The influence of the intestinal microbiota in humanized mouse models of nonalcoholic fatty liver disease and its role as target using bacteriophage therapy.
Final Report Abstract
Whereas several studies demonstrated that patients with non-alcoholic fatty liver disease (NAFLD) have changes in the composition of the gut bacterial microbiota, we could show that NAFLD is also associated with a lower viral diversity and compositional changes of the intestinal virome. We could further demonstrate that the intestinal virome could contain information about the underlying disease stage, which might be helpful in the future to noninvasively identify patients at risk for disease progression. Viruses are the most abundant microbes in the gut. The majority belongs to bacteriophages, viruses that infect bacteria, replicate inside, and destroy them. In the setting of alcohol-associated liver disease (ALD) and particularly in alcoholic hepatitis, we demonstrated, that, in parallel to a decreased bacterial diversity, the diversity of the intestinal virome is increased. Besides, we observed a lower diversity of intestinal fungi with an overgrowth of Candida sp. in patients with alcoholic hepatitis and alcohol-use disorder when compared with non-alcoholic controls. Serum levels of Saccharomyces cerevisiae antibodies, as systemic immune response to fungal products or fungi were in parallel increased in ALD patients with more advanced disease and high levels were associated with a lower probability of survival. We further identified cytolysin, a twosubunit exotoxin that is secreted by Enterococcus faecalis (E. faecalis) to be highly associated with worse outcome in patients with alcoholic hepatitis. To determine whether cytolysin contributes to liver damage mediated by E. faecalis, mice were gavaged with a cytolytic E. faecalis strain or a non-cytolytic E. faecalis strain; the mice were then placed on a chronicbinge ethanol diet. Compared to mice gavaged with phosphate-buffered saline, mice fed with ethanol after they were gavaged with cytolytic E. faecalis developed more severe liver injury. Using humanized mice that were colonized with bacteria from the feces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Altogether, the projects that I worked on during the fellowship allow a better understanding of the connection between the gut microbiota and the liver, which will eventually lead to improved health outcomes in the setting of NAFLD and ALD.
Publications
- Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. 2019; 575(7783):505-511
Duan Y, Llorente C, Lang S, Brandl K, Chu H, Jiang L, White RC, Clarke TH, Nguyen K, Torralba M, Shao Y, Liu J, Hernandez-Morales A, Lessor L, Rahman IR, Miyamoto Y, Ly M, Gao B, Sun W, Kiesel R, Hutmacher F, Lee S, Ventura-Cots M, Bosques-Padilla F, Verna EC, Abraldes JG, Brown Jr RS, Vargas V, Altamirano J, Caballería J, Shawcross DL, Ho SB, Louvet A, Lucey MR, Mathurin P, Garcia-Tsao G, Bataller R, Tu XM, Eckmann L, van der Donk WA, Young R, Lawley TD, Stärkel P, Pride D, Fouts DE, Schnabl B
(See online at https://doi.org/10.1038/s41586-019-1742-x) - Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients with Alcoholic Hepatitis. Hepatology. 2020 Feb;71(2):522-538
Lang S, Duan Y, Liu J, Ventura-Cots M, Lucey M.R., Bosques Padilla FJ, Mathurin P, Louvet A, Garcia-Tsao G, Verna EC, Abraldes J, Brown RS, Vargas V, Altamirano J, Caballería J, Shawcross D, Ho SB, Bataller R, Tu XM, Stärkel P, Fouts DE, Schnabl B
(See online at https://doi.org/10.1002/hep.30832) - Intestinal virome in patients with alcoholic hepatitis. Hepatology 2020 Dec;72(6):2182-2196
Jiang L, Lang S, Duan Y, Zhang X, Gao B, Chopyk J, Schwanemann L, Ventura- Cots M, Bataller R, Bosques-Padilla F, Verna EC, Abraldes JG, Brown Jr RS, Vargas V, Altamirano J, Caballería J, Shawcross DL, Ho SB, Louvet A, Lucey MR, Mathurin P, Garcia-Tsao G, Kisseleva T, Brenner DA, Tu XM, Stärkel P, Pride D, Fouts DE, Schnabl B
(See online at https://doi.org/10.1002/hep.31459) - Intestinal Virome Signature Associated With Severity of Nonalcoholic Fatty Liver Disease. Gastroenterology 2020 Nov;159(5):1839-1852
Lang S, Demir M, Martin A, Jiang L, Zhang X, Duan Y, Gao B, Wisplinghoff H, Kasper P, Roderburg C, Tacke F, Steffen H-M, Goeser T, Abraldes JG, Tu XM, Loomba R, Stärkel P, Pride D, Fouts DE, Schnabl B
(See online at https://doi.org/10.1053/j.gastro.2020.07.005)
