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Unraveling strain-level variation in the induction of anti-inflammatory responses in the intestine

Award Number: R01DK126772
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY: Inflammatory bowel disease (IBD) is an increasingly prevalent disease that currently affects ~1.3% of adults in the US. IBD is characterized by chronic inflammatory immune responses directed against the gut microbiota, and severely impedes the health of its sufferers. Current therapeutic approaches involve neutralization of pathogenic inflammatory pathways. However, many patients are non-responsive or become refractory to treatment, and the requirement for sustained administration of these agents can enhance susceptibility to infection. A major unmet clinical need entails development of improved therapeutic regimens that quell ongoing inflammation while sparing protective immunity. Strategies that seek to restore host immune- gut microbiota homeostasis through introduction of health-promoting immunomodulatory microbes (probiotics), represent an attractive alternative to blockade of immune function. To date, these approaches have demon- strated limited efficacy. Our incomplete understanding of the mechanisms through which microbes induce anti- inflammatory responses, and how transplanted microbes survive the hostile environment of the inflamed intes- tine to establish a niche have severely hampered these efforts. An approach where the optimal features from different microbes are combined, so-called designer probiotics, represents an improved treatment strategy. Knowledge gap: The identity of the bacterial pathways that actively promote intestinal anti-inflammatory im- mune responses and allow probiotic strains to colonize the inflamed intestine have remained enigmatic due to microbiota complexity and difficulties associated with the genetic manipulation of gut microbes. Hypothesis: Strain-specific differences impact the probiotic potential of gut bacterial species. Preliminary studies: Through the study of distinct strains of the genetically tractable gut symbiont Bacteroides thetaiotaomicron, we have (i) identified extensive strain-level variation in the ability of B. thetaiotaomicron strains to induce accumulation of colonic Tregs in monocolonized gnotobiotic mice, (ii) revealed significant strain-level variation in the biofilm- forming capacity of different strains of B. thetaiotaomicron, and (iii) uncovered the existence of a novel, B. the- taiotaomicron-derived, immunomodulatory factor that promotes production of the anti-inflammatory cytokine IL- 10. Our systems provide an opportunity to leverage the relatedness of strains within a species that impart dif- ferential phenotypes to provide insight into pathways related to the optimal function of probiotics. Project ob- jective: To leverage the strain-level variation and genetic tractability of B. thetaiotaomicron to define the bacte- rial genes and molecules that most potently confer anti-inflammatory capacity to gut microbes. Impact: Results of these studies will advance efforts to develop designer probiotic therapeutics that provide durable remission from disease for IBD patients. Aim 1: Define the molecular basis for strain-level variation in bacterial driven colonic Treg induction. Aim 2: Define the B. thetaiotaomicron-derived immunomodulatory factor(s) that limit colitis. Aim 3: Define the genetic determinants mediating bacterial strain-level fitness in the inflamed intestine.


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: 2024 ( Subtotal = $462,009 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/27/2023	NON-COMPETING CONTINUATION	$433,135
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/14/2024	NON-COMPETING CONTINUATION	$28,874
														Subtotal = $462,009

Issue Date FY: 2023 ( Subtotal = $481,261 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/16/2022	NON-COMPETING CONTINUATION	$433,135
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/24/2023	NON-COMPETING CONTINUATION	$48,126
														Subtotal = $481,261

Issue Date FY: 2022 ( Subtotal = $477,011 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/25/2022	NON-COMPETING CONTINUATION	$47,702
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/10/2021	NON-COMPETING CONTINUATION	$429,309
														Subtotal = $477,011

Issue Date FY: 2021 ( Subtotal = $477,011 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/25/2020	NEW	$477,011
														Subtotal = $477,011

Grand Total All Awards = $1,897,292

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Unraveling strain-level variation in the induction of anti-inflammatory responses in the intestine

Award Number: R01DK126772

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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