The structure and function of the murine gut microbiome in sub-therapeutic antibiotic-induced obesity

Obesity represents an important public health concern in the United States and throughout the world. The composition of the gut microbiome is fairly stable unless disturbed by outside variables such as antibiotic treatment. While farmers have exploited sub-therapeutic antibiotic treatment for growth promotion in livestock for over 50 years, the mechanism of action remains unknown. The hypothesis of this dissertation is that the structure and activities of the gut microbiome impact health and disease in the context of obesity. We employed a systems biology approach to examine the murine gut microbiome in sub-therapeutic antibiotic-treated (STAT) and control mice. We generated deep DNA sequence coverage and gene annotation of the gut microbiomes of obese and lean mice and compared the representation of metabolic pathways. While less sensitive than the metagenomics strategy, we also compared profiles of abundant proteins using fractionated mouse microbiome samples derived from lean and obese mice with nLC-MS/MS. The combination of metagenomic and metaproteomic data allowed us to construe a model for major metabolic processes in the mouse gut. We identified differences in under- and over-represented gene/protein functions. Taxonomic analyses revealed that Enterococcaceae were 3-fold higher and Akkermansia muciniphila was reduced 4-fold in STAT compared to control mice. These results suggest that that increases in Enterococcaceae may reflect an elevated inflammatory state in the gut of obese mice, and A. muciniphila may promote gut health by reducing inflammation and improving gut barrier function. The metagenomics data revealed an over-representation of beta-glucosidase as well as increases in carbohydrate binding functions, and the metaproteomics data indicated an elevated production of D-xylose and alpha-D-glucose in STAT compared to control mice. These results suggest that the STAT mouse microbiota harbors an elevated potential for energy harvest from polysaccharides. The signatures of obesity indicate that the development of therapeutic interventions that drive the microbial composition of the gut toward that of healthy individuals may alleviate obesity.