It is increasingly clear that the intestinal microbiota plays a critical role in both normal host physiology as well as pathology during disease states. There is a growing body of data that changes in the microbiota are associated with many inflammatory diseases, however it is unclear if these changes initiate or support disease severity and progression. Data from animal models support both inflammatory conditions inducting dysbiosis as well as dysbiosis leading to disease, but the data supporting microbial dysbiosis causing disease in humans is less convincing. In HIV, a number of studies have identified intestinal dysbiosis which correlates with increased translocation of microbes and microbial products into the bloodstream and is thought to partially underlie the chronic inflammation observed in HIV patients. This increased systemic inflammation is thought to drive many of the co-morbidities associated with HIV including chronic kidney disease (CKD). We believe a positive feedback loop exists in HIV where disease pathology leads to dysbiosis and increased translocation of microbes and microbial products resulting in systemic inflammation and HIV associated comorbidities including CKD. In parallel, we believe HIV expression in kidney cells leads to reduced kidney function and induces intestinal dysbiosis and increased mucosal translocation through breakdowns in the intestinal barrier. We hypothesize that systemic inflammation and kidney disease drive each other through their combined effects on the microbiota. We believe manipulation of the microbiota will short circuit this loop and limit CKD in HIV+ patients. We will use a combination of mouse models and primary patient analyses to test our hypotheses. We will take advantage of our established mouse model of HIV associated kidney disease, Tg26 mice. We observe differential disease progression correlated with differences in the microbiota. We will colonize germfree Tg26 mice with different microbes to identify and characterize pathways impacted by differences in microbiota composition that impacts disease with the goal of identifying therapeutic interventions. Previous human studies have not addressed the combined effect of HIV and kidney disease on the intestinal microbiota. We will apply our expertise in microbiome compositional and functional analysis and in HIV-associated kidney disease, to understand the interrelationship between HIV, microbial dysbiosis, and kidney disease in an HIV+ patient population. Understanding the relationship between HIV, kidney disease and intestinal dysbiosis would open avenues for novel therapeutic strategies targeted toward prevention of CKD-related complications in HIV+ individuals.
Aim 1 : Determine if gastrointestinal microbiome shifts in Tg26 mice underlie kidney disease progression.
Aim 2. Determine if the intestinal microbiota offers protection from kidney disease progression in an animal model of HIV..

Public Health Relevance

It is increasingly clear that the intestinal microbiota plays a critical role in both normal host physiology as well as pathology during disease states. There is a growing body of data that changes in the microbiota are associated with many inflammatory diseases, however it is unclear if these changes initiate or support disease severity and progression. A likely environmental trigger increasing development of kidney disease is shifts in the intestinal microbiota and associated bacterial translocation, both of which are observed in HIV+ patients. Using a combination of primary human patient data as well as an established model of HIV associated kidney disease, this project will investigate the role of the microbiota in chronic kidney disease (CKD) in HIV+ individuals. Understanding the relationship between HIV, kidney disease and intestinal dysbiosis would open avenues for novel therapeutic strategies targeted toward prevention of CKD-related complications in HIV+ individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK056492-19
Application #
9768912
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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