Project Grant R01DK138912

INTERSPECIES MICROBIAL INTERACTIONS IN CKD - ABSTRACT CHRONIC KIDNEY DISEASE (CKD) IS A GRADUAL LOSS OF KIDNEY FUNCTION, WHICH AFFECTS AN ESTIMATED 37 MILLION AMERICAN ADULTS, RESULTING IN 14.6 DEATHS PER 100,000 POPULATION. ONCE KIDNEY DAMAGE OCCURS, IT IMPAIRS REMOVAL OF UREMIC TOXINS, LEADING TO FURTHER DETERIORATION OF PHYSIOLOGICAL FUNCTIONS AND PROGRESSION OF RENAL FAILURE. SURPRISINGLY, MANY UREMIC TOXINS ARE NOT PRODUCED BY THE BODY ITSELF, BUT RATHER DERIVED FROM THE GUT MICROBIOTA. CKD IS ASSOCIATED WITH CHANGES IN THE COMPOSITION OF THE GUT MICROBIOTA (DYSBIOSIS), WHICH IS CHARACTERIZED BY AN INCREASED ABUNDANCE OF ENTEROBACTERIACEAE IN THE FECAL MICROBIOTA, A GROUP OF MICROBES KNOWN TO PRODUCE UREMIC TOXINS, SUCH AS INDOLE. THE OBJECTIVES OF THIS APPLICATION ARE TO UNDERSTAND THE ECOLOGICAL CAUSES OF DYSBIOSIS IN CKD ON A MOLECULAR LEVEL AND TO DETERMINE WHETHER DYSBIOSIS HAS A CAUSATIVE EFFECT ON CKD PROGRESSION. OUR CENTRAL HYPOTHESIS IS THAT ELEVATED EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) IN THE INTESTINE FUELS GROWTH OF ENTEROBACTERIACEAE BY ANAEROBIC NITRATE RESPIRATION. IN TURN, INCREASED INDOLE PRODUCTION BY RESPIRING ENTEROBACTERIACEAE AGGRAVATES CKD DISEASE PROGRESSION. WE WILL TEST DIFFERENT ASPECTS OF OUR HYPOTHESIS USING THE LOGICAL AND INNOVATIVE APPROACH OUTLINED IN THE FOLLOWING SPECIFIC AIMS. SPECIFIC AIM 1: DETERMINE THE ECOLOGICAL CAUSES OF DYSBIOSIS DURING CKD. SPECIFIC AIM 2: DETERMINE WHETHER DYSBIOSIS HAS A CAUSATIVE EFFECT ON CKD PROGRESSION. THE PROPOSED WORK IS INNOVATIVE BECAUSE IT IS AMONG THE FIRST TO PROVIDE MOLECULAR INSIGHTS INTO HOW CHANGES IN THE MICROBIOTA COMPOSITION OCCUR IN CKD, AND HOW MICROBIOTA CHANGES ARE CAUSATIVELY LINKED TO DISEASE PROGRESSION. SUCCESSFUL COMPLETION OF THE PROPOSED WORK WILL ESTABLISH HOW CKD-ASSOCIATED HOST RESPONSES DRIVE CHANGES IN THE ECOLOGY OF THE GUT MICROBIOTA, WHICH IN TURN SET THE STAGE FOR RELEASE OF UREMIC TOXINS BY ENTEROBACTERIACEAE, THUS ACCELERATING CKD PROGRESSION. THIS OUTCOME WILL BE OF BROAD SIGNIFICANCE FOR THE RATIONAL DESIGN OF NEW INTERVENTION STRATEGIES.