During digestion, food moves through the intestines with the help of peristalsis, a wave-like motion that is performed by smooth muscles that contract and relax. Scientists have long known that nerves stimulate this action, and now scientists have learned more about how these intestinal neurons work. Researchers have determined that a molecule called Piezo1, which senses pressure, is crucial to intestinal movement, as well as taming down inflammation. These findings, which need to be confirmed in humans, could aid in the development of therapeutics for gut disorders. The work has been reported in Cell.
Enteric neurons are those that are only located in the intestines, and they are known to control peristalsis. In this work, the scientists analyzed the activity of the Piezo1 gene, and found that it was very active in gut neurons that cause muscle contractions. The protein encoded by this gene can trigger the release of a neurotransmitter called acetylcholine, and this causes muscle movement. These findings were true in a mouse model and in human cells in culture.
The investigators determined that movement in the gut can be affected by pressure, exercise, and inflammation. When intestinal tissue was subjected to pressure, the contractions increased. But when Piezo1 was removed, those contractions stopped.
The researchers suggested that the Piezo1 protein works as a pressure sensor, and when stimulated, can help trigger gut movement. In a mouse model that lacked Piezo1, digestion also slowed down significantly.
Exercise is known to speed movement in the bowels. This was confirmed in mice that ran on a treadmill. But when Piezo1 activity was stopped, the exercising mice showed no increases in intestinal motility. So this gene also seems to be sensing movement from exercise, the study suggested.
Intestinal motility also increases in inflammatory bowel disease (IBD). In a mouse model of IBD, the researchers found that if Piezo1 was eliminated, bowel movements happened more slowly compared to mice with IBD and normal Piezo1 expression. Other symptoms of IBD did get worse in the animals that lacked Piezo1, however; there was disruption to intestinal cells and more weight was lost from animals that lacked Piezo1. These complications appear to be due to the loss of acetylcholine.
Acetylcholine can stimulate muscle activity, but it can also reduce inflammation, the researchers noted. IBD can cause inflammation, and this may cause Piezo1 to signal to enteric neurons to make more acetylcholine to try to reduce that inflammation. This could explain why IBD increases intestinal motility: there is an excess of acetylcholine.
These findings could help scientists develop better treatments for gut disorders. Most gut disease therapeutics aim to turn down inflammation, so using Piezo1 as a target would be a different approach, without immune suppression. The researchers want to explore potential designs for such a treatment.
“Eventually, we might stimulate PIEZO1 to speed up excretion, block it to treat diarrhea, or use it as a novel target to treat intestinal inflammation in IBD patients,” suggested co-senior study author Ruaidhrí Jackson, assistant professor of immunology in the Blavatnik Institute at Harvard Medical School.
Sources: Harvard Medical School, Cell
