Date of Award

Fall 12-16-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Andrew T. Gewirtz

Second Advisor

Benoit Chassaing

Third Advisor

Jun Zou

Fourth Advisor

Didier Merlin

Abstract

Metabolic Syndrome is a constellation of metabolic abnormalities associated with insulin resistance and obesity, including hyperglycemia and hypertension. Metabolic syndrome often progresses to type 2 diabetes, hypertension, cardiovascular disease, and liver disease. Metabolic syndrome is increasingly appreciated to be an inflammatory disease in that is associated with increased expression of pro-inflammatory genes and markers, remodeling of adipose tissue, and markedly increased incidence in the last 50 years. Additionally, both diseases alter the microbiota, specifically with alteration in gut microbiota composition. Metabolic syndrome requires a microbiota in that disease is not observed in germ- free mice, and some aspects of the disease can be transferred by fecal transplant. There is a probable correlation between metabolic disorder and gut microbiota. It’s also been shown that the efficacy of systemic medications can be affected by the gut microbiota and that some medications can alter the microbiota. Metformin is believed to be one of those medications. Accordingly, the results of the present study could be employed to develop novel methods for treating metabolic syndrome using medications such as metformin. Furthermore, this study can set the stage for further research towards the application of fecal transplantation as a treatment strategy for individuals with conditions like metabolic syndrome. The overall goal of my studies was to investigate this hypothesis.

First, I comprehensively examined the existing gut microbiota literature to discern the range of treatment of type 2 diabetes mellitus that have been associated with, or attributed to, changes in microbiota composition. Chapter 1 outlines findings from this effort.

Next, I performed experiments to investigate the extent to which metformin attenuates metabolic syndrome and inflammation by alternation of intestinal microbiota. My results support the notion that metformin induces changes in gut microbiota composition. However, such changes were not necessary for metformin to alleviate parameters of metabolic syndrome indicating that metformin can, at least in part act independently of gut microbiota. Rather Metformin reduced indices of inflammation in both conventional germ-free conditions. These results support a role for metformin’s anti-inflammatory effects rather than its direct action on microbiota for its beneficial metabolic impacts.

DOI

https://doi.org/10.57709/15912536

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