“I’ve Gut a Feeling”: The Effect of Nerve Growth Factor on Gut Microbiota in Obesity, Type II Diabetes Mellitus, and Alzheimer’s Disease in a Mouse Model

Abstract

In recent years, the rates of obesity and diet-induced metabolic disorders have continued to rise. In the United States, obesity and Type II Diabetes Mellitus (T2DM) are at epidemic levels. Obesity and T2DM increase the risk for development of other chronic diseases and place a costly burden upon the individual and healthcare system as a whole. In order to mitigate the risk and lower healthcare costs, affordable and non-invasive preventative measures are being investigated. While all organ systems within the body are affected by this chronic dysregulation, treatments aimed at sites of pathogenesis within the body are of great interest. In the development of obesity and T2DM, the digestive and nervous systems have been implicated for their role in sustained hyperglycemia. If left untreated, sustained hyperglycemia has been linked to the development of cognitive decline and dementia. Alzheimer’s Disease, a form of dementia, is connected with increased systemic inflammation and gut microbiome dysbiosis. The associations between the gut microbiome, obesity, T2DM, and Alzheimer’s Disease are discussed in Chapter 2. In Chapters 3 and 4, a high-fat/high-sugar diet murine model was investigated over a period of 13 weeks. The effect of a neuro-regenerative treatment Neuronal Growth Factor (NGF) on the gut microbiome was investigated. The first study, Chapter 3, was entitled “Impact of Nerve Growth Factor Administration on Gut Microbiota Community in an Obese, Type II Diabetic Mellitus, and Alzheimer’s Disease Mouse Model”. Fecal samples were analyzed from 36 mice using 16S rRNA sequencing techniques. In the HFWD models, (Groups 3-6), significant increases in body weight and insulin resistance were noted as compared to the lean control models (Groups 1 and 2). Additionally, the relative abundance of pro-inflammatory bacterial taxa at the family level was found to be greater in the HFWD groups (Groups 3-6) as compared to the lean control groups (Groups 1 and 2). In summary, diet and diabetes status exerted a greater effect on gut microbiome homeostasis than NGF treatment when compared to controls as seen in body weight, blood glucose and insulin measurements, and relative abundance levels. The second study, Chapter 4, was entitled “Effect of Nerve Growth Factor Administration on Gut Junction Gene Expression in an Obese, Type II Diabetes Mellitus, and Alzheimer’s Disease Mouse Model”. For this study, an investigation was performed on the gut-brain barrier function through analysis of key junction proteins’ expression within the small intestine. Using PCR analysis, the intestinal barrier integrity was compared between groups. Statistical comparisons were not able to be conducted between all six groups due to undetectable levels of RNA as seen in Group 6 with STZ treatment. However, of the groups able to be compared, diet may have a greater effect on gene expression levels than NGF treatment. In future studies, optimizing the dose of STZ administration may be beneficial. In conclusion, future investigation is warranted into the interrelationships of obesity, T2DM, and AD as well as the gut microbiome and gut-brain axis.