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The gut–brain axis mediates sugar preference

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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 artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut–brain axis, and identified 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 findings 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 differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.
Vagal neurons responding to intestinal glucose are also activated by SGLT1 agonists a, Traces of vagal neurons responding to a 10-s pulse of 500 mM intestinal glucose, also challenged with a 10-s pulse of 500 mM 3-OMG. Shown are sample neurons from 2 animals. b, Traces of vagal neurons responding to a 10-s pulse of 500 mM intestinal glucose, also challenged with a 10-s pulse of 500 mM galactose. Shown are sample neurons from two animals for expanded time scales (from Fig. 4d). c, Traces of vagal neurons responding to a 10-s pulse of 500 mM intestinal glucose, also challenged with a 10-s pulse of 500 mM fructose and 500 mM mannose. Shown are sample neurons from three mice. d, Traces of vagal neurons responding to two consecutive 10-s pulses of 500 mM intestinal glucose, before and after treating the intestinal segment with 8 mM phlorizin for 5 min. Note the loss of responses. e, Because responses, in general, show some decay during the time of the experiment (in part due to desensitizing and bleaching of the fluorescent signals), we also analysed the average decay of corresponding glucose responses in the absence of any blocker. The graphs compare the loss of responses during normal decay, and in response to the blocker. For normal decay (left), n = 11 neurons, Pre = 230.8 arbitrary units (a.u.), Post = 172.8 a.u.; for blocker (right), n = 31 neurons, Pre = 229.7 a.u., Post = 67.0 a.u. All values are mean ± s.e.m. Scale indicates average integral of the responses to the two trials before and after inhibition.
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Retrograde labelling from cNST a, A fluorescent retrograde tracer (red RetroBeads, Lumafluor) was stereotactically injected into the cNST to label its inputs. The nodose ganglia and dorsal root ganglia were checked for transfer of the fluorescent label after 6–7 days. The nodose ganglion (vagal neurons), but not the dorsal root ganglion (spinal neurons), was robustly labelled⁶⁰. n = 2 independent experiments. b, RetroBeads were also injected into the cuneate nucleus, a brainstem area near but distinct from the cNST. Vagal neurons were not labelled. By contrast, note robust labelling of spinal neurons (n = 2 independent experiments). Nuclei were counterstained with DAPI (blue). Scale bars, 200 μm (Brainstem), 50 μm (nodose, DRG). c, Validation of TRAPing procedure to confirm that the sugar-activated cNST neurons marked by the expression of Fos are the same as the ones labelled by Cre recombinase in the genetic TRAPing experiments. We genetically labelled the sugar-induced TRAPed neurons with a Cre-dependent fluorescent reporter⁶¹, and then performed a second cycle of sugar stimulation followed by Fos antibody labelling. d, Top, neurons labelled by the Cre-dependent reporter after sugar TRAPing (‘sugar-TRAP’, pseudocoloured red) are the same as those labelled by Fos after a second cycle of sugar stimulation (‘sugar-Fos’, green; see Methods and text for details), >80% of Sugar-Fos neurons are also sugar-TRAP positive (n = 7 animals). Middle, note that the few neurons labelled after water-TRAP in response to water do not overlap with those labelled with Fos antibodies after sugar stimulation. Bottom, the sugar-TRAP neurons are also activated by the non-caloric sugar analogue MDG; >80% of MDG-Fos are sugar-TRAP positive. Scale bar, 20 μm.
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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 articial sweeteners,
and are activated by direct delivery of sugar to the gut. Using functional imaging we
monitored activity of the gut–brain axis, and identied 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 dierences in the behavioural eects of sweeteners versus sugar, and uncover
an essential circuit underlying the highly appetitive eects 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 4.5kg of sugar per year
5
;
today, following the broad availability of refined sugar in consumer
products, the average consumption is more than 45kg 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 24h of expo-
sure to both choices, their preference is markedly altered, such that
by 48h, they drink almost exclusively from the bottle containing sugar
(Fig.1a, b, compare 15h with 48h). 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
... First, in some scenarios, the brain can integrate conflicting sensory cues, potentially creating an illusion (Fig. 1B). For example, mice provided with a choice between sugar and artificial sweetener solutions consume them at equal rates for up to 24 h (Tan et al. 2020). Despite the lack of postingestive effects from artificial sweeteners, the sweet taste drives consumption. ...
... The reliability of sensory cues undergoes dynamic updating, leading to adaptive behavioral modifications. In the case of artificial sweeteners, prolonged exposure results in an increased preference for sugar solutions, likely mediated by postingestive sensing mechanisms (Tan et al. 2020). Similarly, fistulated canine models exhibit increased food consumption over time, reflecting an adaptive response to the persistent absence of detected nutrients (Davis and Campbell 1973). ...
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... For protein-induced effects, there is mostly indirect evidence pointing to vagal afferent signals (de Lartigue and Diepenbroek, 2016), although subdiaphragmatic vagotomies in rats show that it is not an obligatory pathway for the transfer of energy-related information to the brain (L' Heureux-Bouron et al., 2003). Moreover, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits, potentially pointing to specific targets for improved metabolic control (Bai et al., 2019;Tan et al., 2020;Borgmann et al., 2021;Li et al., 2022). ...
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