Gut-specific histamine 3 receptor signaling orchestrates microglia-dependent resolution of peripheral inflammation
Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss
Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss
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Research Article Autoimmunity Immunology

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 effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid propionate revealed one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut/CNS/joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.

Authors

Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss

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Figure 7

Propionate supplementation increases local histamine levels in patients with RA or MS.

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Propionate supplementation increases local histamine levels in patients ...
(A) Histamine levels in stool extracts from patients with RA before and after 28 days of propionate supplementation. (B) Histamine levels in stool extracts from patients with MS before and after 90 days of propionate supplementation. (C) Volcano plot of RNA-Seq data from ex vivo colon culture infused with stool samples from patients before and after 90 days of propionate supplementation. Overlay with pathway genes of H1R and H2R activation (GSEA pathway: pos histamine response network). (D) Example images of histology staining of ileum biopsies from healthy controls or patients with RA stained for H3R. (E) Quantification of histological H3R staining of ileum biopsies from patients and healthy controls. (F) Histamine levels in stool processed into fecal microbiota transplants (FMTs) from healthy donors (107). FMTs were given to patients with active arthritis despite ongoing treatment with a steady-state dose of methotrexate. After 26 weeks, patients were categorized as being either treatment failures or treatment responders, according to the European psoriatic arthritis recommendations (108). FMT products of donors 1, 2, 3, and 4 were given to 6, 4, 3, and 2 patients, respectively. (G) Histamine was measured from the stool of patients with psoriatic arthritis at baseline before FMT. Data are expressed as mean ± SD. Statistical difference was determined by paired t test (A and B) and Student’s t test (E). *P < 0.05, ***P < 0.001.