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Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV

Award Number: R01DK122853
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/11/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV - Project summary Chronic HIV infection produces pathologic inflammation which drives disease progression and contributes to the development of serious co-morbid medical conditions, even in the setting of effective combination antiretroviral therapy (CART); translocation of bacterial products across the gastrointestinal (GI) mucosa is a major antigenic stimulus for this process. Our research focuses on how vagal dysfunction (VD), which occurs commonly as part of HIV-associated neuropathy, affects GI and immune function in HIV. Our prior work has shown that HIV+ individuals with VD have a high prevalence of small intestinal bacterial overgrowth (SIBO), and that SIBO is associated with elevation of the pro-inflammatory cytokine IL-6, which predicts morbidity and mortality in HIV. We have also demonstrated that treatment with the acetylcholinesterase inhibitor pyridostigmine, reduces indirect markers of bacterial translocation (sCD14) and the pro-inflammatory cytokine TNFα. The current proposal builds on this work, with the overarching goal of examining vagally-mediated GI mechanisms which could contribute to chronic inflammation in individuals with well-controlled HIV. Specifically we will seek to establish that small intestinal dysmotility and hypochlorhydria mediate the relationship between VD and SIBO, and to describe the changes in the GI microbiome in PLWH with SIBO. We will also determine whether VD is associated with elevations in IL-6 and TNFα independent of SIBO, establish to what degree the strength of these relationships depend on the presence of HIV infection, and whether they are reversible using pyridostigmine and/or non-invasive vagal nerve stimulation (nVNS). To achieve these aims, we will recruit 150 HIV+ participants who will undergo autonomic function tests for VD, hydrogen methane breath testing for SIBO, Wireless Motility Capsule (WMC, Smartpill) testing for GI regional transit times and pH measurements, oral and stool sample collection for characterization of the GI microbiome, and blood draw for quantification of inflammatory biomarkers. HIV-negative controls (N=100) will undergo the same assessments. Then a subset of 96 HIV+ participants will enter one of two eight-week interventional phases followed by repetition of the same testing battery: 1) double-blind treatment with pyridostigmine vs. placebo (N=86), or 2) open label treatment with non-invasive vagal nerve stimulation (N=10). These procedures will shed light on mechanisms linking VD to immune dysregulation in HIV, and provide support for potential therapies.


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 = $813,598 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	5/10/2024	NON-COMPETING CONTINUATION	$50,850
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/5/2024	NON-COMPETING CONTINUATION	$762,748
2024	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/6/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $813,598

Issue Date FY: 2023 ( Subtotal = $947,022 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/9/2023	SUPPLEMENT FOR EXPANSION	$99,524
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/15/2023	NON-COMPETING CONTINUATION	$847,498
														Subtotal = $947,022

Issue Date FY: 2022 ( Subtotal = $847,498 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/25/2022	NON-COMPETING CONTINUATION	$84,750
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/24/2022	NON-COMPETING CONTINUATION	$762,748
														Subtotal = $847,498

Issue Date FY: 2021 ( Subtotal = $847,498 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/18/2021	NON-COMPETING CONTINUATION	$847,498
														Subtotal = $847,498

Issue Date FY: 2020 ( Subtotal = $847,498 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/11/2020	NEW	$847,498
														Subtotal = $847,498

Grand Total All Awards = $4,303,114

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Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV

Award Number: R01DK122853

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/11/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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