuan Chou from National Taiwan University and colleagues investigated age-related HBV clearance in a mouse model. Mice are not natural hosts for HBV. Instead, HBV DNA is transfected into the livers of mice, resulting in production of viral proteins and partial virus that can be used to study immune responses and test therapies.

The researchers injected different strains of adult (12 weeks old) and young (6 weeks old) mice with HBV DNA. Some mice were then treated with an antibiotic that sterilized or eradicated their normal gut microbes. They also looked at a strain of mutated mice lacking toll-like receptor 4 (TLR4), which plays a role in immune response to lipopolysaccharide produced by gut bacteria.

Results

• Adult C3H/HeN mice cleared HBV infection within 6 weeks after injection.
• Antibiotic sterilization of gut microbiota from 6 to 12 weeks of age, however, prevented adults from rapidly clearing HBV.
• Young C3H/HeN mice continued to test positive for HBV 26 weeks after injection.
• Young C3H/HeJ mice with the toll-like-receptor 4 (TLR4) mutation showed rapid HBV clearance.

"The results suggest that an immuno-tolerating pathway to HBV prevailed in young mice, before the establishment of gut bacteria, through a TLR4-dependent pathway and that the maturation of gut microbiota in adult mice stimulated liver immunity, resulting in rapid HBV clearance," the study authors summarized.

That is, young mice naturally tolerate HBV, but this immune tolerance decreases as the mice -- and their gut microbiota -- mature. Eradicating gut bacteria, however, interferes with this process, and antibiotic-treated older mice retain their immune tolerance and do not clear the virus.

"In adult mice, the maturation of gut bacteria might transmit signals to the liver to break liver tolerance, resulting in rapid HBV clearance," the researchers suggested in their discussion. "The depletion of gut bacteria in the adult C3H/HeN mice [treated with antibiotics] restored the tolerance phenotypes as if they were young mice."

They noted, however, that different mouse strains showed different age-related immune-tolerance patterns. While the TLR4 mutation in the C3H/HeJ mice might have contributed to rapid HBV clearance compared with the C3H/HeN mice, other mouse strains without the TLR4 mutation nevertheless show rapid clearance, indicating that additional factors are involved in immune development.

"The differences between tolerant and resistant strains might help to shed light on the immune activation that determines the outcomes of HBV infection," they wrote. "In conclusion, using the hydrodynamic transfection method, we demonstrated that host genetics and age, and their interaction, are crucial in the generation of strong, diverse immune responses against HBV."

2/5/15

Reference

H-H Chou, W-H Chien, L-L Wu, et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota. Proceedings of the National Academy of Sciences. February 2, 2015 (Epub ahead of print).