PROBIOTICS IN THE FIRST 1000 DAYS

Transcription

1 PROBIOTICS IN THE FIRST 1000 DAYS 25 TH APRIL 2018 Rocio Martin Director Danone Nutricia Research Singapore 1

2 OUTLINE Probiotics Relevance of the first 1000 days Microbiota and health during the 1000 days Benefits of probiotics during this period Maternal supplementation- direct and indirect benefit Infant supplementation Summary 2

3 PROBIOTICS IN THE FIRST THOUSAND DAYS MATERNAL AND INFANT MICROBIOTA MATERNAL AND INFANT MICROBIOTA Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host Live microorganisms in adequate amounts Live cultures, traditionally associated with fermented foods Undefined, faecal microbiota transplants outside the probiotic framework New commensals and consortia comprising defined strains from human samples, with adequate evidence of safety and efficacy Health Benefit Healthy gut microbiota Supports a health digestive system Others. Ie., helps reducing the risk of ADD, helps reinforce natural defences in children... Well designed RCTs, meta-analysis, observational studies Hill, C. et al. Nat. Rev. Gastroenterol. Hepatol. 11, (2014); published online 10 June 2014; doi: /nrgastro

4 FIRST THOUSAND DAYS: KEY WINDOW OF OPPORTUNITY TO IMPACT LONG-LIFE HEALTH 4

5 The change in the global burden of disease and share of non-communicable diseases by world regions ( ) Source: (left panel) IHME Global health data exchange database (2014); (right panel) WHO Global health estimates (2014). Note: DALY refers to Disability Adjusted Life Years, defined by WHO as the sum of Years of potential life lost due to premature mortality and the years of productive life lost due to disability.

6 FIRST THOUSAND DAYS: KEY WINDOW OF DEVELOPMENT RELEVANCE OF EARLY COLONIZATION AND BREASTFEEDING FOR LONG LIFE HEALTH Symbiosis Immune maturation, Tolerance development, Gut and Metabolic health, Brain Development Healthy Adults Microbiome Balanced Microbiota Initial Colonisation Dysbiosis Disease Sensitisation, Allergy, Asthma, Food allergy, -9 months Birth Weaning Adults Eczema, Allergic Rhinitis, NCD s, Diabetes, Obesity, Infections, Discomfort IBD 6

7 ESTABLISHING SYMBIOSIS IN THE FIRST THOUSAND DAYS Subramanian S et al. Cell 2015; 161: Wopereis H, et al. Pediatr Allergy Immunol 2014;25:

8 EARLY MICROBIOME ALTERATIONS & DISEASE RISK Koleva et al., 2015 (7)

9 ROLE OF PROBIOTICS IN THE FIRST THOUSAND DAYS Genetics, stress, diet, environment, hospitalization, antibiotics Maternal microbiota Antibiotics Gestational age Breastfeeding/ Mixed feeding Complementary feeding Environmental exposure 9

10 ASSOCIATIONS BETWEEN FACTORS AND HEALTH OUTCOMES 10

11 FROM A PROTECTED ENVIRONMENT TO A CHALLENGING EXTRA-UTERINE WORLD Breast feeding is important for optimal development of infants Breastfeeding/ Mixed feeding 11

12 HUMAN MILK CONTAINS MULTIPLE BIOACTIVE COMPOUNDS THAT IMPACT IMMUNE & MICROBIOTA DEVELOPMENT Milk Constituent Cells Proteins Bacteria Oligosaccharides Bioactive Component Lymphocytes, Macrophages, Granulycytes Antibodies, Growth Factors, Cytokines Bifidobacterium, Lactobacilli, (HMOs) ~1000 different Effect on microbiota composition- Bifidobacterium dominated microbiota in breastfed infants Fatty Acids Saturated (45%), MUFA (40%), Protein, carbohydrates, others, macromolecules Minerals, Vitamins PUFA (15%): 0.35% DHA 0.60% ARA Allergens, Lactose, Nucleotides Mg, Zn, Fe, Se, Vit A, C, E 12

13 BENEFIT OF PROBIOTICS IN THE FIRST THOUSAND DAYS Prenatal Birth Infancy Toddlerhood Urinary Tract Infections Gestational Diabetes Mastitis Allergy NEC Allergy Prevention Late-onset sepsis Allergy Treatment Digestive health/colics Infections/ AAD Obesity/Metabolic disorders MATERNAL AND INFANT MICROBIOTA 13

14 PROBIOTIC SUPPLEMENTATION DURING PREGNANCY URINARY TRACT INFECTIONS AND PRETERM DELIVERY Othman M, Alfirevic Z, Neilson JP. Probiotics for preventing preterm labour. CochraneDatabase Syst. Rev. 2007)- 81% reduction on the risk of genital infection with probiotics (RR 0.19; 95% CI 0.08-p.48) GROUP B STREPTOCOCCUS Maternal asyntomatic GBS can cause endometritis, chorioamnionitis, and bacteraemia in pregnant women, and may cause stillbirth and is the leading cause of early onset Group B Streptococcal septicaemia and meningitis in infants Up to 50 % of babies born to colonised women acquire the infection and 1 2 % of colonised infants become seriously ill Literature supports the use of probiotics in the prevention of Group B Stretptococcus Hanson L, et al. J Obstet Gynecol Neonatal Nurs. 2014;43: Ho et al., Taiwanese Journal of Obstetrics & Gynecology. 2016: Studies ongoing L. rhamnosus GR-1 and L. reuteri RC-14 14

15 PROBIOTIC SUPPLEMENTATION DURING PREGNANCY GESTATIONAL DIABETES MELLITUS Probiotic supplementation (mixtures) resulted in a significant reduction in insulin resistance in pregnant women diagnosed with GDM. L. rhamnosus HN001 supplementation from 14 to 16 weeks gestation may reduce GDM prevalence, particularly among older women and those with previous GDM Nutrients 2017, 9, 461; doi: /nu Wickens, K.L., et al.british Journal of Nutrition (2017), 117,

16 PROBIOTIC SUPPLEMENTATION DURING PREGNANCY MASTITIS, ONE OF THE MAIN REASONS TO STOP BREASTFEEDING PROBIOTICS MAY HELP TREATING AND PREVENTING MASTITIS 2016;62(5):

17 RECOMMENDATION OF PROBIOTICS FOR ALLERGY PREVENTION Pre and postnatal interventions! World Allergy Organ J Jan 27;8(1):4. 17

18 PROBIOTIC SUPPLEMTATION COULD REDUCE ECZEMA RISK BY 20% Probiotic supplementation and reduced eczema at age 4 years Probiotic supplementation and reduced atopic eczema at age 4 years Garcia-Larsen V et al, PLOS Medicine, 2018;15(2):e ) 18

19 BENEFIT OF PROBIOTICS IN THE FIRST THOUSAND DAYS Prenatal Birth Infancy Toddlerhood Urinary Tract Infections Gestational Diabetes Mastitis Allergy NEC Allergy Prevention Late-onset sepsis Allergy Treatment Digestive health/colics Infections/ AAD Obesity/Metabolic disorders MATERNAL AND INFANT MICROBIOTA 19

20 PROBIOTICS MAY PREVENT LATE-ONSET SEPSIS AND NEC META-ANALYSES Associations between the use of probiotics and LOS in the overall population of preterm infants Cumulative pooled meta-analysis of the effects of probiotics on NEC Including observational studies HM-fed preterm infants Probiotic mixtures vs single strain R.M. Patel, M.A. Underwood / Seminars in Pediatric Surgery 27 (2018) Aceti A, et al., Nutrients 9 (2017)

21 CHALLENGES TO IDENTIFY THE STRAINS WITH THE GREATEST EFFICACY Most strains or combinations of strains are only studied in one or a few RCTs Dose tested from cfu/ daily No clear overlap of strains which were effective on multiple outcome domains (mortality rate,los, NEC ) Single strains Combination Mixtures B. lactis L. reuteri L. rhamnosus, LGG B. breve (M-16V; BBG- 001, YIT4010) S. boulardii B. longum L. sporogenes B. clausii B. bifidum L. acidophilus, B. infantis LGG, B. infantis L. casei, B. breve B. lactis, B. longum L. acidophilus, B. bifidum B. longum, LGG B. infantis, S. thermophilus, B. bifidum B. infantis, B. bifidum, B. longum, L.acidophilus B. breve, B. bifidum, B. infantis, B. longum, LGG L. acidophilus, L. rhamnosus, B. longum, S. boulardii L. acidophilus, L. rhamnosus, L.casei, L. plantarum, B. infantis, S. thermophilus B. infantis, B. lactis, S. thermophilus L. acidophilus, E. faecium, B. infantis L. acidophilus, B. longum, B. bifidum, B. lactis L. acidophilus, L delbrueckii subspp bulgaricus, L.casei, L. plantarum, B. infantis, S. thermophilus, B. breve, B. longum B. longum R00175, L. helveticus R0052, L. rhamnosus R0011, and Sa. Boulardii CNCM I-1079 Probiotics for Preterm Infants: a strain specific systematic review and network meta-analysis van den Akker et al., 2018, JPGN ahead of print 21

22 PROBIOTICS FOR PREVENTION OF ANTIBIOTIC-ASSOCIATED DIARRHEA Ranking for efficacy and tolerability of probiotic therapies in network meta-analysis The incidence of diarrhea versus total occurrence of adverse events Clostridium difficile infection rate versus total occurrence of adverse events Cai et al., United European Gastroenterology Journal 2018, Vol. 6(2)

23 PROBIOTICS FOR PREVENTION OF ANTIBIOTIC-ASSOCIATED DIARRHEA Strain combination reported no superiority over single strain alone in either efficacy or tolerability for patients with AAD Cai et al., United European Gastroenterology Journal 2018, Vol. 6(2)

24 EVIDENCE IN CHILDREN IS LIMITED 24

25 PROBIOTICS FOR PREVENTION OF INFECTIONS 4,500 newborns from 149 villages in the Indian province of Odisha and followed them for their first 60 days Reduced incidence of sepsis in infants in India by 40 percent Reduced lower-respiratory tract infections Daily cost of only $1 per infant. 25

26 PROBIOTICS FOR INFANTILE COLIC L. reuteri DSM17938 is effective and can be recommended for breastfed infants with colic. Its role in formula-fed infants with colic needs further research 25 minutes per day more reduction in crying and/or fussing duration from baseline than the placebo Nutrients 2018, 10, 195; doi: /nu Sung V, D Amico F, Cabana MD, et al. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics. 2018;141(1):e

27 PROBIOTICS IN PREVENTION AND TREATMENT OF CHILDHOOD OBESITY Koleva et al., 2015 (7) Probiotics have physiologic functions that contribute to the health of gut microbiota, can affect food intake and appetite, body weight and composition and metabolic functions through gastrointestinal pathways and modulation of the gut bacterial community Lack of large studies to assess the role of probiotics in childhood obesity Hints from studies on the role of maternal supplementation (Luoto et al., 2010, Vähämiko et al., 2018). 27

28 BENEFIT OF PROBIOTICS IN THE FIRST THOUSAND DAYS Challenged microbiome as specific target Prenatal Birth Infancy Toddlerhood Urinary Tract Infections Gestational Diabetes Mastitis Allergy Antibiotic treatment Use in infancy & childhood: Up to courses 11 Up to 40% of newborns exposed to perinatal antibiotics 12 Use in pregnancy: Antibiotics routinely given to pregnant women in 1/3 to ½ of cases 11 NEC Allergy Prevention Late-onset sepsis Allergy Treatment Digestive health/colics Infections/ AAD Obesity/Metabolic disorders MATERNAL AND INFANT MICROBIOTA C-section Global Prevalence: EU: 15%-35% 10 Asia Urban: Up to 45% 10 South America: up to 45% 10 28

29 DIFFERENT MICROBIOTA COMPOSITION IN C-SECTION BORN INFANTS MAY EXPLAIN HIGHER RISK OF ALLERGY A Figure based on Roduit et al. (2009) Thorax 64: Figure based on Dominguez- Bello et al. (2010) PNAS 107: Martin et al, (2016) PlosOne 11(6)

30 SYNBIOTIC RESTORE THE DELAYED COLONIZATION BY BIFIDOBACTERIUM IN CS BORN INFANTS FROM THE FIRST DAYS OF LIFE Restores the numbers of bifidobacteria Restores the delayed colonisation in C-section born infants Potential protective effect* on skin rash especially eczema in early life *p< *p=0.031 N=153 randomised C-section Chua MC et al. Effect of synbiotic on the gut microbiota of Caesarean delivered infants: a randomized, double-blind, multicenter study. JPGN 2017;65: ) Vaginal delivery Less Incidence of reported skin related disorders & eczema during the study

31 SUMMARY Probiotics during the first 1000 days may influence long-life health Potential benefits are prevention of NEC, allergies and infections (AAD), colics and microbiome modulation There is a need to harmonize probiotic use/research in the 1000 days Different strains and combination used (sometimes in combination with prebiotics) difficulty to draw strong conclusions on efficacy Different populations Define optimal probiotic dosages, time of initiation, and duration of intervention Aligned definitions of health parameters (eczema, GDM ) There seem not to be safety concerns on the use of probiotics during this period Special attention needed for specific populations (ie., premature infants) High quality control of commercial products is key Strain identification and safety evaluation remains a critical point 31

32 ACKNOWLEDGMENTS Prof. Jan Knol Dr Kaouther Ben Amor and many paediatricians, Parents and infants 32