Bile acid sequestration reverses liver injury and prevents progression of nonalcoholic steatohepatitis in Western diet-fed mice

J Biol Chem. 2020 Apr 3;295(14):4733-4747. doi: 10.1074/jbc.RA119.011913. Epub 2020 Feb 19.


Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal bile acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of bile acids can greatly disrupt metabolic homeostasis. Bile acid sequestrants are orally administered polymers that bind bile acids in the intestine, forming nonabsorbable complexes. Bile acid sequestrants interrupt intestinal reabsorption of bile acids, decreasing their circulating levels. We determined that treatment with the bile acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet-induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and bile acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.

Keywords: bile acid; bile acid sequestrants; lipid metabolism; liver injury; liver metabolism; metabolomics; microbiome; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / chemistry
  • Bile Acids and Salts / metabolism*
  • Cecum / microbiology
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Cholesterol / analysis
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • Diet, Western*
  • Disease Models, Animal
  • Feces / chemistry
  • Gastrointestinal Microbiome / drug effects
  • Lactobacillus / drug effects
  • Lipid Metabolism / drug effects
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Non-alcoholic Fatty Liver Disease / prevention & control
  • Sevelamer / chemistry
  • Sevelamer / pharmacology*
  • Sevelamer / therapeutic use
  • Severity of Illness Index
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism


  • Bile Acids and Salts
  • Chemokine CCL2
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Transforming Growth Factor beta
  • Cholesterol
  • Sevelamer