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Impact of gut bacterial metabolites on lung function and disease

Award Number: K08HL165106
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Impact of gut bacterial metabolites on lung function and disease - Project Summary/Abstract Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), is common in COVID-19 and was a major driver of the now >1 million deaths in the USA since March 2020. Rigorous work has emphasized the key role the immune system and the microbiome plays in lung diseases like ALI. This includes an important role for pro-inflammatory T helper 17 (Th17) cells, which expand and increase their activation in lung tissue during ALI and lead to pulmonary fluid accumulation. While select gut bacteria can induce Th17 cells, the causal role of the microbiome in ALI and ARDS remains a major knowledge gap. Bifidobacterium adolescentis is a gut isolate with the highest Th17 inducing capacity of any human gut bacterium. My own preliminary data show that colonization of germ-free (GF) mice with B. adolescentis is sufficient to markedly alter the expression of many genes in lung tissue, including hundreds of genes implicated in ARDS. My data also indicates that B. adolescentis and other bifidobacteria secrete small molecules that activate Th17 cells, providing a plausible mechanism by which bifidobacteria could contribute to lung injury. My K08 application will build on a set of tools based on our laboratory’s recent discovery that the host ketone body, β-hydroxybuytrate (βHB), uniquely suppresses the growth of Bifidobacterium species. I hypothesize that Bifidobacterium, which are suppressed by gut epithelial βHB, secrete small molecules that reach lung tissue and activate Th17 cells during ALI. The proposed research plan will provide multiple training opportunities leading to a unique and sustainable research program. As a clinical fellow in the Turnbaugh lab (UCSF), I have learned microbiome data analysis, anaerobic microbiology, and gnotobiotic mouse husbandry. This project, coupled to in-depth support by lung experts Drs. Sheppard and Matthay (UCSF), will help me develop an independent research area that builds upon my past training. I will develop skills quantifying ALI severity in two ALI models and pair these ALI models with state-of-the-art tools in microbiome research. This proposal is both technologically and conceptually innovative. We will leverage resources available in our laboratory to selectively manipulate Bifidobacterium colonization levels in conventionally raised mice using βHB. My proposed experiments will help elucidate the metabolites produced by gut Bifidobacterium that induce pulmonary Th17 phenotypes, emphasizing the importance of considering bacterial metabolism for immune function and lung physiologic impairment. Our proposed studies will shift the focus to remote communication between prevalent human gut bacteria and lung tissues, mediated by secreted bacterial metabolites. For patients with ALI, this work will define putative mechanisms by which gut microorganisms contribute to devastating physiologic impairment and provide a conceptual basis to understand the scope and molecular impact of the gut microbiome on lung function in both health and disease.


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: 2026 ( Subtotal = $169,020 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	4	3/19/2026	NON-COMPETING CONTINUATION	$169,020
														Subtotal = $169,020

Issue Date FY: 2025 ( Subtotal = $169,020 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	3	1/9/2025	NON-COMPETING CONTINUATION	$169,020
														Subtotal = $169,020

Issue Date FY: 2024 ( Subtotal = $169,020 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	2	1/8/2024	NON-COMPETING CONTINUATION	$169,020
														Subtotal = $169,020

Issue Date FY: 2023 ( Subtotal = $169,020 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	1	3/22/2023	NEW	$169,020
														Subtotal = $169,020

Grand Total All Awards = $676,080

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Impact of gut bacterial metabolites on lung function and disease

Award Number: K08HL165106

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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