The Microbiota‐Derived Metabolite Deoxycholic Acid Regulates Enteric Neuron Activity and Connectivity

Secondary bile acids (BAs) are metabolites produced by the gut microbiota and shown to impact digestive functions, at least in part through the enteric nervous system (ENS). In the ENS, enteric neurons express the BA receptor Takeda G protein-coupled receptor 5 (TGR5), making them potential direct cellular targets of secondary BAs, although their effects on enteric neuronal functions remain poorly understood. Enteric neuronal activity and connectivity form the basis of the regulatory control exerted by the ENS on gut functions. Yet, the influence of microbiota-derived metabolites, such as secondary BAs, on enteric neuron connectivity and synaptic activity remains largely unexplored. To address this question, we studied the effects of secondary BAs on neuronal connectivity using a model of rat primary culture of enteric neurons. We found that exposure to deoxycholic acid (DCA) increased the expression of key presynaptic proteins, synapsin-1 and synaptophysin, and enhanced synaptic density in enteric neurons. Moreover, DCA enhanced synaptic activity by increasing synaptic vesicle exocytosis upon KCl depolarisation, potentially through amplified phosphorylation of synapsin-1 at the Ser62-67 sites. In addition, we found that DCA modulated the intracellular Ca²⁺ response induced by acetylcholine, a major excitatory neurotransmitter in enteric neurons, through a mechanism mediated by the TGR5 receptor. Overall, this study identifies DCA as a microbiota-derived compound capable of reshaping the enteric neuronal functional network. These findings highlight the potential of bacterial metabolites like DCA to link the microbiome with modulation of enteric neuronal activity and connectivity, supporting the relevance of secondary BAs in digestive physiology and their possible roles in gastrointestinal disorders.