Genetic and Environmental Factors Affecting The Human Gut Microbiom In Obesity

Abstract

The human microbiota is defined as the collective microbes living on and in the human body. Microbes can confer many benefits to the host including pathogen protection, complex carbohydrate breakdown and essential compound biosynthesis. Imbalances in the microbiome have been linked to disease, in particular obesity. The aim of this thesis is to explore the genetic and environmental effects on the human gut microbiome in twins, and characterise the microbiome species related to obesity. The primary dataset included gut microbiome 16s profiles of 982 twins from the TwinsUK cohort with extensive phenotype data. I first explored the heritability of the gut microbiome and obesity using twin modelling. The results revealed several heritable families, including the most heritable family, Christensenellaceae, which was also associated with lean BMI and measures of adiposity, including visceral fat. In addition, I found further associations between Christensenella and immune-related phenotypes such as white blood cell count, as well as host immune genetic variants. The next major analysis focused on identifying gut bacterial species that significantly differed between obese and lean individuals. I refer to these analyses as a Microbiome-Wide Association Study (MiWAS). The majority of the significant MiWAS results in obesity were obtained for members of the Ruminococcaceae and Lachnospiraceae. A candidate gene analysis was performed which aimed to identify obesity-associated human variants linked to these microbes. The strongest association was obtained between Lachnospiraceae and a variant within the human RPTOR gene, which controls the insulin-signalling pathway in response to nutrient availability by either binding or dissociating from MTOR. This finding and further associations of Lachnospiraceae with insulin, diet and cholesterol measures implicate a role for Lachnospiraceae in insulin resistance as well as obesity. The final project explored the association between the gut microbiome and metabolites in serum, plasma and faeces. First I identified associations between serum and plasma metabolites. The peak serum & plasma metabolite signals were obtained with the metabolites palmitate and cholesterol, which both play an important role in human metabolic health. The top associations were with the family Christensenellaceae indicating the importance of this microbial family not only in obesity, but also in extended metabolic phenotypes. Next, I obtained strong signals both between adiposity and faecal metabolites as well as with 16S microbial profiles. This indicates a useful role for faecal metabolomics as well as serum/plasma metabolomics in future phenotypic analyses. In conclusion, my thesis explored the genetic and environmental basis of the human microbiome in twins, identifying host genetic influences on the gut microbiome. The project also aimed to characterise the human gut microbiome in obesity. The results confirm and extend previous findings of obesity-related microbiome profiles, and identify interesting host genes that may provide a starting point to understand the interaction of host genetics with the gut microbiome in human metabolism and obesity.

Date of Award	2016
Original language	English
Awarding Institution	King's College London
Supervisor	Jordana Bell (Supervisor) & Tim Spector (Supervisor)