Matthew Carson, PhD

American Liver Foundation Postdoctoral Research Fellowship Award
$25,000 over one year

University of Pittsburgh

Dysbiosis in the Gut-Liver Axis Drives Bone Loss During Cholestatic Liver Disease

Mentor: Kari Nejak-Bowen, MBA, PhD

Cholestatic liver disease (CLD) refers to liver conditions with reduced or blocked bile flow from the liver. Currently, there are a few effective treatments for CLDs, and the only life-extending treatment is liver transplantation. There are several causes for CLDs. Of interest is the disruption in the gut-liver axis. The gut-liver axis is the relationship and interactions between the gut microbiota and the liver. The gut microbiota comprises trillions of microbes that can contribute to health and disease. Changes in the gut microbiota composition and function can have harmful effects on host health. This study, in part, focuses on how changes in the gut microbiota contribute to CLD progression and its comorbidities.

CLD patients have less bone mass and lose bone faster than healthy individuals. However, the causes are largely unknown. Further, there is no consensus treatment for bone loss in CLD patients. In health, the gut-liver axis has been shown to impact bone cell actions through bile acids, which are synthesized in the liver from cholesterol and metabolized by microbes in the gut. Bile acids can signal at bone cells through the farnesoid X receptor (FXR). Activation of FXR supports bone formation, while inhibited FXR signaling promotes bone resorption. However, the role of bile acid signaling on bone cell functions during CLD is currently unknown.

In our study, mice with CLD have shifts in their gut microbiota and lower bone mass. In their bone marrow, there are increases in bile acids that inhibit FXR signaling. Since FXR activity promotes bone formation and suppresses bone loss, it is likely that disruption in the gut-liver axis and bile acid signaling contribute to bone loss in CLD mice. Findings from this award will define the relationship between the gut microbiota, cholestasis, and bone loss and support future studies targeting the gut microbiota to treat cholestasis and bone loss.