Members of the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) have developed a new approach for personalized medicine in patients with inflammatory bowel diseases.
People with inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, suffer from chronic diarrhea, fever and pain, as well as psychological stress. In Germany, around 320,000 people are affected. On the functional level IBD is characterized by disturbed immune response in the gastrointestinal tract leading to a chronic inflammation, which clinically present as flares of disease activity.
Targeted therapies using antibodies directed against key molecules of the inflammatory pathway, such as anti-TNF antibodies, are established therapies in IBD. As a consequence inflammation is dampened leading to the absence of clinical symptoms, defined as a clinical remission. However, these drugs – commonly referred as “biologicals”- do not work in all patients. A substantial proportion of patients does not benefit from biologic treatment at all, while in other patients, clinical efficacy, despite initial treatment success, fades away over treatment time. Optimizing individual treatment success prediction would represent significant progress, for both doctors as well as the affected patients.
Members of the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) have taken a major step towards this goal, in a study published in the renowned scientific journal "Gastroenterology". The scientists from fundamental research and the clinic of the Faculty of Medicine at Kiel University (CAU) and the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, wanted to investigate whether treatment with biologicals influences the intestinal microbiome, i.e. the totality of all microorganisms living in the intestine, in IBD patients, and whether this can provide information about individual treatment success.
Biologicals change intestinal microbiome
The research embarked from previous studies, which had already shown that the diversity of the intestinal microbiome is lower in IBD patients than in healthy people. The Kiel researchers were able to show in their study that treatment with biologicals changes the diversity of IBD patients shifting it more toward the microbiome of healthy people. "However, unlike originally hoped, diversity assessment was not helpful in drawing conclusions on the individual treatment success of IBD patients," reported the first author of the study, Dr Konrad Aden, a scientist at the Institute of Clinical Molecular Biology at the CAU, and specialist in internal medicine at the USKH.
"This is probably due to the fact that the current methods of analysis of the microbiome data look at which bacteria are present, and not what these bacteria do, for example what substances they produce," explained Professor Philip Rosenstiel, Director of the Institute of Clinical Molecular Biology at the CAU, and Director of the Competence Centre for Genome Analysis Kiel (CCGA Kiel), which is responsible for the sequencing analysis.
In order to gain a deeper understanding of the functioning of the microbiome in IBD patients during treatment with biologicals, a systems biology approach was adopted. "We used a computational approach to simulate the nutrient exchanges of bacteria and calculated which metabolic end products are produced in the bowel by the microbiome," explained Professor Christoph Kaleta, head of the Medical Systems Biology research group at the CAU. Interestingly, this showed that patients for whom treatment with biologicals successfully combates the symptoms, already exhibited an entirely different exchange of substances in the microbiome before treatment started, compared with patients for whom the treatment does not work. Thus, the intestinal bacteria in patients who later responded to treatment produce, amongst other things, more short-chain fatty acids, which have a well-known protective effect on intestinal cells.
"Our data suggests that a deeper understanding of the nutrient exchange of bacteria might be helpful to unravel novel pathomechanism in IBD. It is presumable that a targeted dietary intervention to restore nutrient deficits of the microbiota in IBD patients might be a therapeutic option in the future, explained Rosenstiel, coordinator of the study.
"The findings are an important step towards precision medicine in chronic inflammatory bowel diseases. On this basis, we hope to be able to recognize earlier and more precisely in the future, whether the individual patient will benefit from treatment with biologicals or not," said Professor Stefan Schreiber, Spokesperson of the Cluster of Excellence "Precision Medicine in Chronic Inflammation", Director of the Department of Internal Medicine I at USKH Kiel, and Director of the Institute of Clinical Molecular Biology at the CAU. For patients where the biologicals will not help, this could save a lot of time and effort, and possible side-effects.
Konrad Aden, Ateequr Rehman, Silvio Waschina, Wei-Hung Pan, Alesia Walker, Marianna Lucio, Alejandro Mena Nunez, Richa Bharti, Johannes Zimmerman, Johannes Bethge, Berenice Schulte, Dominik Schulte, Andre Franke, Susanna Nikolaus, Johann Oltmann Schroeder, Doris Vandeputte, Jeroen Raes, Silke Szymczak, Georg H. Waetzig, Rainald Zeuner, Philippe Schmitt-Kopplin, Christoph Kaleta, Stefan Schreiber, and Philip Rosenstiel: Metabolic Functions of Gut Microbes Associate With Efficacy of Tumor Necrosis Factor Antagonists in Patients with Inflammatory Bowel Diseases, Gastroenterology, in press, available online 18 July 2019.
The Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) is being funded from 2019 to 2025 through the German Excellence Strategy (ExStra). It succeeds the "Inflammation at Interfaces” Cluster, which was already funded in two periods of the Excellence Initiative (2007-2018). Around 300 members from eight institutions at four locations are involved: Kiel (Kiel University, University Medical Center Schleswig-Holstein (UKSH), Muthesius University of Fine Arts and Design, Kiel Institute for the World Economy (IfW), Leibniz Institute for Science and Mathematics Education (IPN)), Lübeck (University of Lübeck, University Medical Center Schleswig-Holstein (UKSH)), Plön (Max Planck Institute for Evolutionary Biology) and Borstel (Research Center Borstel - Leibniz Lung Center).
The goal is to translate interdisciplinary research findings on chronic inflammatory diseases of barrier organs to healthcare more intensively, as well as to fulfill previously unsatisfied needs of the patients. Three points are important in the context of successful treatment, and are therefore at the heart of PMI research: the early detection of chronic inflammatory diseases, the prediction of disease progression and complications, and the prediction of individual responses to treatment.
Dr Konrad Aden
Department of Internal Medicine I, UKSH Kiel
Institute of Clinical Molecular Biology, Kiel University
+49 (0)431 500 15167
Prof. Dr Christoph Kaleta
Institute of Experimental Medicine, Kiel University
+49 (0)431 500 30340
Prof. Dr Stefan Schreiber
Department of Internal Medicine I, UKSH
Institute of Clinical Molecular Biology, IKMB, Kiel University
+49 (0)431 500 15101
Prof. Dr Philip Rosenstiel
Institute of Clinical Molecular Biology, IKMB, Kiel University
+49 (0)431 500 15111