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Mechanisms of arsenic detoxification by the human microbiome

Award Number: R01CA215784
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Mechanisms of arsenic detoxification by the human microbiome - Project Summary The proposed project addresses the role of the human microbiome in the detoxifying arsenic following ingestion. Arsenic poisoning is a significant worldwide threat to public health that leads to a variety of human diseases, including cancer. Polymorphisms in genes involved with arsenic metabolism and transport have been epidemiologically linked to increased risk of lung, skin, bladder, and liver cancer, but there is large inter-individual variability in cancers among similarly exposed individuals, indicating other important factors are involved in disease penetrance. We showed the gut microbiome is an important determinant in arsenicosis and this project continues to evaluate which microbiome-arsenic interactions provide the most benefits during exposure. This includes engineering bacteria to evaluate specific microbiome-driven arsenical metabolisms in the gut of gnotobiotic mice, focusing specifically on reduction, methylation, and thiolation pathways (Aim 1). We also found antibiotic perturbation of the murine microbiome significantly increases the toxicity of inorganic arsenic and leads to inter-individual differences in lethality. At least some of these differences appear to result from sepsis or sepsis-like disease also observed in human arsenic poisoning. We will quantify the impact of commonly prescribed antibiotics on arsenic toxicity and test whether microbiome manipulation can be used to rescue arsenic-attributable sepsis (Aim 2). This information is important given the large number of individuals treated with antibiotics in the US and countries around world. PD/PI's Walk and McDermott have had success leading this multidisciplinary research program since 2017. The research new team members and collaborators with years of training and technical expertise in murine models of the gut microbiome, microbial ecology, molecular biology, arsenical speciation, clinical pharmacology, and immunology. Collectively, the assembled team will ensure the continued success of a highly productive research effort into microbiome-arsenic-host interactions.


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: 2025 ( Subtotal = $363,451 )
2025	2025	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Biology Research	000	7	2/19/2025	NON-COMPETING CONTINUATION	$327,106
2025	2025	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Biology Research	001	7	5/22/2025	NON-COMPETING CONTINUATION	$36,345
														Subtotal = $363,451

Issue Date FY: 2024 ( Subtotal = $374,699 )
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Biology Research	001	6	3/22/2024	COMPETING CONTINUATION	$374,699
2024	2021	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Cause and Prevention Research	000	5	3/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $374,699

Issue Date FY: 2021 ( Subtotal = $330,579 )
2021	2021	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Cause and Prevention Research	000	5	7/7/2021	NON-COMPETING CONTINUATION	$330,579
														Subtotal = $330,579

Issue Date FY: 2020 ( Subtotal = $330,579 )
2020	2020	MONTANA STATE UNIVERSITY, INC	307 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Cause and Prevention Research	000	4	7/1/2020	NON-COMPETING CONTINUATION	$330,579
														Subtotal = $330,579

Issue Date FY: 2019 ( Subtotal = $320,665 )
2019	2019	MONTANA STATE UNIVERSITY, INC	307 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Cause and Prevention Research	001	3	7/15/2019	NON-COMPETING CONTINUATION	$320,665
2019	2018	MONTANA STATE UNIVERSITY, INC	307 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Cause and Prevention Research	000	2	11/2/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $320,665

Issue Date FY: 2018 ( Subtotal = $330,579 )
2018	2018	MONTANA STATE UNIVERSITY, INC	307 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Cause and Prevention Research	001	2	7/25/2018	NON-COMPETING CONTINUATION	$330,579
2018	2017	MONTANA STATE UNIVERSITY, INC	307 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Cause and Prevention Research	000	1	3/12/2018	NEW	$0
														Subtotal = $330,579

Issue Date FY: 2017 ( Subtotal = $328,787 )
2017	2017	MONTANA STATE UNIVERSITY, INC	307 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Cancer Cause and Prevention Research	000	1	7/31/2017	NEW	$328,787
														Subtotal = $328,787

Grand Total All Awards = $2,379,339

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Mechanisms of arsenic detoxification by the human microbiome

Award Number: R01CA215784

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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