Road to discovery for combination probiotic BB-12 with LGG in treating autism spectrum disorder

项目摘要 组合益生菌BB-12与LGG的发现之路 自闭症谱系障碍 胃病在自闭症儿童中很常见。拟议的研究项目将 研究患有自闭症谱系障碍（ASD）的儿童，4-15岁，他们抱怨 复发性胃肠道（GI）症状，如腹痛、便秘和呕吐。 这些胃肠道问题通常与异常行为有关，例如 易怒我们的团队计划测试两种不同剂量的益生菌（定义为 细菌产品，当消耗足够的数量，改善健康）可以受益 这些有胃肠道症状的孩子口服我们选择的益生菌（乳酸杆菌 鼠李糖乳杆菌GG和乳双歧杆菌BB-12、BB-12+LGG）的吸管为： 10亿集落形成单位（CFU）的吸管、具有100亿CFU的吸管和安慰剂吸管。我们计划 入组70例确诊ASD的合格受试者，并将其随机分配至安慰剂组、低剂量组和 高剂量BB-12+LGG，每日一次，比例为1：2：2。添加到食物中的益生菌可以 改善腹部不适，我们假设这可能会导致自闭症行为的改变 伴随着这些胃肠道症状。 尽管益生菌广泛存在，但美国食品和药物管理局要求 我们证明这种特殊的益生菌组合对儿童是安全的， 进行一项大型多中心试验，看看BB-12+LGG在不同剂量下是否有效， ASD儿童根据以前在成人和青少年中的试验，我们预计不会有严重的副作用。 使用BB-12+LGG的效果。90天内将有4次访视。我们希望看到一种趋势 在56天的治疗结束时， 用BB-12+LGG以最高剂量处理。疼痛和异常行为将 使用经过验证的问卷进行记录。 本研究采用了综合组学方法。几个血液和粪便测试将 作为ASD肠道健康的潜在有用的生物标志物进行测试，包括肠道试验。 渗透性（zonulin），全身性炎症的血液试验（S100 A9），以及 炎症（钙卫蛋白）。我们将同时测量粪便中的细菌群落 （使用16 S核糖体DNA测序），我们将测量血液中的关键代谢物， 粪便已被提出有助于ASD儿童的胃肠道症状（使用高 高效液相色谱法）。如果发现BB-12 + LGG的最佳剂量是安全的， 显示出改善GI或自闭症症状的信号，我们计划研究 这种益生菌在一个更大的，多中心的试验，使用适应性试验设计。

Project Abstract Road to discovery for Combination Probiotic Strain: BB-12 with LGG in treating autism spectrum disorders Stomach problems are common in children with autism. The proposed research project will study children with autism spectrum disorders (ASD), 4-15 years of age, who are complaining of recurring gastrointestinal (GI) symptoms, such as abdominal pain, constipation, and vomiting. These gastrointestinal problems are often associated with abnormal behavior, such as irritability. Our group is planning to test if at two different doses of a probiotic (defined as a bacterial product which when consumed in adequate quantity improves health) can benefit these children with GI symptoms. Oral doses of the probiotic we have selected (Lactobacillus rhamnosus GG and Bifidobacterium lactis BB-12, BB-12+LGG) to be tested are: a straw with 2 billion colony forming units (CFUs), a straw with 10 billion CFUs, and a placebo straw. We plan to enroll 70 eligible subjects with confirmed ASD and randomize them to placebo, low dose, and high dose of BB-12+LGG once daily at 1:2:2 ratio. The probiotic, to be added to food, may improve abdominal complaints which we hypothesize may produce changes in autistic behaviors that accompany these GI symptoms. Even though probiotics are widely available, the U.S. Food and Drug Administration requires that we demonstrate that this particular combination probiotic is safe in children before we can undertake a large multi-center trial to see if BB-12+LGG is effective at different doses in children with ASD. Based on previous trials in adults and adolescents, we expect no serious side effects from the use of BB-12+LGG. There will be 4 visits over 90 days. We expect to see a trend toward improvement of autistic behavior and GI symptoms by the end of the 56 days of treatment with BB-12+LGG at the highest dose. The pain and abnormal behaviors will be recorded using validated questionnaires. This study incorporates an Integrated Omics approach. Several blood and stool tests will be tested as potentially useful biomarkers of intestinal health in ASD, including a test of gut permeability (zonulin), a blood test for systemic inflammation (S100A9), and a stool test for inflammation (calprotectin). We will concomitantly measure bacterial communities in the stool (using 16S ribosomal DNA sequencing) and we will measure key metabolites in the blood and stool that have been proposed to contribute to GI symptoms in children with ASD (using high performance liquid chromatography). If an optimal dose of BB-12 + LGG is found to be safe and shows a signal toward improvement with respect to GI or autistic symptoms, we plan to study this probiotic in a larger, multi-center trial, using adaptive trial design.