Discovery could lead to new way to combat deadly effects of diarrhea
When activated, the calcium-sensing receptor protein reversed the two life-threatening conditions that occur when a person has diarrhea — dehydration and metabolic acidosis, a build-up of acid in the bloodstream, according to results published this summer in the American Journal of Physiology - Gastrointestinal and Liver Physiology.
With these findings, the researchers hope to develop a commercial drink, similar to oral rehydration solutions Pedialyte or Gatorade, that combats both dehydration and acidosis, said Sam Cheng, M.D., Ph.D., a professor of pediatrics in the UF College of Medicine.
“(Oral rehydration solutions) save millions of people’s lives each year,” Cheng said. “That is considered one of the most important medical inventions in the last century. But this is the 21st century and people are still dying from these simple issues.”
The calcium-sensing receptor is key, because it plays a crucial role in stopping all the mechanisms that cause diarrhea. Its job in the gut is to prevent calcium overload in the body and to avoid dehydration. Normally, the gut is in an absorption mode, taking in needed water and electrolytes. However, when a person has diarrhea, absorption is typically blocked, and secretion is stimulated, causing the body to lose the water and electrolytes it needs. UF Health researchers found a way to cause the fluid balance to flip back, allowing the body to resume normal absorption mode.
“We can reduce diarrhea in 15 minutes with this,” Cheng said.
In the current study, Cheng and his team found that activation of the calcium-sensing receptor in colon cells triggered absorption when a person is healthy and inhibited secretion of bicarbonate during diarrhea. This is important because bicarbonate is an electrolyte that helps the epithelial cells that line the colon fight off invasion from pathogens. However, when too much bicarbonate is lost from the bloodstream, as happens during severe diarrhea, acid can build up, causing acidosis.
By directly measuring the loss of bicarbonate, the researchers showed that the calcium-sensing receptor is stimulating a channel that allows epithelial cells to absorb salt as well as nutrients called short-chain fatty acids. Like sodium chloride salt, short-chain fatty acids help intestinal cells absorb water. When a person has diarrhea, absorption is typically inhibited, as are the processes that control intestinal healing.
But with this study and past studies by his group, Cheng and his team have shown that activation of the calcium-sensing receptor can correct all of these problems when specific nutritional substances that stimulate the calcium-sensing receptor are given orally or through the blood.
“The beauty is that the same substances that activate the calcium-sensing receptor also reduce inflammation and promote gut healing,” Cheng said.
The researchers are now working to develop a formula that will combat diarrhea, using simple, child-friendly ingredients, that helps trigger the calcium-sensing receptor when taken orally. The team is currently developing formulas to test in clinical trial.
Interestingly, the origin of the calcium-sensing receptor in humans dates back millions of years in the evolutionary chain to our earliest fish ancestors, Cheng said.
“We are from the sea,” Cheng said. “Seawater is salty and higher in calcium, and this receptor was needed to prevent calcium overload and dehydration. We still need it today to help keep our water and that is why it is still present in the gut.
“I think this concept is very promising,” Cheng said. “We learn from the sea and use this knowledge to help children.”