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

项目摘要 发现益生菌组合菌株BB-12与LGG治疗的途径 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4-15岁儿童，他们抱怨 反复出现的胃肠道(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 适量食用可改善健康的细菌产品)可受益 这些有胃肠道症状的孩子。我们选择的益生菌的口服剂量(乳杆菌 鼠李糖GG和乳双歧杆菌BB-12、BB-12LGG)被检测的是：一根吸管 10亿个集落形成单位(CFU)，一根有100亿CFU的吸管，以及一根安慰剂吸管。我们计划 招募70名确诊为ASD的符合条件的受试者，并随机给予安慰剂、低剂量和 大剂量BB-12LGG，每日1次，比例为1：2：2。添加到食品中的益生菌可能 改善腹部主诉，我们推测这可能会改变自闭症行为 伴随着这些胃肠道症状。 尽管益生菌随处可得，但美国食品和药物管理局要求 我们先证明了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 患有自闭症的儿童。根据之前在成年人和青少年中进行的试验，我们预计不会有严重的副作用 使用BB-12LGG的效果。在90天内将有4次访问。我们预计会看到一种趋势 自闭症行为和胃肠道症状在56天结束前的改善 BB-12免疫球蛋白治疗剂量最大。疼痛和异常行为将是 使用经过验证的问卷进行记录。 这项研究结合了一种集成的OMICS方法。几项血液和粪便测试将 被测试为ASD肠道健康的潜在有用生物标记物，包括肠道测试 通透性(氮球蛋白)，全身炎症的血液测试(S100A9)，以及粪便测试 炎症(钙保护素)。我们将同时测量粪便中的细菌群落 (使用16S核糖体DNA测序)，我们将测量血液中的关键代谢物和 导致自闭症儿童胃肠道症状的大便(使用高剂量 高效液相色谱)。如果发现最佳剂量的BB-12免疫球蛋白是安全的和 显示出胃肠道或自闭症症状改善的信号，我们计划研究 该益生菌在较大规模、多中心试验中，采用适应性试验设计。

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.