PhD Position in BioMedical Research

University of Bern Department for BioMedical Research

PhD Student Position

Disambiguation and reconstitution of an elastic network of microbiota and host in the small intestine upon a feeding challenge

Background

The human intestine represents a large interface between the host and the environment. Intestinal functionality is critically shaped by the intestinal microbiota, comprising bacteria, eukaryotes, viruses and archaea colonizing the gastrointestinal tract. The intestinal microbiota mediates digestion of nutrients, uptake of calories and profoundly interacts with the intestinal immune system and microbiota-derived metabolites shape many aspects of human physiology in health and disease. Up to now, most microbiota studies focused on stool samples or the colonic microbiota. Due to the inaccessibility of the small intestine, its microbiota is rarely, if ever investigated. However, the small intestine is an essential organ, mediating resorption of >90% of calories, making it a crucial interphase for the microbiota – host interaction. The small intestinal microbiota has unique properties compared to colonic microbiota: the small intestine is nearly sterile close to the stomach but very densely populated at its distal end. Further, the composition is fluctuating and constantly adapting to nutritional changes. These changes are best understood as responses of a complex interaction network of intestinal microbes to a nutritional challenge. Assessing and deeply characterizing the small intestinal microbiota and its temporal changes upon intake and digestion of nutrients is a central challenge in microbiota research and the focus of this PhD project.

Research Work
 
We will use an ileostomy as a convenient access to the small intestine. We will recruit otherwise healthy individuals with an ileostomy who will ingest a high-fat challenge and a high-sugar challenge on two occasions in a randomized cross-over study design. In small intestinal samples, we will determine bacterial composition via 16S rRNA sequencing using IonTorrent and shotgun metagenomic sequencing. We will quantify microbial biomass using flow cytometry. Metabolite concentrations will be assessed by mass spectrometry. Ecological microbial co-occurrence analysis will identify small intestinal microbial networks which we will test for consistency across individuals.
 
Mechanistic reasons for bacterial shifts upon high-fat challenge will be modeled in vitro. We will generate a library of small intestinal bacterial strains from aerobic and anaerobic culturing. We will select bacteria with strongest interactions in the co-occurrence analysis upon high-fat challenge for full genome sequencing. Genomic information will predict metabolic properties (i.e., preferred carbon sources). We will test bacterial growth in the presence of predicted carbon sources using minimal media or sterile filtered small intestinal fluid. We will follow production or consumption of metabolites by mass spectrometry. We expect to identify bacteriametabolite interactions where i) a metabolite is a carbon source for a bacterial taxon, ii) is produced by a taxon, iii) is inhibitory for a taxon. We aim to identify instances of bacteria-bacteria interactions where metabolites produced by one bacterium will be metabolized by, or are inhibitory for, another.
 
Revelance
 
This study will be the first to combine advanced microbiota and metabolome analysis for assessment of dynamics within the small intestine. Our advanced analysis techniques provide sufficient power for a comprehensive functional analysis of the complex network of small intestinal bacteria and metabolites.

The PIs Benjamin Misselwitz and Bahtiyar Yilmaz will jointly supervise the project with support from the group leader Andrew Macpherson, thus offering input from different perspectives (microbiology, bioinformatics, clinical sciences).

Benjamin Misselwitz is a clinician-scientist working 40% in the lab, 60% as a gastroenterologist in the hospital. He has worked in the labs of Tom Rapoport (Dept. of Cell Biology, Harvard Medical School)(1-3), Wolf-Dietrich Hardt (Dept. of Microbiology, ETH Zurich) (4-8) and started his own group in 2014 at University Hospital Zurich with supervision of PhD students (9-11). He contributed to >100 scientific publications (basic science and clinical studies). My promise: "I am fully committed to the project, supervision and mentoring and will always be easily available in person or via e-mail".

Bahtiyar Yilmaz is a senior researcher in the lab of Andrew J. Macpherson with deep and long-standing experience in experimental and bioinformatics analysis of the human and murine intestinal microbiota. In the last 5 years, he has been working on understanding the role of intestinal microbial communities in patients diagnosed with chronic inflammation in the intestines. He addressed the impact of the microbiota on human health with multiple important papers in the microbiota field (12-15).

The group of Andrew J. Macpherson is a world-leading group in gut immunology and microbiota research (12, 16-21). The group offers a creative atmosphere with inspiring interactions with excellent colleagues, exceptional conditions for work in basic science and translational research with world-class laboratory equipment including a germ-free mouse facility, and a hospital in short distance (2 min indoor walking) with frequent exchange for sample acquisition. Students will have a chance to get mechanistic insights into microbiota research, mucosal immunology and advanced bioinformatic analyses of human and mouse-based research via the interaction with group members. Both students will be fully integrated in the group of Andrew J. Macpherson with lab meetings and journal clubs. Link Macpherson Lab
 
Requirements
 
An exceptional interest in the intestinal microbiota, and an interest in basic microbiology, commitment and dedication to scientific work (similar to the supervisors). A strong bioinformatics background (e.g., scripting in R or Python) and experimental experience (e.g., microbial culturing, in vivo experiment) are of advantage. The student should be committed to teamwork but also able to develop and pursue ideas independently. The topic does not involve animal experimentation ('organ experiments'). A Master's degree in a life science (or medicine, bioinformatics in exceptional cases) is a requirement.
 
What can the student expect:
 
We offer an exciting opportunity to work on the human small intestinal microbiota, an emerging and unexplored field in microbiology and translational medicine. We offer close supervision with ample support and interesting discussions. However, we also encourage and enable independent scientific work. We aim to mentor the student for an independent scientific career throughout and after the project.

The project offers on the job training in bioinformatics, experimental microbiology and translational medicine with a direct link to clinical medicine. Students will also be integrated into the PhD program of Bern University with courses for structured scientific training. The student will be able to attend additional bioinformatics courses for their research via the Swiss Institute of Bioinformatics (SIB). Attendance with data presentation at international research conferences and international courses such as the One Health Summer School is encouraged expected.

Students will be paid with benefits according to the internationally attractive guidelines of the Swiss National Science Foundation. The vibrant and charming City of Bern at the river Aare is situated in a beautiful mountainous Swiss landscape.

The project involves two PhD students. Project start: as soon as possible (Ethics permission has been granted). Project duration: Funding for 4 years PhD work has been granted (funded by Swiss National Science foundation, SNF).

Benjamin Misselwitz, benjamin.misselwitz@dbmr.unibe.ch
Bahtiyar Yilmaz, bahtiyar.yilmaz@dbmr.unibe.ch
Department for Biomedical Research, University of Bern, Murtenstrasse 35, 3008 Bern.