NU

TRITION

The Probiotic EffectHow probiotics can support the immune system and gut health in infants and young children

Dr Shikha Pundir Senior Research Scientist, Paediatrics

1

Introduction

HUMAN MILK AND BREASTFEEDING

Human milk is the ideal source of nutrition for newborn infants as it provides all of their nutritional requirements and helps develop the infant immune system. The World Health Organisation and other health agencies around the world recommend exclusive breastfeeding from birth to six months of age and further advise to breastfeed until two years of age, along with the introduction of appropriate complementary foods1.

Human milk composition is highly dynamic and is a perfect combination of nutritive and non-nutritive compounds essential for the optimal growth and development of the infant (see NZMP SureStartTM White Paper “Infant Nutrition and Breastfeeding” for more information). For babies where normal breastfeeding is not an option, human milk substitutes such as infant formula milk are considered the only safe alternative by the World Health Organisation2,3.

KEY DEFINITIONS

• Microbiota: The community of microorganisms living in a particular environment e.g. the human microbiota is the collection of microorganisms living in and on the human body.

• Microbiome: The collective genome of the microorganisms within a particular environment e.g. the human gut microbiome is the genetic material of the human gut microbiota.

• Gut-Brain Axis: The bidirectional connections or links between the gut and the brain. Consists of multiple pathways, including the nervous, endocrine, and immune systems.

INFANT GROWTH AND IMMUNE SYSTEM DEVELOPMENT

The first 1000 days of human life are a critical window of growth trajectories, defined by rapid maturation of metabolic, endocrine, neural and immune pathways4. These pathways are highly interdependent on individual genetic makeup and dietary intake5.

At birth, all newborns have an immature immune system6, which then undergoes profound growth, morphological changes and functional maturation7. The immune system consists of specialised organs and tissues that protect the body against pathogens and maintain its state of constant regulation, called homeostasis. The skin is the first line of immune defence. If a pathogen enters through the skin, it stimulates innate and adaptive immunity, protecting the body from the inside7. Besides the skin, a considerable proportion of the human immune system resides in the gastrointestinal (GI) tract, illustrating the importance of gut health in infants, children and adults. In adults, the GI tract is typically nearly nine meters long, consisting of a series of hollow organs extending from the mouth to the rectum (mouth, oesophagus, stomach, small and large intestines)8, serving dual roles in human physiology. The primary function of the GI tract is to digest and absorb nutrients from the food, followed by the more complex task of maintaining immune homeostasis (protecting the body from harmful microbes and keeping the balance between good and bad bacteria) and playing a role in immune development9.

2

EARLY LIFE GUT MATURATION: A MICROBIAL VIEWPOINT

In recent years, through studies in human gut health, it has become evident that the human GI tract houses trillions of commensal bacteria, maintaining a symbiotic relationship with the host10. The human microbiota is a unique collection of microorganisms that live on and within an individual. Microbes can be found on the skin, mouth, throat, airways and urogenital system, and their distribution increases along the GI tract with the highest concentration in the colon11. Most of these microbes are a collection of bacteria, archaea, fungi and viruses, which is unique to an individual12. Microbes living in the GI tract are referred to as the gut microbiota, estimated to be made up of 1013 to 1014 microbes comprising of 500-1000 different bacterial species13,14.

It is generally believed that the infant GI tract is sterile at birth, but is rapidly colonised by microorganisms, even during the birth process15, which gives the baby’s immune system its initial boost. Exposure to several factors, including mode of birth (vaginal or caesarean birth), diet (the type of feeding, dietary supplements), the environment, and use of antibiotics and other drugs contributes to the diversity and establishment of an infant microbiome16. By 2-5 years of age, microbial diversity and composition merge and resemble that of an adult microbiota15.

IMPORTANCE OF A HEALTHY GI TRACT

A healthy GI tract is thought to promote a healthy immune system in many ways: by helping to prevent the onset of many functional digestive disorders, for example diarrhoea, by reducing the risk of infection for example colds and flu, by protecting against immune disorders such as allergy and asthma, by improving the link between the gut and the immune system, by reducing inflammation, and by maintaining healthy brain development (Figure 1)17–20.

The GI tract provides nutrition and protection for the microbial community residing in the gut. These gut microbes are commonly referred to as friendly bacteria or good bacteria. In turn, gut microbes metabolise and ferment dietary components to produce important nutrients, including short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), neurotransmitters, vitamins and other bioactives, which have the potential to influence physiological functions of the host such as inflammation and immune responses (Figure 2)21. Furthermore, microbes produce several chemical metabolites which lower the pH in the GI tract, thereby promoting the absorption of minerals that are critical to the body’s everyday functions14.

Gut microbiota

development

Immune function

Digestion and

absorption

Gut - brain axis

Mood, Anxiety, Cognition

Growth and Development

Protect Balance

Figure 1: Health benefits of healthy GI tract microbiota17-20

3

Figure 2: Regulatory function of the GI tract microbiota on metabolism.21-24

Cortisol

Hypothalamicpituitary adrenal(HPA) axis

GutBarrier

Brain

GutMicrobiota

Microbiota

Gut epithelial cell

Enteric muscle

Cytokines

Bacterial metabolites

Immune cell

Nerve cell

The Microbiota-Gut-Brain Axis

Key Components of the Microbiota-Gut-Brain Axis

A. Neutotransmitters:Chemical messengers such as serotonin transmit signals between the brain and other parts of the body. The gut microbiota have been shown to produce, as well as consume, neurotransmitters.

B. Cytokines:Small proteins secreted by immune cells. Cytokines are important signalling molecules in inflammation with potential to influence depression and anxiety. The gut microbiota can influence cytokine production.

C. Vagus nerve: Carries two-way information between the gut and the brain. Can affect emotional regulation, depression and sensitivity to stress. Some microbes in the gut have been shown to activate the vagus nerve to influence behaviour.

C. Vagus nerve

B. Cytokines

A. Neuro-transmitters

D. Bacterial metabolites

D. Bacterial metabolites:Gut microbes can make small molecules, or metabolites. Some of these can enter the bloodstream to reach the brain and regulate neurological function. For example, microbes can ferment dietary fibre in the gut to produce short chain fatty acids which can regulate mood and anxiety.

Nutrients

It is thought that the human microbiota can also influence cognitive factors, such as stress, mood and anxiety via the gut-brain axis (as described below) linking the nervous system, endocrine and immune systems (Figure 2)22. This complex bidirectional communication between the Central Nervous System (CNS) and Enteric Nervous System (ENS) links emotional and cognitive centres of the brain with the gut, influencing physiological and behavioural characteristics22. For instance, the GI tract microbes have been shown to have an indirect effect on tryptophan (an essential amino acid) metabolism and synthesis of serotonin (5-HT), so by improving gut health it can also improve the regulation of sleep, mood and growth22,23.

Furthermore, the GI microbiota is important for intestinal epithelial homeostasis (the constant renewal of cell lining) and to develop the full functionality of the intestinal mucosa25. Animal studies using germ-free mice (animals devoid of any microbiota) showed impaired intestinal epithelial cell turnover, deficiency of several immune cell types and lymphoid structures, and the appearance of either a thinner or locally absent

mucus layer in the colon11. Microbiota diversity is considered as a biomarker of the health status of the host. Evidence suggests that lower microbiota diversity or “dysbiosis” (compositional deviations from gut homeostasis) is associated with poorer health outcomes26 such as increasing the risk of asthma, allergy and gastrointestinal disorders27,28. Therefore, the early establishment and development of an effective microbial community (or healthy gut) is an important step in the maturation of a balanced immune system. (Further details regarding the immune system can be found in the NZMP SureStartTM White Paper “Stimulating the Body’s Defences”).

Taken together, the quality of diet, as well as maternal and infant related factors, all interact and can influence the composition and diversity of the gut microbiota in the young infant. However, it also suggests that these relationships are modifiable and dietary modification and manipulation of the microbiota through the supplementation of prebiotics and probiotics may be a potential strategy to influence gut health.

4

PREBIOTICS AND PROBIOTICS – FOOD FOR A HEALTHY GUT

Diet is considered as one of the key factors in shaping gut health, by supporting GI tract integrity or digestive function or by helping to maintain a healthy GI tract microbiota. Interestingly, it is becoming recognised that diet can determine the composition of the gut microbiota by promoting the growth of organisms that are best suited for metabolising regularly consumed foods29. Dietary prebiotics or probiotics are the most commonly recommended foods to support gut health (Figure 3).

Prebiotics are defined as “a substrate that is selectively utilised by host microorganisms conferring a health benefit”30; in other words, prebiotics are non-digestible components which are the primary substrates for microbial fermentation, and usually consist of complex sugars, fibres and carbohydrates. Commonly consumed prebiotics include inulin (found in fruit, vegetables and wheat), fructooligosaccharides (FOS, predominately present in fruits), and galactooligosaccharides (GOS, present in human milk). Human studies have demonstrated that prebiotics promote the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus species.

In contrast, probiotics are defined as the “live microorganisms that, when administered in adequate amounts, confer a health benefit to the host”31. Evidence suggests that the inclusion of specific probiotics shortened the duration of diarrhoea and reduced the length of hospitalisation in children with acute gastroenteritis32.

For newborn infants, human milk is the natural supplier of both prebiotics and probiotics to support the maturation of the GI tract and to optimise microbial colonisation. Human milk oligosaccharides (HMOs; carbohydrate structures known to have prebiotic functions) and milk microbiota are naturally present in human milk and help to shape the infant’s

PREBIOTICSNon-digestible

components (e.g. carbohydrates)

stimulating the growth of gut bacteria

PROBIOTICSNon-pathogenic

live microorganisms administered to

improve microbial balance

HEALTHY GUTA healthy gut promotes

healthy growth by improving immunity & providing protection

Figure 2: Proven nutrients for a healthy gut

gut microbiota. Synthetic HMOs, nature-identical ingredients, are now available to help more closely match the composition and function of human milk33. Prebiotics such as GOS and FOS can also be added to infant formulae to bring the functionality of formula milk closer to human milk34. GOS has been reported to reduce diarrhoea35 and is thought to play a role in improving intestinal motility in both pre-term and term infants33.

Bifidobacterium animalis subspecies lactis and Lacticaseibacillus rhamnosus (previously known as Lactobacillus rhamnosus) are two of the most studied probiotics, which help to modulate the gut microbiota and to protect against a range of infections, including diarrhoea, and to reduce the risk of eczema19,20,36. A large body of scientific evidence supports the ability of SureStart™ BifidoB HN019™ and SureStart™ LactoB HN001™ to confer a range of immune and gastrointestinal health outcomes, and includes the comprehensive evaluation for safety and efficacy of the strains19,36–38. SureStart™ BifidoB HN019™ and SureStart™ LactoB HN001™ are proprietary strains of probiotic bacteria developed and patented by Fonterra and further details regarding the strains and their benefits can be found in additional SureStart™ white papers.

5

ConclusionThe human GI tract harbours trillions of microorganisms, and the first 2-3 years of human life is a critical period in the establishment of healthy gut bacteria and microflora. The GI tract microbiome offers many benefits to the host, ranging from nutrient absorption, to immune health and protection from pathogenic bacteria, to promoting cognitive development. During infancy, several factors contribute to the establishment of the gut microbiota, with diet including human milk and baby milk powder considered to be key factors in shaping the gut microbiota across the lifetime. Consumption of specific health ingredients, such as prebiotics and specific probiotics with proven physiological benefits, in sufficient quantities may help to promote the colonisation and establishment of a healthy GI microbiome and infant immune system, which is important for long-term health benefits.

REFERENCES1. World Health Organisation (2017) WHO | Global strategy for infant and young child feeding. WHO 2. National Health and Medical Research Council (2012) Infant feeding guidelines: Summary. 3. World Health Organization (2004) Guiding principles for feeding infants and young children during emergencies. WHO 4. Mameli C, Mazzantini S, Zuccotti GV (2016) Nutrition in the first 1000 days: The origin of childhood obesity. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph130908385. National Research Council (US) Committee on Diet and Health (1989) Diet and Health: Implications for reducing chronic disease risk Washington, DC: The National Academies Press, 1989. https://doi.org/10.17226/12226. Stras SF, Werner L, Toothaker JM, Olaloye OO, Oldham AL, McCourt CC, Lee YN, Rechavi E, Shouval DS, Konnikova L (2019) Maturation of the human intestinal immune system occurs early in fetal development. Dev Cell 51:357-373.e57. Simon AK, Hollander GA, McMichael A (2015) Evolution of the immune system in humans from infancy to old age. Proc R Soc B Biol Sci. https://doi.org/10.1098/rspb.2014.30858. Carolyn J (2015) Physical examination and health assessment, 6th ed. Elsevier, Saint Louis9. Wu HJ, Wu E (2012) The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 3:4–1410. Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI (2005) Host-bacterial mutualism in the human intestine. Science (80- ) 307:1915–1920

11. Thursby E, Juge N (2017) Introduction to the human gut microbiota. Biochem J 474:1823–183612. Blum HE (2017) The human microbiome. Adv Med Sci 62:414–42013. Sender R, Fuchs S, Milo R (2016) Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164:337–34014. Hillman ET, Lu H, Yao T, Nakatsu CH (2017) Microbial ecology along the gastrointestinal tract. Microbes Environ 32:300–31315. Rodríguez JM, Murphy K, Stanton C, et al (2015) The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Heal Dis. https://doi.org/10.3402/mehd.v26.2605016. McBurney MI, Davis C, Fraser CM, Schneeman BO, Huttenhower C, Verbeke K, Walter J, Latulippe ME (2019) Establishing what constitutes a healthy human gut microbiome: State of the science, regulatory considerations, and future directions. J Nutr 149:1882–189517. Zhuang L, Chen H, Zhang S, Zhuang J, Li Q, Feng Z (2019) Intestinal microbiota in early life and its implications on childhood health. Genomics, Proteomics Bioinforma 17:13–2518. Houghteling PD, Walker WA (2015) Why is initial bacterial colonization of the intestine important to infants’ and children’s health? J Pediatr Gastroenterol Nutr 60:294–30719. Dekker JW, Wickens K, Black PN, Stanley T V., Mitchell EA, Fitzharris P, Tannock GW, Purdie G, Crane J (2009) Safety aspects of probiotic bacterial strains Lactobacillus rhamnosus HN001 and Bifidobacterium animalis subspecies lactis HN019 in human infants aged 0-2 years. Int Dairy J 19:149–15420. Wickens K, Black PN, Stanley T V., Mitchell E, Fitzharris P, Tannock GW, Purdie G, Crane J (2008) A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 122:788–79421. Ihekweazu FD, Versalovic J (2018) Development of the pediatric gut microbiome: impact on health and disease. Am J Med Sci 356:413–42322. Martin CR, Osadchiy V, Kalani A, Mayer EA (2018) The Brain-Gut-Microbiome Axis. CMGH 6:133–14823. O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF (2015) Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 277:32–4824. Krajmalnik-Brown R, Ilhan ZE, Kang DW, DiBaise JK (2012) Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract 27:201–214

6

Talk to the paediatric dairy ingredient experts We’re passionate about sharing our deep dairy expertise to help you grow your business. Talk to us today about your paediatric dairy ingredient needs.To find out more or to purchase our ingredients please visit www.nzmp.com/surestart

25. Schroeder BO (2019) Fight them or feed them: How the intestinal mucus layer manages the gut microbiota. Gastroenterol Rep 7:3–1226. Tanaka M, Nakayama J (2017) Development of the gut microbiota in infancy and its impact on health in later life. Allergol Int 66:515–52227. Farzi A, Fröhlich EE, Holzer P (2018) Gut microbiota and the neuroendocrine system. Neurotherapeutics 15:5–2228. Barouei J, Moussavi M, Hodgson DM (2012) Effect of maternal probiotic intervention on HPA axis, immunity and gut microbiota in a rat model of irritable bowel syndrome. PLoS One 7:e 4605129. Lobionda S, Sittipo P, Kwon HY, Lee YK (2019) The role of gut microbiota in intestinal inflammation with respect to diet and extrinsic stressors. Microorganisms. https://doi.org/10.3390/microorganisms708027130. Gibson GR, Hutkins R, Sanders ME, et al (2017) Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 14:491–50231. Food and Agricultural Organization of the United Nations & World Health Organization (2006) Probiotics in food: Health and nutrition properties and guidelines for evaluation. Rome32. Chau TTH, Chau NNM, Le NTH, et al (2018) A double-blind, randomized, placebo-controlled trial of lactobacillus acidophilus for the treatment of acute watery diarrhea in vietnamese children. Pediatr Infect Dis J 37:35–42

33. Fanaro S, Boehm G, Garssen J, Knol J, Mosca F, Stahl B, Vigi V (2007) Galacto-oligosaccharides and long-chain fructo-oligosaccharides as prebiotics in infant formulas: A review. Acta Paediatr 94:22–2634. Gopal PK, Sullivan PA, Smart JB (2001) Utilisation of galacto-oligosaccharides as selective substrates for growth by lactic acid bacteria including Bifidobacterium lactis DR10 and Lactobacillus rhamnosus DR20. Int Dairy J 11:19–2535. Drakoularakou A, Tzortzis G, Rastall RA, Gibson GR (2010) A double-blind, placebo-controlled, randomized human study assessing the capacity of a novel galacto-oligosaccharide mixture in reducing travellers’ diarrhoea. Eur J Clin Nutr 64:146–15236. Oswari H, Prayitno L, Dwipoerwantoro PG, Firmansyah A, Makrides M, Lawley B, Kuhn-Sherlock B, Cleghorn G, Tannock GW (2013) Comparison of stool microbiota compositions, stool alpha1-antitrypsin and calprotectin concentrations, and diarrhoeal morbidity of Indonesian infants fed breast milk or probiotic/prebiotic-supplemented formula. J Paediatr Child Health 49:1032–103937. Hemalatha R, Ouwehand AC, Forssten SD, Geddan JJB, Mamidi RS, Bhaskar V, Radhakrishna K V. (2014) A community-based randomized double blind controlled trial of Lactobacillus paracasei and Bifidobacterium lactis on reducing risk for diarrhea and fever in preschool children in an urban slum in India. Eur J Nutr Food Saf 325–34138. Prescott SL, Wickens K, Westcott L, et al (2008) Supplementation with Lactobacillus rhamnosus or Bifidobacterium lactis probiotics in pregnancy increases cord blood interferon-γ and breast milk transforming growth factor-β and immunoglobin A detection. Clin Exp Allergy 38:1606–1614

CONTACT US Disclaimer: The content in this document is based on scientific evidence at the time of writing and intended for informative purposes only. The FONTERRA, DAIRY FOR LIFE, NZMP and SURESTART, LACTOB HN001 and BIFIDOB HN019 trade marks all belong to the Fonterra Group of Companies.

Fonterra Co-operative Group 109 Fanshawe Street Auckland 1010, New Zealand +64 9 374 9000

© Fonterra Co-Operative Group Limited 2020.