Elucidation of Host Genetics -

Download or read book Elucidation of Host Genetics - written by Julia Hill Kemis and published by . This book was released on 2018 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.