Enteric Neurons utilize mechanoreceptor Piezo1 to sense force and regulate intestinal motility and inflammation

Abstract

The enteric nervous system (ENS) controls many gastrointestinal (GI) functions including motility which occurs via peristalsis— the rhythmic wave-like contractions that transit food boluses through the intestines, creating a plethora of mechanical stimuli. However, whether the enteric neurons that control this process can sense these self-generated mechanical stimuli is unknown. During digestive dysfunction in inflammatory bowel disease (IBD) there are major alterations in motility and pressure in the intestines which are concurrent with inflammation. As enteric neurons control motility which creates abundant mechanical stimuli, and since mechanical stimuli as well as enteric neurons can modulate inflammation, I wanted to investigate the role of mechanosensation in enteric neurons. I hypothesized that enteric neuronal sensation of mechanical force is required for regulating tissue homeostasis and inflammation. Herein, I establish that the mechanosensor Piezo1 is functionally expressed in cholinergic enteric neurons. Piezo1-deficiency reduces neuronal activity and slows peristalsis. Further, I uncover that Piezo1-dependent enteric cholinergic responses prevent aberrant inflammation during colitis. Finally, I discover that enteric neurons release canonical cholinergic neurotransmitter acetylcholine in response to mechanical stimuli which can mediate both motility and immune response. This work is the first to determine how the ENS senses and responds to mechanical force.