Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice

Abstract

The enteric nervous system (ENS) regulates the motor, secretory and defensive functions of the gastrointestinal tract. Enteric neurons integrate mechanical and chemical inputs from the gut lumen to generate complex motor outputs. How intact enteric neural circuits respond to changes in the gut lumen is not well understood. We recorded intracellular calcium in live‐cell confocal recordings in neurons from intact segments of mouse intestine in order to investigate neuronal response to luminal mechanical and chemical stimuli. Wnt1‐, ChAT‐ and Calb1‐GCaMP6 mice were used to record neurons from the jejunum and colon. We measured neuronal calcium response to KCl (75 mM), veratridine (10 μM), 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP; 100 μM) or luminal nutrients (Ensure®), in the presence or absence of intraluminal distension. In the jejunum and colon, distension generated by the presence of luminal content (chyme and faecal pellets, respectively) renders the underlying enteric circuit unresponsive to depolarizing stimuli. In the distal colon, high levels of distension inhibit neuronal response to KCl, while intermediate levels of distension reorganize Ca2+ response in circumferentially propagating slow waves. Mechanosensitive channel inhibition suppresses distension‐induced Ca2+ elevations, and calcium‐activated potassium channel inhibition restores neuronal response to KCl, but not DMPP in the distended colon. In the jejunum, distension prevents a previously unknown tetrodotoxin‐resistant neuronal response to luminal nutrient stimulation. Our results demonstrate that intestinal distension regulates the excitability of ENS circuits via mechanosensitive channels. Physiological levels of distension locally silence or synchronize neurons, dynamically regulating the excitability of enteric neural circuits based on the content of the intestinal lumen. Key points How the enteric nervous system of the gastrointestinal tract responds to luminal distension remains to be fully elucidated. Here it is shown that intestinal distension modifies intracellular calcium levels in the underlying enteric neuronal network, locally and reversibly silencing neurons in the distended regions. In the distal colon, luminal distension is integrated by specific mechanosensitive channels and coordinates the dynamics of neuronal activation within the enteric network. In the jejunum, distension suppresses the neuronal calcium responses induced by luminal nutrients. Physiological levels of distension dynamically regulate the excitability of enteric neuronal circuits.

Piezo1 in Digestive System Function and Dysfunction

“…There was a positive correlation between gastrointestinal mechanosensitive neurons and Piezo1-positive neurons, but the latter do not significantly contribute to the mechanosensitivity of gastrointestinal plexus [ 51 ]. Another study showed that distension in distal colon induced Ca 2+ elevations in neurons and regulated the excitability of ENS circuits via mechanosensitive channel, unaffected by GsMTx4 but suppressed by KCa1.1 channel inhibition [ 136 ]. Thus, the role of Piezo1 in direct ENS mechanotransduction should be interpreted cautiously.…”

Development of a microfluidic device to observe dynamic flow around the villi generated by deformation of small intestinal tissue

“…The intestinal activity can be maintained for several hours by the perfusion of Krebs solution. 13 However, to suppress the digestive reaction, the flow rate of Krebs solution should be much higher than that in the SI tract in vivo . Organotypic devices that apply the microfluidic technique have succeeded in prolonging the lifetime.…”

Making ‘sense’ of what happens on the inside: il‘LUMEN'ating the effects of intestinal distention on calcium activity in enteric neurons

“…The availability of genetically encoded Ca 2+ indicators like GCaMP and cell‐specific Cre lines have made it possible to image Ca 2+ signals in a variety of cells including enteric neurons and glia (Boesmans et al., 2018). In the current issue of The Journal of Physiology , Cavin and colleagues (2023) have developed a method to examine Ca 2+ signalling and propagation within enteric neurons of an intact intestinal preparation from mice expressing GCaMP6s in all enteric neurons (Wnt1‐GCaMP6s). This approach is advantageous in better recapitulating the natural environment of enteric neurons.…”