饮食和益生菌对婴幼儿菌群的影响.pptx

Role of Diet and Probiotics on Microbiota of Young Kids 饮食和益生菌对婴幼儿菌群的影响,Workshop on Gut Microbiome in Infants and Young Kids and Health ILSI, Beijing 10.10.2016,Liisa Lehtoranta, PhD Scientist DuPont Nutrition&Health,Growing up is a challenge 成长伴随着各种挑战,Childrens every-day life full of environmental challenges 孩子的日常生活充满了挑战 Daycare centers; schools; large group sizes 日托中心、学校、大的团体 Habit to put everything in the mouth 习惯把手伸进嘴里 Prevalent use of antibiotics (otitis media treatment, etc.) 抗生素的普遍使用（中耳炎的治疗等） Poor/choosy appetite 挑食,Louhiala, P.J., et al., Day-care centers and diarrhea: A public health perspective. The Journal of Pediatrics, 1997.,Growing up is constant change 成长是一个不断变化的过程 High demand for nutrients and vitamins 对营养成分和维生素的高需求 Dietary changes (weaning new foods introduced) 饮食习惯的改变（从断奶到辅食的介入） Immune system developing 免疫系统的建立 Gut microbiota developing 肠道菌群的建立 The age between 0-2 years is important for the development of the immune system and microbiota 0-2岁是免疫系统和肠道菌群建立的关键时期 Early life window of opportunity for balanced development of immune system 生命早期的窗口期对免疫系统平衡的建立,Infant immune system develops in tight interaction with the intestinal microbiota 婴儿的免疫系统与肠道系统紧密结合,Diet 饮食,Delivery mode 分娩方式,Immune system免疫系统,Breast feeding 母乳喂养,Antibiotics 抗生素,Gut microbiota development肠道菌群的建立,Health later in life,Birth出生,2 yrs 2岁,diet, health and microbiota are interconnected 饮食、健康和微生物相互关联,How can diet modify microbiota? 饮食如何调节微生物？,Modifying existing bacterial community 调节现有的菌群 Providing substrates (e.g. Prebiotics) 提供底物（例如：益生元） Regulating transit time and pH 管理运载时间和pH Regulating host secretions (bile, mucin, digestive enzymes) 调节宿主分泌物（胆汁、粘蛋白、消化酶） Regulating gene expression in host and microbiome 调控宿主和微生物的表达,Introducing new bacteria to the ecosystem 引入新的细菌 Fermented foods 发酵食品 Probiotic products/supplements 益生菌膳食补充剂,Salonen & de Vos Annual Rev Food Tech Sci 5:2014,Modulators of our microbiota composition 人体微生物组成的调节器,Antibiotics 抗生素 Large effects 主要作用,Diet, including prebiotics 饮食，包括益生元 Moderate effects 中度影响,Probiotics 益生菌 Small but specific effects 小而具体的影响,Microbiota and immune system FUNCTION 菌群和免疫系统功能,Lahti et al. 2013 Peer J 1e:32. Lactobacillus rhamnosus GG intervention does not alter microbiota composition,Antibiotics are major determinant of microbiota development and composition in kids 抗生素是儿童菌群的发展和组成的关键因素,Study in Finnish children aged 2-7 对芬兰2-7岁的儿童进行研究 Information on antibiotic purchases from national records: children had 1.81.5 courses/year 国家对抗生素购买情况的信息记录：儿童每年 1.81.5次 Microbiota composition/metabolism analyzed from fecal samples,compared between ctrl, and penicillin and macrolide user groups in different time intervals 对粪便样品进行菌群成分和代谢分析，与对照组和服用抗生素（青霉素和大环内酯）使用组进行比较。 Macrolide use was associated with a long-lasting shift in microbiota composition and metabolism 大环内酯的使用与微生物组成和代谢持久的转变有关。 Children who received antibiotics before weaning/shortly after had an increased abundance of Bacteroidetes, decreased abundance of Bifidobacterium at age of 2-7 years compared to those who did not receive antibiotics in early life 在生命早期，2-7岁时，与不服用抗生素的小孩相比，在断奶前或 断奶后不久服用抗生素的儿童，其拟杆菌丰度增加，双歧杆菌丰度减少。,Korpela et al. Nat Commun. 2016 Jan 26;7:10410. doi: 10.1038/ncomms1041,Use of penicillin-type antibiotics was not associated with large functional or compositional changes in microbiota. 青霉素类抗生素的使用与大量微生物功能和组成的改变无关。 Abundance of Bifidobacterium and Bacteroidetes normalized within 12 months after macrolide course. Abundance of Collinsella, Lactobacillus and Anaerostipes +total richness and maturity of microbiota, remained reduced for up to 2 years after macrolide course. 双歧杆菌和拟杆菌的丰度在大环内酯服用的12个月内恢复正常，而柯林斯菌，乳酸杆菌和丁酸弧菌的总丰度以及微生物的成熟度在服用大环内酯后的两年内仍处于减少状态。 When antibiotics are used annually/more frequently, microbiota may not have time to recover and the antibiotic-associated microbiota composition may persist. 当抗生素使用越来越频繁，微生物菌群可能没有时间恢复，而且抗生素相关的微生物可能持续存在。 Dysbiosis of microbiota has been associated with Inflammatory Bowel Disease, Autism Spectrum Disorders, Obesity, Asthma and Allergies. 菌群失调与炎症性肠道疾病，自闭症谱系障碍，肥胖，哮喘和过敏有关。,1/17/2012,7,Antibiotics are major determinant of microbiota development and composition in kids 抗生素是儿童菌群的发展和组成的关键因素,Probiotics can balance disturbed microbiota clinical evidence 益生菌可以平衡肠道菌群紊乱 临床证据,8,Influence of long-term Lactobacillus rhamnosus GG intake on Finnish preschool childrens antibiotic use, and antibiotic-associated gastrointestinal complaints in a double blind, randomized placebo-controlled trial with 231 children aged 27 长期摄入鼠李糖乳杆菌Lactobacillus rhamonosus GG对芬兰学龄前儿童使用抗生素的影响,以及抗生素相关性肠胃不适症状, 双盲，随机，安慰剂实验，受试人群为231名2-7岁儿童。 7 mo intervention during the cold season 寒冷季节里进行7个月的干预 Microbiota was analyzed from 88 children with antibiotic purchase records, and with fecal samples at baseline and end of intervention 根据抗生素购买记录，以及干预期始末的粪便样品检测，来分析88名儿童的菌群。 Using the Finnish drug purchase registry, it was possible to accurately follow the antibiotic use of children during and for nearly 3 years after intervention. 使用芬兰药品购买记录登记，可以尽可能精确地跟随干预期后三年内使用抗生素情况。 Cumulative number of antibiotic courses was consistently lower in L. GG group 抗生素累计使用次数在Lactobacillus rhamonosus GG组表现为始终偏低。,Korpela et al. 2016 PLOS ONE | DOI:10.1371/journal.pone.0154012,L. rhamnosus GG alleviates penicillin-associated changes in microbiota 鼠李糖乳杆菌Lactobacillus rhamonosus GG缓解青霉素引起的微生物变化,L.GG treatment prevented many of penicillin associated changes in the microbiota such as the increase in E. coli and Haemophilus 鼠李糖乳杆菌Lactobacillus rhamonosus GG的使用阻止了青霉素相关性菌群改变，例如：大肠杆菌和嗜血杆菌的增长。 Macrolide-associated reduction in bifidobacteria was not prevented by L. GG consumption one lactobacillus strain alone is not sufficient to prevent the microbiota changes associated with all antibiotic types; different species may be efficacious in association with different types of antibiotics. 大环内酯引起的双歧杆菌减少并不能通过鼠李糖乳杆菌Lactobacillus rhamonosus GG的摄取来改变。 单株乳杆菌并不能有效阻止所有抗生素引起的微生物菌群的改变；不同种的微生物可能会更有效地应对不同种抗生素带 来的改变。 L. GG significantly reduced the infection rate (determined by the reduction in antibiotic prescriptions) of preschool children for up to 3 years after cessation of the probiotic trial 在干预结束后，长达3年的跟踪期内，鼠李糖乳杆菌Lactobacillus rhamonosus GG有效减少了学龄前儿童（由于抗生素使用量减少而引起的）感染率。,9/10/2019,L. rhamnosus GG alleviates penicillin-associated changes in microbiota 鼠李糖乳杆菌Lactobacillus rhamonosus GG缓解青霉素引起的微生物变化,The effect of L. acidophilus NCFM + B. lactis Bi-07+FOS on recovery from antibiotic therapy 嗜酸乳杆菌NCFM、乳双歧杆菌Bi-07和低聚果糖的组合对抗生素治疗后菌群恢复的影响,Acutely ill children (n = 129) aged 16 years receiving antibiotic therapy were randomized to receive a nutritional supplement with (PS) or without (P) synbiotics or a fruit flavored drink (D) with their medications. 接受抗生素治疗的，年龄在1-6岁的重病儿童患者（N = 129），随机接受营养补充剂与（PS）或无（P）营养补充剂或果味饮料（D）与他们的药物。 PS: 3.5 g/L of FOS and 1 109 CFU/g of NCFM and Bi-07. Physician assessed children before and after antibiotic therapy 在服用抗生素前后，医生对儿童的情况做了评估,11,Schrezenmeier et al. 2004 Clinical Pediatrics,The effect of L. acidophilus NCFM+B. lactis Bi-07+FOS on recovery of microbiota from antibiotic therapy 嗜酸乳杆菌NCFM、乳双歧杆菌Bi-07和低聚果糖的组合对抗生素治疗后菌群恢复的影响,Levels of Lactobacillus were higher 14 days post antibiotic therapy (p=0.045) 抗生素治疗14天后的菌群变化，服用NCFM+Bi-07+FOS后，乳杆菌含量明显高于其他组,12,Schrezenmeier et al. 2004 Clinical Pediatrics,HN001 survives in GI tract children and contributes to healthy microbiota HN001能够存活在儿童的肠道中，并有利于建立健康的微生物菌群,It has been shown that consumption of HN001 increases lactobacilli numbers in the intestine of healthy adults (Tannock et al. 2000 Appl Env Microbiol) children 1-5 yrs of age (Caceres et al. 2011 J Ped Inf Dis) 实验表明，服用HN001可以增加乳杆菌数量在以下人群的肠道中： 健康成人 1-5岁儿童,13,Caceres et al. 2011 J Ped Inf Dis,B. lactis HN019 and L. paracasei LPC-37 for reducing diarrhea risk 乳双歧杆菌HN019和副干酪乳杆菌Lpc-37减少急性腹泻,379 children (2-5 years of age) 379名儿童（2-5岁） Double blind randomised, 12 Months, India 双盲，随机试验，为期12个月，印度 Lactobacillus paracasei Lpc-37 (n=125) 2x109 CFU/day 副干酪乳杆菌Lpc-37 (n=125) 2x109 CFU/day Bifidobacterium lactis HN019 (n=130) 2x109 CFU/day 乳双歧杆菌HN019 (n=130) 2x109 CFU/day Placebo (n=124) 安慰剂(n=124) Primary outcome: Incidence and duration of intestinal symptomes; in particular diarrhea 主要结论：发病率和肠道症状的持续时间，尤其是腹泻有所减轻。 Socondary outcome: Incidence and duration of fever and symptoms of respiratory tract infection (e.g. coughing and runny nose) 结论二：腹泻发病率以及发烧和上呼吸道感染的症状（例如：咳嗽、流鼻涕等）减轻。,L. paracasei Lpc-37 and B. lactis HN019 reduced the incidence of diarrhea and fever 乳双歧杆菌HN019和副干酪乳杆菌Lpc-37减少急性腹泻,Hemalatha et al. 2014, European Journal of Nutrition & Food Safety 4(4): 325-341,Placebo,痢疾发病率,发烧发病率,Systemic effects,Probiotics that modulate the gut immune system may have far-reaching effects in the host. 调节免疫系统的益生菌可能会进一步影响到宿主。,Cold & Flu,Atopy & Eczema,Probiotics modulate gut immune system 益生菌调节肠道免疫系统,Probiotics can promote health beyond the gut - clinical evidence 益生菌能够促进人体健康不仅仅局限于肠道健康 临床证据,Atopic dermatitis in infants & toddlers 婴幼儿特应性皮炎,18,Atopic dermatitis also called atopic eczema is a recurring, non-infectious, inflammatory skin condition. 过敏性皮炎又称特应性皮炎，是一种易复发，无传染性的皮肤炎症。 The skin becomes red, dry, itchy and scaly, and in severe cases, may weep, bleed and crust over, causing the sufferer much discomfort1. 患处皮肤变红，干痒，还有皮屑，严重的话有可能渗出组织液，流血，表皮脱落等，让患者十分不适。 Atopic dermatitis usually appears in early childhood, between two to six months of age1 过敏性皮肤炎大多发生在幼年时期，在2-6个月大时。 About 50% of the children who get AD will have it as an adult2 约50%的患病儿童在成年后依然患病。 There is no known cure for eczema and it can be a lifelong condition1 目前还没有明确的治愈办法，而且可能终生相伴。,1- .au/ 2- /skin-conditions/dermatology-a-to-z/atopic-dermatitis,PREVALENCE OF ALLERGIES AND ECZEMA IS INCREASING GLOBALLY 过敏性湿疹在全球范围内盛行,Probiotics and Allergies/Eczema 益生菌与特应性湿疹,Microbiota has a profound influence on development of the immune system during fetal and postnatal period 微生物对胎儿期和出生后期的免疫系统发展完善有深远的影响,19,Microbiota directs the development of the immune system. 微生物指导免疫系统的发展 Fetal and postnatal periods are especially crucial for protection against allergic diseases (Hawrylowicz et al. Nat Med 2010) 胎儿期和刚出生时期对敏感性疾病的防卫至关重要。 Allergic children that have differences in their microbiota compared to non-allergics (Kalliomki et. al. 2001; Watanabe et al. 2003). 过敏儿童与不过敏儿童的微生物菌群有明显差别。 Allergic children are more prone to develop allergic immune responses (Tulic et al. 2011) 敏感儿童更容易发展为过敏性免疫反应。 Overactive T helper cell 2 type (Th2) immune responses are characteristic of allergic individuals. 过度的T辅助细胞类型（Th2细胞）免疫反应是过敏的特征。,What causes atopic eczema? 是什么导致了过敏性湿疹？,20,Tendency for developing allergy is associated with developing atopic eczema 过敏的发展趋势与过敏性湿疹的发展趋势有关 Allergic children have differences in their microbiota compared to non-allergics and they are prone to develop allergic immune responses (Th2) 过敏儿童与非过敏儿童的微生物菌群不同，且他们更易发生过敏反应（Th2） Risk factors 风险因素 Infants whose parents are allergic are more at risk (Genetic susceptibility) 父母有过敏症的儿童患病风险更高（遗传易感性） Environmental triggers like pollutants, allergens, living in cities 环境因素：如污染，过敏原，城市生活 Skin barrier and immune system defects are associated with AD 皮肤屏障和免疫系统缺陷与过敏性湿疹有关 Antigenic exposure via skin 通过皮肤使抗原暴露 Tendency to promote Th2 responses 提高Th2反应的趋势 (Hamid Q 1996 J Allergy Clin Immunol) As a result, generation of IgE antibodies 因此，生产血清免疫球蛋白抗体 IgE antibodies are an accepted marker of allergic sensitization IgE抗体是过敏性致敏的一个公认的标记。,Efficacy of probiotics in children for eczema at 2, 4, and 6 years 益生菌在缓解儿童湿疹方面具有长效表现，在服用后的第2年，第4年，第6年时仍有效果,AIM OF THE STUDY 实验目的 To study whether daily intake of Lactobacillus rhamnosus HN001 or B. lactis HN019 would reduce the incidence and the severity of eczema in children. 研究日常服用鼠李糖乳杆菌HN001或乳双歧杆菌HN019对减少湿疹发病率和严重性是否有影响。 STUDY DESIGN 实验设计 Pregnant mothers treated daily from 5 weeks pre-term to 6 months post-term for breastfeeding mothers. Infants treated daily from birth to 24 months old treatments given as supplement to infant feeds (breast milk, infant formula, weaning food). Health assessment was done at 2, 4, and 6 years. 怀孕妈妈从小孩出生前五周开始服用益生菌直至小孩母乳喂养的第六周。婴儿从出生后一直服用到24个月，通过膳食补充剂的形式添加到婴儿食品中（母乳，婴儿配方奶粉，断奶辅食）。健康评估在2岁，4岁，6岁时进行。 SUBJECTS 受试者 Infants with family history of allergy Approx 150 infants/children/treatment group 受试者为有过敏史家庭的婴儿，将受试者分为三组，每组约150人 Placebo 安慰剂 B. lactis HN019 at dose of 6 billion per day (9*109 cfu/day) HN019，每日9B L. rhamnosus HN001 at dose of 6 billion per day (6*109 cfu/day) HN001，每日6B,21,Source: Wickens et al. 2008; Wickens et al. 2012; Wickens et al. 2013;,22,The following outcomes were assessed at 2, 4, and 6 years of age 以下结论在2岁，4岁，6岁时分别评估 Atopy was assessed by using Australasian Society of Clinical Immunology and Allergy guidelines. 过敏体质采用澳大利亚临床免疫和过敏准则来评估 Skin prick tests were done against egg white, peanut, cows milk, cat pelt, D.pteronyssinus and mixed grass pollen 皮肤点刺试验：使用对蛋清，花生，牛奶，猫的毛发，尘螨及混合花粉。 Wheeze and rhinoconjunctivitis was assessed by using International Study of Asthma and Allergies in Childhood criteria. 气喘及鼻炎：使用儿童哮喘及过敏国际研究标准进行评价 Questionnaire 调查问卷 Eczema prevalence was evaluated by 湿疹患病率评估 using the UK Working Partys Diagnostic Criteria (UK criteria) for atopic dermatitis modified for use in infants 使用英国诊断标准工作小组为婴幼儿修订的特异性皮炎的标准（英国标准） using SCORing Atopic Dermatitis (SCORAD) cut off =10 (to differentiate from rash) 使用SCORAD评分进行隔断=10 （与皮疹区分）,HN001 decreases probability of eczema and its severity at 2, 4 and 6 years 在2岁，4岁，6岁时，HN001受试者组湿疹发病率均明显降低,Cumulative prevalence at 6 years 六年累计发生率,8/20/2013,HN001,HN001,No influence of B. lactis HN019 而乳双歧杆菌HN019没有影响,HN001 reduces the risk of allergic sensitization in children at 6 yrs HN001减少了6岁时过敏性致敏的风险,Children in HN001 (n=142) group had a significant risk reduction for allergic sensitization (Skin Prick Test) compared with children taking placebo HN001组（142人）过敏性致敏的风险（点刺测试）比安慰剂组儿童明显下降 cumulative prevalence (HR 0.69; p=0.04) 累计患病率 point prevalence (RR 0.72, p=0.048) of. 实时患病率 The effect was significant among children that were sensitized to aeroallergens (HR=0.65; p=0.03), but not among those that were allergic to food (HR 0.70; p=0.2). 对过敏原敏感的儿童，其效果是显著的，但是对食物过敏的人群效果并不明显。 Total IgE levels showed trend of reduction in HN001 HN001组中IgE水平呈减少趋势 In a sub group of children that had not used any other L. rhamnosus strains between 2-6 yrs, the total plasma IgE levels were significantly reduced (p=0.03) 在HN001组中， 2-6岁期间，未服用HN001，总的血浆IgE水平仍显著降低。,24,p=0.07,Short term effect at 1-2 years of age on reducing the risk of eczema 1-2岁期间，各菌株在减少湿疹患病风险方面的短期影响,HN001,HN019,LGG,LGG,GOS/LGG+3 strains,LAVRI A1,L. reuteri,PandA,LGG/La-5/Bb-12,1 year of age,2 years of age,OR (95% CI),Smaller risk,Higher risk,Source Ismail et al. 2013 Journal of Pediatrics and Child Health Kim et al. 2013 Korean Journal of Pediatrics,Specific probiotics reduce the risk of eczema in a long term 特定的益生菌可长期降低湿疹患病风险,Long term follow-up only with L. rhamnosus HN001, B. lactis HN019, and L. rhamnosus GG, L.reuteri ATCC5730 长期跟踪单独服用鼠李糖乳杆菌HN001、乳双歧杆菌HN019、鼠李糖乳杆菌 LGG、罗伊氏乳杆菌ATCC5730的人群 HN019, L.reuteri ATCC5730 was ineffective (strain specificity) 乳双歧杆菌HN019与罗伊氏乳杆菌ATCC5730是无效的 Both HN001 and LGG show long-term benefits against eczema HN001和LGG均显示可以长期对抗湿疹 However, for both rhinitis and asthma, LGG showed trends for increased risk 然而，对于鼻炎和哮喘，LGG显示出患病风险增加的趋势。 HN001 showed no harmful effect on asthma/rhinitis, but showed a benefit at 4 years with a decreased risk of rhinitis (at 4y; p=0.02) HN001对鼻炎和哮喘显示无害作用，而且在第四年评估时，显示出有利于降低鼻炎患病风险。,26,Source: Wickens et al. 2012; Wickens et al. 2013; Kalliomki et al. 2003 Lancet; Kalliomki et al. 2007 J Allergy Clin Immunol,Potential probiotic mechanisms against eczema 益生菌对抗湿疹的潜在机制,Intestinal barrier Degradation of immunogenic antigens Improved IgA response Probiotic influence on intestinal and skin barrier function Th1-Th2 balance Ehanced Th1 or decreased Th2 Stimulation of regulatory T-cells, anti-inflammatory cytokines (IL-10, TGF),1,Kim 2013; zdemir 2013,微生物作用,微生物竞争调制,免疫作用,上皮细胞作用,增加调节性T细胞数量及功能,调制Th1和Th2平衡,紧密连接蛋白表达,受体粘附竞争 预防潜在病原体入侵,先天免疫调制（树突细胞成熟）,上皮细胞屏障调制,产生短链脂肪酸（丁酯、醋酸盐）促进上皮屏障和强效抗炎作用,产生细菌素 预防潜在病原体生长,Common cold or flu 普通感冒和流感,Most prevalent disease worldwide 全球最普遍流行的疾病 Adults have 1-5 episodes / year 成人每年1-5次 Children 5-10 episodes /year 儿童每年5-10 Illness duration is typically 5-10 days 病程一般5-10天 High economical costs due to missed work days and daycare 误工和缺课带来了高成本,*Source: Heikkinen and Jrvinen 2003 Lancet,Common cold is one of the most prevalent disease worldwide 普通感冒是世界上最常见的疾病之一,No effective cures available! 无有效的治疗方式！,鼻病毒 流感 冠状病毒 其它,All probiotics are not the same in efficacy for providing respiratory health benefits 在提供呼吸健康方面，并不是所有的益生菌都具有相同的功效,International Scientific Association for Probiotics and Prebiotics indicated in their consensus statement that immunological effects of probiotics are strain specific (Hill et al. 2014 Nat Rev Gastroent Hepatol). 国际益生菌和益生元科学协会在他们的共同声明中指出，益生菌的免疫作用具有菌株特异性(Hill et al. 2014 Nat Rev Gastroent Hepatol)。 Data from one strain to another cannot be extrapolated. 从一株菌的功效不能推断另一组菌的功效。 Microbiotas of children, adults and elderly have different features. 小孩、成人和老年人的微生物菌群具有不同的特点。 Requirement for specific probiotic strains? 对特定菌株的需求？,29,Absence from daycare, school, work (King et al. 2014 Br J Nutr),AIM OF THE STUDY 研究目的 To study the effect of probiotics on incidence and severity of cold and flu symptoms in children. 研究益生菌在儿童伤风感冒和流感的发病率和严重程度的作用。 SUBJECTS 受试人群 Children aged 3-5 years attending daycare in Shanghai, China. 上海市3-5岁在日托所的儿童 STUDY DESIGN 实验设计 26-week, prospective, double-blind, placebo controlled study 26-week, from November to May. Three arms 实验为期26周，从11月到次年5月，随机，双盲，安慰剂试验，将受试者分为三组： Placebo (n=104) 安慰剂 L. acidophilus NCFM (n=110) 嗜酸乳杆菌NCFM Lactobacillus acidophilus NCFM 5 x 109 CFU + Bifidobacterium lactis Bi-07 5 x 109 CFU 嗜酸乳杆菌NCFM 5 x 109 CFU +乳双歧杆菌Bi-07 5 x 109 CFU OUTCOMES 结论 Symptoms of respiratory tract infection 呼吸道感染症状 Gastrointestinal compla