Background and current state of research
Chronic inflammatory diseases result from the interaction of genetic susceptibility factors and environmental factors, broadly defined as infectious, chemical, physical, nutritional, and behavioral factors. While major progress has been made in identifying genetic susceptibility factors, comparatively little is known about environmental risk factors or the forces that lead to variation in genetic susceptibility in nature. Within the body of a healthy individual, microbial cells are estimated to outnumber human cells by a factor of ten to one. Recent advances in the field of metagenomics have begun to define these microbial communities, but knowledge of their influence on immunity and susceptibility to disease remains in its infancy. Important questions remain regarding the extent to which the microbiota is influenced by genetic variation in the host genome and whether disease susceptibility may be mediated by the microbiota. Indirect evidence (i.e. cellular fatty acid profiles of the fecal bacteria) suggests a prominent role of host genetic background on the composition of the microbiota, and single gene studies support the notion that the host genome is capable of fostering a communicable, pro-inflammatory microbiota. We hypothesize that naturally occurring variation in the host mitochondrial and nuclear genomes influence the composition of the resident microbiota, and this in turn influences susceptibility to chronic inflammatory diseases. To test this hypothesis we will systematically manipulate the microbiota of genetically distinct mouse inbred and mutant strains that differ in susceptibility to chronic inflammatory skin diseases.
* To identify mitochondrial and nuclear genes influencing the composition of resident microbiota in the skin and Gut.
* To culture and characterize microbial species influencing disease and define their influence on the immune system
* To define the pathways involved in the gene-microbiota interactions.
How to get there
Our groups have already fine-mapped a few microbial QTL down to single genes (1-2). We also demonstrated that mutations in mtDNA lead to significant differences in the composition of gut microbial communities in mice (3). We plan to extend the number of genes influencing microbiota composition by screening additional conplastic strains. The expression of the relevant genes will be examined in relevant tissues (immune cells, skin and gut epithelium). Depending on the gene in question, strategies to inactivate or overexpress it will be implemented.
We will then culture at least two OTUs with confirmed association to host genome variants. To further characterize the strains we will fully sequence their genomes (see our published report Wang J et al. Genome Announc. 2014;2(1). pii: e01148-13).
To confirm their role in disease we will expose germ-free mice to bacterial communities differing in the presence/absence abundance of candidate bacteria, followed by disease induction. The same will be applied to knockout/mtDNA mutants of identified relevant genes. To confirm the interaction we will perform cross-fostering experiments under germ free conditions. To identify the potential pathways involved, we will perform a series of Bone Marrow transplantation, immune cell transfer experiments isolated from control or mutant mice with and without candidate bacteria. The effect on cytokine production, cell death, activation, proliferation and gene expression and skin inflammation will be evaluated.
1- Srinivas G, Möller S, Wang J, Künzel S, Zillikens D, Baines JF, Ibrahim SM. Genome-wide mapping of gene–microbiota interactions in susceptibility to autoimmune skin blistering. Nature Communications, 2013; 4 DOI: 10.1038/ncomms3462
2. Belheouane M, Gupta Y, Künzel S, Ibrahim S, Baines JF. Improved detection of gene-microbe interactions in the mouse skin microbiota using high-resolution QTL mapping of 16S rRNA transcripts. Microbiome. 2017 Jun 6;5(1):59. doi: 10.1186/s40168-017-0275-5.
3. Hirose M, Künstner A, Schilf P, Sünderhauf A, Rupp J, Jöhren O, Schwaninger M, Sina C, Baines JF, Ibrahim SM. Mitochondrial gene polymorphism is associated with gut microbial communities in mice. Sci Rep. 2017 Nov 10;7(1):15293. doi: 10.1038/s41598-017-15377-7.
The project is ideally suited for a Biologist/MD with background or interest in microbiology, advanced molecular genetics or computational biology.
Lübeck Institute of Experimental Dermatology LIED
Institute of Experimental Medicine, Kiel University