Discovery: the “brain of the intestine” regulates blood sugar and insulinemia

The one we often call our “second brain”, through abuse of language, still has many surprises in store for us. Today’s menu is the discovery of the independent action of the intestinal nervous system on our blood sugar.

The discovery is not surprising to specialists in the field: they suspected it. But in science, to suspect something, in other words, to have the intuition of it thanks to indirect evidence or mechanistic reasoning, is not enough. The experience we are going to tell you about today provides formal proof that, in the animal model,  our enteric nervous system has the ability to regulate our  blood sugar (a vital function of the body) without involving our central nervous system .

A few reminders about our enteric nervous system

The intestine has its own nervous system. For this reason, it is often referred to as our “second brain” . If this name has nothing scientific, that is to say that it does not refer to any serious concept or tool in the work of researchers, it is a way of letting the general public understand complex knowledge. 

The enteric nervous system has a huge number of neurons (as many as your spinal cord ) and serves several functions such as motor function (moving our intestinal muscles), immune function (defending us against pathogens ) and hormonal function (informing the system). central nervous system of various parameters). The experiment we are about to discuss shows that the enteric nervous system also innervates vital organs and participates in the regulation of blood sugar and insulinemia independently of our central nervous system.

cientific discovery

We knew that the makeup of our microbiota was correlated (that is, statistically related) to changes in our blood sugar. But a correlation is not a causality. Even if we suspected that a causal link existed, it must be demonstrated, in which case the statistical link may be due to confounding factors. This experiment provides evidence that there is at least one causal mechanism that depends on the microbiota for the purpose of regulating glucose and insulin . So let’s talk about this discovery published in the journal  Science .

The researchers set up a methodology called  “RiboTag”  making it possible to collect all the messenger RNAs during translation (the transcriptome ) produced by different parts of the intestine of mice and to sequence them. How do they do ? They create transgenicmice expressing a small protein sequence (a tag) intended to be expressed specifically in the part of the messenger RNA which will undergo translation (the exon ). The tools of genetic engineering allow them to make this tag specific to certain cells (the neurons in this experiment). The cells will begin to express the tag. Then just an antibodytag-specific to isolate and concentrate (this is called an immunoprecipitation) the messenger RNAs being translated. We can then sequence them and know the transcriptome of the cells studied.

They compared, for their study, mice with or without microbiota. First interesting thing: the less the microbiota is rich (in species ), the more the transcriptome differs, especially in the ileum and colon regions . The microbiota, this organ in its own right, generates the expression of various and varied metabolites including neuropeptides, such as the one that has caught the attention of researchers: the neuropeptide CART + (for  Cocaine and amphetamine regulated transcript ).

CART is a neuropeptide particularly well known to those working in basic research to understand the determinants of food intake. It is also expressed in the hypothalamus , participates in body weight regulation functions and that of reward, to name just these two parameters.

The presence of this peptide intrigued investigators. They wanted to know where it came from and where it was finished. To do this, they used a virus modified  to infect only CART-secreting neurons and express a fluorescent protein when infection is effective. The experimenters make use of a property intrinsic to viruses : they infect neurons in a retrograde fashion (that is, by returning to their starting point). Thanks to this, they were able to observe that the CART neurons left the intestine to go to the viscera (they are said to be “viscerofuge”) and that they specifically innervate the superior mesenteric ganglion, pancreas and liver  via the sympathetic nervous system .

The enteric nervous system regulates blood sugar independently of the central nervous system.  © Kateryna Kon, Adode Stock

After having solved the enigma of the neural labyrinth, we wonder what the use of these neurons can be. What are their functions? We then proceed to experiments where we will activate and then deactivate the CART-producing cells and observe what happens. To do this, the researchers inserted a modified receptor into CART neurons which can only be activated with the presence of a synthetic ligand (a synthetic molecule that activates the modified receptor, here Clozapine-N- oxide). So what happens when we turn CART neurons on and off?

When they are active, there is a decrease in food intake in mice, coupled with an increase in blood sugar and a decrease in insulinemia. By specifically deactivating the CART neurons, we see opposite reactions: decrease in blood sugar, increase in insulinemia. This deactivation also interferes with the “normal” functioning of gluconeogenesis (the metabolic pathway that creates glucose from other substrates ). This is because the production of hepatic glucose from pyruvateis reduced. We therefore have here proof that these neurons have a glucoregulatory function, which is not surprising given the organs they innervate (the liver and the pancreas which are the two major players in the regulation of blood sugar).

To simply summarize and conclude on this discovery: thanks to this experiment, we now know that the microbiota induces a more or less important secretion (depending on its composition) of a family of neuropeptides (CART) by certain neurons of the enteric nervous system, which indirectly innervate the liver and pancreas, resulting in glucoregulatory function (a vital function of the body) without the intervention of the central nervous system.

The questions that this poses

As often in science, a discovery is not an end in itself. On the contrary, it generally generates additional questions. What happens between the microbiota and the secretion of peptides? By what mechanisms is blood sugar regulated by these neurons? What are the specificities of the composition of the microbiota that induce the secretion of these neuropeptides? Are they similar in all people? Do they differ according to the environment? Would it be possible to imagine a treatment  via diet or  via drug treatment to optimize the secretion of these peptides and fight diseases such as diabetes or obesity?? Will this be enough to overcome these complex, systemic diseases with multiple mechanisms? Is this the only intestinal mechanism allowing this glucoregulation? 

A discovery generally leads to more questions than answers.  © Tierney, Adobe Stock

As you will have understood, there are many questions. Findings generally make us better measure the extent of our ignorance than that of our knowledge. Remember that this experience comes from basic research. Here too, there are real political and economic questions that arise regarding our relationship to knowledge. We think about the fact that most research is only funded if it has a well-established project and predictable economic returns. However, to take one of the most hackneyed example, if we remember the consequences of Albert Einstein’s theory of relativity, we can conclude the following: biased human forecasts are not good indicators of what a fundamental theory or discovery will entail in terms of profound change and social and economic impact. It is a paradigm shift that must be made in the way research is carried out today. As the name suggests, basic research is … fundamental.

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