Gut-specific histamine 3 receptor signaling orchestrates microglia-dependent resolution of peripheral inflammation.

ABSTRACT: Chronic inflammatory diseases like rheumatoid arthritis (RA) have been described to cause CNS activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such a factor. We showed that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord, and restore homeostatic microglia, thereby reducing inflammation in the joints. We found that elective histamine 3 receptor (H3R) signaling in the intestine was critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving ef

SUBMITTER: Durholz K 

PROVIDER: S-EPMC12435854 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature