The research into gut sensory responses to sugar identifies individual cells that recognise sugar and stimulate specific sensory transmissions that control behaviour.
The neuropod cells work just like the retinal cone cells that are able to sense the wavelength of light, explains lead scientist and Associate Professor of Medicine and Neurobiology in the Duke University School of Medicine, Diego Bohórquez.
“They sense traces of sugar versus sweetener and then they release different neurotransmitters that go into different cells in the vagus nerve, and ultimately, the animal knows ‘this is sugar’ or ‘this is sweetener.’”
The mechanism at work
When sugar and artificial sweeteners are consumed, cholecystokinin (CCK)-labelled neuropod cells in the small intestine, or duodenum, stimulate sensory transmission to the brain via the vagal nerve.
However, the two components elicit distinct neural pathways that provoke different behavioural responses.
While sweeteners trigger purinergic (taste receptor) neurotransmission, the duodenum reacts to the d-glucose in sugar and stimulates glutamatergic (excitatory) neurotransmission, which conditions a “robust preference” response.
“These cells use the neurotransmitter glutamate to transduce a d-glucose stimulus from the gut to the brain in milliseconds,” the authors explain.
The ability to identify d-glucose vanishes when the small intestine is by-passed, suggesting the duodenal epithelium is where the ‘sugar transducer’ cell resides, they say.
“Up until now, the identity of these cells has remained elusive because of the lack of tools to control gut sensory processing with temporal and spatial precision.”
To investigate the specific role of neuropod (enteroendrocrine) cells on behaviour, the team developed a technique called optogenetics, comprising a flexible fibre that delivers light to the gut to turn neuropod cells on and off.
The technology was used to gauge reactions to different stimuli and demonstrate whether the preference for sugar was being driven by signals from the gut.
Several tests were conducted to examine the link between duodenal neuropod cells, vagal nerve responses to stimuli and the triggers for glutamatergic transmission.
Lab-grown organs from mouse and human cells were used to represent the small intestine and duodenum (upper gut).
An experiment to test responses to sugar and sweetener confirmed that sugar activates the glutamate transmitter, as opposed to sweeteners that released adenosine triphosphate (ATP) to stimulate purinergic receptors.
When light was delivered to the gut of live mice to trigger a genetic response that switched off the neuropod cells, there was no clear preference for sugar.
Almost all sugars initiated a significant increase in vagal response. D-fructose (in sugar) was the only exception.
The authors report that d-fructose diffused passively through the epithelium and failed to condition a preference when infused into the intestine.
Neither d-glucose nor sucralose (in sweeteners) elicited excitatory responses when cultured alone.
However, when co-cultured with duodenal CCK neuropod cells significant excitatory postsynaptic currents were observed, and particularly in the presence of d-glucose.
CCK-labelled neuropod cells are necessary to transmit stimuli from both sugar and artificial sweeteners but have a particular preference for sugar.
These findings can serve as a foundation to determine how other stimuli, such as fats, proteins, or microbial molecules, are sensed and transduced in different regions of the intestine to drive appetitive decisions and future research will show how these cells also recognise other macronutrients.
“Many people struggle with sugar cravings, and now we have a better understanding of how the gut senses sugars (and why artificial sweeteners don’t curb those cravings),” says co-first author Kelly Buchanan, former Duke University School of Medicine student and Internal Medicine resident at Massachusetts General Hospital. “We hope to target this circuit to treat diseases we see every day in the clinic.”
Source: Nature Neuroscience
Published online: doi.org/10.1038/ s41593-021-00982-7
‘The preference for sugar over sweetener depends on a gut sensor cell’
Kelly L. Buchanan et al .