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 1

Propionate-induced microbial metabolites transfer pro-resolving effects.

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Propionate-induced microbial metabolites transfer pro-resolving effects....
(A) Clinical arthritis score shown as paw thickness (mm) of CIA mice ± 150 mM C3 (n = 4–5) in drinking water starting at 30 dpi. (B) Flow cytometric analysis of IL-17+ CD4+ T cells in the spleen of healthy mice and CIA mice ± C3. (C) quantification of bone mass (BV/TV) and representative μCT images of the trabecular part of tibial bone of healthy mice and CIA mice ± C3, analyzed at 77 dpi. (D) SCFA levels in the cecum content of CIA mice ± C3. (E) 16s rRNA-Seq of the cecum content of healthy mice, CIA mice, and CIA mice ± C3. (F) Alpha-diversity measure of 16s rRNA-Seq data. (G) Experimental layout of FMT experiment. This overview was generated with BioRender. (H) Clinical arthritis score shown as paw thickness (mm) of CIA mice treated with FMT of naive donors, C3-treated donors, pellet of C3-treated donors, or supernatant of C3-treated donors. (I) PCoA plot of 16s rRNA-Seq of mice after control or C3 FMT. (J) Relative abundance of the bacterial families identified by 16s rRNA-Seq. Permutational multivariate analysis of variance (ADONIS) was significant (R2 = 0.27225, P = 0.0167). (K) Relative abundance of most strongly changed Lactobacillaceae strains. (L) Volcano plot of untargeted metabolomics analysis of stool supernatant fraction obtained from control versus C3-treated FMT donors (cutoffs: P < 0.05 and –1 < log2FC < 1). Data are expressed as mean ± SD. Statistical difference was determined by ADONIS (L), 1-way ANOVA (B, C, F), Student’s t test (D), and AUC (A and H). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. CIA, collagen-induced arthritis; C3, propionate; BV, bone volume; TV, tissue volume; FMT, fecal microbiota transfer; PCoA, principal coordinates analysis.