Enteric glial S100B controls rhythmic colonic functions by regulating excitability and specificity in gut motor neurocircuits

J Physiol. 2025 Oct;603(19):5723-5749. doi: 10.1113/JP289410. Epub 2025 Sep 11.

ABSTRACT

Patterns of gut motility, such as colonic motor complexes, are controlled by central pattern generators (CPG) in the enteric nervous system; however, the mechanisms that co-ordinate enteric neural networks underlying this behaviour remain unclear. Evidence from similar CPGs in the brain suggests that glia play key roles through mechanisms involving the S100 calcium-binding protein B (S100B). Enteric glia are abundant in enteric neural networks and engage in bi-directional interactions with neurons, but whether enteric glia shape enteric CPG behaviours through similar mechanisms remains unclear. Here, we show that S100B release by myenteric glia is necessary to sustain colonic motor complex behaviour in the gut. Calcium imaging experiments in whole mounts of myenteric plexus from Wnt1^{Cre2GCaMP5g-tdTom} mice revealed that the effects of manipulating S100B using selective drugs are a result of changes in neuron and glial activity in myenteric neurocircuits. S100B exerts major regulatory effects over cholinergic neurons, which are considered essential for colonic motor complex initiation and control, and recordings in samples from ChAT^{CreGCaMP5g-tdTom} mice showed that S100B regulates spontaneous activity among cholinergic neurons and their interactions with other neurons in myenteric networks. These results extend the concept of glia in CPGs to the gut by showing that enteric glial S100B is a critical regulator of rhythmic gut motor function that acts by modulating glial excitability, neuronal behaviours and functional connectivity among neurons. A deeper understanding of this previously unknown glial regulatory mechanism could, therefore, be important for advancing therapies for common gastrointestinal diseases. KEY POINTS: Patterns of gut motility such as colonic motor complexes (CMC) are considered to be controlled by central pattern generators housed in the myenteric plexus of the enteric nervous system. Brain central pattern generators studies suggest that glia play key roles through mechanisms involving the protein S100 calcium-binding protein B (S100B). This work identifies enteric glial S100B as a regulator of enteric glial and neuronal excitability, through mechanisms of Ca²⁺ regulation that are independent of the RAGE (i.e. receptor for advanced glycation end-products) signalling pathway. Enteric glial S100B also controls cholinergic neuronal rhythmic behaviours and functional interactions inside enteric excitatory neurocircuits. Our data suggests a novel mechanism by which enteric glia control patterns of gut motor activity through actions of S100B. These observations provide major new insight into mechanisms that regulate fundamental patterns of gut motility and suggest that changes in S100B may be important for understanding changes in gut physiology that occur following disease.

PMID:40936303 | PMC:PMC12487589 | DOI:10.1113/JP289410