Safety and Effect of L. reuteri on Biomarkers of Inflammation in Healthy Infants

罗伊氏乳杆菌的安全性及其对健康婴儿炎症生物标志物的影响

• 批准号: 8304030
• 负责人: JON Marc RHOADS
• 金额: $ 11.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304030
• 关键词: Abdominal colic; Adult; Affect; B-Lymphocytes; Bacteria; Basic Science; Biological Markers; Blood; Cattle; Cells; Characteristics; Clinical; Clinical Markers; Crying; Data; Dose; Double-Blind Method; Drops; Effector Cell; Enrollment; Escherichia coli; Evolution; Feces; Flow Cytometry; Future; Hand; Health; Hour; Incidence; Infant; Inflammation; Inflammatory disease of the intestine; Intestines; Investigation; Klebsiella; Laboratories; Lactobacillus; Lactobacillus reuteri; Leukocyte L1 Antigen Complex; Leukocytes; Life; Lipopolysaccharides; Measurement; Measures; Mediating; Milk; Modeling; Molecular; Mononuclear; Necrotizing Enterocolitis; Neonatal; Newborn Infant; Oral cavity; Organism; Outcome; Peripheral Blood Mononuclear Cell; Phase; Placebo Control; Play; Population; Postpartum Depression; Prevalence; Probiotics; Production; Publishing; Randomized Controlled Trials; Rattus; Regulatory T-Lymphocyte; Role; Safety; Serum; Severities; Shaken baby syndrome; Stress; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Time; Toll-like receptors; automobile accident; cytokine; feeding; gastrointestinal; improved; mortality; novel; pup; receptor expression; volunteer

DESCRIPTION (provided by applicant): Colic is a severe problem characterized by fussing, crying and screaming for more than 3 hours daily and affecting ~15% of otherwise normal infants in the first 3 months of life. We recently published our trial defining key clinical and microbiological characteristics of infants with colic. Compared to normal infants, those with colic demonstrated a four-fold increase in crying time, a doubling in the level of fecal calprotectin (a measure of gut inflammation), and changes in the fecal microbiota characterized by reduced bacterial diversity and an increase in the prevalence of Klebsiella. These results suggested a novel hypothesis: that the infants are crying because their bowels are inflamed, possibly as a result from an abnormal microbiota. Our investigation will focus on a population of healthy infants with colic to show safety of a probiotic that has been shown to reduce crying time in infants with colic. Our basic science laboratory trials showed that feeding of L. reuteri reduced gut inflammation and reduced mortality by > 50% in a neonatal rat model of necrotizing enterocolitis. We are currently close to completion of a double-blind placebo-controlled Phase 1 safety trial of L. reuteri in adult volunteers (U01AT003519). In this study, we are measuring how the probiotic influences the effector cells that modulate inflammation. We are quantifying circulating T cells, B cells, mononuclear cells, T cell subsets (by flow cytometry). We are measuring cytokine production by peripheral blood mononuclear cells, fecal calprotectin, and fecal microbiota. This trial includes measurement of regulatory T-cells (Tregs), the cells proposed to mediate the immunomodulatory effects of probiotics. Thus, our Primary Aim is to demonstrate (in a two-year trial) if Lactobacillus reuteri is safe in healthy newborns with colic (n=45), at 3 different doses: 5 x 106, 5 x 107, and 5 x 108 c.f.u. given by mouth once daily for si weeks. Our Secondary Aim is to compare outcomes to determine the optimal dose for a future randomized controlled trial (RCT). Dose-effect relationships will be determined for the following measures: (a) crying + fussing time; (b) fecal calprotectin; (c) serum cytokines; (d) toll-like receptor expression on peripheral blood mononuclear cells; (e) circulating regulatory T-cells; and (f) fecal levels of colic-related organisms (Klebsiella and E. coli, determined by qPCR) and diversity of fecal microbiota (assessed by 454 pyrosequencing). PUBLIC HEALTH RELEVANCE: Colic is a severe condition affecting ~ 15% of otherwise normal infants and is associated with postpartum depression, marital stress, and shaken baby syndrome. Babies that we studied in Houston cried for an average of 5 hours daily and had intestinal inflammation associated with an abnormal population of resident bacteria (microbiota) in their stools. Our study will determine the safety of a probiotic (health-promoting bacteria) called Lactobacillus reuteri in normal babies with colic. Furthermore, we will determine if Lactobacillus reuteri influences crying/fussing time, alters measurements of gut inflammation (in the stool and blood), and/or changes the resident fecal microbiota (using molecular techniques).

描述（由申请人提供）：疝气是一种严重的问题，其特征是每天大惊小怪，哭泣和尖叫超过3小时，影响到约15%的正常婴儿在生命的前3个月。我们最近发表了我们的试验，确定了肠绞痛婴儿的关键临床和微生物特征。与正常婴儿相比，那些有绞痛的婴儿