The connection between gut microbiome, brain function and glucose metabolism is currently a hot area of research. As a result, the enteric nervous system (ENS) has emerged as a new target in the management of type 2 diabetes (T2D), while the underlying mechanisms remain unknown.
Together with professor Claude Knauf and our teams, we previously showed that bioactive peptides present in the gut of mice can modulate duodenal contractility via the hypothalamus, thus controlling peripheral glucose utilization. This discovery led us to the identification of bioactive molecules originating in the gut and that we called ‘enterosynes’. These molecules target the ENS to improve insulin sensitivity.
Even though strategies that modulate the gut microbiome, such as probiotics, prebiotics and fecal transplants, have been shown to alleviate features of metabolic syndrome, a characterization of intestinal actors with potential antidiabetic properties is lacking.
In a new study published in Gut, with Dr Anne Abot and Eve Wemelle we sought to identify novel gut molecules and receptors involved in glucose metabolism by exploring the action of prebiotics within the gut microbiota in diabetic versus normal mice.
The administration of the prebiotic oligofructose decreased duodenal contraction frequency by modulating enteric neurons activity, which, in turn, led to attenuated hyperglycemia and decreased inflammatory markers in the diabetic mice’s white adipose tissue. By using lipidomic analysis, we discovered that the modulation of the microbiota observed upon prebiotic feeding was associated with a selective increase in the colonic levels of 12-hydroxyeicosatetraenoic acid (12-HETE)—an intestinal bioactive lipid derived from arachidonic acid. Then, when we decided to test whether this 12-HETE was acting, we found that it improved glucose metabolism by eliciting gut-to-brain to peripheral organ signals that resulted in an increased glucose uptake and eventually lower blood glucose in the mice’s.
We confirmed ex vivo the effects of the identified intestinal lipid on duodenal contractility, which were dependent on the presence of mu-opioid receptors (MOR)—activated by enkephalin—and eventually signal through the nuclear receptor proliferator-activated receptor gamma (PPAR-g). Altogether, the signaling pathway known as 12-hydroxyeicosatetraenoic acid/ENK-MOR/PPAR-g can transmit the signal originated within the colon to the brain, highlighting how prebiotic effects within the gut act systemically. As a result, the final outcome was an improvement in the diabetic mice’s inflammatory state and glucose utilization compared to control mice.
The aforementioned preclinical findings were supported by human data showing a reduction in the levels of 12-hydroxyeicosatetraenoic acid and a decreased expression of the proenkephalin and MOR messenger ribonucleic acids in the duodenum of patients with T2D.
Overall, in the study, we identified novel intestinal bioactive compounds that could aid in the development of new antidiabetic drugs. In the light of the findings, enkephalin and 12-hydroxyeicosatetraenoic acid emerge as new targets with a potential role in treating T2D. As the new bioactive lipid discovered in the study can also be produced by certain gut bacteria beyond production by the body, we argue that both approaches could serve as a therapeutic target.
Fournel A, Drougard A, Duparc T, et al. Apelin targets gut contraction to control glucose metabolism via the brain. Gut. 2017; 66(2):258-269. doi: 10.1136/gutjnl-2015-310230.
Abot A, Wemelle E, Laurens C, et al. Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signalling in humans and mice. Gut. 2020. doi: 10.1136/gutjnl-2019-320230.