The gut microbiome mediates energy gain from different dietary fats

Abstract

While dietary fat has played an important role in shaping modern human physiology, surprisingly little is known about the metabolic processes involved in fat digestion. Modern nutrition guidelines treat the energetic contribution of fat as equal regardless of fat type. However, this framework of fat metabolism does not adequately explain why differences in dietary fat are linked to such varying metabolic health outcomes, particularly in the case of obesity. One potential contributor to these discrepancies is the gut microbiome. Recent advances in microbiome research have shed light on the digestive partnership between humans and our resident gut microbes, and evidence suggests that gut microbes respond rapidly and reproducibly to dietary shifts, including changes in total fat consumption. Therefore, in order to understand the impacts of dietary fat type on energy gain and metabolic health, we must consider humans as holobiont systems comprised of both host and microbial mechanisms for energy harvest. This dissertation (1) addresses whether different dietary fat types alter metabolic phenotypes via host and microbial mechanisms, and (2) investigates the extent to which the gut microbial community plays a role in shaping host phenotype under different dietary fat conditions. Chapter 1 presents a perspective on the potential host-microbial interactions involved in a holobiont view of dietary fat metabolism. Chapter 2 addresses the role of dietary fat type in shaping host energy gain and metabolic response, including metrics of fat absorption, bile acid production, and inflammation. Chapter 3 explores how the metabolic effects of fat type induce downstream changes to the structure and function of the gut microbiome. Chapter 4 investigates the direct gut microbial contributions to host physiology under different dietary fat conditions. Finally, the findings of Chapters 2-4 are summarized in a general discussion presented in Chapter 5. When empirically testing each aspect of the holobiont model outlined in Chapter 1, significant trends emerge regarding both host and microbial responses to fat type. In experimental feeding trials using C57BL/6J mice, isocaloric high-fat diets that vary in fat type resulted in significantly different effects on total body mass and percent adiposity, particularly when comparing saturated versus ω-3 polyunsaturated fat sources. Saturated fats were associated with enhanced energy gain, as well as increased expression of host markers for bile acid production, inflammatory response, and gut epithelial integrity. Dietary fat type also impacted downstream gut microbial community composition and abundance. Saturated versus ω-3 polyunsaturated fat intake led to the enrichment of microbial taxa implicated in enhanced energy harvest and inflammation, as well as changes in microbial function including an increase in secondary bile acid production. The differential effects of saturated versus ω-3 polyunsaturated fat on host phenotypes were negated by the absence of microbes, indicating that the absence of a gut microbiome negates differences in host metabolic status between fat types. Finally, gnotobiotic transplant experiments detected long-term effects of microbial preconditioning, where recipients of donor communities saturated fat-fed donors experienced reduced gut microbial contributions to energy gain and inflammation when administered a ω-3 polyunsaturated fat diet. Together, the findings of this dissertation illuminate the integral role of host-microbial interactions in fat metabolism for energy gain and inflammation. Such interactive pathways have likely shaped human adaptations to diet over the course of our evolution, and contribute to the rise of diet-associated metabolic disease in industrialized populations today.