BRIGHT SCIENCE. BRIGHTER LIVING.

Probiotics for the first 1000 days of lifeby Søren B. Thomsen

Speaker

▪ Founder & CEO of Biocare Copenhagen, a

Danish biotech company based on technology

from Copenhagen University Hospital.

▪ Biocare Copenhagen is a subsidiary of DSM

Nutritional Products since 2017

▪ 14 years experience from the probiotic

industry

About probiotics

Anti-inflammation

Biosurfactant production

Productionof volatile

acids

Release ofhormones

Vaccine adjuvant

Tight junction

Enzyme production

Competitive exclusion

Antimicrobialsubstances

Reduce permeability

Regulation of cytokines

Fermentationaid

Co-aggregation

Oral care

Gut-brain axis

Inflammation

Urogenital

Respiratory

Digestion

Immunity

Gut-skin-axisWHO definition: “Live microorganisms which when

administered in adequate amounts confer a health

benefit on the host”.

Bifidobacteria Lactobacillus Streptococcus. Lactococcus

Conception

Improve fertility

Prevent preeclampsia

Baby

Prevent autoimmunity

later in life

Prevent or reduce

infant colic & allergy /

eczema

The 1000 days in lifepossible impact of probiotics

Pregnancy

Prevent preeclampsia

Prevent premature birth

Prevent allergy, eczema &

respiratory tract infection

for the baby

Mother

Prevent mastitis

Toddler

Immunity

Weig

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man

ag

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Imm

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ity

How the microbiome affects fertility

Female fertility

Vaginal dysbiosis and/or yeast infection may be associated with poor reproductive outcomes.

A cohort study [1] of 130 infertile patients, showed a significant higher prevalence (P =

0.004) of bacterial vaginosis (defined by higher concentrations of G. vaginalis and/or A.

vaginae).

Introducing probiotics directly into the vaginal area may be helpful to support fertility. An

IVF (in vitro fertility) study [2] showed promising results after vaginal colonisation with

lactobacilli. Oral administered probiotics may offer same effect, with a slight delay.

Male fertility

Bacteria such as Prevotella and Pseudomonas in semen seems to be involved in male

infertility. A study [3] with metagenomic sequencing of semen, involving 96 couples who had

been unable to conceive, revealed that when friendly Lactobacillus dominates the semen

microbiome, the sperm is much more likely to be healthy and normal.

1. Haahr, T. (2016). Journal of Reproductive Immunology, 115, 47-48

2. Sirota et al. (2014). Seminars in Reproductive Medicine, 32(01), 035-042

3. Weng et al.(2014), PLoS ONE, 9(10), e110152

Preeclampsia

Probiotics have been suggested to modify placental trophoblast inflammation, systemic inflammation,

and blood pressure, all potentially interesting aspects of preeclampsia. A Norwegian Cohort Study [1]

with 33.000 women, suggest that regular consumption of probiotics could be associated with lower risk

of preeclampsia in primiparous women.

Prevention of preterm birth

Bacterial vaginosis increase the risk of preterm birth with upto 40 % (Hillier et al.). Oral or vaginal

administration of Lactobacillus has been suggested for prevention of bacterial vaginosis and possibly

reduced risk of preterm birth [2].

An open label study [3] with 45 BV women showed full recovery from BV in 29 women (64,4%) after 7

days with vaginal administered lactobacilli (L. Reuteri & L. Gasseri).

Probiotics and pregnancy

Prevention of allergy + eczema

A meta-analysis [4], including evidence from 19 intervention trials suggests

that oral supplementation with probiotics during late pregnancy and lactation

may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68–0.90; I2 = 61%)

1. Brantsaeter et al (2011), The Norwegian Mother and Child Cohort Study. American

Journal of Epidemiology, 174(7), 807-815.

2. Frontiers in Immunology, February 2015, Volume 6 , Article 62

3. Dr. Jean-Marc Bohbot, Fournier Institute Paris, 2019.

4. PLOS Medicine, February 28, 2018

Delivery of the baby matters

Vaginal birth vs caesarean

Vaginal delivered babies get colonized with bacteria from the mothers vaginal flora.

The bacteria contribute to the early bacterial colonization of the infants [1]. 69% of the vaginal delivered microbiota still

colonize in the infant after 36 weeks after birth.

A nationwide Swedish cohort study [2] with more than 1 million children, showed that children

born by C-section run a 21 % higher risk of developing food allergies than children born by

normal delivery.

1. The human microbiota in early life. Initial colonization and development. Mortensen et al. Copenhagen University 2016

2. Journal of Allergy and Clinical Immunology (2018)

Vaginal delivery

Lactobacillus

Bifidobacterium

Prevotella

C-section

Staphylococcus

Chlostridium difficile

Bacteroides

Diversity

Development of the dominant bacterial taxa by birth mode

Early colonisation matters

Initial colonization of the infant gut by microbes sets the stage for the lifelong, relatively stable adult microbiome [1].

The first gut bacteria may have a ”lasting impact” on risk reduction of chronic diseases [2].

A Norwegian Birth Cohort with 165 children showed that the gut microbiome at 2 years of age can offer useful

information about risk of obesity at age 12. The study found that early abundance with bifidobacteria was associated

with lower BMI later in life [3].

1. Turnbaugh et al. Nature. 2009; 457(7228):480–4.

2. Martınez et al. eLife 2018;7

3. Stanislawski, American Society for Microbiology, 2018 vol. 9

A healthy start in lifelong term benefits from early colonisation

“normal flora” “missing / dysbiotic flora”

Altered immune

Development

Altered Metabolism

Altered Enteric

Nervous System

development

Autoimmunity / allergy?

Obesity=

Autism?

Normal

Development

Environmental Chemicals, the Human Microbiome, and

Health Risk: A Research Strategy (2018) Chapter 2

A healthy start in lifelong term benefits from early colonisation

Reduced risk of autoimmunity

A multinational cohort study with 8676 children, showed that early probiotic supplementation (at the age of 0-

27 days) was associated with a significant decreased risk of islet autoimmunity. Probiotics could therefore

theoretically prevent type 1 diabetes, sclerosis, arthritis etc.

1. JAMA Pediatr. 2016 Jan 1;170(1):20-8.

First probiotic exposure of the Child to probiotics and risk of Islet Autoimmunity (AI)

Infant colic & latobacilli

Colic is one of the most common problems within the first three months of life & affect 10%-30% of

newborn children.

Colic’s exact cause is unknown, however immature digestive system, excessive gas production and

digestive upset is often some of the key causes associated with colic

Research shows that lower counts of intestinal lactobacillus were observed in colicky infants, in

comparison with healthy infants [1] and that presence of pathogens such as Escherichia, Klebsiella,

Serratia, Vibrio, Yersinia, and Pseudomonas may lead to development of colic [2]

Research [3] in 1999 has linked causes of colic to lactose intolerance. Transient lactase deficiency, a

temporary lactose intolerance in young infants, has been shown to be a cause of colic in 40% of

infants with the condition.

A 28 days, open label case-control study [4] with 168 breastfed infants with a history of prolonged

cry/fussing without evident background illness, showed that daily administration of baby drops with

L. Rhamnosus 19070 and L. Reuteri 12246, significantly reduce crying and fussing time compared with

control (P=0.005).

…. the word "colic" is

derived from the ancient

Greek word for intestine…

1. Savino F, Bailo E, Oggero R, et al. Bacterial counts of intestinal Lactobacillus species in infants with colic. Pediatr Allergy Immunol.2005;16 :72– 75

2. De Weerth et al., 2013. Intestinal microbiota of infants with colic. Pediatrics. 2013 Feb;131(2):e550-8

3. Improvement of symptoms in infant colic following reduction of lactose load with lactase". Journal of Human Nutrition and Dietetics 14 (5): 359–63

4. Gerasimov et al. Infant Colic:, Nutrients 2018, 10, 1975

Allergy & ezcema

The prevalence of AD is rising and affect 15-30 % of children in the western

world.

Up to 40% of children with moderate to severe AD also have some type of

food allergy. But experts don't agree on whether foods can cause AD.

Over 50% of those with atopic dermatitis also develop asthma (American

Academy of Allergy Asthma & Immunology)

Impairment of the intestinal mucosal barrier appears to be involved in the

pathogenesis of atopic dermatitis. Studies suggests that probiotic

supplementation may stabilize the intestinal barrier function and decrease

gastrointestinal symptoms in children with atopic dermatitis

2 RCT intervention studies [1,2] from Copenhagen University

Hospital, showed that L. rhamnosus 19070 and L. reuteri 12246

helped to reinforce the intestinal barrier function and suppress

the eczema

1. Rosenfeldt et al J allergy clin immunol february 2003

2. Rosenfeldt et al J Pediatr 2004;145:612-6

1117

6

1622

6

ACTIVE PLACEBO

Number of patients

Unchanged Worse Better

P = 0.001

Result of 6 weeks intervention [1]. The clinical severity of the eczema

was evaluated by using the scoring atopic dermatitis (SCORAD) score.

After active treatment, 56% of the patients experienced improvement of

the eczema, whereas only 15% believed their symptoms had improved

after placebo (P = .001)

Immunity - gastroenteritis

Rotavirus is responsible for upto 70 % of gastroenteritis in infants and

young children worldwide.

The virus infects the villous epithelium of the upper small intestine &

infectious particle are released and replicate further in the distal small

intestine.

Colonizing lactobaccili may prevent the rotavirus from invading the

enterocytes and replicate.

2 RCT intervention studies [1,2] from Copenhagen

University Hospital, showed that L. rhamnosus 19070

and L. reuteri 12246 helped to strengthen the

immune system & shorten duration of gastroenteritis

1. Rosenfeldt et al Pediatr Infect Dis J, 2002;21:411–16

2. Rosenfeldt et al Pediatr Infect Dis J, 2002;21:417–9

A 5 days randomized placebo contolled trial [2] with 43 day-care children

(25 with rotavirus antigen identified) showed that a combination of L.

rhamnosus 19070-2 and L. reuteri DSM 12246 could reduce duration of

diarrhoea.

78.8

138.9

0

60

120

180

treatment groupplacebo group

Mean duration of

diarrhoea after treatment Hours

P = 0.02

Summary

The microbiome play an important role in fertility & healthy pregnancy

Probiotics may help to prevent preeclampsia, which can lead to serious complications for the mother & baby

Probiotics may also help against vaginal infections, which is one of the main reasons for premature birth

Beneficial bacteria can be passed on from the mother to the baby when delivered through the normal birth

canal and help to prevent allergy & eczema

Babies who receive probiotics within the first 27 days of life, has significantly reduced risk of developing auto-

antibodies later in life, which could lead to autoimmune diseases and diabetes

We have a window of two years to colonize the permanent flora with beneficial bacteria

Lactobacilli administered to the baby / young infant may help to reduce infant colic, allergy / eczema &

support immunity

Disclosure

Disclosure of speaker’s interests

(Potential) conflict of

interestSee below

Potentially relevant

company relationships in

connection with event 1 None

• Sponsorship or research

funding2

• Fee or other (financial)

payment3

• Shareholder4

• Other relationship, i.e.

…5

• None

• None

• None

• None