In Lille, researchers have discovered a mechanism that regulates the expression of the gene that codes for lactase, the enzyme that breaks down lactose in the intestines. This mechanism entails PPARg, a nuclear receptor that may be modulated by molecules that are naturally present in food. Now these molecules just need to be identified!
A remedy for lactose intolerance? Following a chance discovery, a team at the Lille Inflammation Research International Center may well be the one to manage it…
Researchers at this laboratory* study chronic inflammatory bowel diseases (IBD), especially ulcerative colitis. One of the treatments used to combat this disease is based on the use of an anti-inflammatory agent, 5-aminosalicylic acid (5-ASA). This drug targets a nuclear receptor present in the intestinal epithelial cells: the PPARγ receptor. This receptor transmits signals to the genome, which leads to changes in the expression of various genes.
While looking for more effective and safer treatments for ulcerative colitis, the team tested new PPARγ agonists in intestinal epithelial cell lines in culture. In order to understand the effects of the molecules tested, the researchers carried out a transcriptome analysis. This is an analysis that is able to identify and quantify all of the RNA present in the cells, and as a result show changes in gene expression caused by the agonists tested. This is how the researchers noted, to their surprise, a considerable over-expression of the gene for lactase, the enzyme that breaks down lactose. “The results were unequivocal, it was the gene that is most highly regulated by PPARγ,” clarifies Benjamin Bertin, who led this project. This discovery led the researchers to look more closely into problems of lactose intolerance, caused by defective lactase production.
Lactase production varies from one adult to the next
“In all mammals, lactase production ends after weaning. But in humans, mutations that have appeared throughout the course of our evolution have meant that synthesis of this enzyme is maintained into adulthood, although these mutations vary considerably across populations. Between 70 and 80% of people of Caucasian origin produce this enzyme in adulthood, but only around 10% of people of Asian origin do,” explains Bertin. While lactose intolerance does not constitute a problem in itself, some studies have found an association with an increased risk of presenting certain diseases – such as hypertension and osteoporosis – due to routine exclusion of certain foods. “Lactose intolerance has no need, in my opinion, to be treated pharmacologically. Nonetheless, some substances that are found naturally in our diet regulate PPARγ, in particular certain fatty acids. The idea would therefore be to offer people with lactose intolerance supplementation with these nutrients so that they can increase their lactase production and consume dairy products if they wish,” the researcher suggests.
Nutrients to stimulate lactase production
In the meantime, the team has confirmed its results and is moving on to additional experiments. The researchers inactivated PPARγ using specific antisense RNA and observed a fall in lactase production in intestinal cells in culture. Next, a PPARγ agonist currently under development to treat ulcerative colitis was orally administered to mice and rats. What they noticed was the opposite: an increase in the production and function of lactase. These animals cannot digest lactose after weaning, presenting with diarrhea and a build-up of fermented products in the intestines if they consume them. Their symptoms decreased after taking this agonist.
After this, the scientists hope to identify these sought-after molecules that occur naturally in our diet and which could be offered to people with lactose intolerance. The team has already tested conjugated linoleic acid, which is mainly present in meat from ruminants. This acid is known to interact with PPARγ and has been found to increase lactase production in mice.
*Inserm unit 995/Université de Lille 2/CHU de Lille, Lille Inflammation Research International Center
M Fumery et al. EMBO Mol Med, internet edition of 25 September 2017