Deciphering and predicting ecologically sensitive gut microbiome contributions to human metabolic health

About This Grant

ABSTRACT Metabolic health depends on acquiring an appropriate amount of energy and allocating it efficiently across tissues. The human gut microbiome modulates energy acquisition and allocation and exhibits high sensitivity to modifiable lifestyle factors such as diet, exercise, and social contact, resulting in gut microbiome contributions to metabolic health that differ across individuals and within individuals over time. Ecological plasticity of the gut microbiome is a double-edged sword: it may increase disease risk if the microbiome departs from profiles to which the human body has adapted, but it may also confer protection by affording humans some capacity to adapt rapidly to changing ecological conditions. However, health outcomes of lifestyle-associated alterations in the gut microbiome remain untested. This situation complicates the interpretation of human gut microbiome variation, hinders efforts to develop equitable microbiome-targeted therapeutics, and obscures our view of features characterizing a ‘healthy’ human microbiome. In the coming five years, we will perform experiment-based, causally informative research toward three synergistic themes that elucidate when, why, and how lifestyle affects gut microbiome contributions to metabolic health. In Theme 1, we interrogate how ecological factors such as dietary digestibility, caloric intake, and exercise shape gut microbiome contributions to host metabolic health and the conditions favoring inflection points between beneficial and detrimental contributions. In Theme 2, we evaluate how ecological context shapes the metabolic health consequences of host-microbiome interactions and whether it may benefit health to restore putatively beneficial taxa depleted in industrialized or non-industrialized gut microbiomes. In Theme 3, we investigate how social microbial transmission may mediate metabolic disease risk and resilience, testing the idea that non-communicable conditions have a communicable component by virtue of the social exchange of risk-associated microbes. To address Themes 1 and 2, we will exploit natural variation in human microbiomes and controlled diet and exercise interventions in mice to foster conditioned gut microbiomes that can then be transplanted into germ-free animals to study the causal health impacts of a given microbiome profile. To address Theme 3, we will examine the transmissibility of microbes between focal individuals with metabolic disease and their social partners, varying focal and partner social networks to evaluate the risk landscape of social transmission in relation to social position and connectivity. Work toward Themes 1-3 will be enhanced by three overarching principles guiding our work: (1) consideration of both bacterial and non-bacterial constituents of the gut microbiome, (2) rigorous host and microbiome phenotyping enabling the elucidation of underlying mechanisms, and (3) development of machine learning models that identify metagenomic and metabolomic features predicting gut microbiome contributions to metabolic health. Collectively, our proposed research will enhance our understanding of human energy metabolism and help lay the groundwork for future health-directed manipulation of the gut microbiome.