9/9/2015 The ‘Developmental Origins’ of Disclosures the microbiome • President –DOHaDSociety (ANZ) • Chair -WUN in-FLAME network • Director-World Allergy Organisation Probiotics and prebiotics • Co-Director ORIGINS Project • Advisory Boards in disease prevention? – NNI, Danone – Speakers fees (ALK Abello, NNI, Danone) • Author: ‘Allergy Epidemic’, ‘The Calling’ and ‘Origins’ ‘Getting the early life origins message out’ All author royalties donated to research in-(cid:9)FL ME! Prof Susan Prescott The International School of Paediatrics& Child Health, UWA inINT-E(cid:9)RFNATIOLNAL IN FL AM MMATION NEETWORK!! inflammation Network New book Overview (inflammation is a central theme) • Microbial ecosystems - in the evolution and function of human health On Amazon, Kindle or • ‘Developmental origins’ of the microbiome direct from publisher - Modifying factors - Implication for health and disease • Strategies to promote microbial diversity All author royalties donated to research - The role of prebiotic’s and probiotics - Current recommendations - Future prospects WEB orders http://uwap.uwa.edu.au EMAIL to order [email protected] Our remarkable and unique world… ‘Life’ beganwith simple unicellular organisms… Stromatolites, Shark Bay, Western Australia …provides a perfect environment for life. …similar to primitive life forms today (Archaea). 1 9/9/2015 Microbes are essential to the Archeaand Bacteria (Prokarya) biodiversity that sustains all life formed the foundation of all life …and still contribute at least half Earth’s biomass. More complex life co-evolved with microbes in symbiotic mutualism. Some evidence that microbes may have Vertebrates evolved complex‘adaptive’ driven speciation throughout evolution … immune systems: promote symbiosis • Not just for ‘better defense’ • Selective promotion of beneficial microbes Has many physiological and metabolic benefits for the host Targeted responses and more efficient Every species of plant and animal use of energy Bruckeret al. Science 2013: 341 667-669 has a distinctive microbiome Bacterial ‘jumping genes’ inserted into host DNA have …and continue to drive host physiology, function and behaviour. contributed to evolution of the immune system Many vast and diverse eco-systems Many diverse ecosystems cover all our inner and outer surfaces “Humans are like a mobile warm blooded coral-reef, home to vast numbers of microbial ecosystems rich in biodiversity” Robert Rowntree, USA Highly vulnerable to subtle changes in the environment 2 9/9/2015 Variations in microbial diversity We are a composite of microbes and human cells: with different human habitats ‘We are moremicrobial than human’ Humans habour: >100 trillion bacteria • 90% of ‘our’ cells are microbial • 99% of ‘our’ genes are microbial 99% of our genetic material subject to ‘rapid’ change in response to the environment (an important therapetictarget) Shannon Diversity Index Also see variations in diversity of molecular signals Critical role in function of virtually all systems Role of declining biodiversity in the NCD pandemic? Immune development Brain development Cancer Joint Neurotransmitters and bone Barrier defence Obesity disease and metabolic Mood disease Diabetes, Metabolism Autoimmune Behaviour Cardiovascular disorders Cardiovascular health Appetite Disease Autism, Anti-inflammatory Hormones Chardaycstreergisueladtiboyn imanmd une hirgehsepro nstsreesss MScohDoidezo mdpiehsnorteridnaei ar,s, Digestion low-grade systemic Dysbiosis: can inflammation Inflammatory COPD, asthma Bowel Diseases allergic disease Detoxification adversely affect all of these body functions Effect of dysbiosison the immune system? Susan Prescott 2012 Living in a ‘new age’ Increase in early-onset NCDs: inINT-E(cid:9)RFNATIOLNAL IN FL AM MMATION NEETWORK!! of chronic inflammation Impact of modern environmental change on ‘immune health’ Autoimmune and Child mental ill health Childhood obesity allergic disease Developmental disorders associated NCDs Early environmental impact on health and development Inflammation and immune dysregulationare Effects apparent in very early childhood key factors in all of these conditions 3 9/9/2015 Immune function has a fundamental Reduced measures of diversity effect on all systems and functions linked to poor health Allergy Asthma Any factor that influences Autism our immune health can Acne have multisystem effects Disease Autoimmune diseases Associations • Diabetes (T1D) • Rheumatoid arthritis Links to virtually all • Ankylosingspondylitis Inflammatory bowel disease inflammatory diseases irritable bowel syndrome Colorectal cancer Obesity, Diabetes (T2D), Multisystem influences of the Fatty liver disease microbiomemediated by immune and metabolic effects Cause of effect –or both? Transplanting bacteria: Differences in gut Allergy: reduced diversity predates the disease bacteria of obese and can change disease risk lean people Bacteria from Bacteria from obeseperson leanperson Shannon&diversity&index& In the first monthreduced induce obesity 2.0( diversity of life associated with in mouse ( 1.5( • Increased risk of eczema1,3 ( 1.0( • allergic sensitization2 ( • blood eosinophils2 0.5 (( *(p=0.01( • allergic rhinitis2 • Increased asthma4 Nonallergic((Allergic(( infants( infants( ‘Obese’ bacteria promote inflammation and metabolic dysregulation In animals: changing the gut bacteria changes weightgain, brainand 123... ABIsibmsrgaaahial aermdt aseslt.o aPnle. edJtAi aaCtlrI., JA2Al0lCe1Ir1 g2;y 01 I12m28m;: 61u42n69o-:5l4223 04e11-42-05; ,.2 .430:6 e714--2 Stronglysuggestsearlyeffects immunedevelopment, heartdisease and diabetesrisk and longevity. 4. 8A1brahamssonet al. CEA 2014 in press. on the immune system 5. Björksténet al. JACI 2001; 108:516-20. Development is complex, beautiful, and resilient The critical importance of a ‘developmental’ perspective …with an inbuilt capacity to adapt to different conditions we might encounter 4 9/9/2015 A long road to maturity and a The effects of the early lot can happen along the way exposures can last a lifetime Early environment (diet, microbes, toxins, stress) Early challenges can steer us from our predestined course Influence developmentand functionof Subtle shifts in structure, physiology and behaviour all organ systems and risk of Risk of later disease (NCDs) both earlyand lateonset NCDs Examples of diseases that are The early environment shapes developing developmentally programmed structures, functions and behaviours Food allergy, eczema Through epigenetic changes Asthma, allergic rhinitis Obesity and metabolic disease (diabetes) in gene expression Autism, learning and behaviouraldisorders (adaptive vsmaladaptive). DEVELOPMENTAL Depression and anxiety EXPOSURES Infertility Breast cancer Nutrition cardiovascular disease Microbes osteoporosis Pollutants Prostate, lung cancer Alzheimers, Parkinsons AGE: 2 12 25 40 60 70 years The basis of ‘DOHaD’ a new health discipline Short-term adaptations may have long term (Developmental Origins of Health and Disease) consequences: disease predisposition Changes in our developmental trajectory Earlyevents also shape microbiome patterns Earlyevents can have lastingeffects on patterns of gene expression Variations associated with exposures and disease patterns Programming the epigenetic clock? Healthy Healthy Solid food Impact of the early environment C-section Obese 56-80 yrs (esp. nutrition) on epigenetic program Formula-fed malnutrition >100 yrs Breast-fed Antibiotics In-utero seeding Firmicutes Bacteroidetes Actinobacteria Proteobacteria Others Unborn Infant Toddler Adult Elderly Modification of ‘Inherited’ Modification of the developmental trajectory adult phenotype Adapted from OttmanFront. Cell. Inf. Microbio. 2012 2:104. 5 9/9/2015 Unique microbial ‘finger print’ by adulthood • Significant individual variability • Modifiable by external factors (diet, infection etc.) Establishing our • Once established: Relatively stable across time microbiome -- Early influences and Developmental patterns Importance of early influences in establishment of these patterns This relationship “The womb is not Howand wherewe arrive has a begins before birth sterile after all” major impact on our microbiota • Microbes detected in placenta and fetaltissues in normal pregnancies • Antenatal source of immunostimulation • Patterns reflect maternal health, microbiome, diet and environment Significant capacity to shape 1. RautavaS, et al.. Nat Rev GastroenterolHepatol2012; 9:565-76 2. Funkhouseret al. PLoSBiol2013; 11:e1001631. many aspects of development 3. Gosalbeset al.. ClinExpAllergy 2013; 43:198-211 Delivery mode is a key driver Breastfeeding also has a major of gut microbiotaassembly effect on developing microbiota Vaginal delivery Breast feeding: major determinant of Early infant gut colonizers normally microbial communities at 12 months resemble mother’s vaginal flora (Bifidobacteriumand Lactobacillus)vs non-breast fed (more Clostridia)1; C-section: altered composition • less Bacteroidesand Life-long legacy effect: persistent Bifidobacterium differences in adult community types2, • Increased skin /mouth bacteria1-2 and persistent immune effects3. Starting solid foods: effects not major until breast-feeding ceased 1.Bäckhedet al. Cell Host & Microbe 2015 2.Dominguez-Bello et al., 2010 1.Bäckhedet al. Cell Host & Microbe 2015 Breastfeedingrather than introduction 2.Ding and Schloss, Nature 509, 357–360. 2014 3.Ardeshiret al. Sci. Transl. Med. 6, 252ra120–ra252ra120. of solid foods is the dominant factor. 6 9/9/2015 Instability of the Microbiomestability Overuse of antibiotics: permanent changes early microbiome improves with age Evidence that beneficial commensals is do not Yatsunenko et al. Page 12 Blaseret al. Nature 2011; 476:393-394. recover completelyfrom antibiotics and replaced by resistant organisms NIH-PA Author M IOmnfsi cttrhaoebb ieliioatmyrlye ••Wiiitnnhtt reaarg--ieinn:ddiivviidduuaall svtaarbiailbitiyli ty “bSetnoepf itchiael kbiallcintegr oiaf ” Cporno—cteebrcnutistv fepo efclroumrsa ao ncnoe ‘nubtlad cc hbteaern miagleo rsre ets osis eotrauionr uces’ anuscript N • Early Gut flora unstable <3yrs, Role for early IH-PA Author M • idnetsrpa-itined inivtiedru-ainl dsitvaibdiuliatyl vinarciraebaislietys with age Yatsuneinnkoteet arl. vNaetunret 2i0o12n; 486:222-227 Immpicarcotb gioretaatbeer cino meaer leys tliafeb lbisehfeodre anuscript Fo(inafi g)te .hU a1ec. n hUDi FSpifrAofaep caru tedl ndaisctifitefoasenn ricn.e e nEtstha beac gehfeet wpscaoelie nmnt iscchrhooilbwdirase la ncn oa manvdme auradnguitelit esds i dosetfa cMnrecaaels abew ewitawintehs,e iAnn mcar ecerhaiisnliddni gaa nnasdg aean lold f a rcdehusiilldtdsernetns unrelated to that child but from the same country. Results are derived from bacterial V4-16S rRNA datasets. (b) Large interpersonal variations are observed in the phylogenetic configurations of fecal microbial communities at early ages. Malawian and Amerindian children and adults are more similar to one another than to USA children and adults. UniFrac distances were defined from bacterial V4-16S rRNA data generated from the NIH-PA Author M OgrmMyASsavehdeebioaaueceablwrl raTrtsorstew nabo.vue biiliiaodnlarnset; tta is 3hSeo io01en3f m . s F0r f:o1eo3i 8s*gr–ipf1 u d3pa r e u<eaycann.0oe trc(.samne0c rlo5t)spat f ; lPto iee*ttClhtbdd*heeo ,p a diAU2<adeo1 u0Sson l.c3Atf0trs –0 iui p10(5wcn≥t7. wi0(1s oSy8ee8nt:e–i u gay3o dhreff ksey tat eaneohrndtasle’r drs Uooss; l ttnod3-awtil)0teFdi ass,rAt nta6i mdccw2 a d 2ielst ir0hassi4m int1ga du0pnnin0lcaiefren0idecss Bl M aaalf0anotts.oe c0re3nd er8–tt he–ceo1et3h f7 C a i f ayllyae.dl eercNlr alaaeacorrltnos ussm m r(oioemnilpf cd=2 aura0,3ro lg12ia1b1se9to;ii) oo.4n3tn7s–a6s1 ):o37.f93-394. Ecleofvfneetlcastm so iofn faa nteeatditbi nwiogit tifhco sol?odws anuscript Bacteria have lived withmulti-cellular organisms for over 1 billion years Murine models: Each ‘cleaner’ generation may be starting Low doses of antibiotics in early life Nature. Author manuscript; available in PMC 2012 Delciefmeb wer i1t4h. a smaller emdowmentof ancient microbes and than the last (akin to contaminating levels) • Altered gut flora • Metabolic effects • 10-15% increase in weight gain Implicated in the rising risk of obesity, diabetes, heart disease, allergy and other immune diseases, We don’t really even know neurocognitive disorders: multisystem effects what we have lost Cho Nature 2012 488: 621-626 Many factors adversely affecting establishment What can we do to restore the balance? and maintentanceof the human microbiome Host genetics Diet Stress Vitamin D Nature C-section Hospital birth breastfeeding Antibiotics Antacids NSAIDS 7 9/9/2015 Systematic review of studies: Probiotics for preventing allergy Role of probiotics and • Over 15 studies: different protocols, prebiotics different strains and different outcomes1 -- what do we recommend? • Collectively (meta-analyses): Reduction in eczema by 21% (RR=0.79; 95%CI 0.71-0.88)2 • Less consisenteffects on other allergic outcomes, ongoing follow-up. “Probiotics may be effective in the primary 1.Pfefferle, Prescott, Kopp JACI 2013;131:1453- prevention of atopy(mainly eczema)”. 63 2.Pelucchi, Epidemiology 2012; 23:402-414 Evidence of eczema reduction Meta-analysis: allergic sensitisation Dang et al. J IntMed Res 2013: 41(5) 1426–1436 Elazabet al. Pediatrics 2013;132:e666–e676 RRR: 0.69 (95% CI: 0.62, 0.78). Effects when prenatally and postnatally RRR: 0.90 (95% CI: 0.80, 1.00). RR: 0.88 [95% CI: 0.78 to 0.99; P = .035) Greatest effects if mixed strains were used: 0.58 (95% CI: 0.44, 0.76). but not when given only postnatally AND no effect on asthma or allergic rhinitis Meta-analysis: asthma and wheeze Elazabet al. Pediatrics 2013;132:e666–e676 Progress in developing recommendations? RR: 0.96 (95% CI: 0.85, 1.07). No effects on asthma/wheeze 8 9/9/2015 Until2015: NO specificrecommendations • NIAID from keyglobal organisations1-4 • EAACI • WGO ‘GRADE’ approach* • FAO/WHO • ASCIA • Pregnancy: No specific recommendations on the use of probiotics. • Lactation: No recommendations. • Infants: No recommendations But comment (by WGO) “the strongest evidence is for the prevention of atopic dermatitis when certain probiotics are administered to pregnant mothers and newborns up to 6 monthsof age”4 *Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach 1.BoyceJA. (NIAID-sponsored expert panel). J Allergy ClinImmunol2010;126:S1–58 The first EBM recommendations to 23..BGruaaergngeerrFC. .( W(EoSPrlGd HGAaNst)r.o Je Pnetdeiraotlro gGyasOtrrgoaenntiseartoilo Nn)u.t Jr .C 2li0n1G1a;5s2tr:o2e3n8t–e5r0ol. 2012;46:468–81 use probiotics in allergy prevention 4.Morelli L. (FAO/WHO). J ClinGastroenterol. 2012;46(Suppl):S1–2 Desirable consequences Takingthe GRADE approach Grading of Recommendations, Assessment, Modest reduction in risk of eczema in children with probiotic supplementation Development and Evaluation (GRADE) approach during pregnancy only and/or during breastfeeding and/or to the infant. Clinician and Patient focused recommendations • Recommendation and strength Reduction in eczema: • Benefits and harms PROBIOTICS Number Difference Relative effect (RR) Certainty of the Balancing desirable and undesirable consequences (p(9e5r% 1C0I0)) (95%CI) evidence(GRADE) • Confidence of the estimate Pregnancy n=1520 9 fewer RR 0.72 (0.6to 0.86) VERY LOW Quality of evidence (+/-lactation and infancy per 100 ⊕⊝⊝⊝ • Preferences and values Lactation N=573 16 fewer RR 0.58 (0.47to VERY LOW • Resourses (+/-pregnancy & infancy per 100 0.72) ⊕⊝⊝⊝ • Rationale Infants N=1614 5 fewer RR 0.82 (0.7to 0.96) MODERATE (+/-pregnancy & lactation per 100 ⊕⊕⊕⊝ Establisedin 2000 and widely adopted (McMaster University) WAO / McMaster working group. GuideLinesfor Allergic Disease Prevention. WAO Journal, 2015; 8:3, 28 January 2015 For all outcomes For all outcomes Probiotics in pregnantwomen: infant outcomes Probiotics in lactatingwomen: infant outcomes Outcome With Without Difference Relative Certainty of Outcome With Without Difference Relative Certainty of (per 100) effect (RR) the evidence (per 100) effect (RR) the evidence (95%CI) (95%CI) (GRADE) (95%CI) (95%CI) (GRADE) Eczema (follow-up 1 365/1520 484/1515 9 fewer per RR 0.72 (0.6 ⊕⊝⊝⊝✔ Eczema 129/573 213/548 16 fewer RR 0.58 (0.47 ⊕⊝⊝⊝ ✔ to 5 years) (24%) (31.9%) 100 to 0.86) VERY LOW (follow-up 6 months) (22.5%) (38.9%) per 100 to 0.72) VERY LOW A(sftohllmowa/-wuph e2e tzoin 7g 1(4134/.49%92) 1(3194/.29%82) 0 few10e0r per RR t0o. 917.2 (20).77 ⊕⊕LO⊝W⊝✗ A(sftohllmowa/-wuph e1e tzoin 4g 3(112/.215%6) 2(69/.82%66) 3 m1o0re0 per RR t1o. 229.8 (60).58 V⊕ER⊝Y ⊝LO⊝W✗ years) years) Food allergy(follow- 36/279 41/284 1 more per RR 1.08 (0.73 ⊕⊝⊝⊝✗ Food allergy 8/82 5/85 4 more per RR 1.7 (0.58 ⊕⊝⊝⊝✗ up 1 to 2 years) (12.9%) (14.4%) 100 to 1.59) VERY LOW (follow-up 2 to 4 (9.8%) (5.9%) 100 to 4.96) VERY LOW years) Adverse effects 101/394 88/397 3 more per RR 1.13 (0.82 ⊕⊝⊝⊝✗ ✗ (25.6%) (22.2%) 100 to 1.52) VERY LOW (foAldlovwer-suep e 2f fyeecatsr s) (3454/.37%9) (2344/.37%0) 10 m1o0r0e per RR t1o. 219.7 (70).85 V⊕ER⊝Y ⊝LO⊝W WAO / McMaster working group. GuideLinesfor Allergic Disease Prevention. WAO Journal, 2015; 8:3, 28 January 2015 WAO / McMaster working group. GuideLinesfor Allergic Disease Prevention. WAO Journal, 2015; 8:3, 28 January 2015 9 9/9/2015 For all outcomes Undesirable consequences Probiotics in infants: infant outcomes Outcome With Without Difference Relative Certainty of The guideline panel considered the risk of adverse effects low. (per 100) effect (RR) the evidence (95%CI) (95%CI) (GRADE) Eczema (follow-up 373/1607 457/1614 5 fewer per RR 0.82 (0.7 ⊕⊕⊕⊝✔ • The burden of taking daily probiotic supplement is low. 0.5 to 6 years) (23.2%) (28.3%) 100 to 0.96) MODERATE • Any estimate of potential adverse effects was of low certainty • Certain preparations of probiotics might not be acceptable to As(tfhomlloaw/w-uhpe teoz i9n g 15(133/.171%1)7 1(7115/.111%3)6 p1e5r f e1w00e0r RR t0o. 91 .(20).68 ⊕⊕LO⊝W⊝✗ some children because of unpleasanttaste. months) Food allergy(follow- 29/323 33/321 1 fewer per RR 0.9 (0.57 ⊕⊝⊝⊝✗ up 1 to 6 years) (9%) (10.3%) 100 to 1.41) VERY LOW Adverse effects 118/408 114/421 2 more per RR 1.07 (0.71 ⊕⊝⊝⊝✗ (follow-up 4 to 24 (28.9%) (27.1%) 100 to 1.53) VERY LOW months) WAO / McMaster working group. GuideLinesfor Allergic Disease Prevention. WAO Journal, 2015; 8:3, 28 January 2015 WAO / McMaster working group. GuideLinesfor Allergic Disease Prevention. WAO Journal, 2015; 8:3, 28 January 2015 Conditional The Recommendation Considering all critical outcomes: there is a net benefit All recommendations are conditional and supported by very low resulting primarily from prevention of eczema quality evidence. • Lack of evidence that probiotics prevent any other allergy This recommendation places a relatively highvalue on • Not to be used if immunocompromised. prevention of eczemain children, and a • Does not apply to the use of probiotics for other indications, relatively lower value on avoiding possible adverse effects. e.g. prevention of antibiotic-associated diarrhea or enterocolitis in premature infants. • No differences in the effects among probiotics The WAO guideline panel suggests usingprobiotics in BUT the strain of probiotic may be important in efficacy • Policy making will require substantial debate and involvement of pregnant and lactating women, and in infants when variousstakeholders. there is high risk*of allergyin the children. More researachneeded: to define optimal strains. timing, and other interactions * High risk for allergy in a child = a biological parent or sibling with existing or history allergic disease. WAO / McMaster working group. GuideLinesfor Allergic Disease Prevention. WAO Journal, 2015; 8:3, 28 January 2015 In Practice? What? When? How? • The timing, duration, and choiceof probiotic (strain and dose) are not specified in the WAO guidelines. • Probiotics were given in the last four to six weeks of pregnancy in most of the studies reviewed, • But there was much greater variability in timing and duration of postnataltherapy in the infant and/or breastfeeding mother. • In addition, the only probiotic strain with reproducibledata is LactobacillisrhamnosisGG (LGG). How does the WAO document translate to practice guidelines for families and practitioners? How did we address this? West, Prescott| UpToDate| Last updated: Jun 23, 2015 West, Prescott| UpToDate| Last updated: Jun 23, 2015 10