Bile acids(BAs)are cholesterol-derived molecules that are produced in the liver,secreted into the duodenum,absorbed by the small intestine and recycled back to the liver[1].BAs regulate cholesterol metabolism,promote ...Bile acids(BAs)are cholesterol-derived molecules that are produced in the liver,secreted into the duodenum,absorbed by the small intestine and recycled back to the liver[1].BAs regulate cholesterol metabolism,promote bile secretion,and emulsify and facilitate the digestion and absorption of dietary fats;in addition,there is growing evidence that BAs also act as endocrine cell signaling mediators that activate nuclear or membrane-localized receptors to trigger specific signaling pathways and regulate various biological processes,including immunity[2,3].Findings from studies in patients and cell or mouse models support the notion that BAs are critical regulators of the development of liver diseases,including chronic hepatitis B(CHB)[4],liver cirrhosis(LC)[5],and hepatocellular carcinoma(HCC)[6].Here,we discuss the emerging roles of BAs in the progression of CHB,LC,and HCC.展开更多
Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood...Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3^(+)CD8^(+) T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3^(+)CD8^(+) T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3^(+)CD8^(+) T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.展开更多
基金This work was supported by the National Natural Science Foundation of China(grant numbers 82030063,82102467)the Fujian Provincial Health Technology Project(grant number 2020QNA040).
文摘Bile acids(BAs)are cholesterol-derived molecules that are produced in the liver,secreted into the duodenum,absorbed by the small intestine and recycled back to the liver[1].BAs regulate cholesterol metabolism,promote bile secretion,and emulsify and facilitate the digestion and absorption of dietary fats;in addition,there is growing evidence that BAs also act as endocrine cell signaling mediators that activate nuclear or membrane-localized receptors to trigger specific signaling pathways and regulate various biological processes,including immunity[2,3].Findings from studies in patients and cell or mouse models support the notion that BAs are critical regulators of the development of liver diseases,including chronic hepatitis B(CHB)[4],liver cirrhosis(LC)[5],and hepatocellular carcinoma(HCC)[6].Here,we discuss the emerging roles of BAs in the progression of CHB,LC,and HCC.
基金We thank all the staff and patients of our hospital for the provision of the samples used in this study.This work was supported by the National Natural Science Foundation of China(Grant numbers 81971996,82030063,81672101,81702073)the Joint Funds for the Innovation of Science and Technology,Fujian Province(Grant number 2019Y9017).
文摘Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3^(+)CD8^(+) T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3^(+)CD8^(+) T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3^(+)CD8^(+) T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.
