Mutual interactions between the pathobiont Helicobacter hepaticus and the mouse intestinal microbiota: Ecology, mechanisms and relevance to the induction of IBD

• Applicant: Professor Dr. Sebastian Suerbaum
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2013 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 237552742

The prototype pathobiont, Helicobacter hepaticus, induces inflammatory bowel disease in susceptible immunocompromised mouse strains, and H. hepaticus infection has become a widely used model to investigate bacterial factors involved in IBD pathogenesis. Available data indicate that the pathology induced by H. hepaticus infection depends on both specific pathogenic mechanisms of the bacterium, as well as the composition of the intestinal microbiota. We showed that C57BL/6 IL-10 ko mice reared at two different institutions (MHH and MIT) display very different susceptibilities to IBD after H. hepaticus infection. Microbiota analyses of these mice by deep sequencing of 16S rDNA amplicons (454 FLX technology) have identified multiple culturable bacterial species that are only present in one group of mice and therefore might be involved in augmenting or suppressing inflammation. In a first part of the project, we will test the hypothesis that the presence of these single bacterial species affects susceptibility to H. hepaticus-induced colitis. Candidate species will be added to the microbiota, followed by H. hepaticus infection, and the resulting pathology and shifts in microbiota composition will be analyzed. In a second part, we will investigate the influence of H. hepaticus colonization on the composition of the intestinal microbiota in both inflamed and non-inflamed conditions.The H. hepaticus genome contains a pathogenicity island termed HHGI1. This island encodes a type 6 secretion system (T6SS) capable of transporting multiple proteins out of the bacterial cell. Loss of a part of the island, or inactivation of one single gene, vgrG1, was previously shown to strongly attenuate the ability of H. hepaticus to induce colitis. A further objective of this project is to understand how loss of the T6SS function affects the interaction of H. hepaticus with the microbiota. Finally, we will study the genomic adaptation of H. hepaticus to mice under conditions where H. hepaticus is part of a complex microbiota in comparison with mice that are monoassociated with H. hepaticus. In summary, to better understand the complex interactions between a model pathobiont, the gut microbiota and the host, this project combines an experimentally versatile persistent infection model with state -of-the-art microbiota analysis and whole genome comparison technology. We hope that findings obtained during this project will be transferable to interactions between other epsilon proteobacteria (e.g. Campylobacter species) and the physiological microbiota in mice and humans, and to contribute to understanding their complex interplay within the intestinal host ecosystem, and to positively influence it.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1656: Intestinal Microbiota - A Microbial Ecosystem at the Edge between Immune Homeostasis and Inflammation
• Participating Person: Professorin Dr. Christine Josenhans