益生布拉酵母菌不能预防克罗恩病复发

《临床胃肠病学和肝脏病学》(Clinical Gastroenterology and Hepatology)8月刊发表的一项研究显示，使用非致病性益生酵母菌布拉酵母菌不能预防克罗恩病复发。

在这项为期1年的随机、双盲、安慰剂对照研究中，法国CHU de Nantes医院的Arnaud Bourreille医生及其同事对来自32个中心的159例急性期克罗恩病成人患者进行了研究。患者根据各个研究者的喜好接受4周的糖皮质激素、布地奈德和/或氨基水杨酸治疗直至缓解。患者随后被随机分组，口服布拉酵母菌(每日1 g)或安慰剂治疗直至52周研究结束或复发时，以先到者为准。每12周进行1次随访。

复发定义为随访期间记录到的克罗恩病活动性指数(CDAI)＞220分；记录到的CDAI介于150~220且相对基线值增加至少70分；或需接受针对克罗恩病的手术或药物治疗。

研究者发现，1年时，80例患者出现克罗恩病复发：布拉酵母菌组38例(47.5%)，安慰剂组42例(52.5%)，差异不显著(P＜0.05)。研究者还发现，两组的至复发中位时间无统计学差异：布拉酵母菌组为40.7周(范围，2.6~56.0周)，安慰剂组为39.0周(范围，0.1~55.0周)(P=0.78)。唯一具有统计学显著性的结果为，根据吸烟状态分析得出：安慰剂组非吸烟者的复发发生率(72.0%)高于布拉酵母菌组非吸烟者(34.5%；P=0.016)。然而，在吸烟者和既往吸烟者中未观察到组间复发发生率存在显著差异。

在安全性方面，各组仅超过半数的患者发生不良事件，包括腹泻、关节痛、便秘和腹痛。布拉酵母菌组1例患者发生口腔真菌感染。所有的药物相关不良事件均不严重。两组的依从率均高于90%。

该研究的局限在于使用临床复发作为终点而不使用根据内镜结果定义的复发。研究者表示，使用临床复发作为主要终点是因为认为对于非重度克罗恩病的监测没有必要使用内镜评估。此外，在设计该研究时，黏膜愈合的概念不像现在这样被视为具有相关性。然而，研究者在各次访视时均对炎症生物学指标进行了测定，以确保临床复发与客观炎症相关。

Bourreille医生及数名研究者声明与布拉酵母菌生产商Biocodex等多家药企存在联系。两名研究者为Biocodex员工。

专家点评：益生菌对克罗恩病无效

加州大学圣地亚哥分校胃肠病科主任William J. Sandborn医生表示，上述研究加深了我们对益生菌治疗克罗恩病和预防术后复发的认识。包括上述研究在内的现有随机对照研究数据不支持使用益生菌(包括大肠杆菌属Nissle 1917、布拉酵母菌、鼠李糖乳杆菌GG、约氏乳杆菌)治疗克罗恩病。在术后复发的预防方面，随机对照研究观察到美沙拉嗪具有轻微预防作用、环丙沙星无预防作用、咪唑类抗生素甲硝唑和奥硝唑具有预防作用(但也具有治疗限制性毒性)、硫唑嘌呤和6-巯基嘌呤具有中等预防作用、抗肿瘤坏死因子抗体具有显著预防作用，但这些研究均存在样本量小的局限性。

上述使用布拉酵母菌的研究和既往使用约氏乳杆菌的研究均未观察到这些益生菌具有预防术后复发的作用。上述研究表明使用益生菌治疗克罗恩病仍属于试验性应用，同时提示有必要探讨可改变菌群的替代性治疗策略(如粪便菌群移植)和可代替患者体内缺失的特定菌群的个体化药物益生菌组合。Sandborn医生无相关经济利益冲突。

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By: DENISE NAPOLI, Internal Medicine News Digital Network

Treatment with the nonpathogenic probiotic yeast Saccharomyces boulardii does not prevent relapse in Crohn’s disease.

The finding – which nevertheless does "not allow the exclusion of the potential therapeutic efficacy of probiotics" – comes from the third study to assess S. boulardii in Crohn’s, wrote Dr. Arnaud Bourreille and colleagues. The results are in the August issue of Clinical Gastroenterology and Hepatology.

In a yearlong, randomized, double-blind, placebo-controlled study, Dr. Bourreille, of the CHU de Nantes, France, and colleagues looked at 159 adult patients enrolled at 32 centers during the acute phase of Crohn’s disease.

Patients were treated for 4 weeks with corticosteroids, budesonide, and/or aminosalicylates, according to the preference of each investigator, until remission. They were then randomized to receive either oral S. boulardii at 1 g daily or a placebo until the end of the study at week 52 or earlier, in the case of relapse, with follow-up conducted every 12 weeks.

Relapse was defined as registering a Crohn’s disease activity index (CDAI) higher than 220 points on follow-up; registering a CDAI between 150 and 220 with an increase of at least 70 points over the baseline value; or requiring a surgical procedure or medical treatment specifically for CD.

The authors found that by 1 year, 80 patients had experienced relapse of Crohn’s: 38 in the S. boulardii group (47.5%) and 42 in the placebo group (52.5%), a nonsignificant difference (P less than .05).

The authors also found that the median time to relapse was not statistically different between groups, at 40.7 weeks for the treatment group (range, 2.6-56.0) and 39.0 weeks for patients taking placebo (range, 0.1-55.0) weeks (P = .78).

Indeed, the only finding that did reach statistical significance was among treatment group and smoking status, where nonsmokers given placebo had more relapses (72.0%) than did those treated with S. boulardii (34.5%; P = .016 for the difference between cohorts).

"However, in smokers and former smokers, the proportion of relapse was not significantly different," added the authors.

Looking at safety, Dr. Bourreille reported that just over half of patients in each group complained of adverse events, including diarrhea, arthralgia, constipation, and abdominal pain.

"One oral fungal infection occurred in one patient treated with S. boulardii," he added. "None of the drug-related AEs was serious."

Compliance was greater than 90% in both the treatment and placebo groups.

Dr. Bourreille conceded that the study was limited by the use of clinical relapse as an endpoint, versus relapse defined by endoscopic findings.

"Clinical recurrence was chosen as the primary endpoint because endoscopic evaluation was not deemed necessary for the surveillance of nonsevere CD," wrote the investigators. "Moreover, at the time the study was designed, the concept of mucosal healing was not considered to be as relevant as it now is."

They added, however, that biological parameters of inflammation "were measured at each visit to ensure that clinical recurrence was associated with objective inflammation."

Dr. Bourreille and several coauthors disclosed ties with multiple pharmaceutical companies, including Biocodex, the maker of S. boulardii. Two coauthors were Biocodex employees.

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Probiotics don't seem to be working for Crohn's

This article by Bourreille and colleagues provides some incremental insights into both probiotic therapy for Crohn’s disease and the prevention of postoperative recurrence.

With regard to probiotic therapy, to date, there has been one small trial of Escherichia coli Nissle 1917 for active Crohn’s disease that was negative, one small trial of Saccharomyces boulardii for maintenance of medically induced remission that showed a benefit, one small trial of Lactobacillus rhamnosus GG for medically induced remission that was negative, and two small trials of Lactobacillus johnsonii for prevention of postoperative recurrence that were negative.

The current trial of S. boulardii for prevention of postoperative recurrence is also negative. Taken in total, the existing randomized controlled trial data do not support treatment of Crohn’s disease with probiotic therapy using E. coli Nissle 1917, S. boulardii, L. rhamnosus GG, or L. johnsonii.

As for prevention of postoperative recurrence, randomized controlled trials have demonstrated minimal efficacy for mesalamine, no efficacy for ciprofloxacin, efficacy for the imidazole antibiotics metronidazole and ornidazole (but also treatment limiting toxicity), modest efficacy for azathioprine and 6-mercaptopurine, and marked efficacy for anti–tumor necrosis factor antibody therapy (but these data are limited by small sample size).

The current trial of probiotic with S. boulardii as well as previous trials with L. johnsonii did not demonstrate efficacy for prevention of postoperative recurrence, thus indicating that at present there is not a role for probiotics for this treatment indication. This study highlights the investigational nature of probiotic therapy for Crohn’s disease, and the need to investigate alternative treatment strategies to alter the microbial flora, such as fecal microbiota transplantation and personalized medicine probiotic cocktails that replace specific missing microbial flora in individual patients.

Dr. William J. Sandborn is professor of medicine and adjunct professor of surgery, chief of the division of gastroenterology, and director of the UCSD IBD Center, University of California San Diego and UC San Diego Health System. He had no relevant conflicts of interest.