Investigation of the role of the gut microbiome in cholestatic liver diseases
1. Purpose
Primary sclerosing cholangitis (PSC) is a chronic inflammatory biliary disease affecting young individuals. The prevalence of PSC is up to 16.2 per 100 000 population, being highest in northern Europe. PSC is associated with a considerable risk of gastrointestinal malignancies, mainly cholangiocarcinoma and colorectal cancer and PSC patients have fourfold increased mortality risk compared to the general population. Effective medical therapy is currently lacking due to unclear pathogenesis, therefore liver transplantation is the only life-extending therapeutic intervention in patients with end-stage PSC liver disease. Extensive previous work at our center has shown that the gut microbiome (i.e., all microbes of the intestine) is different in patients with PSC compared with controls. Sequencing of all bacterial genes also suggests that they have different functions, i.e., microbial metabolism in PSC patients generates different by-products than in healthy individuals. In presented project, we would like to investigate the role of gut microbiome and its components from patients with PSC or recurrent PSC and how they contribute to biliary disease in human-microbiota associated mouse model.
2. Distress
Planned feeding with 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) diet will result in a gradual and marked weight loss. Faecal microbiota transfer by oral or rectal gavage will cause transient mild distress during physical restraint.
3. Expected benefit
Detection of microbial drivers of PSC, contribution to understand mechanisms of the disease and ultimately novel finding might lead to development of new treatment options.
4. Number of animals, and species
Mus musculus, 560 animals in total.
5. 3R
The replacement option is not applicable since our hypothesis needs to be tested in a complete animal. In vitro experiments without animals have already been performed.
Refinement: we have previously established a relevant pain score sheet that was used in a pilot study with DDC diet in GF and conventional mice to be able to set a clear human endpoint. Moreover, we are currently running a pilot study to evaluate the efficacy of the oral and rectal routes of tranferring human microbiota.
The n-value is 5-16 in each group depending on the type of the experiment, the lowest possible number to ensure trustworthy repeatability.
Primary sclerosing cholangitis (PSC) is a chronic inflammatory biliary disease affecting young individuals. The prevalence of PSC is up to 16.2 per 100 000 population, being highest in northern Europe. PSC is associated with a considerable risk of gastrointestinal malignancies, mainly cholangiocarcinoma and colorectal cancer and PSC patients have fourfold increased mortality risk compared to the general population. Effective medical therapy is currently lacking due to unclear pathogenesis, therefore liver transplantation is the only life-extending therapeutic intervention in patients with end-stage PSC liver disease. Extensive previous work at our center has shown that the gut microbiome (i.e., all microbes of the intestine) is different in patients with PSC compared with controls. Sequencing of all bacterial genes also suggests that they have different functions, i.e., microbial metabolism in PSC patients generates different by-products than in healthy individuals. In presented project, we would like to investigate the role of gut microbiome and its components from patients with PSC or recurrent PSC and how they contribute to biliary disease in human-microbiota associated mouse model.
2. Distress
Planned feeding with 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) diet will result in a gradual and marked weight loss. Faecal microbiota transfer by oral or rectal gavage will cause transient mild distress during physical restraint.
3. Expected benefit
Detection of microbial drivers of PSC, contribution to understand mechanisms of the disease and ultimately novel finding might lead to development of new treatment options.
4. Number of animals, and species
Mus musculus, 560 animals in total.
5. 3R
The replacement option is not applicable since our hypothesis needs to be tested in a complete animal. In vitro experiments without animals have already been performed.
Refinement: we have previously established a relevant pain score sheet that was used in a pilot study with DDC diet in GF and conventional mice to be able to set a clear human endpoint. Moreover, we are currently running a pilot study to evaluate the efficacy of the oral and rectal routes of tranferring human microbiota.
The n-value is 5-16 in each group depending on the type of the experiment, the lowest possible number to ensure trustworthy repeatability.