Gut Microbiome and Obesity

The role of gut microbes in human physiology was largely underestimated until the past two decades. Once characterized as bystanders in the intestinal tract, the gut microbiota is now being viewed from an ecological perspective by the scientic community, providing the biomedical community with a robust framework for hypothesis formation. From an ecosystems’ point of view, ecological studies can help to explain how interactions with the environment may inuence species distribution over space and time. From the rst observations by Antonie van Leeuwenhoek using the microscope to the use of culture-based methods and the more recent development of high-throughput sequencing and metagenomics technologies, we have moved from descriptive approaches to the assessment of complex functional interactions not only within microbial communities but also within complex ecosystems such as human gut microbiota. The previous paradigm, in which microbes were mainly held responsible for severe diseases and mortality or worldwide epidemics, led medical research to address basic questions such as how can we fight microbes (pathogens) to avoid diseases? However, since two Nobel Prizes were awarded in the 1900s to Robert Koch and Ilya Mechnikov, scientists who established the link between microbes and human health, an intricate set of relationships between microbiota and humans has been unraveled. Thus, considerable efforts through international projects are now underway to identify and characterize the collection of microbes that inhabit our gut, and the gut microbiota has been reconsidered in a more positive way.1,2 The human gut microbiome has been shaped by the continuous

coevolutionary history of the host-microbe interaction, and both humans and microbes have been affected by this intimate association. Consequently, the gut microbiota is now considered as a key partner that helps balance important vital functions for the host, including immunity and nutritional status, and participates in the maintenance of health.3,4

We and others have uncovered a fascinating potential link between alterations in the gut microbiome and obesity and associated disorders (i.e., insulin resistance, type 2 diabetes, nonalcoholic fatty liver diseases, and metabolic inammation).5,6 Changes in the composition of the gut microbiota, as well as specic gut microbial communities, have been associated with obesity and type 2 diabetes in both animal and human studies. This chapter discusses the most recent evidence linking the gut microbiome and obesity, exploring links between gut microbiota composition and specic components or metabolites that may interfere with or initiate metabolic interactions with the host. For instance, it is evident that the gut microbiota provides essential genetic and metabolic attributes, sparing us from the need to evolve on our own. The processes affected by the gut microbiota include epithelial cell proliferation, immune system and barrier function against enteric pathogens, nutrient and drug metabolism, synthesis, and the bioavailability of several vitamins.7-9

Recently conducted investigations have shown that 99% of bacteria are members of ve phyla: Bacteroidetes (encompassing gram-negative genera, e.g., Bacteroides, Porphyromonas, and Prevotella), Firmicutes (encompassing gram-positive genera,

16.1 Introduction ..................................................................................................................................................................... 183 16.2 Gut Microbiota ................................................................................................................................................................. 183 16.3 Experimental Evidence of the Interplay between Gut Microbiota and Energy Homeostasis ......................................... 184

16.3.1 Gut Microbiota and Adipose Tissue Development .............................................................................................. 184 16.3.2 Gut Microbiota Can Transfer an Obesity Phenotype .......................................................................................... 185 16.3.3 Are SCFAs the Culprit Metabolites? ................................................................................................................... 186 16.3.4 Potential Mechanisms Linking Gut Microbiota Fermentation and Host Metabolism in the Context of Obesity ..... 186

16.4 Gut Microbiota Composition upon Obesity: Evidence from Rodents to Humans .......................................................... 187 16.4.1 Animal Models .................................................................................................................................................... 187 16.4.2 Human Studies ..................................................................................................................................................... 187

16.5 Gut Microbiota and Metabolic Inammation Associated with Obesity ......................................................................... 188 16.6 Metabolic Endotoxemia as a Causal Factor? ................................................................................................................... 188 16.7 Conclusion ....................................................................................................................................................................... 189 Acknowledgments ..................................................................................................................................................................... 189 References ................................................................................................................................................................................. 189

e.g., Clostridium, Ruminococcus, Lactoba cillus, Butyrivibrio, Anaerostipes, Roseburia, and Faecalibacterium), Actinobacteria (encompassing gram-negative genera, e.g., Bifidobac terium), Proteobacteria (encompassing gram-negative genera, e.g., Helicobacter and Escherichia), and Verrucomi crobia (encompassing the gram-negative species Akkermansia muciniphila).10-13 Each phylum is subdivided at the class, order, family, genus and species levels. Most gut microbiota data reported to date have focused on changes at the phylum level, but numerous studies have also identied the potential impact of one or several specic species that may play an important role in host metabolism.