The Intestinal Microbiota and the Developing Immune System 4 Feb 2016 The Intestinal Microbiota 10 fold more bacterial cells than human cells 100-1000 fold more bacterial genes than human genes Why does this matter? Commensals and development Dysbiosis and disease Shaping the microbiota? Stomach 10 3 /g ph 1-3 Jejunum 10 3-10 4 /g ph 6-7 Ileum 10 5 10 8 /g ph 6-8 Colon 10 10-10 12 /g ph 5-7 1
Mode of Delivery Dominguez-Bello M G, 2010 PNAS Mode of Delivery 2
Diet Breast feeding: higher abundance of commensals (bifidobacteria and lactobacilli) Formula feeding: higher abundance of pathogens (clostridia and enterobacteriaceae) Jost T 2012 PLoS ONE Human Milk Oligosaccharides Complex non-digestible carbohydrates found in abundance in human milk Zivkovic A, PNAS, 2011 3
Why? Tremendous energy expenditure Impressive diversity of structures Between women Over time in a given woman Term vs preterm Production preserved in famine Hypothesis: HMOs shape the neonatal microbiota Mechanism: Consumption of HMOs by specific bacteria Bacterial Species (n) HMO Structure 2 FL 3-FL LDFT 3 SL 6 SL E. coli (1) - - - - - Clostridium (2) - - - - - Lactobacillus (2) -(1)/+(1) -(1)/+(1) - - -(1)/++(1) Enterobacter (2) - - - - - Enterococcus (2) -(1)/+(1) -(1)/+(1) - - - Staphylococcus (2) - - - - - Streptococcus (1) + + - - - Bacteroides (3) ++ ++ -(1)/++(2) -(1)/+(1)/++(1) +(1)/++(2) Bifidobacterium (10) +(1)/++(9) ++ +(1)/++(9) -(2)/+(1)/++(7) -(1)/+(1)/++(8) Data from Yu, ZT, Glycobiology, 2013 4
Bifidobacteria species differ in capacity to deconstruct HMOs Species/subspecies Total glycoside α-sialidase α-l-fucosidase hydrolases B. adolescentis 22 0 0 B. angulatum 13 0 0 B. bifidum 17 2 2 B. breve 19 1 1 B. catenulatum 21 0 0 B. dentium 31 0 1 B. longum subsp. longum 26 0 0 B. longum subsp. infantis 24 2 5 B. minimum 2 0 0 B. pseudocatenulatum 25 0 1 B. pseudolongum 14 0 1 B. subtile 3 0 0 B. thermacidophilum 9 0 0 Data from Sela DA, Am J Clin Nutr 2014 Dysbiosis and Disease Associations: Diarrhea (antibiotic associated, traveler s, C diff) Atopy (allergic rhinitis, eczema, asthma, food allergies) Obesity, CV disease, DM Cancer, Alzheimers, IBD Colic NEC Vaccine response 5
2001 (1) 69-75 Dysbiosis and Atopic Disease Decreased diversity in the first month of life: Increased asthma at age 7 (Abrahamsson TR 2014) Increased eczema at age 2 (Ismail IH 2012) Increased allergic rhinitis at age 6 (Bisgaard H 2011) Antibiotic exposure in infancy: Increased allergic rhinitis in adolescents (Yang SI 2014) Increased childhood asthma (meta-analysis of 18 longitudinal studies, Penders J 2011) C-section Increased food allergy in 4 of 13 cohort/cross-sectional studies (Marrs T 2013) Increased allergic rhinitis (Li Y, PLoS One 2015) Increased asthma (meta-analysis Huang L J Asthma 2015) 6
Summary of Multiple Clinical Trials Altering the gut microbiota with probiotics: modest decreases in eczema in > 1 year, modest decrease in atopic disease, no effect on asthma 10,000 kcals/day Weight = 190 lbs (86 kg) 116 kcal/kg/day 60 kcal/day Weight = 1 lb (460 gm) 130 kcal/kg/day 7
Dysbiosis and NEC Circumstantial evidence Human milk Antibiotics Dysbiosis and NEC Clinical trials Human Milk and NEC Meinzen-Derr J, J Perinatol, 2009 8
% Enterobacteria 2/14/2016 Antibiotics and NEC 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% Alexander VN, J Pediatrics, 2011 2.00% 0.00% Antibiotics No Antibiotics N=42 N=564 Fallani M, JPGN, 2010 Dysbiosis and NEC Actinobacteria Bacteroidetes Firmicutes Others Proteobacteria Tennericutes Mai V, PLoS One 2011 6:e20647 9
Probiotics and NEC AlFaleh K, Cochrane Database 2014 Summary Dysbiosis is common in preemies and associated with NEC Human milk decreases the risk of NEC Human milk oligosaccharides shape the microbiota Lactoferrin, Igs, growth factors, glycolipids, glycoproteins Antibiotics increase NEC risk Probiotics decrease NEC risk 10
Obesity Germ free mice remain lean on very high calorie diet Obese mice treated with antibiotics lose weight Genetically obese mice (leptin mutants) and obese humans: Firmicutes Bacteroidetes After gastric bypass: Firmicutes Bacteroidetes Transplant experiments Obesity: mechanisms Gut microbes influence Satiety Energy harvest Inflammation Triglyceride incorporation Fatty acid oxidation Gut permeability Bile salt metabolism Secretion of PYY and GLP-1 11