Thursday, November 21, 2024 11/21/2024

Role of epithelial ROS signaling in mediating psychological stress-induced mucosal dysfunction and colitis predisposition

Award Number: R01DK131133
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/ABSTRACT: Inflammatory bowel diseases (IBD) are becoming more prevalent in the US and represent a major societal health concern. Exposure to psychosocial stressors increases the likelihood of developing IBD in genetically predisposed individuals, implicating a brain-gut axis in the IBD etiological framework. An emerging line of work has established that stress-induced disruptions to the gut microbiota (i.e. dysbiosis) may be the most proximate cause of stress-induced IBD predisposition. This includes data from our laboratory where we showed that a mouse adaptive pathogen (C. rodentium) was more effective at colonizing and inducing colitis in mice colonized by a microbiota from mice exposed to a chronic social defeat stressor. Moreover, our new preliminary data provides evidence stress exacerbates chronic, immune mediated (T-cell) colitis. However, how the gut microbiota and mucosal layer becomes dysregulated in response to stressors and why those changes predispose worsened colitis, is not yet understood. We recently demonstrated that stress induces large shifts in intestinal epithelial cell (IEC) activity that tightly corresponded to changes in gut microbiota function and thinning of the mucus layer. Of those changes observed in IECs, our preliminary data indicate that the reactive-oxygen species (ROS)-generating capacity of IECs may be the most proximate causes of stress-induced dysbiosis and mucosal disruption. Signs of stress in IECs were absent in germ-free (GF) mice at baseline, thus implicating the microbiota in IEC responsiveness. Nevertheless, IECs were still primed to respond differentially to an ex vivo bacterial challenge (evidenced by an increased expression in the ROS-generating enzyme dual oxidase (DUOX2), suggesting that host stress signaling molecules and the gut microbiota are together involved in regulating IEC activity. Intriguingly, the upregulation in DUOX2 and ROS activity in IECs corresponded to expansion of ROS-resistant bacteria that are capable of mucus degradation. These data led us to build a cohesive framework underlying this proposal, whereby stress hormones ‘prime’ IECs to respond to endogenous microbiota signaling/adhesion through heightened ROS generation. This enhanced ROS activity at the mucosal interface creates a unique niche for mucosal associated microbes that are resistant to ROS activity and survive by degrading mucus glycans that normally provide a barrier against both endogenous microbes and pathogens. We hypothesize that this IEC-directed expansion of ROS-resistant, mucus-degrading endogenous microbes is what underlies IBD susceptibility in organisms exposed to chronic, unabated stress.


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 = $626,888 )
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/20/2024	NON-COMPETING CONTINUATION	$626,888
														Subtotal = $626,888

Issue Date FY: 2023 ( Subtotal = $665,574 )
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/5/2023	NON-COMPETING CONTINUATION	$665,574
														Subtotal = $665,574

Issue Date FY: 2022 ( Subtotal = $685,464 )
2022	2022	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/18/2022	NEW	$685,464
														Subtotal = $685,464

Grand Total All Awards = $1,977,926

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Role of epithelial ROS signaling in mediating psychological stress-induced mucosal dysfunction and colitis predisposition

Award Number: R01DK131133

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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