A preview of this full-text is provided by Springer Nature.
Content available from Nature
This content is subject to copyright. Terms and conditions apply.
Nature | Vol 580 | 23 April 2020 | 511
Article
The gut–brain axis mediates sugar
preference
Hwei-Ee Tan1,2,4, Alexander C. Sisti1,3,4, Hao Jin1,3, Martin Vignovich1,3, Miguel Villavicencio1,3,
Katherine S. Tsang1,3, Yossef Goffer3 & Charles S. Zuker1,3 ✉
The taste of sugar is one of the most basic sensory percepts for humans and other
animals. Animals can develop a strong preference for sugar even if they lack sweet taste
receptors, indicating a mechanism independent of taste1–3. Here we examined the
neural basis for sugar preference and demonstrate that a population of neurons in the
vagal ganglia and brainstem are activated via the gut–brain axis to create preference for
sugar. These neurons are stimulated in response to sugar but not articial sweeteners,
and are activated by direct delivery of sugar to the gut. Using functional imaging we
monitored activity of the gut–brain axis, and identied the vagal neurons activated by
intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in
this gut-to-brain circuit was genetically silenced, and prevented the development of
behavioural preference for sugar. Moreover, we show that co-opting this circuit by
chemogenetic activation can create preferences to otherwise less-preferred stimuli.
Together, these ndings reveal a gut-to-brain post-ingestive sugar-sensing pathway
critical for the development of sugar preference. In addition, they explain the neural
basis for dierences in the behavioural eects of sweeteners versus sugar, and uncover
an essential circuit underlying the highly appetitive eects of sugar.
Sugar is a fundamental source of energy for all animals, and corre-
spondingly, most species have evolved dedicated brain circuits to seek,
recognize and motivate its consumption4. In humans, the recruit-
ment of these circuits for reward and pleasure—rather than nutritional
needs—is thought to be an important contributor to the overconsump-
tion of sugar and the concomitant increase in obesity rates. In the 1800s
the average American consumed less than 4.5kg of sugar per year
5
;
today, following the broad availability of refined sugar in consumer
products, the average consumption is more than 45kg per year6.
Sweet compounds are detected by specific taste receptor cells
on the tongue and palate epithelium7,8. Activation of sweet taste
receptor cells sends hardwired signals to the brain to elicit recogni-
tion of sweet-tasting compounds
9,10
. We and others have studied the
circuits linking activation of sweet taste receptors on the tongue to
sweet-evoked attraction
8,11,12
. Surprisingly, even in the absence of a
functional sweet-taste pathway, animals can still acquire a preference
for sugar1,2,7. Furthermore, although artificial sweeteners activate the
same sweet taste receptor as sugars, and they may do so with vastly
higher affinities
7
, they fail to substitute for sugar in generating a behav-
ioural preference13.
Together, these results suggested the existence of a sugar-specific,
rather than sweet-taste-specific pathway, that operates independently
of the sense of taste to create preference for sugar and motivate con-
sumption2,14. Here, we dissect the neural basis for sugar preference.
Sweet versus sugar preference
When non-thirsty, wild-type mice are given a choice between water
and sugar they drink almost exclusively from the sugar solution
7
. If,
however, they are allowed to choose between an artificial sweetener
(for example, acesulfame K (AceK)) and sugar, using concentrations
at which both are equally attractive, naive mice initially drink from
both bottles at a similar rate (Fig.1a). However, within 24h of expo-
sure to both choices, their preference is markedly altered, such that
by 48h, they drink almost exclusively from the bottle containing sugar
(Fig.1a, b, compare 15h with 48h). This behavioural switch also hap-
pens in knockout (KO) mice lacking sweet taste (Trpm5−/− (hereafter
TRPM5 KO)15,16 or Tas1r2−/−Tas1r3−/− (hereafter T1R2/3 KO)7; Fig.1c).
Similar observations have been made in several studies, primarily using
flavour-conditioning assays
1,2
. Thus, although taste-knockout mice
cannot taste sugar or sweetener, they learn to recognize and choose
the sugar, most probably as a result of strong positive post-ingestive
effects17.
Notably, the preference for sugar does not rely on its caloric
content18. For example, if sugar is substituted for the non-metabolizable
glucose analogue (methyl-α--glucopyranoside (MDG))19 mice still
develop a strong preference for MDG, just as they do for glucose (Fig.1b;
Extended Data Fig.1). Thus, the signalling system recognizes the sugar
molecule itself rather than its caloric content or metabolic products.
https://doi.org/10.1038/s41586-020-2199-7
Received: 12 April 2019
Accepted: 21 February 2020
Published online: 15 April 2020
Check for updates
1Zuckerman Mind Brain Behavior Institute, Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. 2Department
of Biological Sciences, Columbia University, New York, NY, USA. 3Department of Neuroscience, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. 4These
authors contributed equally: Hwei-Ee Tan, Alexander C. Sisti. ✉e-mail: cz2195@columbia.edu
Content courtesy of Springer Nature, terms of use apply. Rights reserved