Microbiomes in One Health – Doctoral Training Unit
P12: Gut microbiota derived bile acids in chronic liver and metabolic diseases
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- P12: Gut microbiota derived bile acids in chronic liver and metabolic diseases
Principal Investigator Jochen Schneider
Host Institution LCSB
Project Research Question: Role of microbiota derived metabolites in processes that lead to chronic liver diseases using 3D liver organoids
Abstract
The gut microbiota is implicated in a range of chronic liver diseases from NAFLD to liver fibrosis. Many of these effects occur either through secondary metabolite signalling (bile acids) or by the spilling of bacterial endotoxins in the liver leading to inflammation and liver parenchymal death. Bile acids are also involved in the regulation of metabolic homeostasis and we have shown that distinct changes in bile acid composition introduced through weigh loss are associated with improved insulin sensitivity. Bile acids (BA) are intricately implicated in important functions of the liver especially via their direct effects on the nuclear receptors namely Farnesoid X receptor (FXR) and the small heterodimer partner (SHP). Many of the effects of BA have been studied in animal models and have provided important insights into the mechanism of regulation. There are also several clinical studies that point to the potential of using BA as therapeutic agents and as metabolic modulators. The beneficial effects of bariatric surgery on glucose metabolism and weight loss, for instance, has partly been attributed to bile acid changes in the small intestine. Hence, there is an unmet need for a human hepatic in vitro model that could be used in a high throughput way for the screening of compounds that modulate human BA homeotasis. 3D in vitro organoid cultures resemble in vivo by retaining liver functions and maintaining cell communications and signalling. Cell shape also effects epigenetic plasticity which is also very important in BA homeostasis. Therefore, such 3D cultures have high potential in BA research especially since these are amenable to co-culture with the microbiome. We will study the effects of bacterial secondary metabolites of bile acids on glucose homeostasis in human liver cultures. On the other hand, co-cultures of liver organoids and gut microbiome in the HuMix system will be established to study microbiome dependent changes in the hepatocyte function and physiology.
Methods
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3D cell culture and co-cultures
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ELISA, GC-MS, LC-MS
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Gene expression analysis
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Epigenetics
