Pre and Probiotics and Prevention of Allergic Disease

16 Pages·2015·7.51 MB·English

by  Susan Prescott

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).
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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
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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
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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
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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.
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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.
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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
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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
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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
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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
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