Periodic Reporting for period 4 - StopAutoimmunity (Recurrent disease in the liver transplant: window to identify and stop gut signals driving autoimmunity)
Reporting period: 2023-10-01 to 2024-03-31
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 may 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.
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.
Regarding gut microbiota composition and gut microbial genes, these have been investigated both before and after liver transplantation. We find extensive differences in the microbiome in PSC, which is not improved after liver transplantation. Rather, the gut microbiome seems to be more severe altered after liver transplantation compared with healthy people, irrespective of whether a recurrence of the disease has taken place. Overall, this suggests that gut microbiome after liver transplantation could also be a source of driving factors for the disease, and provides a strong rationale for studying PSC and recurrent PSC further in parallel. Furthermore, the findings suggest that gut microbial functions (gut signals) are of importance.
Following the characterisation of the altered gut microbial functions, we found clear signs of reduced potential to produce of certain essential nutrients in the gut bacteria, including some vitamins and amino acids. Importantly, we found that the corresponding levels of these nutrients in blood are reduced in patients with PSC, and low levels associate with poor prognosis. In particular, this was the case for the essential vitamin B6. Deficiency of active vitamin B6 (pyridoxine-5-phoshate, or PLP) was highly prevalent and associated with increased chanced of liver transplantation-free survival. Vitamin B6 therefore seems to be an important biomarker of disease severity. In addition it is a potential treatment target, and as part of this project we have developed and now opened a clinical trial to test the effect of vitamin B6 therapy in PSC.
In addition, we have performed a large scale analysis of >1000 different biochemical substances in blood, some of which are of bacterial origin. Since the liver is a major regulator of the human metabolism, many of the measued biochemicals are altered just because liver disease is present and not because they are important for disease. We have used this project to develop analytical approaches to detect which are really important, and we believe we have detected key microbial factors that could be driving liver disease and thus represent important project in this field.
Although many of these observations are already published, we are still working on some of the findings, thus the project is a rich source of new data on PSC. However, the perhaps most important output is the potential of new biomarkers and therapy, which could influence clinical care within a fairly short timeframe.
Following the characterisation of the altered gut microbial functions, we found clear signs of reduced potential to produce of certain essential nutrients in the gut bacteria, including some vitamins and amino acids. Importantly, we found that the corresponding levels of these nutrients in blood are reduced in patients with PSC, and low levels associate with poor prognosis. In particular, this was the case for the essential vitamin B6. Deficiency of active vitamin B6 (pyridoxine-5-phoshate, or PLP) was highly prevalent and associated with increased chanced of liver transplantation-free survival. Vitamin B6 therefore seems to be an important biomarker of disease severity. In addition it is a potential treatment target, and as part of this project we have developed and now opened a clinical trial to test the effect of vitamin B6 therapy in PSC.
In addition, we have performed a large scale analysis of >1000 different biochemical substances in blood, some of which are of bacterial origin. Since the liver is a major regulator of the human metabolism, many of the measued biochemicals are altered just because liver disease is present and not because they are important for disease. We have used this project to develop analytical approaches to detect which are really important, and we believe we have detected key microbial factors that could be driving liver disease and thus represent important project in this field.
Although many of these observations are already published, we are still working on some of the findings, thus the project is a rich source of new data on PSC. However, the perhaps most important output is the potential of new biomarkers and therapy, which could influence clinical care within a fairly short timeframe.
The project has made multiple observations bringing us beyond state of the art. I think key observations are 1) microbiome changes are similar before and after liver transplantation, 2) microbial functions are altered and vitamin B6 may be a mediator of poor prognosis which could potential measure disease severity and be treated and 3) new microbial metabolites may actually directly link the gut to the liver and thus explain the close association betwen PSC and inflammatory bowel disease. Overall, we believe the findings will contribute to changes in clinical practice and guide further research.