Lactogenic immunity/probiotics: Effect on neonatal gut immunity

泌乳免疫/益生菌：对新生儿肠道免疫的影响

• 批准号: 8090115
• 负责人: Linda J. Saif
• 金额: $ 6.17万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090115
• 关键词: Acute; Adhesions; Adoption; Affect; Age-Months; Anaerobic Bacteria; Animal Model; Antibiotics; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Bacteria; Bacterial Luciferases; Bifidobacterium; Binding; Biological Products; Breast Feeding; CD14 gene; Cells; Child; Colostrum; Cytotoxic T-Lymphocytes; Dendritic Cells; Derivation procedure; Developing Countries; Development; Diarrhea; Disease; Dissection; Dose; Down-Regulation; Ecology; Effectiveness; Enteral; Epithelial Cells; Equilibrium; Evaluation; Exclusive Breastfeeding; Family suidae; Food; Food Hypersensitivity; Future; Gastroenteritis; Gastrointestinal Physiology; Generations; Gnotobiotic; Goals; Gram-Positive Bacteria; Health Benefit; Homeostasis; Housing; Human; Human Milk; Human poliovirus; Humoral Immunities; IL4 gene; Image; Immune; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologics; Immunomodulators; In Vitro; Incidence; Indigenous; Individual; Infant; Infant Health; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-10; Interleukin-12; Interleukin-4; Interleukin-6; Intestinal Content; Intestinal Mucosa; Intestines; Investigation; Lactobacillus; Lactobacillus acidophilus; Lactobacillus casei rhamnosus; Licensing; Life; Link; Luc Gene; Lymphocyte; Lymphoid Tissue; Maintenance; Maternal antibody; Measures; Mediating; Mediator of activation protein; Metabolic; Methods; Microbe; Milk; Modeling; Modification; Molecular; Mothers; Mucosal Immune Responses; Mucosal Immunity; Mucous body substance; Neonatal; Oral; Oral Administration; Pathogenesis; Pattern; Polioviruses; Predisposition; Probiotics; Production; Recovery; Rehydrations; Reporter; Research; Role; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Rotavirus disease; Secretory Immunoglobulin A; Seminal; Serum; Sterility; Supplementation; Syndrome; T cell response; T-Lymphocyte; Testing; Toll-like receptors; Virulent; Virus; Virus Diseases; Work; cost; cytokine; enteric pathogen; experience; feeding; gut microbiota; gut microflora; immunoregulation; imprint; improved; in vivo; innovation; insight; lactic acid bacteria; macrophage; mast cell; microorganism; monocyte; neonate; novel; novel strategies; pathogen; peripheral blood; pregnant; prevent; public health relevance; receptor; response; synergism

DESCRIPTION (provided by applicant): Breast milk contains maternal antibodies (MatAbs) that promote infant health and moderate diarrhea, and soluble immunomediators (TGF2, IL4, sCD14, etc) whose role is largely unexplored. Rotavirus (RV) is a leading cause of diarrhea in infants worldwide. Newly licensed oral RV vaccines have unproven or lower efficacies in developing countries and high costs remain obstacles to universal adoption. Although lactic acid bacteria (LAB) reduce RV diarrhea in infants, mechanisms are undefined and the effect of providing concurrent MatAb/mediators with LAB is unexplored. Our innovative studies will first assess the impact of colostrum (col)/milk and key maternal immunomediators (TGF2, IL4) on colonization by probiotics. We then determine the individual and combined effects of col/milk and LAB on immunologic maturation, moderation of RV diarrhea and homeostasis in the neonatal gut. Bifidobacteria and lactobacillus strains differ in breastfed vs formula fed infants. We hypothesize that col/milk promotes colonization by these 2 probiotic LAB, requiring fewer or lower LAB doses, and this synergism enhances gut immune maturation and homeostasis leading to moderation of rotavirus diarrhea. Preliminary studies showing that L rhamnosus GG (LGG) colonized col/milk-fed pigs long-term after a single oral dose support our novel idea. Our unique neonatal gnotobiotic (Gn) pig model is colostrum- deprived (no MatAb pre-col/milk), allowing MatAb/mediator manipulation and free of microbes (caesarean-derived, sterile housing), permitting evaluation of defined probiotics. Importantly their gastrointestinal physiology, mucosal immune responses and susceptibility to human RV diarrhea mimic that of infants. In Aim 1, we determine if col/milk containing MatAb/mediators (or TGF2+IL4) influence a) Bifidobacterium lactis and LGG colonization, persistence and distribution in the gut and b) maturation of neonatal gut immune responses. In Aim 2 we elucidate a) if col/milk with low titer RV antibody (naturally exposed sows) in concert with LAB modulates HRV pathogenesis and immunity, thereby moderating HRV diarrhea and b) if an enteropathogenic viral infection affects gut homeostasis and the LAB microflora. We will use in vivo bioluminescent imaging to study LGG interactions with/without B. lactis in the neonatal gut, and the influence of col/milk or HRV infection on these interactions. This novel approach to in vivo bacterial ecology will elucidate probiotic LAB interactions within the host. Intestinal and systemic immunologic parameters to be assessed include: 1) innate responses; 2) virus- specific, LAB-specific and total isotype B cell responses focusing on gut IgA; 3) T cell responses (Th1, Th2, Th3, Tr1 cytokines). Our innovative studies will provide improved understanding of maturation of neonatal immunity and new insights into the beneficial effects of novel col/milk MatAb/mediators in concert with probiotics in protective immunity to RV. Further, our findings will suggest new strategies to limit RV diarrhea in infants in developing countries through short-term co- administration of probiotics and col/mlk mediators to breastfed infants or pregnant mothers. This approach will promote stable LAB colonization and gut immune maturation in infants leading to disease moderation. Immunomodulation and enhancement of neonatal immune responses also have fundamental implications for tolerance to food antigens or commensals to control food allergies or inflammatory bowel syndromes as well as antibiotic-induced diarrheas.

描述(申请人提供)：母乳含有促进婴儿健康和中度腹泻的母体抗体(MatAbbs)，以及可溶性免疫调节剂(TGF2、IL4、sCD14等)，其作用在很大程度上尚不清楚。轮状病毒(RV)是全球婴儿腹泻的主要原因。新批准的口服轮状病毒疫苗在发展中国家的效果未经证实或较低，高昂的成本仍然是普遍采用的障碍。尽管乳酸菌(LAB)可减少婴幼儿轮状病毒腹泻，但机制尚不明确，同时为LAB提供Matab/介体的效果也未被探索。我们的创新研究将首先评估初乳(COL)/牛奶和关键母体免疫调节剂(TGF2、IL4)对益生菌定植的影响。然后，我们确定了COL/牛奶和LAB在免疫成熟、缓解轮状病毒腹泻和新生儿肠道内稳态方面的单独和联合作用。双歧杆菌和乳酸菌菌株在母乳喂养的婴儿和配方奶喂养的婴儿中不同。我们假设，COL/牛奶通过这两个益生菌实验室促进定植，需要更少或更低的实验室剂量，这种协同作用增强肠道免疫成熟和动态平衡，从而缓解轮状病毒腹泻。初步研究表明，L鼠李糖GG(LGG)经口单次给药后长期定植于饲喂COL/牛奶的猪体内，支持我们的新观点。我们独特的新生灵芝(Gn)猪模型是缺乏初乳的(没有Matab预冷/牛奶)，允许Matab/介体操作，并且没有微生物(剖腹产，无菌环境)，允许对定义的益生菌进行评估。重要的是，他们的胃肠生理、粘膜免疫反应和对人类轮状病毒腹泻的敏感性与婴儿相似。在目标1中，我们确定含有Matab/介体(或TGF2+IL4)的COL/牛奶是否影响a)乳双歧杆菌和LGG在肠道的定植、持续和分布，以及b)新生儿肠道免疫反应的成熟。在目标2中，我们阐明了a)含有低滴度RV抗体的COL/牛奶(自然暴露的母猪)是否与LAB一起调节HRV的致病和免疫，从而缓解HRV腹泻，以及b)肠道致病病毒感染是否影响肠道内环境平衡和实验室微生物区系。我们将使用体内生物发光成像来研究新生儿肠道中与乳酸杆菌或不与乳酸杆菌的免疫球蛋白相互作用，以及COL/牛奶或HRV感染对这些相互作用的影响。这种体内细菌生态学的新方法将阐明宿主内的益生菌实验室相互作用。肠道和全身免疫学参数包括：1)先天免疫反应；2)病毒特异性、实验室特异性和全同型B细胞反应，重点是肠道IgA；3)T细胞反应(Th1、Th2、Th3、TR1细胞因子)。我们的创新研究将提供对新生儿免疫成熟的更好理解，并对新型COL/MATAB/介体与益生菌在保护RV免疫中的有益效果提供新的见解。此外，我们的发现将提出新的策略，通过对母乳喂养的婴儿或孕妇短期联合使用益生菌和COL/MLK介体来限制发展中国家婴儿的轮状病毒腹泻。这种方法将促进婴儿稳定的实验室定植和肠道免疫成熟，从而缓解疾病。免疫调节和增强新生儿免疫反应对于控制食物过敏或炎症性肠综合征以及抗生素引起的腹泻的食物抗原或共生体的耐受性也具有基本意义。

项目成果

Lactobacilli and bifidobacteria promote immune homeostasis by modulating innate immune responses to human rotavirus in neonatal gnotobiotic pigs.

• DOI: 10.1371/journal.pone.0076962
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Vlasova AN;Chattha KS;Kandasamy S;Liu Z;Esseili M;Shao L;Rajashekara G;Saif LJ
• 通讯作者: Saif LJ

Divergent immunomodulating effects of probiotics on T cell responses to oral attenuated human rotavirus vaccine and virulent human rotavirus infection in a neonatal gnotobiotic piglet disease model.

• DOI: 10.4049/jimmunol.1300678
• 发表时间: 2013-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Chattha KS;Vlasova AN;Kandasamy S;Rajashekara G;Saif LJ
• 通讯作者: Saif LJ

Comparison of probiotic lactobacilli and bifidobacteria effects, immune responses and rotavirus vaccines and infection in different host species.

• DOI: 10.1016/j.vetimm.2016.01.003
• 发表时间: 2016-04
• 期刊: Veterinary immunology and immunopathology
• 影响因子: 1.8
• 作者: Vlasova AN;Kandasamy S;Chattha KS;Rajashekara G;Saif LJ
• 通讯作者: Saif LJ