Gut Microbial Response To Host Metabolic Phenotypes

The Food Forum convened a public workshop on February 22-23, 2012, to explore current and emerging knowledge of the human microbiome, its role in human health, its interaction with the diet, and the translation of new research findings into tools and products that improve the nutritional quality of the food supply. The Human Microbiome, Diet, and Health: Workshop Summary summarizes the presentations and discussions that took place during the workshop. Over the two day workshop, several themes covered included: The microbiome is integral to human physiology, health, and disease. The microbiome is arguably the most intimate connection that humans have with their external environment, mostly through diet. Given the emerging nature of research on the microbiome, some important methodology issues might still have to be resolved with respect to undersampling and a lack of causal and mechanistic studies. Dietary interventions intended to have an impact on host biology via their impact on the microbiome are being developed, and the market for these products is seeing tremendous success. However, the current regulatory framework poses challenges to industry interest and investment.

This book provides a comprehensive overview of metabonomics and gut microbiota research from molecular analysis to population-based global health considerations. The topics include the discussion of the applications in relation to metabonomics and gut microbiota in nutritional research, in health and disease and a review of future therapeutical, nutraceutical and clinical applications. It also examines the translatability of systems biology approaches into applied clinical research and to patient health and nutrition. The rise in multifactorial disorders, the lack of understanding of the molecular processes at play and the needs for disease prediction in asymptomatic conditions are some of the many questions that system biology approaches are well suited to address. Achieving this goal lies in our ability to model and understand the complex web of interactions between genetics, metabolism, environmental factors and gut microbiota. Being the most densely populated microbial ecosystem on earth, gut microbiota co-evolved as a key component of human biology, essentially extending the physiological definition of humans. Major advances in microbiome research have shown that the contribution of the intestinal microbiota to the overall health status of the host has been so far underestimated. Human host gut microbial interaction is one of the most significant human health considerations of the present day with relevance for both prevention of disease via microbiota-oriented environmental protection as well as strategies for new therapeutic approaches using microbiota as targets and/or biomarkers. In many aspects, humans are not a complete and fully healthy organism without their appropriate microbiological components. Increasingly, scientific evidence identifies gut microbiota as a key biological interface between human genetics and environmental conditions encompassing nutrition. Microbiota dysbiosis or variation in metabolic activity has been associated with metabolic deregulation (e.g. obesity, inflammatory bowel disease), disease risk factor (e.g. coronary heart disease) and even the aetiology of various pathologies (e.g. autism, cancer), although causal role into impaired metabolism still needs to be established. Metabonomics and Gut Microbiota in Nutrition and Disease serves as a handbook for postgraduate students, researchers in life sciences or health sciences, scientists in academic and industrial environments working in application areas as diverse as health, disease, nutrition, microbial research and human clinical medicine.

The metabolic phenotype of any complex organism is dependent on a complex series of host and gut microbial gene (microbiome) interactions with diet. The microbiome itself can be affected by environmental factors such as stress, exposure to xenobiotics, lifestyle, and alterations in the mammalian-microbial-metabolic axis are associated with changes in disease factors. To understand further the impact of the commensal microbiota on the host metabolism, germ-free (GF) animals, inoculated with individual bacterial strains or complex microbiota, and conventional mice were characterised using 1H NMR spectroscopy and UPLC-MS-based metabolic profiling approaches, and by recording the physiological and immunological parameters. Higher systemic level of (D)-3-hydroxybutyrate and lower levels of circulating VLDL were observed in GF compared to conventional animals, indicating that the absence of gut microbiota stimulated lipolysis while it inhibited hepatic lipogenesis. Subsequently, the best inoculation procedure was obtained by inoculating single bacterial strains into individual animals followed by allowing the animals to exchange their microbes. Metabolic fingerprints showed that a 9 bacteria community is more able to regulate lipoprotein and circulating lipid levels compared to a 3 bacteria community. The origin of the inocula (mouse or human) impacts differently on the host metabolism since humanised mice were strongly disturbed (higher plasma triglyceride level) and displayed metabolic profiles similar to GF mice. Conversely, mouse-associated animals were physiologically, immunologically and metabolically similar to conventional animals. Finally, metabolic profiles and gut microbiota composition were statistically regressed and helped to identify specific bacteria, such as Ruminococcus lactaris and Faecalibacterium prausnitzii, and their putative role in the host homeostasis. To conclude, these results confirmed the influence of gut microbes on the host physiology and metabolism. This PhD thesis provides new insights into the role of gut bacteria to understand the microbial-related mechanisms that participate in the host lipid metabolism, potentially leading to development of obesity.

The book provides an overview on how the gut microbiome contributes to human health. The readers will get profound knowledge on the connection between intestinal microbiota and immune defense systems. The tools of choice to study the ecology of these highly-specialized microorganism communities such as high-throughput sequencing and metagenomic mining will be presented. In addition the most common diseases associated to the composition of the gut flora are discussed in detail. The book will address researchers, clinicians and advanced students working in biomedicine, microbiology and immunology.

Bringing together expert researchers in the fields of microbiome, metabolism, and nutrition research, this book compiles the current state of knowledge from authorities specifically on how diet regulates microbial function with metabolic implications for the human host. Chapters cover the broad concepts of microbial-host interactions under the dietary influences of specific macronutrients, micronutrients, small molecule generation and bile acid circulation, with inclusion of later clinical chapters encompassing topics like bariatric surgery and our current understanding of probiotics, prebiotics, and synbiotics. Covering a timely topic from a functional standpoint, the book fills a gap in the existing literature. While increased attention is placed on descriptive work, it will importantly highlight emerging functional and mechanistic research findings that illustrate the inner workings of the dietary-microbial-host orchestration of metabolic regulation. Providing an exciting summary of the importance of current microbial function, it will also summarize the next major directions in the field of microbiome research.

The population of microbes that inhabit the mammalian intestine have profound effects on host physiology. The gut microbiome varies substantially among healthy individuals, and its composition is shaped by a complex interplay of environmental and genetic factors. Alterations in its composition are associated with the development of metabolic diseases, including obesity and type 2 diabetes. Therefore, manipulation of the intestinal microbiome ecosystem is a promising target for emerging therapies. However, it remains largely unknown how host genetics interacts with environmental factors (e.g. diet) to shape microbiota profiles, and how these interactions may contribute to metabolic disease susceptibility. The objective of this thesis research was to investigate the effects of host genetic variation on gut microbiota composition, evaluate how these interactions influence host diet-induced metabolic phenotypes, and to identify genetic variants that influence the abundance of gut microbes. In Chapter 2, I evaluate the relative contributions of host genetics and diet on gut microbiota composition and metabolic phenotypes using a panel of eight genetically diverse inbred mouse strains. In a controlled laboratory environment, I found gut microbiota composition and metabolic phenotypes are shaped by both genetics and diet. Guided by the results of this screen, I went on to demonstrate that in a gnotobiotic mouse model transplantation of genotype-associated microbiota can alter pancreatic islet function and confer sustained metabolic phenotypes despite chronic high-fat high-sucrose (HF/HS) feeding. In Chapter 3, I identify host genetic loci that influence gut microbiota and bile acid profiles. I performed quantitative trait loci (QTL) mapping to find genetic variants associated with abundance of gut microbes and bile acid levels using the Diversity Outbred (DO) mouse stock, which is derived from the eight strains profiled in Chapter 2. I found novel genetic variants associated with both microbial taxa and bile acids, including an association between the intestinal bile acid transporter, Slc10a2, the abundance of Turicibacter sp. and plasma cholic acid levels. Subsequent investigation revealed direct interactions between Turicibacter sp. and bile acids in vitro, supporting a role of genetics in elucidating host-microbe interactions. Together, this thesis work contributes to our understanding of host-microbe interactions and provides a foundation for future mechanistic studies.

Microbial endocrinology represents a newly emerging interdisciplinary field that is formed by the intersection of the fields of neurobiology and microbiology. This book will introduce a new perspective to the current understanding not only of the factors that mediate the ability of microbes to cause disease, but also to the mechanisms that maintain normal homeostasis. The discovery that microbes can directly respond to neuroendocrine hormones, as evidenced by increased growth and production of virulence-associated factors, provides for a new framework with which to investigate how microorganisms interface not only with vertebrates, but also with invertebrates and even plants. The reader will learn that the neuroendocrine hormones that one most commonly associates with mammals are actually found throughout the plant, insect and microbial communities to an extent that will undoubtedly surprise many, and most importantly, how interactions between microbes and neuroendocrine hormones can influence the pathophysiology of infectious disease.