Probiotics:Potential Therapeutic Roles in Diarrhea

益生菌：腹泻的潜在治疗作用

• 批准号: 8101090
• 负责人: Pradeep K Dudeja
• 金额: $ 25.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101090
• 关键词: APPBP2 gene; Acute; Address; Anions; Apical; Bacteria; Bicarbonates; Caco-2 Cells; Cell Line; Cells; Chloride Ion; Chlorides; Clinical Trials; Colon; Coupling; Data; Diarrhea; Disease; Dose; Electrolytes; Epithelial Cells; Escherichia coli; Escherichia coli Infections; Event; Experimental Models; Functional disorder; Gastrointestinal Diseases; Goals; Health; Health Benefit; Homeostasis; Human; Impairment; In Vitro; Infection; Inflammatory; Inflammatory Bowel Diseases; Intestines; Investigation; Ions; Kinetics; Lactobacillus; Lactobacillus acidophilus; Lactobacillus casei; Liquid substance; Maintenance; Mediating; Modeling; Molecular; Mus; Oral Administration; Physiological; Pouchitis; Prevention strategy; Probiotics; Process; Protein Isoforms; Regulation; Role; SLC26A3 gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Sodium Chloride; Sodium Dextran Sulfate; Therapeutic; Time; Water; Water Movements; absorption; design; enteric pathogen; enteropathogenic Escherichia coli; gastrointestinal; ileum; immunoregulation; in vivo; in vivo Model; insight; microorganism; monolayer; mouse model; novel; pathogen; response; trafficking

DESCRIPTION (provided by applicant): Probiotic microorganisms confer beneficial effects on human health. These include promotion of gut barrier function, inhibition of pathogen infection, maintenance of intestinal homeostasis, and immune modulation. Probiotics have been used to treat a variety of gastrointestinal ailments including IBD, IBS, pouchitis, and several types of diarrhea. Diarrhea may result from increased chloride secretion, impairment of NaCl absorption, or both. Recent studies showed inhibition of pathogen-induced chloride secretion by Lactobacillus species. To date, however, the effects of probiotics on intestinal NaCl absorptive processes have not been investigated. Electroneutral NaCl absorption in the human ileum and colon involves coupling of luminal Na+/H+ exchange and Cl-/OH-(HCO3-) exchange activities. We hypothesized that, in addition to inhibition of increased chloride secretion by probiotics in diarrheal disorders, the beneficial effects of probiotics may also arise from stimulation of NaCl absorption as well. Our preliminary studies utilizing Caco-2 cell monolayers as an experimental model for human intestine, demonstrated significant enhancement of Cl-/OH-(HCO3-) and Na+/H+ exchange activities in response to acute treatment with Lactobacilli, and also their culture supernatant, suggesting that bacteria-secreted soluble factors are involved in mediating these proabsorptive effects. Our preliminary studies further indicated involvement of Lactobacillus-induced signaling pathways and trafficking events warranting a detailed investigation of the mechanisms involved. The current proposal is focused at elucidating the cellular and molecular mechanisms underlying the modulation of luminal Cl- absorption in response to treatments with Lactobacilli in in vitro and in vivo models. Three specific aims have been designed: 1. Examine the acute effects of Lactobacillus species and their secreted soluble factors on chloride transport in Caco-2 and T-84 (model human colonic) cells under normal conditions and in response to infection with enteropathogenic E. coli (EPEC); 2. Dissect out the role of DRA and PAT1 in activation of Cl-/OH-(HCO3-) exchange activity by Lactobacilli and elucidate signaling and molecular trafficking mechanisms involved in stimulation of Cl- absorption; and 3. Examine the effects of oral administration of Lactobacilli on NaCl absorption in normal mouse intestine and under diarrheal conditions, induced by dextran sodium sulfate (DSS) or EPEC infection. Our proposed studies are critical for providing novel insights into the role of probiotics in regulating intestinal electrolyte absorption under normal and pathophysiological conditions and may provide better strategies for the prevention and treatment of diarrheal and inflammatory disorders. PUBLIC HEALTH RELEVANCE: Probiotica are bacteria that confer beneficial effects on human health. In recent years, probiotics have been used to treat a variety of gastrointestinal diseases including inflammatory bowel diseases and several types of diarrhea. However, the detailed mechanisms underlying the beneficial effects of probiotics are not known. The proposed studies are critical to provide novel insights into role of probiotics in regulating intestinal salt and water absorption under normal and disease conditions and may provide better strategies for the prevention and treatment of diarrheal and inflammatory diseases.

描述（由申请人提供）：益生菌微生物对人类健康赋予有益影响。这些包括促进肠道屏障功能，抑制病原体感染，维持肠内稳态和免疫调节。益生菌已被用来治疗各种胃肠道疾病，包括IBD，IBS，小袋炎和几种类型的腹泻。腹泻可能是由于氯化物分泌增加，NaCl吸收障碍或两者都会导致的。最近的研究表明，乳酸菌抑制病原体诱导的氯化物分泌。但是，迄今为止，尚未研究益生菌对肠NaCl吸收过程的影响。人回肠和结肠中的电荷NaCl吸收涉及腔内Na+/H+交换以及Cl-/OH-（HCO3-）交换活性的偶联。我们假设，除了抑制益生菌在腹泻疾病中的氯化物分泌增加外，益生菌的有益作用也可能是由于刺激NaCl吸收的刺激。我们的初步研究利用CACO-2细胞单层作为人类肠道的实验模型，表明Cl-/OH-（HCO3-）和Na+/H+交换活性显着增强，以响应乳酸杆菌的急性治疗，以及它们的培养物，以及它们的培养物上午，表明细菌与替代性溶液因子施加了这些效果。我们的初步研究进一步表明，乳酸杆菌诱导的信号通路和贩运事件涉及详细研究涉及的机制。当前的建议集中于阐明对腔吸收调节的细胞和分子机制，以响应在体外和体内模型中用乳杆菌治疗的响应。已经设计了三个特定的目的：1。检查乳酸杆菌物种及其分泌的可溶性因子对氯化物-2和T-84（模型人类结肠）细胞在正常条件下的氯化物转运的急性作用，并响应于感染性衰老大肠杆菌（EPEC）； 2。剖析DRA和PAT1在乳酸杆菌激活Cl-/OH-（HCO3-）交换活性中的作用，并阐明涉及刺激Cl-吸收的信号传导和分子运输机制；和3。检查口服乳酸杆菌对正常小鼠肠和腹泻条件下NaCl吸收的影响，硫酸葡萄糖钠（DSS）或EPEC感染诱导。我们提出的研究对于提供益生菌在正常和病理生理状况下调节肠道电解质吸收的作用的新颖见解至关重要，并且可以为预防和治疗腹泻和炎症性疾病提供更好的策略。公共卫生相关性：益生菌是对人类健康产生有益影响的细菌。近年来，益生菌已被用来治疗多种胃肠道疾病，包括炎症性肠病和几种类型的腹泻。但是，尚不清楚益生菌的有益作用的详细机制。拟议的研究对于在正常和疾病条件下提供益生菌在调节肠道盐和吸水方面的作用的新见解至关重要，并且可以为预防和治疗腹泻和炎症性疾病提供更好的策略。