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Beneficial ureolytic microbes and urea nitrogen salvage: examinations in an extreme animal model

Award Number: R15DK110784
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2020

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Beneficial ureolytic microbes and urea nitrogen salvage: examinations in an extreme animal model - Urea-nitrogen salvage occurs when urea, generated in the liver and passed to the bloodstream, diffuses into the gut where it is hydrolyzed by ureolytic microbes into NH3 and CO2. Microbially-liberated urea-N can then be utilized in biosynthesis by gut microbes as well as the host. Although long-understood to be important in ruminants, UNS in non-ruminants is not well described; however, it has recently been implicated in protein conservation in monogastric mammals, including humans, especially under conditions of dietary nitrogen deficiency or increased host nitrogen demand. While these studies suggest an important role for ureolytic microbes and UNS in human health, little is known about the degree to which UNS contributes to host biosynthetic processes, or about beneficial ureolytic microbes in the gut. Therefore, the goal of this study is to exploit the extreme phenotype of the arctic ground squirrel to discover interrelationships between host physiology and the gut microbial community important for host nitrogen metabolism. The hypotheses for this investigation are that 1) reliance upon UNS to meet nitrogen needs varies with dietary nitrogen content and host nitrogen demand and across the annual cycle of hibernation and activity, and that 2) the gut microbial community contains active ureolytic microbes that contribute significantly to host nitrogen homeostasis via UNS. The proposed experimental approach 1) utilizes injections of 13C/15N labeled urea to assess ureolytic activity and UNS in vivo via measurements of 13CO2 in breath (evidence of ureolysis in the gut) and 15N in tissues (evidence of use of microbially-liberated urea-N in host biosynthetic processes), 2) links phylogenic and functional diversity of the gut microbiota using next generation sequencing techniques (metagenomics and metatranscriptomics) and 3) specifically examines the abundance and activity of ureolytic bacteria in the gut using qPCR and qRT-PCR of microbial urease genes, respectively. Through comparison of relative changes in d15N of tissues of hibernating arctic ground squirrels injected with labeled or unlabeled urea, studies in Specific Aim 1 will demonstrate the degree to which microbially-liberated urea-N is incorporated into host tissues under a long term fast. In Specific Aim 2, manipulation of dietary protein content will be used to determine the degree to which euthermic animals rely upon UNS for protein conservation under conditions of protein insufficiency. Similar diet manipulations in gestating and lactating squirrels will be conducted to evaluate the influence of dietary protein content and high nitrogen demand on the incorporation of microbially-liberated urea-N in mothers and pups in Specific Aim 3. Our experiments promise to yield an increased knowledge about interrelationships between the gut microbial community and host nitrogen homeostasis, ultimately contributing to our understanding of the relationship between the gut microbial community and human health, in particular under states of compromised nutrition (starvation, low dietary protein) and elevated N demand (gestation and lactation).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = -$732 )
2021	2016	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/4/2021	NEW	-$732
														Subtotal = -$732

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2016	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/14/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	10/26/2017	NEW	$454,405
2018	2016	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	10/24/2017	NEW	-$454,405
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $454,405 )
2016	2016	UNIVERSITY OF ALASKA FAIRBANKS	OFC GRANTS & CONTRACTS ADMIN	FAIRBANKS	AK	99775	FAIRBANKS NORTH STAR	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/20/2016	NEW	$454,405
														Subtotal = $454,405

Grand Total All Awards = $453,673

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Beneficial ureolytic microbes and urea nitrogen salvage: examinations in an extreme animal model

Award Number: R15DK110784

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/21/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2020

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