Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease in the US. The clinical burden of NAFLD is not restricted to liver-related morbidity or mortality, but it also increases the risk of cardiovascular disease (CVD), type 2 diabetes and cancer. As yet, there currently is no FDA-approved drug therapy. Thus, NAFLD imposes an important health problem and huge economic burden in the US. Increased dietary fructose consumption is an important risk factor in the pathogenesis and progression of NAFLD. Emerging evidence supports the concept that gut microbiota dysbiosis and gut barrier dysfunction play critical roles in the development of NAFLD, including dietary high fructose-induced NAFLD. However, how dietary fructose intake alters the gut microbiome has not been elucidated. Cross-talk between host and gut microbiota is key for maintaining ?physiologic hypoxia? in the intestinal epithelial cells, which is important for a healthy gut and disease resistance. A balanced gut microbiota is characterized by the dominance of obligate anaerobic bacteria of Firmicutes and Bacteroidetes phyla, whereas increased abundance of Proteobacteria is generally considered a signature of dysbiosis. Obligate anaerobic bacteria prevent pathogenic facultative anaerobic bacteria expansion, in part by limiting the generation of hostderived nitrate and oxygen. Our preliminary data showed that male rats fed chronically with either 10% glucose (w/v) or 10% fructose (w/v) in the drinking water results in gut microbiota dysbiosis. We hypothesize that fructose metabolism in the intestinal epithelial cells results in metabolic reprogramming which switches the host metabolic pathway from mitochondrial ?-oxidation to glycolysis. This leads to the disruption of ?physiologic hypoxia?, and intestinal oxygenation, thus inhibiting the growth of obligate anaerobic bacteria and facilitating the expansion of pathogenic bacteria. We will test our hypothesis in three specific aims.
Aim 1. Determine whether fructose induces metabolic reprogramming in intestinal epithelial cells and determine if this results in gut microbiota dysbiosis.
Aim 2. Determine whether modulation of glycolytic activity in intestinal epithelial cells alters gut microbiota composition.
Aim 3. Determine whether fructose induced gut microbiota dysbiosis is mediated by HIF-1.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM113226-05
Application #
10116867
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Bernal, Federico
Project Start
Project End
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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