Nowadays, melatonin, previously considered only as a pharmaceutical product for rhythm regulation and sleep aiding, has shown its potential as a co‐adjuvant treatment in intestinal diseases, however, its mechanism is still not very clear. A firm connection between melatonin at a physiologically relevant concentration and the gut microbiota and inflammation has recently established. Herein, we summarize their crosstalk and focus on four novelties. First, how melatonin is synthesized and degraded in the gut and exerts potentially diverse phenotypic effects through its diverse metabolites. Second, how melatonin mediates the activation and proliferation of intestinal mucosal immune cells with paracrine and autocrine properties. By modulating T/B cells, mast cells, macrophages and dendritic cells, melatonin immunomodulatory involved in regulating T‐cell differentiation, intervening T/B cell interaction and attenuating the production of pro‐inflammatory factors, achieving its antioxidant action via specific receptors. Third, how melatonin exerts antimicrobial action and modulates microbial components, such as lipopolysaccharide, amyloid‐β peptides via nuclear factor κ‐light‐chain‐enhancer of activated B cells (NF‐κB) or signal transducers and activators of transcription (STAT1) pathway to modulate intestinal immune function in immune‐pineal axis. The last, how melatonin mediates the effect of intestinal bacterial activity signals on the body rhythm system through the NF‐κB pathway and influences the mucosal epithelium oscillation via clock gene expression. These processes are achieved at mitochondrial and nuclear levels to control the host immune cell development. Considering unclear mechanisms and undiscovered actions of melatonin in gut‐microbiome‐immune axis, it's time to reveal them and provide new insight for the outlook of melatonin as a potential therapeutic target in the treatment and management of intestinal diseases.

中文翻译：

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褪黑素介导粘膜免疫细胞，微生物代谢和节律性串扰：减轻肠道炎症的治疗靶标。

如今，褪黑激素以前仅被认为是用于节律调节和睡眠辅助的药物，它已显示出其在肠道疾病中作为辅助治疗的潜力，但是，其作用机理尚不十分清楚。最近建立了生理相关浓度的褪黑激素与肠道菌群和炎症之间的牢固联系。在这里，我们总结了它们的串扰，并重点介绍了四个新颖性。首先，褪黑激素如何在肠道中合成和降解，并通过其多种代谢物发挥潜在的多种表型效应。其次，褪黑素如何介导具有旁分泌和自分泌特性的肠道粘膜免疫细胞的活化和增殖。通过调节T / B细胞，肥大细胞，巨噬细胞和树突状细胞，褪黑素免疫调节作用涉及调节T细胞分化，干预T / B细胞相互作用并减弱促炎因子的产生，并通过特定受体实现其抗氧化作用。第三，褪黑素如何通过活化B细胞的核因子κ轻链增强子（NF-κB）或信号转导和转录激活子（STAT1）途径发挥抗微生物作用并调节微生物成分，例如脂多糖，淀粉样β肽调节免疫松轴中的肠道免疫功能。最后，褪黑素如何通过NF-κB途径介导肠道细菌活性信号对人体节律系统的作用，并通过Clock基因表达影响粘膜上皮振荡。这些过程是在线粒体和核水平上实现的，以控制宿主免疫细胞的发育。考虑到褪黑素在肠道微生物组免疫轴中的机制不清楚和尚未发现的作用，是时候揭示它们并为褪黑素作为肠道疾病的治疗和管理的潜在治疗靶点提供新的见解了。