Soutenance de thèse :

Long-term alteration of host-microbiota intestinal symbiosis by dietary modulation in a murine model

In recent times, dietary habits in Western populations have undergone significant changes. Concurrently, an increase in the incidence of chronic diseases such as obesity and type 2 diabetes has been observed. Alterations in the gut microbiota have been associated with many of these diseases. The gut microbiota, which encompasses the microorganisms in the digestive tract, plays a crucial role in maintaining the health of the host organism through a symbiotic relationship. Recent dietary changes, characterized by increased consumption of sugar and fats and a continuous decrease in fiber intake, significantly influence the composition and activity of the gut microbiota, thereby altering the host-microbiota symbiotic relationship and compromising its homeostasis. Discrete configurations and alternative stable states have been identified in the human gut ecosystem and in preclinical models. These states represent basins of attraction for the ecosystem, where it tends to remain. However, modifications in the system’s external conditions can trigger a transition to an alternative state. Returning to pre-transition conditions does not necessarily guarantee a return to the initial state of the ecosystem, due to the possible coexistence of multiple alternative stable states under the same condition. This phenomenon, known as hysteresis, has been observed in previous dietary intervention studies. To understand the dynamics of the gut ecosystem following dietary changes, and examine if these changes alone could induce a state transition, we conducted experiments on a preclinical animal model.

Mice were given different diets, each followed by a return to initial conditions. We studied several purified diets, reduced in fiber-content or fiber-reduced with high fat and sugar content, compared to a standard chow diet. The state of the gut microbiota and the host was characterized longitudinally to identify alternative stable states. We also assessed the susceptibility of the animals to chemically induced colitis based on their dietary history. Our results show that the reduction of dietary fibers has a drastic impact on the composition and diversity of the gut microbiota, an effect more pronounced than that of fat and sugar. The consumption of a fiber-free diet led to a decline in the abundance of numerous bacterial taxa. After returning to initial conditions, the abundance of certain taxa was not restored to control levels, and the diversity of the gut microbiota was not restored in two of our experiments. We also observed signs of alternative stable states in two of our experiments through multivariate analyses and sample clustering based on gut microbiota composition. However, temporary consumption of a fiber-free diet did not make the host more susceptible to an inflammatory stress that was applied eight weeks after the return to a chow diet. These findings highlight the importance of dietary fibers in maintaining the composition and diversity of the gut microbiota and the complexity of gut ecosystem dynamics following dietary modifications.

Membres du jury :

• Petra Louis, Senior Research Fellow, University of Aberdeen, Rapporteur & Examinatrice

• Jeroen Raes, Full Professor, KU Leuven, Rapporteur & Examinateur

• Benoît Chassaing, Directeur de recherche, Institut Pasteur/INSERM/Université Paris Cité, Examinateur

• Claire Janoir, Professeure des universités, Micalis/Université Paris-Saclay/INRAE/AgroParisTech, Examinatrice

• Eric Pelletier, Directeur de recherche, CEA/Genoscope, Examinateur

Encadré par :

Maarten van de Guchte, Stanislas Mondot and Joël Doré