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Recurrent disease in the liver transplant: window to identify and stop gut signals driving autoimmunity

Periodic Reporting for period 2 - StopAutoimmunity (Recurrent disease in the liver transplant: window to identify and stop gut signals driving autoimmunity)

Reporting period: 2020-10-01 to 2022-03-31

Autoimmune disease is an increasing health concern. When immunosuppression fails there is little to offer in terms of therapy. However, diseases of autoimmunity are often strongly associated with changes in the microbes of the gut, i.e. an altered gut microbiome. We have coined the term "gut signals" to describe microbial factors from the intestine. In the present project we investigate the hypothesis that "gut signals" unaffected by immunosuppression are key drivers of autoimmune diseases. We consider the gut microbiome as a biochemical factory, from which products and by-producs are generated and may be absorbed to our bodies. These microbial products circulate and may influence health and disease. We can identify "gut signals" either by identifying genetic alterations in the gut microbiome that may be increasing or decreasing the ability to make specific products, or by investigating the presence of such products in blood.

This hypothesis is investigated by using a an autoimmune disease of the bile ducts of the liver as a model system. The disease is called primary sclerosing cholangitis (PSC), and during the disease course, chronic inflammation of the bile ducts leads to scarring, accumulation of bile in the liver and ultimately liver failure. PSC is therefore one of the most common reasons for liver transplantation. After transplantation there is unfortunately a high risk of recurrent PSC (rPSC) although the patients receive special immunosuppressive therapy in order to tolerate their new liver. There is no medical treatment available that has been shown to slow or prevent the disease or disease progression in either PSC or rPSC. These conditions are therefore both challenging clinical and societal problems. In the context of research, however, the phenomenon of recurrent disease after a transplantation also represents an opportunity to study disease mechanisms in detail, because the patients are followed closely. This is what we like to call "the post transplant window". The mechanisms of autoimmunity, which we discover in PSC/rPSC, could be relevant also for other autoimmune diseases. Our projects may therefore serve both disease-specific and more general purposes.

The overall objectives of the study are to identify "gut signals" that are present in both PSC and rPSC (suggesting that the same signals are driving disease all the time). We will do this by investigating microbial genes in the intestine and microbial products in blood. In the next phase we will look for possible treatments to alter these "gut signals" and finally we will perform a pilot trial to test the potential of such a treatment to influence the disease. The outcome of StopAutoimmunity will be gut signals useful as novel biomarkers and treatment targets. These may directly translate into improved patient care but also provide a foundation for understanding the mechanisms of autoimmunity.
We have so far investigated in detail the gut microbial genes before liver transplantation, while the details after transplantation are pending. We have found clear signs of reduced potential to produce of certain essential nutrients in the gut bacteria, including some vitamins and amino acids. Importantly, we see that the corresponding levels of these nutrients in blood are reduced in patients with PSC, and low levels associate with poor prognosis. Overall, we therefore speculate that altered microbial metabolism may influence the disease course, opening for testing of potential treatment. Further studies will reveal if these phenomena also are relevant for recurrent disease.
We have also performed a large scale analysis of >1000 different biochemical substances in blood, some of which are of bacterial origin. This is a very important discovery tool and we already have interesting observations that we follow up on.
We already know a lot more than at the beginning of the project. Based on published and preliminary data I believe we will be able to link more than one "gut signal" to disease progression within the project time, and we will be way underway in running a clinical trial testing how and whether relevant therapy may work. We believe the findings will contribute to changes in clinical practice.