Fatty liver versus autoimmunity of the bile ducts - defining the gut signals driving steatosis and inflammatory disease of the gut-liver axis

Introduction

The obesity epidemic has caused a surge of metabolic-dysfunction associated steatotic liver disease (MASLD), an important cause of morbidity and mortality. This also leads to other liver diseases presenting with steatotic (fatty) liver as a “second hit,” with unpredictable impact on clinical outcome.

Project Overview

In the present project, I will use the co-existence of two different liver diseases to study how the gut microbiome interacts with steatosis and autoimmunity. Both MASLD and primary sclerosing cholangitis (PSC), an autoimmune disease of the bile ducts, are more common in inflammatory bowel disease (IBD) than in the population, suggesting they are driven by gut microbial activity (gut signals).

However, MASLD and PSC co-exist less frequently than expected, appearing to protect against each other. Separate gut signals could therefore influence these conditions, and a driver of one disease could even protect against the other. Studies of PSC-MASLD-IBD provide a unique window to define how gut signals interact to cause and drive liver health, which would be of great importance in MASLD and PSC, where few effective therapies are available.

Research Motivation

I have in the ongoing ERC Starting Grant StopAutoimmunity shown that PSC is associated with large changes in microbial functions, motivating the novel hypothesis that distinct gut-derived signals drive autoimmunity of the bile ducts and steatotic liver disease.

Methodology

I will use an extensive set of methods established in my group to define the gut signals acting in PSC and MASLD and liver health. I have available unique cohorts and materials from these conditions, and experimental models based on the human microbiome.

Expected Outcomes

The expected outcomes include:

1. The first detailed description of this clinical problem.
2. The identification of distinct gut signals driving and protecting against steatosis and biliary autoimmunity.
3. Serving as a basis for diagnostic and prognostic tools.
4. New targets relevant for trials to prevent and treat liver disease.