Tackling the fatty liver by targeting the gut

BERAZA_Q23DTP1

Obesity has epidemic proportions in the UK as more than 60% of adults are overweight and 33% have fatty liver. Western diets are the main contributors to liver fat accumulation but have also broader effects, including profound changes in the gut microbiome and promoting intestinal permeability that allows the leak of bacteria products from the intestine to the liver where contribute to inflammation and disease progression.

This project aims to define the mechanisms mediating the crosstalk amongst the liver, the intestine and the microbiome during the progression from a fatty liver to chronic inflammation. This will enable the student to propose targets to preserve gut-liver health and prevent disease progression associated to poor dietary habits, which will be investigated in this project.

This cross-disciplinary and collaborative project provides the unique opportunity for the successful candidate to receive broad training on ‘dry-’ and ‘wet’-science techniques. The project will be supervised by a molecular biologist (Beraza) and co-supervised by a bioinformatician (Hildebrand). This team will train the student in a series of preclinical in vivo models; molecular biology and immunology methodologies; and complex techniques like confocal microscopy and flow cytometry-based cell sorting.

In parallel, the student will receive training on metagenomics and metatranscriptomics analysis with state-of-the-art bioinformatics analytical tools, which will be used to characterise the intestinal microbiome.

This collaborative project will enable the student to work in different labs and research areas and to present their results to wide-ranging audiences in conferences and meetings. The multidisciplinary nature of this project will contribute to build a broad network and will provide the student valuable transferable skills essential for the progression of their scientific career.

This project will be carried out at the Quadram institute, which combines research laboratories with clinical facilities, located at the core of the Norwich Research Park.

References

1. Blokker, B. A. et al. Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease. Hepatology 69, 699-716, doi:10.1002/hep.30275 (2019).

2. Isaacs-Ten, A. et al. Metabolic Regulation of Macrophages by SIRT1 Determines Activation During Cholestatic Liver Disease in Mice. Cell Mol Gastroenterol Hepatol 13, 1019-1039, doi:10.1016/j.jcmgh.2021.12.010 (2022).

3. Isaacs-Ten, A. et al. Intestinal Microbiome-Macrophage Crosstalk Contributes to Cholestatic Liver Disease by Promoting Intestinal Permeability in Mice. Hepatology 72, 2090-2108, doi:10.1002/hep.31228 (2020).

4. Hildebrand, F. et al. Dispersal strategies shape persistence and evolution of human gut bacteria. Cell Host Microbe 29, 1167-1176 e1169, doi:10.1016/j.chom.2021.05.008 (2021).