La production endogène de glucose est une fonction cruciale de l'organisme, permettant de maintenir l'homéostasie glycémique. Alors que la production accrue de glucose par le foie a des effets délétères, la néoglucogenèse intestinale (NGI) exerce des effets bénéfiques sur l'équilibre métabolique de l'organisme. Les régimes hyperprotéiques sont connus pour leurs effets de satiété. Grâce à des travaux physiologiques et moléculaires chez le rat et la souris, nous montrons dans une première partie que l'effet bénéfique des régimes hyperprotéiques passe par une induction de la NGI. Lors de la digestion des protéines alimentaires, des di- et tripeptides sont libérés dans la veine porte. Ces molécules agissent comme des antagonistes des récepteurs μ-opioïdes de la veine porte, initiant un arc réflexe intestin-cerveau induisant la NGI et la satiété. Dans un deuxième temps, nous proposons un modèle rendant compte des effets bénéfiques des régimes riches en fibres, tels que l'amélioration de la sensibilité à l'insuline et l'induction de la dépense énergétique. Les fibres solubles sont fermentées par le microbiote intestinal, produisant des acides gras à chaîne courte (AGCC), acétate, propionate et butyrate, à l'origine des effets métaboliques observés. Nous montrons que le butyrate active directement les gènes de la NGI dans les entérocytes, et que le propionate se lie aux récepteurs FFAR3 dans le système nerveux périportal, initiant un mécanisme de communication entre l'intestin et le cerveau induisant la NGI. De plus, nous montrons que la modification de la composition du microbiote par les fibres alimentaires n'est pas suffisante en soi pour induire les effets bénéfiques en absence de NGI / Endogenous glucose production is a crucial function for the organism, accounting for the maintenance of glucose homeostasis. While an increase in hepatic glucose production has deleterious effects, intestinal gluconeogenesis (IGN) has beneficial effects on the metabolic balance of the organism. Protein-rich diets are knows for their satiety effects. Thanks to physiological and molecular studies on rats and mice, we first show that the beneficial effects of protein-rich diets are dependent on activation of IGN. When dietary protein is digested, di- and tri-peptides are released into the portal vein. These molecules act as μ-opioid receptor antagonists in the portal vein, initiating a gut-brain neural reflex arc inducing IGN and satiety. In a second study, we propose a model accounting for the beneficial effects of fiber-enriched diets, such as increased insulin sensitivity and induction of energy expenditure. Soluble dietary fiber is fermented by the gut microbiota, producing short-chain fatty acids (SCFAs), acetate, propionate and butyrate, which are responsible for the observed metabolic effects. We show that butyrate directly activates IGN in the enterocytes, while propionate binds to FFAR3 receptors in the portal vein nervous system, initiating a gut-brain neural communication mechanism inducing IGN. Moreover, we show that modifications in the microbiota composition by dietary fiber are not sufficient to induce metabolic beneficial effects in the absence of IGN

Recent research shows, that gut microbiome can influence various functions of the organism and is able to communicate with the brain. The data also show that changes in the composition of gut microbiome can influence behavior and stress reactions and vice versa, psychological state of the organism can cause changes in gut microbiome. The aim of this master's thesis was to examine changes of HPA activation and local metabolism of glucocorticoids caused by stress in the presence or absence of gut microbiome. We therefore used germ-free mice and studied the effect of stress in pituitary, adrenal gland, colon and spleen. We found that, stress has different impact on gene expression in adrenal gland, colon and spleen in the presence or absence of gut microbiome. In contrast, there wasn't any significant effect of stress on pituitary in germ free mice and their conventionaly colonized counterparts.

<p>The gut and brain are involved in a bi-directional communication system, referred to as the gut-brain axis. While it has been established that antimicrobials induce dysbiosis in the gut, which further disrupts immune and metabolic homeostasis, research on brain and behaviour development is becoming a topic of interest. We propose that alterations via antibiotics at the level of the gut microbiota impacts the gut-brain axis. The primary interest of this thesis is to understand the effects that antibiotics have on brain and behaviour development in conjunction with changes in the immune system and metabolism using the antibiotic mouse model. Mice treated with antibiotics revealed behavioural differences in the open field apparatus and three-chamber social behaviour apparatus, but not in the elevated plus maze and auditory fear conditionings enclosures. Evaluation of intestinal permeability revealed that female Balb/C mice administered a combination of bacitracin, neomycin and primaricin and another group administered a combination of ampicillin, neomycin and primaricin showed reduced intestinal permeability. Furthermore, the immune system condition was evaluated using flow cytometric analysis of spleens, which revealed no effect of treatment on immune cell profiles in CD1 mice treated with ampicillin. Evaluation of serum cytokine levels showed minimal differences in Balb/C and C57Bl/6 mice treated with antibiotics. Body weight and water and food consumption were evaluated in mice administered antibiotics. Weight loss differences were observed in two groups of female Balb/C mice, with the first group administered bacitracin, neomycin and primaricin and the second group administered ampicillin , neomycin and primaricin. Antibiotic treatment dependent differences in water and food consumption were observed. Serum insulin and leptin level investigation revealed that female Balb/C mice administered ampicillin, neomycin and primaricin had reduced serum insulin levels compared to strain matched controls. These findings indicate that antibiotic treatment impact metabolic function. This pilot study using antibiotic treated mouse models provides insight on the microbiota’s effects on the gut-brain axis, which can help to potentially identify methods of preventing gut microbiota mediated pathology in humans.</p> / Master of Science (MSc)