TY - JOUR
T1 - Modeling dysbiosis of human NASH in mice
T2 - Loss of gut microbiome diversity and overgrowth of Erysipelotrichales
AU - Carter, James K.
AU - Bhattacharya, Dipankar
AU - Borgerding, Joshua N.
AU - Fiel, M. Isabel
AU - Faith, Jeremiah J.
AU - Friedman, Scott L.
N1 - Publisher Copyright:
© 2021 Carter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2021/1
Y1 - 2021/1
N2 - Background & aim Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that is responsible for a growing fraction of cirrhosis and liver cancer cases worldwide. Changes in the gut microbiome have been implicated in NASH pathogenesis, but the lack of suitable murine models has been a barrier to progress. We have therefore characterized the microbiome in a well-validated murine NASH model to establish its value in modeling human disease. Methods The composition of intestinal microbiota was monitored in mice on a 12- or 24-week NASH protocol consisting of high fat, high sugar Western Diet (WD) plus once weekly i.p injection of low-dose CCl4. Additional mice were subjected to WD-only or CCl4-only conditions to assess the independent effect of these variables on the microbiome. Results There was substantial remodeling of the intestinal microbiome in NASH mice, characterized by declines in both species diversity and bacterial abundance. Based on changes to beta diversity, microbiota from NASH mice clustered separately from controls in principal coordinate analyses. A comparison between WD-only and CCl4-only controls with the NASH model identified WD as the primary driver of early changes to the microbiome, resulting in loss of diversity within the 1st week. A NASH signature emerged progressively at weeks 6 and 12, including, most notably, a reproducible bloom of the Firmicute order Erysipelotrichales. Conclusions We have established a valuable model to study the role of gut microbes in NASH, enabling us to identify a new NASH gut microbiome signature.
AB - Background & aim Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that is responsible for a growing fraction of cirrhosis and liver cancer cases worldwide. Changes in the gut microbiome have been implicated in NASH pathogenesis, but the lack of suitable murine models has been a barrier to progress. We have therefore characterized the microbiome in a well-validated murine NASH model to establish its value in modeling human disease. Methods The composition of intestinal microbiota was monitored in mice on a 12- or 24-week NASH protocol consisting of high fat, high sugar Western Diet (WD) plus once weekly i.p injection of low-dose CCl4. Additional mice were subjected to WD-only or CCl4-only conditions to assess the independent effect of these variables on the microbiome. Results There was substantial remodeling of the intestinal microbiome in NASH mice, characterized by declines in both species diversity and bacterial abundance. Based on changes to beta diversity, microbiota from NASH mice clustered separately from controls in principal coordinate analyses. A comparison between WD-only and CCl4-only controls with the NASH model identified WD as the primary driver of early changes to the microbiome, resulting in loss of diversity within the 1st week. A NASH signature emerged progressively at weeks 6 and 12, including, most notably, a reproducible bloom of the Firmicute order Erysipelotrichales. Conclusions We have established a valuable model to study the role of gut microbes in NASH, enabling us to identify a new NASH gut microbiome signature.
UR - http://www.scopus.com/inward/record.url?scp=85099331843&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0244763
DO - 10.1371/journal.pone.0244763
M3 - Article
C2 - 33395434
AN - SCOPUS:85099331843
SN - 1932-6203
VL - 16
JO - PLoS ONE
JF - PLoS ONE
IS - 1 January 2021
M1 - e0244763
ER -