褪黑素常用于改善睡眠，但它可能会加重肠道炎症

https://agencia.fapesp.br/melatonin-commonly-used-to-improve-sleep-can-aggravate-bowel-inflammation/41326

圣保罗大学的研究人员进行的一项研究表明，在实验室小鼠中，这种易于从药店购买并被广泛用作膳食补充剂的激素，会加重克罗恩病和溃疡性结肠炎，具体情况取决于小鼠的肠道菌群组成。

2023-05-10

圣保罗大学的研究人员进行的一项研究表明，在实验室小鼠中，这种易于从药店购买并被广泛用作膳食补充剂的激素，会加重克罗恩病和溃疡性结肠炎，具体情况取决于小鼠的肠道菌群组成。

作者：Ricardo Muniz |圣保罗研究基金会（FAPESP）——发表在《微生物学》（Microorganisms）杂志上的一篇文章指出，褪黑素虽然具有抗氧化作用并能调节睡眠周期，但它也会加剧肠道炎症并损害肠道菌群的功能。肠道菌群由细菌和其他微生物组成，对健康至关重要，有助于控制消化并增强免疫系统。肠道内有害菌群和有益菌群的失衡可能导致体重增加、高血糖、胆固醇升高以及其他疾病。

褪黑素俗称“睡眠激素”，许多睡眠障碍患者会在没有医生处方的情况下将其作为所谓的膳食补充剂服用。

“人们普遍认为褪黑激素无害。毕竟，它是一种激素，有助于调节睡眠。然而，我们的研究表明，人们应该谨慎服用激素补充剂，服用褪黑激素补充剂可能会对健康产生不利影响。”巴西圣保罗州圣保罗大学里贝朗普雷图药学院（FCFRP-USP）免疫学和神经免疫内分泌学教授克里斯蒂娜·里贝罗·德·巴罗斯·卡多索（Cristina Ribeiro de Barros Cardoso）说道。

卡多索的实验室致力于研究炎症性肠病，包括克罗恩病和溃疡性结肠炎。这些疾病是由免疫介导的，是由于免疫细胞对病原体过度反应而导致的异常活跃，会对肠道微生物群造成破坏性影响，并引发严重的临床症状，例如腹痛、持续腹泻、出血和疲劳。

治疗方法包括抑制或阻断免疫反应，以减少对肠道造成损害的过度炎症。除了皮质类固醇和免疫抑制剂外，治疗可能还包括免疫生物制剂，这类药物对中重度病例更为有效，但大多数患者难以负担。在巴西，只有在特定情况下，国家医疗服务体系（SUS，即Sistema Único de Saúde）才会支付此类药物的费用，或者在法院判决的情况下，医疗保险计划才会支付。

“我们的实验室致力于更深入地了解这些疾病，并提出更经济实惠的新疗法，”卡多索说道。她拥有乌贝兰迪亚联邦大学（米纳斯吉拉斯州）的牙科学位和圣保罗大学的基础与应用免疫学博士学位，并在美国哈佛大学牙科医学院附属的福赛斯研究所完成了博士后实习。

她补充说，除了经济负担问题外，许多患者即使接受最先进的治疗也效果不佳，不得不接受部分肠道切除手术。这些侵入性手术对他们的生活质量产生了极其负面的影响。 “因此，近年来我们一直在探索新的治疗方案，主要基于免疫反应的调节或调控，”她说道。

卡多索及其团队在激素研究领域拥有多年经验，最近开始专注于褪黑素的研究。“我绝不是说褪黑素没有益处。恰恰相反，事实上，很少有研究或报告指出它有不良副作用，”她说道。

褪黑素确实可以作为一种抗氧化剂，改善多种生理或病理状况。“我们最初开展这项研究的假设是，我们或许能够开发出一种治疗克罗恩病和溃疡性结肠炎的新方法，但令我们惊讶的是，我们发现了截然相反的结果，患者应该意识到这种风险，”她说道。

这项研究包括一项实验，实验中研究人员在小鼠身上诱发了结肠炎，并用褪黑素进行治疗。结果，小鼠的病情不但没有好转，反而恶化了。 “必须强调的是，这项研究没有涉及任何人类患者。动物的肠道炎症却急剧恶化，”卡多索说道。

“我们随后开始尝试探究其原因。我们发现，如果忽略褪黑素对肠道菌群的影响，并用广谱抗生素清除小鼠体内所有细菌，褪黑素对这种疾病确实有积极作用。”

因此，褪黑素的负面影响取决于肠道内存在的细菌，而这些细菌也与肠道炎症有关。

该地区的炎症性疾病。肠道菌群的某些特征会加剧炎症反应，并导致免疫系统失调，从而损害消化系统。卡多索说：“这一切意味着什么？我认为这意味着并非所有闪闪发光的东西都是金子。我们应该对药物、激素补充剂或作为膳食补充剂出售的激素保持高度警惕。你在药店购买‘膳食补充剂’时，会认为它不是药物，不会改变你身体的任何东西，只会对你有益，毕竟它是作为膳食补充剂出售的，但事实并非如此。它是一种激素，而所有激素与免疫系统之间的相互作用调节非常微妙。”

监管

巴西国家卫生监督局（ANVISA）最近更新了关于褪黑素作为膳食补充剂销售的信息和规定，但即便如此，其监管力度仍比药物宽松。 “强调这一点很重要，因为我们一直在谈论需要注意健康，但人们可能会想，‘哦，我只要去药店买一些就行了，它已经获得巴西国家卫生监督局（ANVISA）的批准了。’没错，但前提是它被标注为膳食补充剂。而我们在这项研究中探讨的是，它是否真的仅仅是膳食补充剂。它存在哪些风险？”卡多索说道。

这项研究是卡多索领导、由圣保罗州研究基金会（FAPESP）资助的项目成果之一。该文章的合著者是 Jefferson Luiz da Silva、Lia Vezenfard Barbosa、Camila Figueiredo Pinzan、Viviani Nardini、Irislene Simões Brigo、Cássia Aparecida Sebastião、Jefferson Elias-Oliveira、Vânia Brazão、José Clóvis do Prado Júnior 和 Daniela Carlos，隶属于 FCFRP-USP 系里贝朗普雷图医学院 (FMRP-USP) 临床分析、毒理学和食品科学系以及生物化学和免疫学系。

文章“褪黑激素对肠道炎症的微生物依赖性恶化作用”位于：www.mdpi.com/2076-2607/11/2/460。

Melatonin, commonly used to improve sleep, can aggravate bowel inflammation

https://agencia.fapesp.br/melatonin-commonly-used-to-improve-sleep-can-aggravate-bowel-inflammation/41326

In laboratory mice, the hormone easily bought from pharmacies and widely consumed as a supplement aggravated Crohn’s disease and ulcerative colitis, depending on the animal’s gut microbiota profile, according to a study by researchers at the University of São Paulo.

2023-05-10

In laboratory mice, the hormone easily bought from pharmacies and widely consumed as a supplement aggravated Crohn’s disease and ulcerative colitis, depending on the animal’s gut microbiota profile, according to a study by researchers at the University of São Paulo 

By Ricardo Muniz  |  Agência FAPESP – An article published in the journal Microorganisms shows that melatonin, despite its antioxidant effects and role in regulating sleep cycles, can worsen inflammation of the intestine and impair the action of gut microbiota. This community of bacteria and other microbes is important to health, helping control digestion and benefiting the immune system. An imbalance of unhealthy and healthy microbes in the intestines may contribute to weight gain, high blood sugar, above-normal cholesterol and other disorders.

Melatonin is popularly known as the “sleep hormone” and is often taken as a so-called food supplement without a doctor’s prescription by people with sleep problems. 

“It’s generally thought to be harmless. After all, it’s a hormone and can help regulate sleep. However, our study shows that people should be careful about taking hormone supplements and that the ingestion of melatonin supplement can have adverse effects on health,” said Cristina Ribeiro de Barros Cardoso, a professor of immunology and neuroimmunoendocrinology at the University of São Paulo’s Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP) in São Paulo state, Brazil.

Cardoso’s laboratory conducts research into inflammatory bowel disorders, including Crohn’s disease and ulcerative colitis. These disorders are immune-mediated, resulting from abnormal activity of the immune cells in overreacting to a pathogen, with destructive effects on the gut microbiome and severe clinical symptoms, such as abdominal pain, constant diarrhea, bleeding and fatigue.

Treatment entails suppressing or inhibiting the immune response in order to reduce the excessive inflammation that damages the intestine. Besides corticosteroids and immunosuppressants, treatment may involve immunobiological medications, which are more effective for moderate and severe cases but unaffordable for most patients. In Brazil, they are paid for only under specific circumstances by the SUS (Sistema Único de Saúde, as the national health service is known) or by health plans in the event of a court order.

“Our lab works to achieve a better understanding of these diseases and propose novel treatments that are more affordable,” said Cardoso, who holds a degree in dentistry from the Federal University of Uberlândia (Minas Gerais state) and a PhD in basic and applied immunology from USP, with a postdoctoral internship at Forsyth Institute, an affiliate of the Harvard School of Dental Medicine (USA). 

Besides the problem of affordability, she added, many patients do not respond well even to the most advanced treatments and have to undergo surgery for removal of parts of the intestine. These invasive procedures have a highly negative effect on their quality of life. “For this reason, in recent years we have pursued novel therapeutic options, primarily based on immune response modulation or regulation,” she said.

Cardoso and her group have years of experience in hormone research and recently began focusing on melatonin. “Look, I’m not saying by any means that melatonin doesn’t have beneficial effects. On the contrary, in fact. There are few studies or reports pointing to adverse side effects,” she said.

Melatonin can indeed act as an antioxidant and improve several physiological or pathological conditions. “We started out in this study with the assumption that we might be able to develop a novel treatment for Crohn’s disease and ulcerative colitis, but to our surprise, we found exactly the opposite, and patients should be made aware of this danger,” she said.

The study involved an experiment in which colitis was induced in mice, and they were treated with melatonin. Their condition became worse instead of improving. “It’s important to stress that no human patients were involved in the study. The animals’ bowel inflammation became much, much worse,” Cardoso said.

“We then began trying to understand why. We found that melatonin had a positive effect on the disease if the effect on gut microbiota was ignored and the mice were treated with wide-spectrum antibiotics to eliminate all the bacteria.” 

The negative effect of melatonin, therefore, depends on the bacteria that live in the intestine and are also associated with inflammatory diseases of the region. Certain features of gut microbiota increase inflammation and dysregulate the immune system in response to treatment with melatonin, damaging the digestive system.

“What is the meaning of all this? I’d say it’s that all that glitters is not gold. We should take great care with medications, hormone supplements or hormones offered as food supplements. You buy a ‘food supplement’ in a pharmacy and think it’s not a drug, it won’t alter anything in your body, it will only do good because after all it’s sold as a food supplement, but it’s not really that at all. It’s a hormone, and regulation of the interaction between all hormones and the immune system is very delicate,” Cardoso said.

Regulation

ANVISA, Brazil’s national health surveillance agency, has recently updated its information and rules on the sale of melatonin as a food supplement, but even so control is looser than for medications. “It’s important to stress this because we talk about the need to take care, but people may think, ‘Oh, but I’ll just pop into the pharmacy and buy some, it’s been approved by ANVISA.’ True, but only when labeled as a food supplement, and what we’re asking in the study is whether it’s really a mere food supplement. What are the risks?” Cardoso said.

The study is one of the outcomes of a project led by Cardoso and funded by FAPESP. The co-authors of the article are Jefferson Luiz da Silva, Lia Vezenfard Barbosa, Camila Figueiredo Pinzan, Viviani Nardini, Irislene Simões Brigo, Cássia Aparecida Sebastião, Jefferson Elias-Oliveira, Vânia Brazão, José Clóvis do Prado Júnior and Daniela Carlos, affiliated with FCFRP-USP’s Department of Clinical Analysis, Toxicology and Food Science and the Department of Biochemistry and Immunology at Ribeirão Preto Medical School (FMRP-USP).

The article “The microbiota-dependent worsening effects of melatonin on gut inflammation” is at: www.mdpi.com/2076-2607/11/2/460.