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

2026/01/01 by Morgane E. Le Dréan, Baptiste Ganachaud, Maëva Rebion +9
Biochemistry, Genetics and Molecular Biology · Medicine · #Gut microbiota and health #Drug Transport and Resistance Mechanisms #Gastrointestinal motility and disorders

paper · doi:10.1111/jnc.70351

Abstract

ABSTRACT 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 Ca 2+ 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. image

Citations

• Nerve Fiber Outgrowth Is Increased in the Intestinal Mucosa of Patients With Irritable Bowel Syndrome
• The Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice
• Short-Chain Fatty Acids Regulate the Enteric Neurons and Control Gastrointestinal Motility in Rats
• The emergence of neural activity and its role in the development of the enteric nervous system
• Enteric neurones modulate the colonic permeability response to luminal bile acids in rat colon in vivo
• The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis
• The enteric nervous system undergoes significant chemical and synaptic maturation during adolescence in mice

Related

• The Effect of Microbiota and the Immune System on the Development and Organization of the Enteric Nervous System
• The enteric nervous system
• The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication
• Enteric neurones modulate the colonic permeability response to luminal bile acids in rat colon in vivo
• From bugs to brain: unravelling the GABA signalling networks in the brain–gut–microbiome axis