Project Details
Projekt
Bacterial evolution during chronic inflammation and its potential for ancestral state restorative therapy
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426660215
The basic evolutionary principle of adaptation by natural selection applies to bacteria in our intestine. Even within a person’s lifetime, bacteria evolve as members of the microbiota in healthy individuals. Evolutionary theory predicts that the intestinal environment during inflammatory bowel diseases (IBD) creates additional selection pressures for the evolution of bacterial traits we are currently not aware of, and that we might take advantage of to help restore a patient’s microbiota. To test this hypothesis, in the first funding period we conducted in vivo evolution experiments using a gnotobiotic mouse model of IBD and developed novel imaging techniques. This revealed higher inflammation levels in affected mice and substantial changes in metabolomic profiles. Notably, bacteria adapted to inflammation showed increased susceptibility to specific antibiotics, along with the identification of mutations associated with adaptation. In the second funding phase, we seek to understand bacterial phenotypes during inflammation in greater depth, exploring three main areas: (i) antibiotic susceptibility, (ii) metabolism and localization, and (iii) bacteria-bacteria interactions. The overarching goal is to develop innovative therapeutic strategies, building upon the insights gained from bacterial evolution within the context of chronic inflammation. This will be achieved by thorough phenotypic characterization of specific mutations identified in the first funding period, further gnotobiotic evolution experiments, and the employment of advanced imaging techniques to visualize microbes, their metabolism, and inflammation within the host. This includes utilizing fluorescence molecular tomography (FMT), photoacoustic imaging (PAI), and hyperpolarized magnetic resonance imaging (MRI). Ultimately, the project seeks to develop innovative therapeutic strategies, rooted in concepts of adaptive evolution in bacteria. This includes the concept of ancestral state restorative therapy, which involves replacing evolved bacterial strains with ancestral strains that exhibit higher fitness in a healthy intestinal environment.
DFG Programme
Research Units
