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. Further, microbiota-derived metabolites shape many aspects of human physiology in health and disease. Up to now, most microbiota studies focused on stool samples and/ or the colonic microbiota and due to 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 the colon: 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 bacteria-metabolite 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.

Requirements

An exceptional interest in the intestinal microbiota, and an interest in basic microbiology. A strong bioinformatics background is of advantage. The topic does not involve animal experimentation ('organ experiments').

The project involves two PhD students. Project start: as soon as possible (Ethics permission has been granted). Both students will be fully integrated in the group of Andrew Macpherson, DBMR, University of Bern.

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.