Dürholz Kerstin, Ehnes Leona, Linnerbauer Mathias, Schmid Eva, Danzer Heike, Hinzpeter-Schmidt Michael, Lößlein Lena, Amend Lena, Frech Michael, Azizov Vugar, Schälter Fabian, Gessner Arne, Lucas Sébastien, Lesker Till-Robin, Taudte R Verena, Hofmann Jörg, Beyer Felix, Bootz-Maoz Hadar, Reich Yasmin, Romano Hadar, Mauro Daniele, Beckervordersandforth Ruth, Kragsnaes Maja Skov, Ellingsen Torkell, Xiang Wei, Haghikia Aiden, Akdis Cezmi A, Ciccia Francesco, Bäuerle Tobias, Sarter Kerstin, Strowig Till, Yissachar Nissan, Schett Georg, Rothhammer Veit, Zaiss Mario M
Department of Internal Medicine 3, Rheumatology and Immunology.
Deutsches Zentrum Immuntherapie (DZI), and.
J Clin Invest. 2025 Jul 10;135(18). doi: 10.1172/JCI184697. eCollection 2025 Sep 16.
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.
像类风湿性关节炎（RA）这样的慢性炎症性疾病已被描述为会导致中枢神经系统（CNS）激活。对于使中枢神经系统能够抑制类风湿性关节炎外周炎症的环境因素，我们了解得较少。在此，我们确定了肠道微生物群衍生的组胺就是这样一种因素。我们发现低水平的组胺会激活肠神经系统，增加脊髓中抑制性神经递质的浓度，并使小胶质细胞恢复稳态，从而减轻关节炎症。我们发现肠道中选择性组胺3受体（H3R）信号传导对于这种效应至关重要，因为全身和鞘内应用均未显示出效果。小胶质细胞耗竭或局部神经纤维的药理学沉默会损害口服H3R激动剂对关节炎的促消退作用。此外，短链脂肪酸丙酸酯的治疗性补充揭示了一种在小鼠和人类中提高局部肠道组胺浓度的方法。因此，我们定义了一种肠道/中枢神经系统/关节轴途径，其中微生物群衍生的组胺通过中枢神经系统启动关节炎的消退。
