Abstract
Obesity is a global epidemic affecting chronic inflammatory diseases. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that can occur as an extraintestinal manifestation of inflammatory bowel disease (IBD). Previously we reported that patients with PSC who are obese have a higher risk of advanced liver disease. Currently it is unknown how obesity accelerates or worsens PSC. We evaluated the progression of PSC in an antigen-driven cholangitis mouse model of diet-induced obesity. Obesity was induced in our murine model of immune-mediated cholangitis (OVAbil). OVAbil mice were fed standard chow or high-fat/sucrose diet for twelve weeks followed by induction of biliary inflammation by OVA-specific T cell transfer. Histopathological damage in portal tracts was scored and serum collected. Neutralizing antibodies against IL-15 were administered daily until study termination. Obese mice developed exacerbated liver inflammation and damage. Immune cell phenotyping in liver revealed greater numbers of neutrophils and CD8+ T cells in obese mice. Higher levels of cytokines and chemokines were found in obese mice with cholangitis. Immuno-neutralizing antibodies against IL-15 greatly attenuated cholangitis in obese mice. Obesity exacerbated experimental PSC in part by overproduction of IL-15. Timely targeting of IL-15 may slow the progression of PSC.
Highlights
The dramatic increase in the world-wide prevalence of obesity is recognized as a risk factor for development of numerous complicated co-morbidities[1]
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by the progressive destruction of bile ducts that can lead to portal hypertension[5]
We have previously identified a subpopulation of patients based on body mass index (BMI) who are overweight (BMI 25–30) or obese (BMI >30) with PSC that had more advanced fibrosis at presentation and more rapid fibrosis progression as measured by ultrasound transient elastography (Fig. S1)[9]
Summary
The dramatic increase in the world-wide prevalence of obesity is recognized as a risk factor for development of numerous complicated co-morbidities[1]. The development of chronic, low-grade inflammation associated with obesity may exacerbate inflammatory diseases in other tissues and organs[4]. No effective treatment strategies exist and the persistent liver inflammation associated with PSC can lead to fibrosis requiring liver transplantation or the development of cholangiocarcinoma (CC)[8]. Continued examination of genetic and environmental factors such as diet and lifestyle triggering chronic, uncontrolled inflammation is required to understand the pathogenesis of PSC and for the development of effective therapeutics. The link between obesity and more severe PSC has yet to be examined In this current study we explored the impact of diet-induced obesity during the development of cholangitis by using an antigen-specific murine model of PSC. In addition we identified IL-15 in our model as a critical factor driving inflammation and tissue damage within the livers of obese mice with cholangitis. We evaluated the neutralization of IL-15 in our murine model to gain greater insight into the underlying pathways triggering or accelerating PSC in individuals with obesity in order to identify potential novel therapeutic targets
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