Gut microbiota modulate the descending pain inhibitory pathway to alter pain processing in the spina

Depletion of microbiota or administration of probiotic candidate (Bacterium X) proved effective in mitigating pain in animal models of neuropathic pain. fMRI unveiled differences in primary somatosensory cortex (S1) activity in response to painful stimuli between mice with intact or depleted microbiota. Neural tracing showed that a subset of pyramidal neurons in layer 5 of the S1 establishes direct synaptic connections with neurons distributed in lamina 3 to 5 of spinal cord dorsal horn. Optogenetic stimulation of the descending pyramidal neurons altered the local field potential in the spinal cord and attenuated mechanical allodynia, indicating a descending pain inhibitory control from S1 to spinal cord. Further spatial transcriptomics determined the identities of the target cells receiving S1 output. Chemogenetic inhibition of the target cells diminished the excitability of spinal cord projection neurons and abolished the pain-alleviating effects observed with microbiota depletion.