NHD CPD eArticle Vol 8.17

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Volume 8.17 - 22nd November 2018

THE GUT MICROBIOTA AND IMMUNITY: IS THERE A ROLE FOR PROBIOTICS? Victoria Avery, ANutr Science Officer, Yakult UK Ltd

This article will explore the role of the gut microbiota in relation to the regulation of the human immune system.

Victoria has a MSc in Nutrition from the University of Surrey and is currently a Registered Associate Nutritionist.

Microbiota is the term given to the collection of microorganisms living on or in our body (or in a specific organ) and includes bacteria, archaea, yeast, and viruses. Across different body sites there are large differences in microbial communities, including both the number and types of microorganisms.1 The most abundant and diverse community of microorganisms reside in the gut (particularly the large intestine)2 and are collectively known as the gut microbiota.

Humans and their gut microbiota have a symbiotic relationship, whereby the human host provides the microbes with a habitat and nutrients, and the gut microbiota perform a number of functions, including; breakdown of nondigestible food, synthesis of vitamins and protection against pathogens.3 One important role is the gut microbiota’s involvement in the regulation of the human immune system.

Dr Louise Durrant (née Wilson) RD, Assistant Science Manager, Yakult UK Ltd Louise is a Registered Dietitian with over eight years’ experience of scientific research and writing publications in the field of nutrition and health.

THE HUMAN IMMUNE SYSTEM

There are a number of vulnerable sites in the human body, in particular the gastrointestinal tract, where we come into contact with foreign pathogens and

food antigens. The mucosa-associated lymphoid tissue (MALT) is located at the common sites on antigen entry. It is involved in detecting foreign antigens and inducing an appropriate immune response to protect against harmful antigens and tolerate harmless ones.4 The MALT can be sub-categorised by body location and includes nasopharynx- (NALT), bronchi- (BALT) and gut- (GALT) associated lymphoid tissue. The GALT constitutes the largest mass of lymphoid tissue in the human body and represents over half of the entire immune system.5 THE GUT-ASSOCIATED LYMPHOID TISSUE

The GALT contains specialised lymphoid structures called Peyer’s patches, which are involved in antigen sampling and the subsequent activation of the immune response to protect the host from harmful pathogens, or inhibit this cascade to induce mucosal tolerance to harmless antigens.6 It is well documented that the gut microbiota is important for educating the immune system and perturbations, particularly

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Table 1: Glossary Prebiotic:

A substrate that is selectively utilised by host micro-organisms conferring a health benefit.19

Probiotic:

Live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host.20

during early life, could potentially have persistent effects on our immunity.7 Much of the current understanding of this interaction comes from studies on germ-free mice.

When mice are raised under conditions where their exposure to microbes is controlled (ie, sterile), resulting in them having no gut microbiota, their GALT is undeveloped.8 Specifically, there are fewer and smaller Peyer’s patches.9 To better understand the role bacteria have in stimulating the immune system, researchers have introduced specific microbes into the environment of otherwise germ-free mice. One example uses Bacteroides fragilis which is an important species of bacteria that colonises the lower gastrointestinal tract of mammals. When germ-free mice were colonised with B. fragilis strain NCTC 9343, their immune systems developed.10 In humans, the important relationship between microbes and the immune system is evident by the increased incidence of allergies in industrialised countries.11 At this time, measures were implemented to limit the spread of infectious diseases, including widespread use of antibiotics; decontaminating drinking water and pasteurising many food products, particularly milk.12 These steps, although successful in helping to limit spread of infectious diseases, reduce our exposure to microbes and may disrupt the development of our immune systems resulting in an increased risk of developing allergic and autoimmune diseases.12 Furthermore, observational studies show that having pets; a larger family size and one or more older siblings is protective against atopic allergy (asthma, atopic eczema, allergic rhinoconjunctivitis/hay-fever),13,14 which has been

attributed to the greater exposure to microbes.

EARLY-LIFE MICROBE-IMMUNE INTERACTIONS

How we are born (vaginal vs caesarean section delivery) has important consequences on the initial microbes that colonise an infant’s gut.

Infants born by vaginal delivery will develop a gut microbiota that resembles the maternal vaginal and faecal microbiota.16 Infants delivered by caesarean section (c-section) are more commonly dominated by microbes that are associated with the skin microbiota16 and are often lower in diversity.17 A meta-analysis published by Thavagnanam et al. identified 23 studies looking at the association between c-section births and asthma in children. Overall, children who were delivered by c-section had a 20% increased risk of developing asthma.15 Mode of feeding during infancy is another factor known to influence the gut microbiota.

Human milk contains oligosaccharides (HMO), a naturally occurring prebiotic that is only partially digested in the small intestine.

In the colon, the HMOs are fermented by Bifidobacterium, resulting in the proliferation of a Bifidobacterium-rich infant microbiota.21 PROBIOTICS AND ALLERGY

Early life events can lead to an aberrant gut microbiota, which has been demonstrated to influence immune health and the development of allergic conditions. Therefore, approaches to increase exposure to microbes are being sought after to see if they can positively influence the immune system and related conditions. One of these approaches is the use of probiotics (see Table 1).

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Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.

WHAT TO LOOK FOR IN A PROBIOTIC A guide for healthcare professionals CHECK THE LABEL AND QUALITY

Does the label state the full strain name of the microorganism(s) in the product?

Does the label state the number of live cells of the probiotic strain(s) in the product?

NOTE: This should comprise three components: genus, species and strain identifier.

Yakult contains 1010 Lactobacillus casei Shirota per 100 ml, when refrigerated.

Genus (e.g. Lactobacillus), species (e.g. casei) and strain (e.g. Shirota) is stated in full on Yakult’s packaging.

This is equivalent to 6.5 billion live cells per 65ml bottle.

Contact the company.

Are there quality control procedures in place?

NOTE: This is necessary to ensure the product contains the correct strains and number of live microbial cells as stated on the label.

Yakult is acknowledged by experts to be a quality probiotic.

CHECK THE SCIENTIFIC EVIDENCE

Contact the company or access their HCP website, to find the supporting research.

NOTE: (i) Regulatory restrictions mean companies can share research information with HCPs but not the general public; (ii) Not all probiotic research papers can be found on medical literature databases.

The research evidence for Lactobacillus casei Shirota can be found at www.yakult.co.uk/hcp or by contacting science@yakult.co.uk

CHECK FOR GI TRACT SURVIVAL

CHECK FOR EFFICACY OF THE STRAIN

For oral probiotics, are there human intervention trials showing survival of the probiotic strain(s) through the gut?

Check for trials and studies for the probiotic and the particular patient problem

NOTE : In vitro or model studies are not proof of gut survival in vivo.

(important for assessment of safety).

There are several research papers describing human studies showing the gut survival of Lactobacillus casei Shirota.

See expert advice in ‘LcS Insight: HCP Study Day 2014’ and ‘Your Guide to Probiotics’.

For further support on what to look for in a probiotic or to access the research behind Yakult, then please visit www.yakult.co.uk/hcp contact science@yakult.co.uk or call 020 8842 7600 This resource is intended for healthcare professionals. Not to be distributed to patients.

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Volume 8.17 - 22nd November 2018

Table 2: Summary of the research supporting the guidelines18 Recommendation 1

Fifteen studies were identified. The risk of eczema is reduced in children whose mothers received a probiotic during pregnancy, compared to placebo (RR 0.72, 95% CI 0.61 to 0.85).

Recommendation 2

Ten studies were identified. The rate of eczema is reduced in children when breastfeeding mothers are supplemented with probiotics, compared to placebo (RR 0.61, 95% CI 0.50 to 0.64).

Recommendation 3

Fifteen studies were identified. The risk of eczema is reduced in children who receive probiotics, compared to placebo (RR 0.81, 95% CI 0.70 to 0.94).

In 2015, the World Allergy Organisation (WAO) convened a panel to assess the evidence for probiotics in the prevention of allergic disease (see Table 2) and resulted in the development of guidelines for using probiotics in:18 1 Pregnant women at high risk of allergy in their children.

2 Women who breastfeed infants at high risk of developing allergy.

3 Infants at high risk of developing allergy.

However, the panel do note that the recommendations are supported by very low quality evidence. Currently, there is no guidance on which is the best probiotic preparation in terms of bacterial strain, dose and administration mode.

PROBIOTICS AND UPPER RESPIRATORY TRACT INFECTIONS

The immune status of an individual may change over time related to factors including age, stress, or seasonal variation. If the immune response does not function at maximum efficiency, susceptibility to common infectious disease will increase. For example, it is well known that the immune response weakens in later life, increasing disease risk.22 Furthermore, both physical23 and psychological24 stress may cause transient immune depression, linked to increased episodes of the common cold.

There are a number of dietary elements that can improve immune responses, but one area where we are starting to see efficacy is from the use of probiotics. A Cochrane review concluded that probiotics reduce both the number of people who experience an episode (P<0.001) and the mean duration of an episode (P<0.001) of acute upper respiratory tract infection (URTI) and

can also reduce antibiotic use and cold-related school absence, compared to placebo.25 Since the 2015 Cochrane review there have been further randomised, controlled trials investigating the use of probiotics and URTI incidence, including a recent trial in healthy male office workers.26 Athletes and sports people have an increased risk of infection due to the effects that physical, psychological and environmental stresses, combined with poor sleep quality, have on their immune system.27 A paper published earlier this year summarised eight placebo-controlled trials evaluating the effectiveness of probiotics for reducing susceptibility to URTIs in active individuals/athletes.28 There was high heterogeneity between the studies, including differences in the supplemented microorganisms (all strains of Lactobacillus and/or Bifidobacterium) and duration of supplementation (28-150 days). There were mixed results from the interventions, with some showing positive effects for reducing the incidence and/or shortening the duration of URTIs and others not demonstrating a significant effect, indicating that the immunomodulatory mechanisms of probiotics may be strain specific.

One study (n=465 healthy active adults) compared two probiotic interventions (1.

Bifidobacterium animalis subsp. lactis Bl-04 (2.0 × 109 live cells) or 2. Lactobacillus acidophilus NCFM and Bifidobacterium animalis subsp. lactis Bi-07 (5 × 109 live cells each)) with placebo, and could only find a significant reduction in URTI risk in those who had received strain Bl-04 (P=0.022), and not in those who received strains NCFM & Bi-07 (P=0.15).29

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NHD CPD eArticle Endurance athletes (n=84) who received a 16-week intervention with Lactobacillus casei Shirota (6.5 x 109 live cells) had a lower incidence of URTI compared to controls (1.2 Vs 2.1, P<0.01), and this was attributed to significantly higher salivary IgA levels (an indicator of mucosal immune status) in the probiotic group (P=0.01).30 However, in a later study by the same research group, endurance athletes (n=66) who received a 16-week intervention with Lactobacillus salivarius (2 x 1010 live cells) did not have a lower incidence of URTI compared to placebo (1.6 Vs 1.4, P=0.71), nor did they have any changes in blood leukocyte counts

Volume 8.17 - 22nd November 2018

or levels of salivary antimicrobial proteins.31 CONCLUSION

There seems to be an ever-increasing body of evidence to suggest that there is an important relationship between microorganisms and our immune system, and that the use of probiotics could be one strategy to optimise immune health, particularly when this relationship has been disrupted. It is important to bear in mind that evidence for probiotic efficacy is considered strain-specific, therefore healthcare professionals are advised to check the supporting research for any probiotic they are considering using or recommending.

References 1 Cho and Blaser (2012). The Human Microbiome: at the interface of health and disease. Nat Rev Genet 13(4); 260-270 2 Sender, Fuchs, Milo (2016). Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biology 14(8): e1002533 3 Guarner and Malagelada (2003). Gut flora in health and disease. Lancet 360: 512-519 4 Janeway, Travers, Walport et al (2001). Immunobiology: The Immune System in Health and Disease (5th ed.). New York: Garland Science. Available from: www.ncbi.nlm.nih.gov/books/NBK27169/ 5 Vighi, Marcucci, Sensi et al (2008). Allergy and the gastrointestinal system. Clin Exp Immunol 153(1): 3-6 6 Jung, Hugot, Barreau (2010). Peyer’s Patches: The Immune Sensors of the Intestine. Int J Inflam 2010: 823710 7 Gensollen and Blumberg (2017). Correlation between early-life regulation of the immune system by microbiota and allergy development. J Allergy Clin Immunol 139(4): 1084-1091 8 Macpherson and Harris (2004). Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 4: 478-485 9 Round and Mazmanian (2009). The gut microbiome shapes intestinal immune responses during health and disease. Nat Rev Immunol 9(5): 313-323 10 Mazmanian, Liu, Tzianabos et al (2005). An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122: 107-118 11 ISAAC (1998). Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 351(9111): 1225-32 12 Okada, Kuhn, Feillet et al (2010). The ‘hygiene hypothesis’ for autoimmune and allergic disease: an update. Clin Exp Immunol 160(1): 1-9 13 Strachan (1989). Hay fever, hygiene, and household size. BMJ 299: 1259-60 14 O’Connor, Lynch, Bloomberg et al (2018). Early-life home environment and risk of asthma among inner-city children. J Allergy Clin Immunol 141(4): 1468-1475 15 Thavagnanam, Fleming, Bromley et al (2008). A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy 38(4): 629-633 16 Dominguez-Bello, Costello, Contreras et al (2010). Delivery more shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. PNAS 107: 11971-5 17 Azad, Konya, Maugham et al (2013). Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ 185: 385-394 18 Fiocchi, Pawankar, Cuello-Garcia et al (2015). World Allergy Organisation - McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics World Allergy Organ J 8(1): 4 19 Gibson, Hutkins, Sanders et al (2017). Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics Nature Reviews. Gastroenterology & Hepatology 14: 491-502 20 Hill, Guarner, Reid et al (2014). The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews Gastroenterology & Hepatology 11: 506-514 21 Marcobal, Barboza, Froehlich et al (2010). Consumption on human milk oligosaccharides by gut-related microbes. J Agric Food Chem 58(9): 5334-5340 22 Gomez, Nomellini, Faunce et al (2008). Innate immunity and aging. Exp Gerontol 43(8)718-728 23 Gleeson (2007). Immune function in sport and exercise. J Appl Physiol 103: 693-699 24 Cohen and Williamson (1991). Stress and infectious disease in humans. Psychological Bulletin 109(1): 5-24 25 Hao, Dong, Wu (2015). Probiotics for preventing acute upper respiratory tract infections. Cochrane Database of Systematic Reviews 2:CD006895 26 Shida, Sato, Iizuka et al (2017). Daily intake of fermented milk with Lactobacillus casei strain Shirota reduced the incidence and duration of upper respiratory tract infections in healthy middle-aged office workers. Eur J Nutr 56(1): 45-53 27 Gleeson, Nieman, Pedersen (2004). Exercise, nutrition and immune function. Journal of Sports Sciences 22(1): 115-125 28 Colbey et al (2018). Upper respiratory symptoms, gut health and mucosal immunity in athletes. Sports Med 48(1): 65-77 29 West et al (2014). Probiotic supplementation for respiratory and gastrointestinal illness symptoms in healthy physically active individuals. Clin Nutr 33(4): 581-587 30 Gleeson, Bishop, Oliveira et al (2011). Daily probiotic’s (Lactobacillus casei Shirota) reduction of infection incidence in athletes. Int J Sport Nutr Exerc Metab 21(1): 55-64 31 Gleeson, Bishop, Oliveira et al (2012). Effects of a Lactobacillus salivarius probiotic intervention on infection, cold symptom duration and severity, and mucosal immunity in endurance athletes. Int J Sport Nutr Exerc Metab 22(4):.235-242 Copyright © 2018 NH Publishing Ltd - All rights reserved. Available for printing and sharing for the use of CPD activities for personal use.

Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.

NHD CPD eArticle NETWORK HEALTH DIGEST

Volume 8.17 - 22nd November 2018

Questions relating to: The gut microbiota and immunity: is there a role for probiotics?

Type your answers below, download and save or print for your records, or print and complete by hand.

Q.1

Explain three of the functions that the microbes in our gut perform.

A

Q.2

What is MALT and how does GALT relate to it?

A

Q.3

What effect can a sterile environment have on the GALT (in mice)?

A

Q.4

Give two examples of early-life events associated with a positive influence on the infant microbiota.

A

Q.5

Describe the changes in the gut microbiota of a breastfed infant compared to that of a formula-fed infant.

A

Q.6

What are the three main guidelines from the World Gastroenterology Organisation on probiotics for the prevention of allergic disease?

A

Q.7

In the study of healthy male office workers, what effect did Lactobacillus casei Shirota have on natural killer cell activity?

Q.8

Give two examples of probiotic bacterial strains that were shown to statistically reduce the risk of upper respiratory tract infections.

A

Please type additional notes here . . .

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Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.