The enteric nervous system (ENS), also referred to as the “second brain,” is a web of sensory neurons, motor neurons, and interneurons embedded in the wall of the gastrointestinal system, stretching from the lower third of the esophagus through to the rectum. While described as a second brain, the enteric nervous system normally communicates with the central nervous system (CNS) through the parasympathetic and sympathetic nervous systems, but can still function when the vagus nerve is severed.

Recent studies have been considering the ENS as a new target to treat type 2 diabetes. An oral treatment with gut peptides has been shown to improve glucose metabolism by stimulating the release of nitric oxide (NO) from enteric neurons, which has the capacity to decrease duodenal contractions and restore the gut-brain axis, improving insulin sensitivity. Researchers now report they have discovered what blocks communication between the gut and the brain, which prevents proper regulation of sugar and causes insulin resistance in people with diabetes.

Their findings, “Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signaling in humans and mice,” is published in the journal Gut and led by Claude Knauf, university professor at the Institut National de la Santé et de la Recherche Médicale (INSERM) in France and Patrice Cani from the Université Catholique de Louvain in Brussels, Belgium.

“The ENS plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes,” wrote the researchers.

Knauf and Cani have been collaborating on molecular and cellular mechanisms in order to understand the causes of the development of type 2 diabetes since 2004. In 2013, they created an international laboratory, NeuroMicrobiota Lab, to identify links between the brain and intestinal bacteria.

Observing when the gut digests food, the researchers noted that the signal that is sent from the gut to the brain to handle incoming fats and sugars, malfunctions in diabetic individuals as a result of intestine hypercontracting.

The researchers measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism in normal and diabetic mice. The team found a particular lipid was deficient in both diabetic mice and diabetic people, which led them to test the impact of the lipid on the contraction of the intestine, the use of sugars, and diabetes.

“The importance of ENS in controlling glucose metabolism is becoming clear. We identified two novel enterosynes (12S-HETE and enkephalin) that are modulated by the gut microbiota as well as novel mechanisms of action and metabolic effects of the bioactive lipid 12S-HETE.”

The new research has opened a door of understanding of gut microbiota in altering the production of bioactive lipids, leading to the restoration of the gut-brain communication.

“Using a combination of nutritional and pharmacological approaches, we have identified a new mode of communication between gut microbes and the host. In addition, we have identified novel targets and their mechanisms of action in rodents and possibly in humans. The identification of specific targets, such as the enteric neuronal population, to treat T2D and its comorbidities represent a ground-breaking solution to develop medications without side effects,” concluded the researchers.

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