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Role of stress-induced reduction in lactobacillus reuteri on colonic inflammation

Award Number: R01AT006552
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2012
PERIOD OF PERFORMANCE END DATE: 04/30/2017

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Role of stress-induced reduction in lactobacillus reuteri on colonic inflammation - DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD, including Crohn's disease and ulcerative colitis) involve disrupted homeostatic interactions between the microbiota and the mucosal immune system as a result of multiple genetic and environmental factors. A major environmental factor that is well recognized to increase the severity of IBD is psychosocial stress. However, the biological mechanisms linking stress to disrupted homeostatic relationships between the microbiota and the mucosal immune system are not well understood. This proposal will test the novel hypothesis that intestinal epithelial cells represent a mechanistic link between stress, alterations of the gut microbiota, and pathogen-induced colitis. Our preliminary data demonstrate that exposing mice to a well characterized and widely used social stressor, called social disruption (SDR) reduces the abundance of commensal Lactobacillus reuteri in the colon. Upon oral challenge with the murine colonic pathogen Citrobacter rodentium, which induces colonic histopathology with similarities to human IBD, mice exposed to SDR (and thus having lower levels of L. reuteri) had a significant increase in pathogen-induced colitis as indicated by a significant increase in colonic histopathology, chemokines (e.g., CCL2), cytokines (e.g., TNF-?), effector molecules (e.g., iNOS), and macrophage infiltration. Importantly, preventing the stressor-induced reduction in L. reuteri by feeding L. reuteri to the mice during stressor exposure abrogated the effects of the stressor on C. rodentium-induced colitis. Like its human homologue (i.e., enteropathogenic E. coli), C. rodentium induces colonic inflammation by colonizing the colonic epithelium. Thus, the use of C. rodentium is an ideal model to determine whether the colonic epithelium is critical in the link between stress, the microbiota, and exacerbation of colitis. This proposal will test the novel hypothesis that when L. reuteri are decreased due to stressor exposure, colonic epithelial cells overproduce chemokines (particularly CCL2) that increase the recruitment of inflammatory macrophages to the colon where they ultimately exacerbate colitis. The first aim will examine the role of CCL2 as a novel primary mechanism (pathway) mediating the effects of stress on colonic inflammation, by assessing the effects of stress-induced alterations of L. reuteri on CCL2 production by colonic epithelial cells and by using CCL2 knockout mice. In the second aim, we will use adoptive transfer experiments to test whether peripheral inflammatory monocytes, which we show are increased in the circulation of stressed mice, traffic to the colon in response to the elevated CCL2, where they can exacerbate colitis through an overproduction of TNF-? and iNOS. Finally, in the third aim, we will determine whether the ability of L. reuteri to affect chemokine production by colonic epithelial cells is dependent upon L. reuteri colonizing the colon, and/or due to the production of immunomodulatory factor(s). This proposal will identify novel mechanism(s) that may lead to new therapeutic targets in the treatment of IBD.


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: 2019 ( Subtotal = -$2,543 )
2019	2016	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	000	6	10/23/2018	NON-COMPETING CONTINUATION	-$2,543
														Subtotal = -$2,543

Issue Date FY: 2016 ( Subtotal = $350,931 )
2016	2016	Research Institute at Nationwide`s Children`s Hospital	700 CHILDREN`S DRIVE	COLUMBUS	OH	43205	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	001	6	5/4/2016	NON-COMPETING CONTINUATION	$0
2016	2016	Research Institute at Nationwide`s Children`s Hospital	700 CHILDREN`S DRIVE	COLUMBUS	OH	43205	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	000	6	4/12/2016	NON-COMPETING CONTINUATION	$350,931
														Subtotal = $350,931

Issue Date FY: 2015 ( Subtotal = $392,838 )
2015	2015	Research Institute at Nationwide`s Children`s Hospital	700 CHILDREN`S DRIVE	COLUMBUS	OH	43205	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	003	5	9/18/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$392,838
2015	2015	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	000	4	4/30/2015	NON-COMPETING CONTINUATION	$372,487
2015	2015	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	001	4	5/6/2015	NON-COMPETING CONTINUATION	$0
2015	2015	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	002	4	9/11/2015	NON-COMPETING CONTINUATION	-$372,487
														Subtotal = $392,838

Issue Date FY: 2014 ( Subtotal = $372,489 )
2014	2014	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	000	3	4/1/2014	NON-COMPETING CONTINUATION	$372,489
														Subtotal = $372,489

Issue Date FY: 2013 ( Subtotal = $372,488 )
2013	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	001	2	5/23/2013	NON-COMPETING CONTINUATION	$26,880
2013	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	000	2	4/11/2013	NON-COMPETING CONTINUATION	$345,608
														Subtotal = $372,488

Issue Date FY: 2012 ( Subtotal = $410,163 )
2012	2012	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Research and Training in Complementary and Integrative Health	000	1	3/20/2012	NEW	$410,163
														Subtotal = $410,163

Grand Total All Awards = $1,896,366

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Role of stress-induced reduction in lactobacillus reuteri on colonic inflammation

Award Number: R01AT006552

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2012

PERIOD OF PERFORMANCE END DATE: 04/30/2017

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