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50
300
Crohn's disease (Th1)
Multiple sclerosis (Th1)
Type 1 diabetes (Th1)
Asthma (Th2)
200
100
1950 1960 1970 1980 1990 2000
Acquisition of Indigenous Flora
by the Newborn
10 10
9 9
8 8
7 7
6 6
5 5
4 4
3 3
2 2
1 2 3 4 5 6 30 1 2 3 4 5 6 30
Days after birth Days after birth
Bifidobacteria Bacteroides Enterobacteria
Enterococci Lactobacilli Staphylococci
(Anaerobic)
Bacteroides
Anaerobes Clostridia
Rapid accumulation of
anaerobic growth Coliforms
Staphylococcus
Klesiella
Salmonella
Facultative anaerobes Shigella
Lactobacillus
Streptococci
Enterococcus
Age
Day 1-3 Day 4 – 10 Day 11 - 120
Microbiota influenced by:
Genetics Microbiota influenced by: Adapted from: Rautava S. et al,
Mode of delivery Feeding type JPGN
Determinants of Intestinal Microflora
Ingested bacteria
Original
bacterial Newborn Environment
inoculum
Breast milk
(Including skin microbes)
Classification of Host Microbial Flora
Tramont EC and Hoover DL. Innate Host Defense Mechanisms. In Mandell GL et al., eds.
Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000:31-
Acquisition of Indigenous Flora by the
Newborn is Influenced by:
• Host Factors
• Environmental Factors
• Type of Feeding
• Mode of Delivery
• Gestational Age
• Host Factors
Acquisition of Indigenous Flora
by the Newborn
Duodenum
104 CFU/g
Candida albicans
500 - 1000
103-104 CFU/g
Bacteroides
Helicobacter pylori
Lactobacillus
species
Candida albicans Streptococcus
Lactobacillus
Streptococcus
Jejunum
Colon 105-107 CFU/g
Bacteroides
1010-1011 CFU/g
Candida albicans
Bacteroides
Lactobacillus
Bacillus
Streptococcus
Bifidobacterium
Clostridium
Enterococcus Ileum
Eubacterium 107-108 CFU/g
Fusobacterium Bacteroides
Peptostreptococcus Clostridium
Ruminococcus Enterobacteriaceae
Streptococcus Enterococcus
Lactobacillus
Veillonella
Surface Areas of Exposure
to the Environment
• Skin 1-2 sq m
• Respiratory mucosa 100 sq m
• Intestinal mucosa 300 sq m
– Gut epithelium 0.03 mm
– Bacterial gut content up to 1012 / ml
• Immune function
• The innate immune response
• The adaptive immune response
Atopic Sensitization and Allergy Symptoms
Among Children Living on Farms and Children in
Same Rural Community from Non-farming Families
40
*
% Children
30
Farm
Non-farm *
20
*
10 *
0
Wheeze Hay fever Positive Positive
*P<0.05; bivariate analysis. RAST to RAST to
Outdoor Indoor
Allergens Allergens
Braun-Fahrlander CH. Clin Exp Allergy 1999;29:28-34.
Influence of Cesarean Delivery on Relative
Risk of Childhood Food Allergy
8 *
Adjusted Odds Ratio
CI = 1.9-32.0
7
6
5
4
3 CI = 1.0-7.0
2
1
0
No Maternal Hx Maternal Hx Vaginal Maternal Hx
Vaginal Delivery Delivery Cesarean Section
*P<0.01; adjusted for covariates.
Food Allergy to egg confirmed by testing at age 1 – 2.
Eggesbo M et al. J Allergy Clin Immunol 2003;112:420-426.
Childhood Antibiotics
and Risk of Allergy
Epithelium
Intestinal Mucosa
Antigen Presentation Activated T cell
Th0
TNF-α IL-4
IFN-γ TGF-β IL-5
IL-2 IL-10
Over Over
Expression Expression
Tolerance
IBD Allergy
Factors Favoring Factors Favoring
the Th1 Response the Th2 Response
• Healthy intestinal flora • Limited bacterial exposure
• Presence of older siblings • Urban/Western lifestyle
• Childhood infections • Indiscriminate antibiotic use
• Rural environment • Early exposure to
• Probiotics allergenic food proteins
Bacteria Antigens
Th1 Th2
Protective Allergy
Immunity
Bifidobacteria in Stool of Infants
mean log10 CFU/g stool After 7 Days of Feeding
11
10
6
Standard Formula + Breastmilk
Formula Probiotic
70% *
Bifidobacteriain
60%
50%
40%
% Infants with
30%
20%
10%
0%
Supplemented Standard Breastmilk
formula
*P<0.05 compared to standard formula.
Adapted from Langhendries JP., et al. JPGN 1995;21:177-186.
Immune Benefits
• Cellular
• Humoral
B. lactis and Innate Cellular Immune
Response in Adults
90 * *
% Tumor cell killing
80
70
60
50
Baseline 3 wks intake 3 wks after intake
120.0
typhi IgA Antibody Titre
Control *
100.0 Probiotics
80.0
*
60.0
40.0
20.0
0.0
Pre-vaccine day 14 day 24
40
30
20
31
10
*
7
0
Not supplemented Supplemented
*P=0.035
50
40
30
20 39 *
10
10
0
*P=0.025 Not supplemented Supplemented
70
60
95%
50 CI = 0.3 – 0.5
40 95%
CI = 0.6 – 0.8
30
20
8 RCTs 15 RCTs
10
0
Szajewska, 2001 Allen, 2003
25
20
% Prevalence
15
10
0
1946 1958 1970 1994
*Secular trends in the UK
Eichenfield L., et al. Pediatrics 2003; 111: 608-616.
Immunologic Management of Antigens
Tolerance
Genetics
+ Antigens
Environment
Sensitization Allergy
Antigenic Exposure
5
incidence of allergic symptoms
Odds Ratio of factors on
4 **
95%
CI = 1.0-14.2
*
3
95%
95% CI = 0.9-7.7
CI = 0.8-4.2
2
95%
CI = 0.3-0.9
1
0
Breast Feeding Parental Intact Protein Intact Protein
Asthma Formula Formula
(1st week) (any time)
*P<0.05; **P<0.0005
Marini A., et. al. Acta Paediatr Suppl 1996; 414:1-22.
Prevalence of Bifidobacteria in Stools of
Atopic and Healthy Infants
70% ***
Atopic **
60% Non-atopic
50% *
% of infants
40%
30%
20%
10%
0%
1 week 3 months 1 year
*P=0.02; **P=0.03; ***P=0.05 comparing prevalence at a given age