Immune regulation of chronic hepatitis B virus infection

• Applicant: Dr. Benedikt Hild
• Subject Area: Gastroenterology ; Virology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394568963

• Final Report Year: 2020

Final Report Abstract

Obesity and its consequences are the greatest future challenges in healthcare. Obesity-associated diseases including diabetes, cardiovascular disease and fatty liver disease cause more deaths than all types of cancer combined. Measures such as education, exercise or diet are ineffective on a population level. Based on the concept that the gut microbiome of humans has significantly changed during industrialization, I set out to identify a microbiota-based therapeutic strategy to confer protection from the impact of a high-fat diet. I chose to change the focus of my project to address the metabolic and immunologic response of the entire organism rather than limiting the project to one inflammatory liver disease. This change allowed me to take advantage of the opportunity to employ an exciting new mouse model. Specifically, I investigated the influence of a wild-derived gut microbiome on weight gain and metabolic syndrome in C57BL/6 mice with wild-derived microbiome in comparison to C57BL/6 with conventional laboratory microbiome. C57BL/6 mice with wild-derived natural microbiome (Wildlings) had significantly reduced weight gain during a 10-week course of high-fat, choline-deficient diet compared to C57BL/6 mice with conventional laboratory mouse microbiome (mean weight 34.13 g vs 26.33 g, p=2.32E-09). Severe fatty liver disease with elevated liver enzymes and markers of metabolic syndrome was observed only in the mice with conventional laboratory microbiome. Interestingly we were able to show a greater resilience of the wild-derived microbiome upon perturbance by high-fat diet. Determining the mechanism behind the microbiota’s resilience and if it is causally related to the observed protection from weight gain will be part of my future work. I will further investigate the underlying metabolic responses of wildling mice in order to explain my observations. The health impact of obesity is tremendous and increasing without improvement in sight. Thus it is ever more important to investigate every aspect of obesity pathophysiology and with the promising results from this study and other findings, the microbiome is a very compelling candidate for future therapeutic approaches.

Publications

• Hepatobiliary and Pancreatic: Fulminant liver failure from diffuse leukemoid hepatic infiltration of melanoma. J Gastroenterrol Hepatol. 2017 Nov;32(11):1795
  Schlevogt B, Rehkämper J, Hild B, Schmidt HH
  
• Ion channels in control of pancreatic stellate cell migration. Oncotarget. 2017 Jan 3;8(1):769-784
  Storck H, Hild B, Schimmelpfennig S, Sargin S, Nielsen N, Zaccagnino A, Budde T, Novak I, Kalthoff H, Schwab A
  
• TRPC6 channels modulate the response of pancreatic stellate cells to hypoxia. Pflugers Arch. 2017 Dec;469(12):1567-1577
  Nielsen N, Kondratska K, Ruck T, Hild B, Kovalenko I, Schimmelpfennig S, Welzig J, Sargin S, Lindemann O, Christian S, Meuth SG, Prevarskaya N, Schwab A
  
• Is de novo hepatocellular carcinoma after transjugular intrahepatic portosystemic shunt increased? United European Gastroenterol J. 2018 Apr;6(3):413-421
  Hüsing-Kabar A, Meister T, Köhler M, Domschke W, Kabar I, Wilms C, Hild B, Schmidt HH, Heinzow HS
  
• Laboratory mice born to wild mice have natural microbiota and model human immune responses. Science. 2019 Aug 2;365(6452)
  Rosshart SP, Herz J, Vassallo BG, Hunter A, Wall MK, Badger JH, McCulloch JA, Anastasakis DG, Sarshad AA, Leonardi I, Collins N, Blatter JA, Han SJ, Tamoutounour S, Potapova S, Foster St Claire MB, Yuan W, Sen SK, Dreier MS, Hild B, Hafner M, Wang D, Iliev ID, Belkaid Y, Trinchieri G, Rehermann B