Background: Chronic peripheral inflammation is well-documented for its ability to alter the activation of the central nervous system (CNS) in diseases such as rheumatoid arthritis (RA) [1]. Furthermore, the CNS is able to regulate inflammatory processes in the periphery [2]. However, the environmental factors facilitating CNS-mediated suppression of peripheral inflammation in RA remain less explored. The intestinal microbiota produces immunomodulatory metabolites, including short-chain fatty acids (SCFA) [3], and neuroactive substances like histamine, which exhibit local and systemic effects [4]. While histamine is commonly associated with allergic reactions, it also possesses immunoregulatory function [5].

Objectives: Our study aimed to elucidate the impact of gut microbiota-derived histamine on peripheral inflammation.

Methods: Mice with collagen-induced arthritis (CIA) were orally treated with histamine-producing and control E. coli from the peak of disease (POD). Additionally, mice received oral histamine or histamine receptor agonists (H1RA-H4RA). To delineate the mode of action, mice were treated orally, intraperitoneally, and intrathecally with an H3RA. Untargeted metabolomics analyzed serum and spinal cord extracts from H3RA-treated and untreated CIA mice. Bulk RNA sequencing and Cytek Spectral Flow cytometry examined intestinal sections, spinal cord, and paw-innervating Nervus plantaris. An ex vivo gut explant model assessed the effects of H3R agonist on the activation of the enteric nervous system. Microglia were depleted using a CSF1R blocker, and peripheral nerves in the inflamed paws were blocked by intra-plantar injection of Bupivacaine and QX-314. Differences in vascular leakage in inflamed areas were monitored through a contrast agent-based MRI approach.

Results: Our findings reveal that low levels of dietary or gut microbial-derived histamine activate the enteric nervous system, enhance thiamine and inhibitory neurotransmitter concentrations locally in the spinal cord, and restore homeostatic microglia, consequently reducing vascular leakage into inflamed joints. Critical to this pro-resolving effect is selective H3R signaling in the intestine, as systemic and intrathecal applications failed to demonstrate similar outcomes. Microglia depletion or pharmacological silencing of local nerve fibers impaired orally delivered H3R agonist-induced pro-resolving effects. Furthermore, therapeutic nutritional application of the SCFA propionate identified a method to augment local intestinal histamine concentrations in mice and humans. Fecal material supernatant transfers from propionate-treated donor mice mirrored pro-resolving effects observed with direct H3R agonist treatments. Consequently, our study defines a novel gut-CNS-joint axis pathway wherein microbial-derived histamine initiates the resolution of peripheral inflammation in the synovium via the CNS.

Conclusion: In conclusion, our study defines a novel gut-CNS-joint axis pathway wherein microbial-derived histamine initiates the resolution of peripheral inflammation in the synovium via the CNS.

REFERENCES: [1] Süß P, Rothe T, Hoffmann A, Schlachetzki JCM, Winkler J. The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain. Front Immunol. 2020 Dec 10;11:612104.

[2] Waldburger, JM., Firestein, G.S. Regulation of Peripheral Inflammation by the Central Nervous System. Curr Rheumatol Rep 12 , 370–378 (2010).

[3] Cummings JH, Macfarlane GT. The control and consequences of bacterial fermentation in the human colon. J Appl Bacteriol. 1991 Jun;70(6):443-59.

[4] Hegstrand, L.R. and R.J. Hine, Variations of brain histamine levels in germ-free and nephrectomized rats. Neurochemical Research, 1986. 11(2): p. 185-191.

[5] Barcik W, Pugin B, Brescó MS, Westermann P, et al. Bacterial secretion of histamine within the gut influences immune responses within the lung. Allergy. 2019 May;74(5):899-909.

Acknowledgements: NIL.

Disclosure of Interests: None declared.