Our Projects
EvoInHi -
Evolution in the Gut in Health and Disease
ERC-2022-AdG, 101096203
The mammalian gut is an exquisite system to study ecology and evolution of microbes, and these processes are key for host-microbiome homeostasis. How microbiome diversity is maintained or lost is a critical question underlying the proper balance of this duet. Yet, our knowledge of the eco-evolutionary mechanisms structuring microbiomes is still in its infancy. Here, we seek to identify dominant modes of natural selection and host factors that modulate the evolution of their microbes. By leveraging knowledge on gene functions in specific strains and the power of mouse genetics and husbandry, we will unravel how natural selection operates to shape diversity in the bacteria that inhabit the guts of healthy and sick hosts. Microbiome evolution will be studied in several mouse models of disease with a focus on Escherichia coli as a pathobiont model, for which a deeper understanding of molecular mechanisms in health vs disease can be reached.
Using long-term experimental evolution in vivo, high-throughput sequencing and theoretical modelling we will quantify the relative roles of directional, diversifying and fluctuating selection in gut evolution. We posit that resource competition drives the dominant selection mode in the healthy gut and that strong fluctuations in the environment, due to phage-bacteria co-evolution and/or due to host-microbe interactions, drive the selection mode in the gut of diseased hosts. We will further test the hypothesis that fluctuating selection leads to an Anna Karenina effect whereby the microbiomes of unhealthy individuals are much more distinct between one another than those of healthy ones. EvoInHi seeks to find the first empirical evidence that the predictability of evolution is higher in health than in disease, which will have a profound impact on understanding bacteria diversity and rates of specialization and how these can be used to modulate host health.
Evolution of commensal bacteria in the mammalian intestine.
PTDC/BIA-EVL/7546/2020
An enormous abundance of bacteria inhabit our bodies, especially our gut. The collection of these intestinal microbes is known as gut microbiota. Microbiota diversity is a key modulator of host health: a species rich gut microbiota is correlated with health while a low diversity microbiota typically associates with disease. Microbiota DIVERSITY IS SHAPED BY BOTH ECOLOGICAL AND EVOLUTIONARY PROCESSES.
The large numbers of bacteria and their well-known capacity to adapt when grown in laboratory environments, suggests that a substantial amount of evolutionary change could occur inside our guts at remarkable speeds. Despite this knowledge from many in vitro studies LITTLE IS KNOWN ABOUT HOW MICROBES EVOLVE WITHIN THE GUT. HERE, WE AIM TO CLOSE THIS KNOWLEDGE GAP BY COMPARING EVOLUTIONARY
CHANGE of a common gut commensal bacteria IN HEALTH & DISEASE. Experimental evolution in mice offers a powerful complementary approach to understand the emergence and maintenance of diversity of a gut pathobiont and how it changes under disease. We have developed an in vivo long-term experimental evolution system, where evolution of Escherichia coli, a commensal that can turn to an infectious pathogen, in the rich ecosystem of the mouse gut can be followed.
Experimental design: New setup for in vivo long term experimental evolution of E. coli.
Animal welfare
Animal welfare is the priority in all of our experiments. Every experimental procedure involving vertebrate laboratory animals is critically reviewed by an independent ethics panel and requires the approval of the DGAV.
While it is desirable to replace the use of live animals in procedures by other methods that do not require the use of animals at all, the use of live animals continues to be necessary.
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We are using laboratory mice (Mus musculus) as a model organism to study the evolution of microbes in the mammalian gut. This provides us with a natural environment whose complexity cannot be met by laboratory conditions. Learning about evolution in a natural context provides important insights for the understanding of how a healthy gut microbial community is maintained but also about how pathogens emerge and thrive. In the vast majority of our experiments the mice are orally inoculated with commensal microbes that naturally occur in the gut (E. coli and yeast).
All our project designs follow the 3R principles to ensure research as humane as possible:
- Replacement of animal procedures with other methods whenever possible
- Reduction to the minimum number of animals possible
- Refinement of methods to avoid or minimize harm and distress
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Predictability in Evolution -
Evolutionary diversification of E. coli in the mouse gut.
DFG Collaborative Research Center 1310, Project A6
Escherichia coli is a colonizer of the gut with an outstanding level of phenotypic and genomic variation. E. coli also contributes to pathologies, such as colitis and cancer, and can evolve increased mutation rates in healthy and sick people. In this project, we investigate gut evolution of E. coli strains in two relevant conditions. First, we aim to characterize genetic and phenotypic diversification to capture long term specialization in real time in the guts of mice in order to study the beginnings of the emergence of new species using mutator strains. Further, we test the hypothesis that tumorigenic E. coli has a higher rate of evolution and that the rate of somatic evolution of the gut epithelia increases with increased abundance of tumorigenic E. coli. These experiments stand in the framework of the DFG Collaborative Research Center which joins projects with investigators from the University of Cologne.
Example of long-term evolution of an E. coli strain. Diversification of an E. coli lineage within a rich mouse gut microbiome (C) is characterized by the long-term maintenance of newly emerging ecotypes (Muller plot of the mutations detected is shown in panel B) with distinct metabolic phenotypes assayed in vitro (maximum growth rate of ancestral and evolved clones in panel D).
From diversity to efficiency -Uncovering how different strains adapt to the same environment and how we can direct evolution towards more efficient microorganisms.
PTDC/BIA-EVL/31528/2017
Experimental evolution studies with microorganisms such as bacteria and yeast have been an increasingly important and powerful tool to draw long-term inferences of how microbes interact.
Initially we perform a genotypic and phenotypic characterization of laboratory and natural strains of the yeast Schizosaccharomyces pombe. Yeast communities composed of distinct numbers of strains are then propagated for hundreds of generations and asked which fitness-related phenotypes - maximum growth rate or relative competitive fitness - would better predict the outcome of a focal strain during the propagations.
We further investigate the co-evolutionary dynamics of a yeast strain that has evolved in the mammalian gut and a commensal E. coli strain.
The project is bringing together experimental, mathematical and computational tools in order to uncover the forces driving fitness convergence in different microbial strains and how they respond to different environments.
