Skip to main content
An official website of the United States government
Grant Details

Grant Number: 4R01CA180030-04 Interpret this number
Primary Investigator: De Araujo, Ivan
Organization: John B. Pierce Laboratory, Inc.
Project Title: (PQA3) the Gut-Brain Axis: a Novel Target for Treating Behavioral Alterations in
Fiscal Year: 2016


DESCRIPTION (provided by applicant): Our proposal addresses NCI's Provocative Question #3 (Group A): We designed a strategy to change cancer- inducing dietary habits, which is based on rescuing normal neural activity in brain circuits of overweight/obese individuals. The relevance of our proposal to cancer prevention is demonstrated by epidemiological studies establishing that several forms of cancer could be prevented by the adoption of healthier dietary habits, with up to 20% of cancer-related deaths being potentially attributable to obesity alone. In both rodents and humans, excessive intake of dietary fats leads to dysregulated neuronal function in dorsal striatum. This diet-derived striatal deficiency leads to an impaired ability to learn about the negative outcomes of one's actions which, in turn, results in the expression of impulsive behaviors such as excessive caloric intake. Our strategy builds on previous animal studies demonstrating that prolonged exposure to a high-fat diet substantially reduces the intestinal synthesis of appetite-regulating lipid messengers. Since our previous work had established that gut- brain signals regulate neurochemical activity in dorsal striatum, we set fort the central hypothesis that rescuing gut-brain communication will restore striatal function. As a corollary, we predict that rescuing gut-brain communication will enhance the ability to learn about negative outcomes, thereby reducing impulsivity behavioral scores and increasing compliance with a low-calorie diet. Accordingly, our Specific Aims are as follows: Specific Aim 1 (Mechanistic studies): To identify which gut N-acylethanolamines rescue striatal function and reduce impulsivity in high-fat fed mice, and to determine the neural and molecular mechanisms of their action; Specific Aim 2 (Translational studies): To determine whether gut N-Acylethanolamines precursors rescue striatal function and reduce impulsivity scores in overweight/obese human subjects. We thus propose that the gut-brain axis is a novel target for treating behavioral alterations in the obese, the normalization of which may greatly contribute to reducing cancer-related dietary habits.


Identification of a brain fingerprint for overweight and obesity.
Authors: Farruggia M.C. , van Kooten M.J. , Perszyk E.E. , Burke M.V. , Scheinost D. , Constable R.T. , Small D.M. .
Source: Physiology & behavior, 2020-08-01; 222, p. 112940.
EPub date: 2020-05-14.
PMID: 32417645
Related Citations

No evidence for an association between obesity and milkshake liking.
Authors: Wall K.M. , Farruggia M.C. , Perszyk E.E. , Kanyamibwa A. , Fromm S. , Davis X.S. , Dalenberg J.R. , DiFeliceantonio A.G. , Small D.M. .
Source: International journal of obesity (2005), 2020 Aug; 44(8), p. 1668-1677.
EPub date: 2020-05-12.
PMID: 32398755
Related Citations

A Neural Circuit for Gut-Induced Reward.
Authors: Han W. , Tellez L.A. , Perkins M.H. , Perez I.O. , Qu T. , Ferreira J. , Ferreira T.L. , Quinn D. , Liu Z.W. , Gao X.B. , et al. .
Source: Cell, 2018-10-18; 175(3), p. 665-678.e23.
EPub date: 2018-09-20.
PMID: 30245012
Related Citations

DRD2: Bridging the Genome and Ingestive Behavior.
Authors: Sun X. , Luquet S. , Small D.M. .
Source: Trends in cognitive sciences, 2017 May; 21(5), p. 372-384.
EPub date: 2017-03-31.
PMID: 28372879
Related Citations

Integrated Control of Predatory Hunting by the Central Nucleus of the Amygdala.
Authors: Han W. , Tellez L.A. , Rangel M.J. , Motta S.C. , Zhang X. , Perez I.O. , Canteras N.S. , Shammah-Lagnado S.J. , van den Pol A.N. , de Araujo I.E. .
Source: Cell, 2017-01-12; 168(1-2), p. 311-324.e18.
EPub date: 2017-01-12.
PMID: 28086095
Related Citations

Circuit organization of sugar reinforcement.
Authors: de Araujo I.E. .
Source: Physiology & behavior, 2016-10-01; 164(Pt B), p. 473-477.
EPub date: 2016-04-26.
PMID: 27126968
Related Citations

Effects of the modern food environment on striatal function, cognition and regulation of ingestive behavior.
Authors: Burke M.V. , Small D.M. .
Source: Current opinion in behavioral sciences, 2016 Jun; 9, p. 97-105.
EPub date: 2016-03-09.
PMID: 29619405
Related Citations

Separate circuitries encode the hedonic and nutritional values of sugar.
Authors: Tellez L.A. , Han W. , Zhang X. , Ferreira T.L. , Perez I.O. , Shammah-Lagnado S.J. , van den Pol A.N. , de Araujo I.E. .
Source: Nature neuroscience, 2016 Mar; 19(3), p. 465-70.
EPub date: 2016-01-25.
PMID: 26807950
Related Citations

Striatal Dopamine Links Gastrointestinal Rerouting to Altered Sweet Appetite.
Authors: Han W. , Tellez L.A. , Niu J. , Medina S. , Ferreira T.L. , Zhang X. , Su J. , Tong J. , Schwartz G.J. , van den Pol A. , et al. .
Source: Cell metabolism, 2016-01-12; 23(1), p. 103-12.
EPub date: 2015-11-19.
PMID: 26698915
Related Citations

Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction.
Authors: Stoeckel L.E. , Arvanitakis Z. , Gandy S. , Small D. , Kahn C.R. , Pascual-Leone A. , Pawlyk A. , Sherwin R. , Smith P. .
Source: F1000Research, 2016; 5, p. 353.
EPub date: 2016-03-15.
PMID: 27303627
Related Citations

Physiological mechanisms by which non-nutritive sweeteners may impact body weight and metabolism.
Authors: Burke M.V. , Small D.M. .
Source: Physiology & behavior, 2015-12-01; 152(Pt B), p. 381-8.
EPub date: 2015-06-03.
PMID: 26048305
Related Citations

Sensing of triacylglycerol in the gut: different mechanisms for fatty acids and 2-monoacylglycerol.
Authors: Kleberg K. , Jacobsen A.K. , Ferreira J.G. , Windeløv J.A. , Rehfeld J.F. , Holst J.J. , de Araujo I.E. , Hansen H.S. .
Source: The Journal of physiology, 2015-04-15; 593(8), p. 2097-109.
EPub date: 2015-02-09.
PMID: 25639597
Related Citations

Back to Top