Fig 4.

Direct interactions between symbiotic microbes and a gut innervating sensory afferent neuron (nociceptor nerve terminal). Symbiontic bacteria  ferment foods high in  fiber to supply SCFAs to the host, including butyrate, propionate and acetate. Nociceptors have been found to express SCFA receptor GPR41/FFAR3 and butyrate has been suggested to have analgesic effects, but the mechanism has not been elucidated. Bacteria expressing the enzyme histidine decarboxylase (HDC) can catabolize histidine into histamine which may bind to receptors histamine receptors (H1R-H4R) on neurons, yet more work to understand which receptor is needed and if this signaling leads to pain. Bacteria such as F. prausnitzii can secrete serine proteases which can bind to protease activating receptor 4 (PAR4) to block activation of nociceptors. Other bacteria, such as E. coli and M. Morganii can process catechols in gut lumen to release free, bioactive dopamine (DA) and molecularly similar molecules, such as PEA. These may then bind nociceptors, but it is unknown their effect on pain perception. Addititonally, bacteria that express a gene for the enzyme glutamate decarboxylase β (GadB)  are able to catabolize glutamate into GABA which can then bind to GABA receptors on nociceptors leading to an influx of the anion, chloride, to hyperpolarize the membrane and block neurotransmission. Image created with BioRender.com.