Role of Gut Microbiome-Host Metabolic Interactions in Metabolic Diseases

Abstract

The metabolic phenotype of any complex organism is dependent on a complex series of host and gut microbial gene (microbiome) interactions with diet. The microbiome itself can be affected by environmental factors such as stress, exposure to xenobiotics, lifestyle, and alterations in the mammalian-microbial-metabolic axis are associated with changes in disease factors. To understand further the impact of the commensal microbiota on the host metabolism, germ-free (GF) animals, inoculated with individual bacterial strains or complex microbiota, and conventional mice were characterised using 1H NMR spectroscopy and UPLC-MS-based metabolic profiling approaches, and by recording the physiological and immunological parameters. Higher systemic level of (D)-3-hydroxybutyrate and lower levels of circulating VLDL were observed in GF compared to conventional animals, indicating that the absence of gut microbiota stimulated lipolysis while it inhibited hepatic lipogenesis. Subsequently, the best inoculation procedure was obtained by inoculating single bacterial strains into individual animals followed by allowing the animals to exchange their microbes. Metabolic fingerprints showed that a 9 bacteria community is more able to regulate lipoprotein and circulating lipid levels compared to a 3 bacteria community. The origin of the inocula (mouse or human) impacts differently on the host metabolism since humanised mice were strongly disturbed (higher plasma triglyceride level) and displayed metabolic profiles similar to GF mice. Conversely, mouse-associated animals were physiologically, immunologically and metabolically similar to conventional animals. Finally, metabolic profiles and gut microbiota composition were statistically regressed and helped to identify specific bacteria, such as Ruminococcus lactaris and Faecalibacterium prausnitzii, and their putative role in the host homeostasis. To conclude, these results confirmed the influence of gut microbes on the host physiology and metabolism. This PhD thesis provides new insights into the role of gut bacteria to understand the microbial-related mechanisms that participate in the host lipid metabolism, potentially leading to development of obesity.