孤独症治疗新突破！广州医科大学附属第二医院证实我国自研菌株脆弱拟杆菌BF839有效干预！
文摘
健康
2024-09-05 17:02
广东
孤独症谱系障碍（autism spectrum disorder，ASD）是一种广泛神经发育障碍性疾病，其主要特点为言语及社交障碍、兴趣狭窄、重复刻板行为等[1]。近年我国ASD患病率逐年上升，患病率达1% [2]。目前以教育康复训练为主的疗效有限，缺乏更有效的治疗方法。肠道微生物组已被报道可通过菌群-肠-脑轴参与ASD的发病机制[3]，影响其胃肠道功能和行为[4,5]。近期，广州医科大学附属第二医院临床营养科开展的一项随机、双盲、安慰剂临床试验发现：采用我国自研菌株脆弱拟杆菌BF839能有效干预自闭症，安全性高，这为广大自闭症患者及家庭带来了曙光。![]()
在这项随机双盲安慰剂对照的试验中，研究团队共招募了2-10岁60名自闭症患者，在不改变两组患者常规康复训练的基础上给予BF839或安慰剂治疗16周。在 0天、第8周和16 周分别进行孤独症行为量表（Autism Behavior Checklist，ABC）、儿童期孤独症评定量表(Childhood Autism Rating Scale,CARS)、社会反应量表(Social responsiveness scale,SRS)、0岁-初中生社会生活能力量表（Normal Development of Social Skills from Infant to Junior High School Children，S-M）、胃肠道症状评定量表(Gastrointestinal symptom rating scale, GSRS)评估以及不良反应监测。同时在第0天、16周收集ASD患者的粪便进行肠道菌群分析。
结果
（一）BF839可显著改善ASD儿童的异常行为及胃肠道症状，尤其是反映刻板行为的运动能力，小于4岁可能是益生菌干预有效的窗口期。与安慰剂组对比，16周时BF839组可显著改善ABC运动能力评分（-4.68±6.29vs -1.07±5.73, P＜0.05）。进一步亚组分析：在小于4岁的ASD儿童中，与安慰剂组对比，16周时BF839组可显著改善ABC运动能力评分(-4.85±4.60 vs 1.50±3.87, P＜0.05)。ABC 总分改善也显著高于安慰剂组3倍（−20.23±23.92 vs −6.42±15.96， p=0.106），接近统计学差异；而在4岁以上的孩子中，与安慰剂相比，BF839组改善稍好，但不明显（-11.27 ± 11.74 vs -8.88 ± 14.93，P= 0.623）。在CARS≥30分的ASD儿童中，与安慰剂组对比，16周时BF839组可显著改善ABC总分（-19.71±24.12 vs -5.05±16.58, P＜0.05）、ABC运动能力评分(-5.71±8.26 vs -0.32±5.88, P＜0.05)以及CARS评分(-5.57±5.79 vs -2.11±3.70, P＜0.05)；与安慰剂对比，8周和16周时BF839组可显著改善GSRS评分[8w, -3.50(-7.36,-1.25) vs 0.00(-3.00,3.00), P＜0.05; 16w, -3.50(-7.13,-1.25) vs 2.00(-3.00,3.00), P＜0.05] 。仅观察到BF839组有2例（6.67%）因轻度腹泻而退出，其余患者未见其他不良反应。安慰剂组和BF839组在 0 d时未显示出显著差异丰度，但与安慰剂组16w比较，BF839组干预16w后BF839组16w 假小链双歧杆菌（Bifidobacterium pseudocatenulatum）、长双歧杆菌（Bifidobacterium longum）、两歧双歧杆菌（Bifidobacterium bifidum）丰度显著增加，同时相关的神经活性化合物的代谢功能显著改善。越来越多的动物研究[6-10]和临床试验[11-21]都报道了单一菌株或复合菌株益生菌可在一定程度上改善ASD行为表现及胃肠道症状，本研究结果提示BF839在改善ASD儿童行为症状方面显示出较为优秀的功效。Zhao的研究显示[18]，通过粪菌移植（FMT）2个月后，CARS评分较基线下降了10.8%（对照组仅下降了0.8%，P<0.001），本研究干预16周后，在基线CARS≥30分的ASD儿童中，BF839降低了14.50%（对照组降低了5.93%，P=0.044），本研究结果与FMT疗效相似。已有研究表明，相较于健康儿童，在ASD患儿中发现双歧杆菌属（Bifidobacterium）[22-24]、韦荣氏球菌属（Veillonella）[25]显著下降。已知某些双歧杆菌可产生γ-氨基丁酸（γ-aminobutyric acid，GABA）[26]，因而在ASD患儿中也呈现较低的GABA浓度。GABA与谷氨酸代谢密切相关，谷氨酸代谢是大脑中主要的兴奋性神经递质[27]。一些研究显示，较低的谷氨酸浓度与ASD典型焦虑以及社交和行为障碍的严重程度相关[28-29]。基于此，有人认为GABA/谷氨酸异常可能在ASD病理学中发挥重要作用[28-30]。自闭症儿童也有氨基酸失调的报道[31]，新的证据强调了肠道微生物群在氨基酸代谢中的作用。另外，长双歧杆菌NCC3001可通过迷走神经途径使感染性结肠炎小鼠的焦虑样行为和海马脑源性神经营养因子（BDNF）正常化[32]。而本研究发现，与安慰剂组及干预前对比，经BF839干预16w后，假小链双歧杆菌（Bifidobacterium pseudocatenulatum）、长双歧杆菌（Bifidobacterium longum）、两歧双歧杆菌（Bifidobacterium bifidum）丰度显著增加，我们的肠道菌群结果提示BF839可以促进ASD儿童肠道内双歧杆菌的生长，致使一些神经活性化合物的代谢功能显著变化，这可能是BF839能有效改善ASD儿童症状原因之一。本研究结果对于人类使用肠道微生态制剂治疗神经发育障碍性疾病有重要的实践和理论意义。由于BF839是一个已上市多年的具有中国自主知识产权的人源性肠菌制剂，这一研究成果可以迅速应用于临床。这一临床研究也证实了前期我们团队[33，34]及国外来自《Cell》[35]的动物实验结果：脆弱拟杆菌可改善孤独症小鼠的部分症状。30%的孤独症孩子合并癫痫发作，而我们前期的临床研究也发现：BF839还可降低癫痫发作，有效治疗难治性和免疫相关性癫痫[36-38]，这进一步说明：肠道微生态失衡是神经发育障碍性疾病中共同的发病原因之一，使用有益微生物去纠正孩子的微生态失衡，对孩子有极大的帮助。然而，我们的研究发现：小于4岁可能是微生态制剂干预有效的窗口期。因此我们呼吁，时间就是大脑！早期干预与良好的预后相关!原文链接：
https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1447059/full
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近年来,营养结合肠道微生态的技术在临床上越来越得到重视，各种治疗性膳食模式(如生酮饮食、低碳饮食、低蛋白饮食、低嘌呤饮食、低热量饮食、抗癌膳食等)在临床上广为应用，取得了较好的效果。而肠道微生态更是大大提高了营养科的治疗效果，二者的结合在神经系统疾病、肿瘤性疾病、自身免疫性疾病、代谢性疾病中都取得了肯定的疗效，而且营养膳食模式是以自然食物为主，肠道微生态(如不同菌株的益生菌、益生元、后生元等)均是能获得国家批准上市的膳食食品。
该技术安全可靠，没有严重的副作用，是未来临床营养科的新技术。
