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

项目摘要 组合益生菌菌株的发现之路：BB-12 与 LGG 的治疗 自闭症谱系障碍 胃部问题在自闭症儿童中很常见。拟议的研究项目将 研究 4-15 岁患有自闭症谱系障碍 (ASD) 的儿童，他们抱怨 反复出现胃肠道 (GI) 症状，例如腹痛、便秘和呕吐。 这些胃肠道问题通常与异常行为有关，例如 烦躁。我们的小组正计划测试两种不同剂量的益生菌（定义为 细菌产品（当摄入足够数量时可以改善健康）可以受益 这些有胃肠道症状的孩子。我们选择的益生菌（乳酸菌）的口服剂量 待测试的鼠李糖 GG 和乳双歧杆菌 BB-12、BB-12 LGG）为：一根吸管，带有 2 个 10 亿菌落形成单位 (CFU)、100 亿 CFU 吸管和安慰剂吸管。我们计划 招募 70 名确诊患有自闭症谱系障碍 (ASD) 的合格受试者，并将他们随机分配到安慰剂组、低剂量组和 高剂量 BB-12 LGG，每天一次，比例为 1:2:2。添加到食物中的益生菌可能 改善腹部不适，我们假设这可能会导致自闭症行为的改变 伴随这些胃肠道症状。 尽管益生菌随处可见，但美国食品和药物管理局仍要求 在我们能够之前证明这种特殊的益生菌组合对儿童是安全的 进行大型多中心试验，看看 BB-12 LGG 在不同剂量下是否有效 患有自闭症谱系障碍的儿童。根据之前对成人和青少年的试验，我们预计不会出现严重的副作用 使用 BB-12 LGG 的效果。 90 天内将进行 4 次访问。我们预计会看到一种趋势 56 天结束时，自闭症行为和胃肠道症状得到改善 用最高剂量的 BB-12 LGG 治疗。疼痛和异常行为将会 使用经过验证的调查问卷进行记录。 这项研究采用了综合组学方法。将进行多项血液和粪便检查 作为自闭症谱系障碍肠道健康的潜在有用生物标志物进行测试，包括肠道测试 渗透性（连蛋白）、全身炎症血液检查（S100A9）和粪便检查 炎症（钙卫蛋白）。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 粪便已被认为会导致自闭症儿童的胃肠道症状（使用高 高效液相色谱法）。如果发现 BB-12 LGG 的最佳剂量是安全且 显示出胃肠道或自闭症症状改善的信号，我们计划研究 这种益生菌采用适应性试验设计进行了一项更大规模的多中心试验。

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.