C-Section Impact on Newborns' Gut Microbiome PDF

C-Section: Impact on Newborns’ Gut Microbiome  E R I S E C-SECTION RATES ARE ON TH C-SECTION ALMOST DOUBLED SINCE 2000 1 1. Boerma T et al. The Lancet, 2018; Vol 392 Oct13:1341–8 ...

C-Section: Impact on Newborns’ Gut Microbiome  E R I S E C-SECTION RATES ARE ON TH C-SECTION ALMOST DOUBLED SINCE 2000 1 1. Boerma T et al. The Lancet, 2018; Vol 392 Oct13:1341–8  Prevalenc Prevalence of C-section in diff erent e countries 30% 24% 20% 15% 56 52 48 47 30 33 30 30 30 28 28 27 27 24 20 20 17 15 15 l zi yp t y n ia ly ar bi a ai t n m ai n ia AE ce an s co co a ke o an Ita at a o is an nd c re Br Eg r an Q ra uw rd gd p n U m lr a ro T u b m iA K Jo n S T u Fr O o O Le Ro Ki he M H aud d et W S te N ni U * Unconstraint potential = 30% of Core Milks category in EU / 20% global core milks Data derived from SN dashboard September 2020 MAT, value 3 3 IN 10 BABIES ARE BORN BY C - SECTION Middle East average is ~30% 4  Why are we concerned? C-SECTION Neal Creative © C-SECTION AND LONG-TERM CONSEQUENCES FOR CHILD HEALTH  C-SECTION IS ASSOCIATED WITH INCREASED RISK 7 OF INFECTIONS AND ALLERGY LATER IN LIFE Adapted from Peters et al., 2018 Relative risk of childhood asthma in cesarean section. Random-effects model2 Peters, Lilian L., et al. "The effect of medical and operative birth interventions on child health outcomes in the first 28 days and up to 5 years of age: A linked data population‐based cohort study." Birth 45.4 (201 357. Darabi et al., 2019 Allergy, Asthma & Clinical Immunology volume 15, Article number: 62 (2019).  C-SECTION BIRTH AND LONG-TERM HEALTH CONSEQUENCES 1. Black M. et al. JAMA. 2015;314(21):2271-9. 2. Metsala J et al. Am J Epidemiol. 2010;171(12):1310-6. 3. Sevelsted A, et al. Pediatrics. 2015;135(1):e92-8. 4. Mitselou N , et al. JACI. 2018;142(5):1510- 1514.e2. 5. Chu S, et al. Sci Rep. 2017; 7: 9762. 6. Papathoma E, et al. PAI. 2016;27(4):419-24. 7. Kristensen et al. Pediatr Infect Dis J. 2015;34(2):145-8. 8. Miller J. et al. PLOS Med. 2020;17(11): e1003429.  C-SECTION IMPACT ON GROWTH AND DEVELOPMENT 1. Miller et al. PLoS medicine. 2020: 17, e1003429. 2. Reyman et al. Commun Biol. 2021;4(1):1233. 3. Sevelsted et al. Pediatrics. 2015; 135:e92-8. 4. Stokholm et al. Sci Trans Med. 2020; 12:eaax9929. 5. Zhou et al. Int J Environ Res Public Health. 2020; 17:2003. 6. Chojnacki et al. Early Hum dev. 2019; 129:52-59. 7. Andersen et al. Clin Epidemiol. 2020; 12:287-293. 8. Deoni et al. AJNR Am J Neuroradiol. 2019; 40:169-177. 9. Huang et al. Brain Res Bull. 2019;144:108-121. 10. Zachariassen et al. Physiol Behav. 2021; 230:113285  What Could be the reason? “Since association is not the same as causation, scientists have looked at possible biological correlates of C-section and how they could be tied to future health problems. C-section deliveries cause health problems by disrupting the infant’s normal gut m i c r o b i o t a.”1 Can you see the difference between these two babies? Can you see the difference between these two babies? Vaginal Birth Cesarean Birth  Vaginally Born Babies – Gut Microbiome Vaginal Birth  Cesarean Born Babies – Gut Microbiome Staphylococcus 1 Corynebacterium Propionibacteriu m spp. Less beneficial bacteria.2 ie Bifidobacterium, Bacteroides Cesarean Birth C - s e c t i o n b o r n i n f a n t s m a y have a d i s t u r b e d g u t m i c ro b i o t a 1 – 3 HEALTHY (EUBIOSIS)4- DYSBIOSIS 4-6 6 Gut microbiota composition of Gut microbiota composition of C-Section born healthy, vaginally delivered Babies breastfed infants Higher levels of potentially Higher harmful levels of bacteria beneficial Reduced bacterial levels of species beneficial Bifidobacteri Bacteroides bacterial Streptococcus Corynebacterium um Enterococc Staphylococcu Propionibacterium Lactobacillus us s species spp MAMI-TRIAL: IMPACT OF C-SECTION ON INTESTINAL COLONIZATION Infants born vaginally have their guts first Infants delivered via Cesarean section are first colonized by the mother’s gut and vaginal exposed to the mother’s skin and hospital microbiota. environment.1,2 17 BIG FACTS ABOUT TINY MICROBES IN THE GUT Gut microbiome and gut microbiota The gut hosts 70-80% of the describe either the collective human body’s genomes of the immune cells, microorganisms and its microbiota that resides in the gut, supports the immune or the microorganisms function and development themselves WHY IS THE GUT MICROBIOTA IMPORTANT? A healthy gut microbiota contains a balanced composition of many classes of bacteria that have health-promoting functions SIGNIFICANCE OF GI TRACT AND MICROBIOTA DEVELOPMENT defense tolerance immune function early life gut & microbiota development metabolism digestion gut – pain and brain satiety absorption crosstalk mood FROM A PROTECTED ENVIRONMENT… Photo: Lennart Nilsson …TO A CHALLENGING EXTRA-UTERINE WORLD… …Breast feeding is important for optimal development of infants  THE MATERNAL GUT MICROBIOME PREPARES FOR DELIVERY.. There is an increase in Bifidobacterium in mother’s microbiome during pregnancy Bifidobacterium belongs to the family of Actinobacteria First trimester Third trimester n=91 pregnant women Koren O et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell, 2012; 150: 470-480 BIFIDOBACTERIA COLONIZATION IN EARLY LIFE Kumar et al, 2020 GUT MICROBIOTA: DYNAMICS AND DEVELOPMENT IN EARLY LIFE Figure based on Mitsuoka & Hayakawa. Zbl Bakt Hyg I Orig. 1973,233: 3 342.  THE FIRST 1000 DAYS: A CRUCIAL PERIOD FOR THE DEVELOPMENT OF IMMUNE SYSTEM THROUGH THE GUT Wopereis H, et al. Pediatr Allergy Immunol 2014;25:428-438 EARLY LIFE MICROBIOME DEVELOPMENT.. Maternal factors Host genetics Breastfeeding Complementary Environmental feeding exposure MODERN LIFE THREADS FOR EARLY MICROBIOME DEVELOPMENT.. Mode Maternal of Early life antibiotic administration factors deliver y Environmental Gestational exposure age THE FIRST 1000 DAYS: A CRUCIAL PERIOD FOR THE DEVELOPMENT OF OUR SYMBIOSIS Adapted from Wopereis H, et al. Pediatr Allergy Immunol 2014;25:428  INTERACTIONS AT THE MUCOSAL IMMUNE SYSTEM Creating an acidic Inhibition of Production of The healthy balanced gut microbiota acts a environment (low pH) pathogen adherence and bacterial metabolites (e.g. barrier against the infiltration and colonization Intestinal translocaion SCFA) and infiltration of pathogens, thereby protecting healthy pathogenic lumen bacteria bacteria Direct competition with the infant against infections1, 2 pathogens Production of Improvement of Examples of factors in a healthy balance gut Mucus antimicobial substances epithelial barrier function microbiota that prevent pathogen growth: layer Competition for adhesion sites and nutrients Tight Production of bacterial metabolites such as SCFA Ephitelial junction Creating an acidic environment (low pH) barrier Production of anti-microbial substances such as anti- Increased adherence to microbial peptides Lamina intestinal mucosa propria Modulation of the immunity Supporting the epithelial and mucosal barrier DC TREG  IL-10, TGF-β Th1  IFN-γ, TNF-α Imature DC Macrophag Interaction of the gut microbiota with the Th2  IL-4, IL-5 e mucosal immune system for the maintenance of Th17  IL-17 immune homeostasis 1.Knol et al. 2005; Scholtens et al. 2012) 2.Zhang M, et al. Front Immunol. 2017;8:942  A HEALTHY MICROBIOME IS LINKED TO IMMUNE RESILIENCE A healthy gut microbiota Gut microbiota dysbiosis Balanced/diverse composition Altered microbiota composition Symbionts Commensals Pathobionts Pathogens Regulation Inflammation Regulation Inflammation Immunological balance Immunological dysregulation Immune Resilience Non-specific inflammation GUT MICROBIOTA DYSBIOSIS HAS BEEN LINKED TO Gut microbiota dysbiosis in infants increases the risk of infections during childhood 1 , 2 DYSBIOSIS IN C-SECTION INCREASED RISK OF INFECTIONS DELIVERED INFANTS 9–13% Higher Higher Higher risk incidence need for Higher levels of potentially harmful* of infections of antibiotics bacterial species3 that required respiratory during the Lower levels of beneficial hospitalization4 infections in first bacterial species3 (i.e. early life2,4 year of life2 Bifidobacterium) *Clostridium & Eubacterium spp. Escherichia coli. Gut microbiota dysbiosis in infants increases the risk of infections during childhood 1 , 2 DYSBIOSIS IN C-SECTION INCREASED RISK OF DISEASES DELIVERED INFANTS Higher levels of X2 risk Higher Higher potentially harmful* of asthma risk of type 2 bacterial species3 even at 6 obesity6,7 diabetes 8 Lower levels of beneficial years.5 bacterial species3 (i.e. Bifidobacterium) *Clostridium & Eubacterium spp. Escherichia coli.  BABIES BORN BY C-SECTION HAVE A DIFFERENT BIFIDOBACTERIA ARE LOWER MICROBIOTA COMPOSITION COMPARED TO VAGINALLY IN C-SECTION BORN BABIES 1-4 BORN BABIES Bifidobacterium4 12 12 Log10 cells/g of feces 10 10 8 8 6 P-value < 4 0.0001 6 2 0 4 15 30 45 60 75 90 D1 D7 M1 M3 M6 Y3 Time (in days) Vaginal delivery Vaginal delivery (n=76) (n=80) C-section (n=13) C-section (n=28) Bifidobacteria delay The effect of C- is statistically section on gut Figure based on Dominguez-Bello et al. PNAS. 2010; 107: 11971–11975 significant in the first microbiota is 1. 2. Shaterian et al. Open Med.. 2021; 16:624-639 Nagpal et al. Sci rep. 2017; 7:10097 3 months of life 2 present at 12 3. 4. Korpela-de Vos Curr Opin Microbiol. 2018; 44:70-78 Martin, et al. PLOS one. 2016; 11:e0158498. months and 5. Roswall et al. Cell Host Microbe. 2021;29:765-776  Lower/absent a less diverse Bacteroides are found up to 1 year of age 1-3 Vaginal delivery (n=80) Normal C-section (n=28) Caesarean 1. Jakobsson et al. Gut. 2014; 63:559-66. 2. Korpela and de Vos Curr Opin Microbiol. 2018; 44:70-78. 3. Martin, et al. How to correct this dysbiosis? Immune homeostasis and HEALTHY tolerance development STATUS Gastrointestinal (EUBIOSIS) homeostasis Healthy metabolism Immune disease (allergy, asthma) DYSBIOSI Gastrointestinal disease (IBD) S Metabolic disease (obesity, diabetes)  NUTRITIONAL STRATEGIES OFFER THE Opportunity TO RESTORE THE COMPROMISED MICROBIOTA AND CONTRIBUTE TO LATER LIFE HEALTH OUTCOMES Microbiome modulation strategies Health Healt h Disease e.g. Allergy, NCD's C- Tim e Pre- Birth section Infancy Weaning Childhood natal Kumar et al. Microorganisms. 2020; 8(12):1855 Ke y M e s s a g e s 39