Metabolism of Dietary Fiber by Human Gut Microbes: Interspecies Interactions and the Influence of Molecular Hydrogen

Abstract

The human gut microbiota is a diverse and abundant community of microbes that colonize the gut. These microbes and their human hosts co-evolved in the context of each other, resulting in a close functional integration of the microbiota into human physiology. Indeed, the gut microbiota has been likened to a “forgotten organ” that plays a wide variety of roles in human health and disease. Despite extensive research characterizing connections between the gut microbiota and human health, development of microbiota-targeted therapies has been hindered by high levels of inter-individual variation coupled with a poor understanding of the interspecies interactions and environmental factors that shape the composition and function of the microbiota itself. The work reported in this thesis addresses this deficiency with respect to a gut microbiota function of particular interest: production of the anti-inflammatory and anticarcinogenic microbial metabolite butyrate. In the second chapter, I characterize the response of the gut microbiota to consumption of resistant starch from potato (RSP), a dietary supplement that has been shown to fuel microbial butyrate production in approximately 60% of individuals. Using data from a large human cohort, I find that while the resistant starch degraders Bifidobacterium adolescentis (Ba) and Ruminococcus bromii (Rb) can both respond to RSP supplementation, the presence of Ba suppresses Rb response. Furthermore, an Rb response to RSP is associated with growth of the butyrogen Eubacterium rectale (Er), while a Ba response is instead weakly associated with growth of the butyrogen Faecalibacterium prausnitzii (Fp). In vitro experiments show this is likely due to greater fitness of Er at the high substrate concetrations produced by Rb growing on RSP compared to adaptation of Fp for low substrate concentration characteristic of RSP degradation by Ba. In the third chapter, I characterize the role of intestinal H2 as a modulator of fermentation in the gut microbiota. In vitro experiments demonstrate that high levels of H2 shift butyrogen metabolism in a predictable fashion that can include stimulation of butyrate production. I also find that hydrogenotrophic gut methanogens can decrease butyrate production by efficiently consuming H2, accounting for some of the inter-individual variation in butyrate production observed during RSP supplementation. In the fourth chapter, I build off these findings by exploring the potential of a variety of dietary supplements to increase intestinal H2. I also use data collected in this research to explore the feasibility of using fasting breath H2 as an indicator of recent fiber consumption. Taken together, this work identifies previously unrecognized factors influencing butyrate production by the human gut microbiota, as well as shedding light on the specifics of RSP degradation by the microbiota. The findings highlight H2 concentration in particular as a factor differentiating individual gut microbiomes with relevance beyond the specific case of RSP fermentation. Accounting for the effect of intestinal H2 will improve understanding of inter-individual differences in gut fermentation, in particular in response to microbiota-targeted supplements. Future work that explores targeted modulation of H2 concentrations could stimulate butyrate production or otherwise manipulate gut microbial metabolism for the benefit of human health.