Interplay between diet, gut microbiome and host responses during the development and management of dysbiosis

Abstract

The mammalian gut contains a metabolically active microbial community that lies at the intersection between the host and its nutrient environment. Compositional changes in the gut microbiome, triggered by chronic diet habits, may lead to aberrant host-microbiome crosstalk and thereby potentiate the development of dysbioses or disease states that have energy balance and immune phenotype as risk factors. Dietary interventions for obesity and associated disorders are known for variable outcomes. The central hypothesis of this thesis is that failure to account for microbial factors limits intervention success. There is a need to establish the role of diet as a modulator of microbiome properties and host-microbiome interactions. In view of this, two broad aims were explored via distinct forms of dietary regimes. The first aim was to assess the relevance of the gut microbiome in human obesity management. This led to the discovery of multiple microbiome properties that define diet-induced weight loss, and these signatures are expected to aid clinical recommendations in stratifying overweight individuals that require distinct interventions for optimal result. The second aim explored the defining features of high-fat diet induced metabolic dysfunction in mouse models. Through meta-analysis of host and microbiome responses to dietary fat intake, the mechanisms by which obesogenic diets trigger the development of dysbiosis had emerged. Most notably, axes of diet-host-microbiome interactions that can be targeted to restore health were also identified. This thesis supports that microbial signatures have applications in informing disease prognosis and intervention plans. A deeper understanding of the interplay between nutrition, microbial dynamics and host responses will open new avenues of personalised and effective interventions for diseases that are driven by dysbiosis.