Human Dietary Interventions: Investigating the Interactions between Metabolism, Gut Microbiome, and Microbiome-Derived Metabolites for Optimized Health

Abstract

Diet is a key factor in modulating the gut microbiome, which plays a pivotal role in human health. Tailored microbiome-targeted dietary strategies are thus a promising approach for the primary and secondary prevention of lifestyle-associated diseases linked to microbial dysbiosis. However, the underlying mechanisms are poorly understood. The objective of this thesis was therefore to investigate the interactions between metabolism, the gut microbiome, and microbiome-derived metabolites in the context of two dietary interventions to optimize human health.<br /> To achieve this, two different oat interventions were conducted in a randomized controlled prospective parallel-design study in individuals with metabolic syndrome (n = 68). Participants were assigned either to a short-term, hypocaloric, high-dose oat diet (modified ‘oat cure’ according to Carl von Noorden: 3 x 100 g oats/day for 2 days) or a six-week, isocaloric, moderate oat diet (1 x 80 g oats/day for 6 weeks). These interventions were compared to an oat-free, macronutrient-adapted control diet or the participant’s habitual Western diet. Blood and fecal samples were collected before, during and after each intervention period to determine the diet-induced effects on metabolism, gut microbiome composition and functional capacity, as well as metabolomic profiles, particularly ferulic and dihydroferulic acids ([DH]FA) in plasma, and to elucidate the underlying mechanisms using an integrative multi-omics analysis.<br /> It was shown that a short-term, high-dose and, to a lesser extent, a six-week, moderate oat diet led to a significant increase in circulating (microbially produced) phenolic metabolites, including (DH)FA. Along with shifts in the gut microbiome and global metabolomic profile, these phenolic metabolites were identified as potential driving factors for the oat-induced reduction in serum total cholesterol and low density lipoprotein cholesterol levels upon the short-term, high-dose oat diet. Moreover, a decrease in gut permeability, observed after the short-term oat diet compared to baseline, was associated with an increase in circulating short-chain fatty acids. The baseline gut microbiome composition was identified as a potential modulator of this response. The six-week, moderate oat diet stabilized metabolic markers and had attenuated effects on the gut microbiome and metabolomic profiles.<br /> In conclusion, the findings of this thesis contribute significantly to the understanding of the complex host-diet-microbiome interaction, emphasizing its key role in human health. Microbiome-derived metabolites, in particular phenolic compounds, have been identified as important mediators in the interplay between gut microbes and the host, offering new therapeutic strategies for the treatment of lifestyle-associated diseases. This is of great potential since dietary strategies such as a short-term, high-dose oat-diet are a suitable and rapid approach to alleviate obesity-related lipid disorders and to reduce intestinal permeability. However, further intervention studies in different populations are needed to verify these results and address the challenge of inter-individual differences in the response to dietary interventions.