AIMS/HYPOTHESIS The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. METHODS We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. RESULTS All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. CONCLUSIONS/INTERPRETATION Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. TRIAL REGISTRATION Netherlands Trial Register: NL4832 (www.trialregister.nl). DATA AVAILABILITY Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. FUNDING The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

中文翻译：

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长期患有1型糖尿病的个体口服丁酸盐不会影响先天免疫和胰岛自身免疫：一项随机对照试验。

目的/假设1型糖尿病的病理生理学与肠道菌群的改变有关，更具体地讲，与短链脂肪酸丁酸酯（SCFA）的肠道生产不足有关，这可能在维持肠道上皮完整性和人类中起关键作用和肠道微生物的新陈代谢。补充丁酸酯可以预防小鼠模型中的自身免疫性糖尿病。因此，我们着手研究口服丁酸酯和安慰剂对长期患有1型糖尿病的人类参与者的葡萄糖调节和免疫变量的影响。方法我们在一项随机（1：1）对照双盲交叉试验中，对30例长期合并1型糖尿病，无合并症或药物治疗的患者，每天口服4 g丁酸钠或安慰剂，共1个月。两者之间的清洗期为1个月。参与者被随机分配到“先口服丁酸钠胶囊”或“先口服安慰剂胶囊”五个研究小组。临床研究者从临床试验药房获得了盲药。所有参与者，进行测量或检查的人员或评估结果的人员都无法进行小组分配。主要结果是先天免疫表型（单核细胞亚群和体外细胞因子产生）的变化。次要结果是胰岛自身免疫性血液标志物（细胞计数，淋巴细胞刺激指数和CD8量子点分析），葡萄糖和脂质代谢，β细胞功能（通过混合餐试验），肠道菌群和粪便SCFA的变化。数据是在阿姆斯特丹大学医学中心收集的。结果对所有30名参与者进行了分析。口服丁酸盐补充对粪便中丁酸盐和丙酸盐的含量有显着影响，丁酸盐治疗是安全的。但是，肠道SCFA的这种调节不会导致适应性免疫或先天免疫或任何其他结果变量发生任何显着变化。在讨论中，我们详细阐述了与以前的动物工作之间的重要差异。结论/解释对于长期患有1型糖尿病的人，口服丁酸补充剂不会显着影响先天或适应性免疫。试用注册荷兰试用注册：NL4832（www.trialregister.nl）。数据可用性原始测序数据可从PRJEB30292研究的欧洲核苷酸档案库（https://www.ebi.ac.uk/ena/browse）中获得。资金这项研究由Le Ducq财团，CVON基金，