In recent years, there has been a growing appreciation that the human gut microbiome, i.e. the entirety of >1014 bacteria, viruses and fungi, plays a pivotal role in human health and is implicated in diseases such as colorectal cancer, inflammatory bowel syndromes but also diabetes and obesity. The human immune system in the gut is in direct proximity to intestinal microbes and acts as a vital sensor and regulator of microbiome diversity and pathogenicity, since microbe-associated molecular patterns (MAMPs) are sensed by the so-called pattern recognition receptors (PRRs). PRR activation coordinates anti-microbial innate and adaptive immune responses which engage the gut microbiota via antimicrobial peptide or Immunoglobulin A (IgA) secretion, respectively. Thus microbiome and host immune system reach a balance of power under steady-state conditions (Figure 1).
Deciphering the complex interplay of host immune system and microbiome has been complicated by great discrepancies in the reported protocols (e.g. sample collection, storage, preparation, sequencing, bioinformatics analysis).
A comprehensive study of the interplay between host immune system and intestinal microbes has the potential to provide profound scientific insights and concrete point of therapeutic intervention. With the fast advances in analysis and sequencing capabilities and falling costs, a well-designed pipeline for high-throughput sampling and analysis may enable the routine analysis of hundreds, if not eventually every, patient at the Tübingen University Hospital, in a few years’ time.
The overall goal of this project is to establish such a pipeline now and apply it in a cohort of patients undergoing bone marrow transplantation (BMT) or stem cell transplantation (SCT). The discovery phase of the project will provide novel insight into the human microbiota, the human immune system and, importantly, their interplay and modulation by host genetics. Additionally, it will yield well-defined and stratifiable host and microbial biomarkers that can be directly used to anticipate and reduce graft vs. host disease (GvHD), infection related complications and long-term morbidities in childhood and adult BMT patients. Additionally, the here identified most critical biomarkers of immune-microbiome interplay can be used for cost-effective and target-focused patient stratification in other diseases.
In order to accomplish this formidable challenge, this project brings together experts of different disciplines – medical microbiology, immunology, pediatrics and bioinformatics – who will work together with the Tübingen Center for Personalized Medicine (ZPMT) and the Center for Quantitative Biology (QBiC) (Figure 2). Together we hope to realize ways for the combined analysis of microbiome, immunological parameters and host genetics in patients in order to contribute to realizing the tremendous potential of personalized approaches in prevention, diagnostics or therapy in the future.