Dietary Manipulation of Metabolic Function in the Human Gut Microbiome

The human gut microbiome is increasingly recognized as having a causal or contributing role in a wide variety of diseases. While mechanisms by which the microbiome contributes to or triggers disease processes are myriad, short-chain fatty acid (SCFA) production has been found to be a powerful regulator of inflammation and gastrointestinal (GI) function, and may be central to the link between host and microbiota. Supplementing the diet with microbially accessible carbohydrates, termed prebiotics, is one mechanism by which SCFA production can be augmented or altered. While prebiotic therapies to increase SCFA in the gut have shown some promise in treating or preventing disease, treatment potential is limited by substantial inter-individual variation in responses to prebiotics. Determining the cause for this variation is necessary to develop treatment approaches that maximize patient responsiveness. Ultimately, tools to predict an individual’s response to a prebiotic and to guide treatment options must be developed. Here, I seek to understand the drivers of inter-individual and intra-individual variation in prebiotic response and to develop strategies to predict this response. In Chapter One, I introduce the human gut microbiome and its roles in maintaining host health and contributing to disease processes. I also present the existing evidence for substantial variation in SCFA productive response to prebiotic supplementation and highlight the need for a more nuanced understanding of the drivers of such variation. In Chapter Two, I explore the contributions of host factors and prebiotic choice to variation in SCFA production. This chapter introduces a novel in vitro fiber fermentation system, which is used throughout this thesis, and shows our methods validation of such. We find not only that host identity and prebiotic choice both impact SCFA production, but that the interaction of these terms is a significant contributor, introducing the possibility of the need for personalization. We then identify multiple host factors, including microbiota community composition and baseline SCFA metabolic state of stool, that explain some portion of inter-individual variation in prebiotic response. In Chapter Three, this relationship is further explored during the first in vivo triple-crossover prebiotic supplementation study. We supply 28 healthy adults with three different prebiotic supplements in a balanced and uniform crossover design, measuring SCFA as the primary outcome. This study makes the major contribution of quantifying the relative contribution of individual identity and prebiotic choice to butyrogenic response, and identifying individual as the vastly stronger predictor. We also identify habitual diet and baseline fecal SCFA concentrations as potential predictors of prebiotic efficacy. As a secondary analysis, we apply co-inertia analysis to draw associations between dietary choices and fecal SCFA metabolism. Together, these works highlight the need for personalization of prebiotic therapy and introduce potential biomarkers of responsiveness. In Chapter Four, we apply the concept of prebiotic therapy to graft-versus-host disease (GVHD) and show efficacy in a murine model. Importantly, we show that efficacy of prebiotics in this model of GVHD is dependent on the starting state of the microbiota, as observed through community composition analysis and functional in vitro fiber fermentation.