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BY BENJAMIN MAKEHAM July 11, 2023
The immune system is found all throughout the body, and it is particularly concentrated in the intestines, lungs and even the genitourinary tract. A high concentration of immune cells are found in these parts of the body because they are the main point of contact with the external environment; they are there to protect these vulnerable areas from bacteria, viruses and fungi that can cause infection. Immune cells travel between these areas and share information, helping to create a coordinated immune response throughout the body.
While the immune system defends the body against harmful microorganisms, there are also beneficial microorganisms which live on the external surfaces of these body parts which are essential for immune health. Dense and diverse communities of microorganisms colonise the lining of the large intestine, the throat and oral cavity, the lungs and the genitourinary tract - all of which have large populations of immune cells near their surface. These communities are commonly called a microbiome e.g. the gut microbiome, and the microorganisms within each microbiome are actually necessary for the immune system to mature during childhood and to function at its best.
As a range of different microorganisms colonise the body's surfaces during childhood, they help to teach immune cells (which are lying just below) how to identify beneficial microorganisms from harmful ones and how to create effective immune responses against those which can cause serious infections. They also help the body to resist infection by acting as a physical barrier, essentially blocking potential invaders from attaching to the body’s cells. This type of resistance is known as ‘colonisation resistance’.
A healthy microbiome also helps to create ‘oral tolerance’ within the immune system, which is what prevents the development of allergies. Interactions between the microbiota and immune cells help to prevent the immune system from reacting to substances which aren’t harmful, such as pollens which enter the respiratory tract and interact with the immune cells in the throat and lungs, or substances in food which interact with the immune cells in the intestines.
The body’s microorganisms begin to benefit immune health at birth, and play an important role throughout the rest of the lifespan. Research suggests that the shaping of the microbiome during the first 1000 days of life is key to both a child’s immediate immune health, and their future risk of disease - particularly disorders of the immune system.
Disturbances to the microbiome can impact immune health in the short term by reducing infection resistance and increasing the risk of respiratory or gastrointestinal infections. However, microbiome disturbances that occur in early childhood can also increase the risk of developing allergies (eczema, asthma, hayfever and food allergies) because this is the time in which oral tolerance is being developed.
Antibiotics, delivery via caesarean section, and formula feeding are some of the major factors which can disrupt the gut microbiome in infants, and have the potential to impact immune system development and future health outcomes (2).
Fortunately, medical research into the link between the gut microbiome and immune system function has identified specific probiotic strains which can benefit immune health in targeted ways - especially in the paediatric population.
In children who are frequently unwell with respiratory infections or have an allergic disease such as asthma or eczema, working on the health of their gut microbiome may help to improve immune system function and assist with the management of their symptoms alongside standard medical care.
Medical research has identified a number of different probiotic strains that demonstrate immune-enhancing and immune-modulating effects in children. Specific strains have demonstrated an ability to improve infection resistance, while others have been shown to prevent and/or manage allergic diseases (eg. eczema). This is because the beneficial effects of probiotics are strain specific, and must be carefully selected (3).
While probiotics primarily impact the immune system in the gut, the transfer of immune cells between different body sites ensures their beneficial effects can be transferred throughout the body – including the respiratory tract.
Respiratory infections in children
Recurrent respiratory tract infections are a common problem in preschool and school aged children. This is due in part to the simple matter of increased exposure – a child goes to daycare or school and is exposed to bacteria and viruses that can cause infection. Another factor is that a child’s immune system is immature and at times does not yet have the ability to prevent an infection. Research demonstrates that children who attend day care centres have 2-3 times more infections than children who stay at home, have more outpatient doctor and emergency room visits and increased usage of prescribed antibiotics (4). While exposure to a diverse range of microorganisms is important for immune system development, supporting the gut microbiome may help to enhance the immune system response and reduce the frequency in which the exposure to infectious bacteria or viruses results in symptomatic infections.
A meta-analysis which pooled the results of four randomised placebo-controlled trials including a total of 1805 children found that when compared to placebo, supplementation with the probiotic strain Lactobacillus rhamnosus GG reduced the incidence of upper respiratory tract infections by 38%, acute middle ear infection by 24% and antibiotic use by 20% (5). Additionally, children older than 1 year old showed significant reductions in the risk of both upper and lower respiratory infections.
Acute gastroenteritis in children
Acute gastroenteritis is another common infection in children and is typically acquired in childcare, school and hospital settings. Rotavirus and norovirus are the two main causes of acute gastroenteritis (AGE), which is defined as a change to loose or liquid stool and/or an increase in stool frequency (>3/day) with or without vomiting or fever (13). The European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommends that the probiotic strain L. rhamnosus GG can be used alongside rehydration for the management of AGE in children (6).
When the results from fifteen randomised controlled trials including a total of 3820 children were pooled together and analysed, they found that L. rhamnosus GG significantly reduced the duration of diarrhoea in AGE compared with placebo or no treatment. It also showed more than a one day reduction in the duration of hospitalisation for those with AGE who were treated with L rhamnosus GG compared with control (7).
The benefits of L. rhamnosus GG in AGE include interference with pathogen attachment (harmful bacteria adhering to a site), interaction with other microbiota and stimulation of immune responses. A combination of these effects seemed to help address the underlying cause (16).
Antibiotic-associated diarrhoea and recovery in children
Where antibiotic use is necessary, specific probiotic strains can play an important role in reducing their side effects such as antibiotic-associated diarrhoea (AAD). AAD occurs in up to 39% of people taking an antibiotic and is a symptom of gut microbiota disruption and overgrowth of pathogenic bacteria, such as Clostridium difficile (8). Toxins released by these bacteria damage the protective mucosal layer, increase gastrointestinal irritation and inflammation and cause diarrhoea (9).
Aggregated results from 12 randomised controlled trials with almost 1500 participants demonstrated that L. rhamnosus GG reduces the risk of antibiotic-associated diarrhoea in children and adults by 51% (10). During antibiotic treatment, L. rhamnosus GG helps to prevent opportunistic infections that contribute to AAD by adhering to the intestinal lining and competing for space and nutrients while also producing chemicals that inhibit growth of harmful microorganisms (11).
Subtle microbial changes caused by antibiotics may not lead to ADD or have immediately apparent consequences, but may affect long term health due to the loss of more specialised microbial activities. For example, the loss of beneficial bacteria can compromise the intestinal barrier and trigger inflammatory immune responses.
Specific probiotic strains such as L. rhamnosus GG and L. plantarum 6595 can help to restore and strengthen the barrier and its mucus layer in a number of ways (20). This can help to provide the environment needed to support the regrowth of the “good” microbiota and reduce the occurrence of chronic inflammatory responses that are suggested to contribute to the increased risk of chronic disease associated with antibiotic use. For example, researchers have found links between increased antibiotic use and many immunological disorders, including asthma, allergies, inflammatory bowel disease and juvenile arthritis (21).
Estimates suggest there has been a two to three-fold increase in the prevalence of allergic disease over the past 30 years (13). Current scientific thinking suggests that the abundance and diversity of the microbiome and important microbial exposures during childhood have been diminishing over time (due to changes in lifestyle, hygiene, and antimicrobial use such as sanitisers). It’s thought that these factors have led to immune response imbalance, loss of oral tolerance and development of allergic diseases such as atopic dermatitis, asthma and food allergies. Due to the immunomodulatory role of the gut microbiota, specific probiotic strains have been studied for their ability to modulate immune cell balance and improve health outcomes in allergic disease.
Atopic dermatitis, the most common form of eczema, is a chronic inflammatory skin disease affecting 20% of children and approximately 5% of adults (14). In atopic dermatitis, an immune system imbalance leads to allergic reactions and the release of histamine in the skin. This creates the inflamed, itchy skin characteristic of atopic dermatitis.
The maternal microbiota is now known to impact the development of the foetus's immune system while in-utero, and may influence the risk of immune dysregulation and allergies after birth (8). A growing body of evidence supports the notion that supporting the maternal microbiome with specific probiotic strains during pregnancy and lactation may help to prevent atopic dermatitis in infants (8).
Lactobacillus rhamnosus GG may help to prevent atopic dermatitis (15). In a randomised, placebo-controlled trial in 159 pregnant women, the administration of placebo or L. rhamnosus GG for 4 weeks before expected delivery and 6 months postnatally significantly reduced the cumulative risk for developing eczema symptoms during the first 7 years of the child’s life (16).
Despite its preventative potential, Lactobacillus rhamnosus GG has not been shown to be effective in treatment of existing atopic dermatitis (17, 18, 19). According to research, one of the most efficacious strains for the treatment of existing atopic dermatitis is Lactobacillus salivarius LS01. This strain has been shown to positively impact immune cell balance in vitro and these shifts can help to facilitate a balanced, healthy immune response.
In one study, 43 patients aged 0-11 years were treated with 2 billion CFU of L. salivarius for eight weeks followed by 1 billion CFU for another eight weeks. A significant reduction in symptoms was observed after four weeks and again at the conclusion of the study. Four weeks after the end of the study, symptom reductions were maintained.
At first, an immune cell imbalance often manifests as atopic dermatitis in an infant. However, through mucosal network communication, this immune dysregulation can begin to manifest in other parts of the body and progress to allergic rhinitis, asthma and food allergies. As allergic asthma shares the same cause as atopic dermatitis, L. salivarius LS01 (in combination with Bifidobacterium breve B632) has also been studied in children with asthma alongside usual medical care. In a large double-blind randomised placebo-controlled trial of 422 children, the children who were given the combination of L. salivarius LS01 and B. breve B632 (1 billion CFU each) alongside their usual medication twice a day for eight weeks and once a day for another eight weeks experienced 64.2% fewer exacerbations of their asthma symptoms compared to placebo (20).
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16. Kalliomäki, M, Salminen, S, Poussa, T, et al. (2007) Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomised, placebo-controlled trial. J Allergy Clin Immunol 119, 1019–1021.
17. Gruber C, Wendt M, Sulser C, et al. Randomized, placebo-controlled trial of Lactobacillus rhamnosus GG as treatment of atopic dermatitis in infancy. Allergy. 2007;62:1270e1276.
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20. Drago, L., Cioffi, L., Giuliano, M., Pane, M., Amoruso, A., Schiavetti, I., Reid, G., Ciprandi, G., & PROPAM Study Group. (2022). The Probiotics in Pediatric Asthma Management (PROPAM) Study in the Primary Care Setting: A Randomized, Controlled, Double-Blind Trial with Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706). Journal of Immunology Research, 2022, 1–7.
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