UC Davis

Diet is known to be a strong determinant of gut microbiome composition and function, and it is also known that gut microbiome dysbiosis is strongly linked to the risk of chronic disease. However, it is not clear how to intervene through diet or supplementation to beneficially alter the gut microbiome in individuals who have dysbiosis or who are at risk for chronic diseases such as cardiovascular disease and Alzheimer’s disease (AD). Hypothesis driven studies to determine how dietary changes affect the diet-gut microbiome-host interrelationship are critical for the discovery of solutions to improve health and mitigate disease risk. In this dissertation, three chapters are included to discuss important aspects of study design and prebiotic selection, and the outcomes of a study investigating the effects of a prebiotic supplement.

In the first chapter, critical factors in successful study design for diet-microbiome research are discussed. For example, the importance of detailed dietary data collection and analysis, tight control of background diet, and stabilizing diet in the days prior to sample collection is critical for reducing noise and amplifying the signal that can be detected of the effects of the intervention diet. Specific recommendations such as including multiple consecutive sampling per study timepoint and collection of multiple consecutive days of diet records, particularly the days prior to sample collection, are discussed. High interindividual variability in gut microbiome composition is a well-established phenomenon that has been known since the early results from the Human Microbiome Project. Because of this high interindividual variability, some study designs are not well suited to discovering the effects of a dietary intervention. Instead, we discuss the double-blinded, randomized order, placebocontrolled, cross-over study design is the optimal study design for gut microbiome research, enabling the detection of the effects of even a subtle diet intervention. We also discuss the importance of precision nutrition approaches for nutritional recommendations. As an example, we discuss nutritional recommendations for egg intake, taking into account the link between egg-derived components (i.e., choline and cholesterol) and their interaction with the gut microbiome and subsequent health outcome measures important in cardiovascular disease.

The second chapter emphasizes why we care about changes in gut microbiome in human health and how we can better utilize certain dietary interventions such as prebiotics to modulate human health and diseases focusing particularly on AD. Prebiotics are oligosaccharide and polysaccharide structures isolated from plants or synthesized from sugars that are shown to modulate the microbiome and are associated with health benefits. We summarized the importance of dietary fiber intake for maintaining a healthy gut microbiota, with a focus on short chain fatty acid production, mucus secretion, and protection from pathogens. The specific links between healthy gut physiology, gut immune function and the brain are also discussed. The importance of anti-inflammatory metabolites produced by gut microbes consuming specific substrates in modulating critical signaling pathways in the brain is discussed in the context of AD prevention. We conclude by discussing which specific bacterial genera are increased and decreased in AD patients and highlight the potential of increasing bifidobacteria abundance through the intake of specific prebiotic substrates as a promising approach for beneficially modulating the gut microbiome and improving health outcomes in AD patients.

The final chapter summarizes the findings from our human clinical trial in healthy subjects consuming a low fiber diet (< 15 g/day) to determine whether a low-dose, easy to use bifidogenic prebiotic supplement formulation increases bifidobacteria and produces measurable metabolomic and metagenomic changes over the course of 4 weeks. We used the double-blinded, placebo-controlled, randomized order crossover study design highlighted as the optimal study design for diet-microbiome studies in chapter 1, to study the effects of the prebiotic supplements in 20 otherwise healthy young individuals consuming diets low in fiber, typical of the average American diet. As hypothesized, the relative abundance of bifidobacteria significantly increased after the prebiotic supplement, as did the gene counts of genes associated with prebiotic utilization, acetate production, and choline oxidation. Importantly, these changes in gut microbiome composition and function were reflected by changes in the concentrations of microbially-derived metabolites in the plasma, and point to novel pathways by which increasing the abundance of bifidobacteria may confer beneficial health effects on the host.