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The role of bile acid-microbiome cross-talk in psychotropic-induced weight gain and cardiometabolic dysfunction

Award Number: R21HD095548
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Weight gain and metabolic dysfunction are common, serious side effects of many psychiatric medications, especially antipsychotic drugs. These effects are amplified in children and can severely compromise physical health and interfere with psychiatric treatment. While the mechanism of antipsychotic-induced weight gain (AIWG) is poorly understood, studies in rodents have argued for a central role of gut microbes. Our team showed a similar effect in children taking the antipsychotic risperidone (RSP). We further hypothesized that gut microbes could impact weight and metabolism by altering bile acid (BA) signaling. Primary BAs made in the liver are converted to secondary BAs by gut bacteria. These two types of BAs have opposing effects on the liver farnesoid X receptor (FXR), involved in metabolism and energy balance. In support of this model, we determined that RSP exposure in youth with autism resulted in plasma BA elevations. The BA balance was distinct between those who gained weight on RSP and those who did not. Higher primary BAs favored weight gain, while higher secondary BAs were protective. This pattern was repeated in a small independent sample of children taking RSP and interestingly, in children taking selective serotonin reuptake inhibitors (SSRIs). Therefore, this proposal seeks to test this novel gut microbe-BA model of AIWG in children started on RSP by their physician for any mental illness. We will follow 60 children during the first 8 weeks of RSP treatment and collect blood and stool to measure BAs and gut microbes respectively. In those who gain weight with RSP treatment compared to those who do not, we predict a decrease in the abundance of gut bacteria capable of converting primary to secondary BAs and a resultant shift in the BA pool toward primary BAs. If proven, this model could guide clinical interventions to prevent metabolic side effects, as several potential treatments impacting this system are currently available for other uses. Additionally, this mechanism may apply more globally to other drug classes and possibly to obesity and metabolic dysfunction in general.


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 = -$4,811 )
2024	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	11/30/2023	NON-COMPETING CONTINUATION	-$4,811
														Subtotal = -$4,811

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	5/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	3/26/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $234,498 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	2/13/2020	NON-COMPETING CONTINUATION	$234,498
														Subtotal = $234,498

Issue Date FY: 2019 ( Subtotal = $209,498 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	1	1/28/2019	NEW	$209,498
														Subtotal = $209,498

Grand Total All Awards = $439,185

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The role of bile acid-microbiome cross-talk in psychotropic-induced weight gain and cardiometabolic dysfunction

Award Number: R21HD095548

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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