Of Microbes, Mice and Men: Targeting Type 2 Diabetes Through Prebiotics and the Gut Microbiota

Abstract

Changes in human diet and lifestyle over recent decades have led to the emergence of a global type 2 diabetes (T2D) epidemic. With an estimated four-fold increase in prevalence over the previous four decades, nearly 600 million people are expected to be affected by the disease by 2035, and the associated economic burden to reach staggering levels. Of particular interest are Asian populations, who exhibit increased susceptibility to T2D, often characterised by distinctive visceral distribution of body fat, associated with fat infiltration into key organs such as the liver and pancreas. Current treatment methods have not been effective in stemming this unprecedented systemic growth, and development of novel therapies has become essential. Growing evidence suggests that the gut microbiota interacts with key host metabolic processes and may be implicated in T2D onset; however its precise role remains unclear. This thesis utilises 16S rRNA gene-based amplicon sequencing (Illumina MiSeq) of faecal samples to investigate the association between T2D and the gut microbiota, specifically exploring the gut microbial communities of transgenic mouse models as well as humans with prediabetes. Influences from potential prebiotic therapies such as dietary flavonol rutin and nuts were further examined in a series of randomised controlled trials, and a direct comparison between gut microbiota profiles of prediabetic Asian Chinese versus European Caucasian individuals was performed. With the exception of transgenic mouse datasets – where both human amylin expression and dietary rutin treatment were observed to have a minor but significant effect on gut bacterial composition – our findings from prediabetic human datasets generally did not identify a significant impact on gut bacterial composition in the context of disease onset or in response to prebiotic treatments (over a 3 month period). However, several butyrate-producing bacteria were positively associated with decreased fasting plasma glucose (a key marker of T2D risk), and in response to nut treatment, with increased alpha diversity. Furthermore, a considerable decrease in ubiquity of highly prevalent bacteria was observed in response to disease onset in all datasets analysed and key differences between prediabetic Asian Chinese and European Caucasian gut microbiota profiles have been characterised. This research represents the first community level investigation into gut microbiota response to dietary rutin and nut supplementation in the context of T2D onset, and provides new insights into their prebiotic potential.