The saying is ‘what happens in Vegas stays in Vegas’, or if you are English ‘what happens in Blackpool….’ but the same cannot be said about what happens in utero, as increasing evidence supports the understanding that the maternal nutritional environment and early feeding affects the health of the foetus beyond infancy and into adulthood., An article in Nature’s Mucosal Immunology this month explores some of the key events in foetal and neonatal immune management. It stimulated a revisit to the area of what to consider for parents to be and mums of young children when they ask ‘is there anything I can do to prevent or reduce the risk of allergy or atopy in my child’.
The first moments, weeks and months of life can determine the health outcomes of an individual over the duration of their lifetime and this knowledge represents a significant choice for prospective parents. Fortunately the remarkable adaptability of the immune and central nervous system means that there are numerous opportunities in the early years of life to positively influence health outcomes even if the early stages were less than optimal.
Early Exposure Equals Long Term Risk
It has become clear that early life nutritional exposures, combined with poor choices in lifestyle in adult life, can result in increased risk of chronic diseases. This represents the fundamental nexus of Nutritional Therapy – that investing in change (food, supplement selection and lifestyle improvements) for the better will produce rewards now and in the future.
In terms of pregnancy and birth, much of the focus on the developmental origins of disease has focused on birth size and growth in postnatal life and the availability and quality of the macro nutrients, energy and protein during these critical developmental periods, but micro nutrient deficiencies also play an important role in foetal growth and development. Micro nutrient status in foetal and early life it seems may alter metabolism, vasculature, and organ growth and function, leading to increased risk of cardio-metabolic disorders, adiposity, altered kidney function, and, ultimately, to type 2 diabetes and cardiovascular diseases as well as psychological problems.
This process is sometimes referred to as ‘programming’ –the process whereby a stimulus or insult occurs at a point of critical impact during development and then has long term effect. Programming our immune system is also the way we develop tolerance to foods – described in more detail later.
As more people live longer, the burden of chronic disease has now largely exceeded that of acute and genetic diseases and represents the largest financial and social burden governments and populations will have to bear in the coming decades. Understanding how to limit future illness risk by manipulating the early nutritional environment is attractive to practitioners – even if as yet there are no 30 year RCT studies to prove it!
Nutrition and Early Life
The role of nutrients and probiotics at the critical stages of our development has been explored by various studies and scientists continue to tease out key developments and relevant pathways. One of the important messages is that existing ‘in utero’ does not exclude the foetus from both immunological and nutritional messages – ‘positive and negative’.
Because the foetus is able to respond to maternal immune communication, including her microbial communities, the role of probiotics during pregnancy and in the early months of breastfeeding has been attracting increasing research, from an outcome and safety perspective. In particular this has attracted attention for the resolution of the increasing burden of atopy – asthma, eczema and allergy.,
Whilst this is a new and as such an emerging and rapidly expanding science, the inclusion of probiotics, essential fatty acids and micro nutrients makes for a safe long term investment in the health of the child in both physical and emotional contexts. The benefit to risk element falls favourably in the benefit camp and whilst there are questions about the forms of micro nutrients and their relevant ratios as well as bacterial species, there is a substantial area of cross referencing that suggests micro nutrients and probiotics will become significant components of early life nutritional programming.
Probiotics Influence Innate Immune Receptors
Innate immunity refers to a means of pathogen and microbe recognition and defence based on a system of highly conserved pattern and microbe recognition molecules that are not generally considered part of the acquired cellular or humoral systems (memory dominated part of the immune system) called Toll Like Receptors (TLR’s).
In evolutionary terms the innate immune system is ancient and conserved, but recent discoveries have highlighted the complexity and importance of this primitive system of host defence in the overall control of our immune systems. The innate immune system remains the first line of defence in humans, and is of paramount importance before the cellular and humoral systems have fully developed or when acquired immunity is disarmed by inherited defects, pathogens or disease. Innate immunity has the additional role of sorting self from non-self or at least applying the principle of the ‘danger model’ and determining which antigen the acquired immune system responds to.
In the mid-1990s, and since, the immunologist Polly Matzinger Ph.D has built upon the self/nonself view by advocating that the immune system utilises an additional layer of cells and signals (in which the specialised antigen presenting cells (Dendritic Cells) are activated by danger/alarm signals derived from injured cells exposed to pathogens, toxins, mechanical damage and others) in its ‘decision-making’ process, which in part is also mediated by the affected tissues. In her view, the immune system provides increased specificity in affected tissues by distinguishing between ‘dangerous and non-dangerous’ entities regardless of whether they are self or foreign, leading to her model being referred to as the “danger model”.
As her explanation has evolved, Matzinger has postulated that some evolutionary level of conserved control is embedded within key organ tissues that cooperatively influences and directs the immune system’s responses. This feedback between immunity and organ tissues is necessary, as the complex combination of tissues are delicately balanced to perform a particular function, which may easily be compromised by the powerful effector mechanisms utilised by the immune system. As a consequence, organ tissues use all sorts of mechanisms to keep the cells and molecules of the immune system out until they need them and then exert some control over them when they arrive.
Toll Like Receptors (TLRs)
One of the most important mechanisms our immune system uses to decide friend from foe, including our own damaged cells are the specialist receptors called TLRs. These are molecules that tell our innate immune system that there is a stranger or friend at the door. In humans, TLRs and other “Pattern Recognition Receptors” warn us against generic bacteria, viruses, protozoa, or even splinters in our fingers or let us know that helpful bacteria are tickling their delicate surfaces. But they don’t tell us whether we’ve met an individual microbe before: they just assist the work of antibodies and cells of our acquired immunity.
The major cells of innate immunity—monocytes, dendritic cells, and neutrophils—are chock full of TLRs. When TLRs recognise a discrete pattern on a microbe, virus, or foreign debris, they signal where contact has been made. The highest concentration of innate immune cells are found in the gastrointestinal tract, where in a single day more immunological decisions are made than the systemic immune system undertakes in a lifetime.
Knowing how the gut interacts with other mucosal membranes is important because an immune reaction in one of these areas can cause changes in others.
When you realise that all the mucosal surfaces talk to each other, it has quite significant impacts on how we interpret their actions and reactions to infection.
One of the areas in clinical immunology that is attracting immune-nutrition attention is the maturing of the important T helper cells. From a clinical perspective, prenatal and postnatal exposure to environmental microbial products that can activate innate immunity might accelerate this maturation process, particularly if the exposure occurs repeatedly over time. This is an important concept in nutritional medicine as many interventions are given inadequate time to be reprogrammed, durations may be in terms of months or even years in slow to resolve immune deficits.
It has been proposed that the coupled equilibrium between potentially harmful and potentially beneficial bacteria in the gut mediates health versus disease. If the balance is altered, say, by changes in diet, the effects of stress, or the use of antibiotics, then the immune response in the intestines is also changed. This altered host–microbe relationship, called dysbiosis, has been linked to IBD and colon cancer as well as to obesity and diabetes and other inflammatory diseases.
The implications that it may be possible to alter Th cell polarity or function either by enhancing Th2 responses or encouraging Th1 or Treg/Th17 polarisation and reducing potential developmental risk of atopy and allergy as well as other immune mediated disorders is an attractive one. Whilst this type of bacteriotherapy is gaining traction there are still many unknowns and relatively few bacterial agents with enough data to support there specific use.
How Might This Happen?
For, if the foetus has no microbial contact due to its ‘exclusionary’ position, how can we clinically impact upon the foetus? The foetus, uterine and placental tissue have a unique distribution of Toll Like Receptors. Whilst the foetal digestive tract is bathed in swallowed sterile amniotic fluid, upon delivery to the mother of nutrients and bacteria a rapid transition to primary gastro intestinal colonisation takes place especially in the later trimester.
One of the long held views and promoted over 100 years ago by Tissier that we are all born sterile is still repeated in articles published today, yet two studies out of Spain demonstrated that in the later part of pregnancy the foetal gut is populated by certain bacteria.,
In fact many papers still also state the lung tissue is free of bacteria but we are populated by thousands of bacterial species in the lungs, every square centimetre of our lungs is home to 2,000 microbes.
So remarkable are our cohabitants that they create quite independent colonies on different sides of our teeth and hands. Some microbes can only survive in one part of the body, while others are more cosmopolitan. And the species found in one person’s body may be missing from another’s. Out of the 500 to 1,000 species of microbes identified just in people’s mouths, for example, only about 100 to 200 actually seem to live in any one person’s mouth at any given moment. Just 13% of the species on two people’s hands are the same. Only 17% of the species living on one person’s left hand also live on the right one.
Probiotics & Pregnancy
The consumption of probiotics during pregnancy and in the early years has been explored using various analytics which include the changes in circulating immune chemicals and outcomes. In particular, probiotics seem to add qualitative benefit to those children where the mother breast feeds, as they change the composition of the breast milk and aid in the delivery of immune maturing mediators.
One of the mechanisms behind this working relates to the ability of the neonate to achieve a functional level of ‘oral tolerance’.
Oral tolerance refers to the observation that prior feeding of an antigen induces local and systemic immune tolerance to that antigen. Physiologically, this process is of central importance for preventing inflammatory responses to the numerous dietary and microbial antigens present in the gut. Defective oral tolerance can lead to gut inflammatory disease, food allergies, and coeliac disease as well as many other health problems.
Oral tolerance in adults requires exposure to an optimal dose of an antigen by the oral route, the translocation of this antigen across the gut barrier, and its presentation by antigen-presenting cells (Dendritic Cells) to T lymphocytes, resulting in antigen-specific tolerance – creating a slow training of the immune system to be non responsive or suppressive.
In infants this at least in part is achieved by the digestive processes in the mother relying on her low gastric pH and her pancreatic enzymes – assuming her digestive system is not compromised. The digested food is then presented via the breast milk to allow oral tolerance to develop. Early studies are also suggesting that a combination of low grade antigen exposure mixed with probiotics/yogurt may mitigate atopy and in particular the increasing burden of peanut allergy. A mouse study also found that a mix of prebiotics and probiotics reduced milk allergy. In addition, environmental exposure in small amounts during these formative years reduces the risk of allergy.
Studies in humans have documented the presence of anti-genically intact food proteins in human breast milk, including bovine β-lactoglobulin, hen egg OVA, gliadin from wheat, and Ara H1 (the major allergen) from peanuts. As well as in mouse models the presence of various airborne antigens – explained by the fact that some 85-95% of airborne antigens present at the gastrointestinal mucosa. Meaning that human milk is a mix of immune modulating bacteria, key proteins and small quantities of antigen.
Oral exposure to dietary and environmental antigens occurs early in life, but both the nature and the amount of the antigens encountered vary according to the mode of feeding: whereas formula-fed children receive large amounts of cow’s-milk antigens exclusively, children who are breast-fed receive daily, from birth until weaning, minute amounts of numerous antigens ingested by the mother.
In addition to its direct antigenic stimulatory effect, it is vital to remember that diet influences the immune system just by introducing factors that influence microbiota development. Diet, therefore provides the opportunity to change to gastrointestinal composition and ratios to improve microbial communication.
Wholism from an immunological perspective -There are wholes, the behaviour of which is not determined by that of their individual elements, but where the parts are themselves determined by the innate nature of the whole….the brain for example, does not simply take the raw data it receives through the senses and reproduces it faithfully.
Instead each sensory system first analyses and deconstructs, then restructures the raw incoming information according to its own connections and rules. Making these individual sections process information more effectively will add to the whole. Each tissue is responsible for its immune interpretation, which in turn must be interpreted by the CNS.
The Golden Egg of Homeostasis
Homeostasis in the immune system is an important principle ensuring that the numbers of peripheral lymphocytes (immune cells in the mucosa and other tissues/fluids) are kept more or less constant despite numerous disturbances in the immune system during the lifetime of an organism by deletion or apoptosis. Clearly the ability to achieve homeostasis has been integral to our survivability, but deviations within immune homeostatic constraints have their roots embedded in the earliest aspects of our life development. The immune system has a remarkable capacity to maintain a state of equilibrium, even as it responds to a diverse array of microbes and in spite of constant exposure to self-antigens. It is a loss of tolerance to these own cellular components that seems to contribute to the development of auto immune diseases.
Matzingers ‘Danger Model’ explains that recognising that ‘bad cell death’ or cellular stress can elicit an immune response via TLRs, she postulates that autoimmune diseases may be caused by mutations in genes governing the normal physiological death and removal process, or by environmental pathogens or toxins that cause cell stress and/ or death and refers to these triggers as Damage Associated Molecular Patterns (DAMPs). In these cases the immune system is actually doing its job by responding to alarm signals; but inappropriately and to the detriment of the host, as can be observed in people with a nickel sensitivity, for example.
It seems clear that today many young people, despite tremendous strides in quality of environment and medicine do not enjoy perfect health. Childhood illness, atopy, asthma, weight problems, psychiatric and neuro-developmental illness and a myriad of other health issues are increasingly encountered. There appears to be an increasingly well established link between these and pre-pregnancy and pregnancy experiences.
The recent increase in the prevalence of immune-mediated diseases has been attributed to environmental factors such as a lack of microbial challenge, or dietary change amongst others.
The implication of this ‘danger’ model is a wide and compelling model for practitioners looking at the immune system’s response less as a series of apparently randomly determined sequences but more as an ‘integrated web like’ driver of health and disease, where immunological health both in local tissues and systemically is a reflection of the individual’s overall health. In optimal health all relevant tissues induce tolerance, maintaining the immune system in a state of observational inactivity. Too often practitioners get the immune system the wrong way around. They become so focused on it responding to events or promoting its response, they forget that for 99.99% of the time, its job, when working properly is not to respond to things. For the immune system and relevant tissues to be healthy they must have adequate and optimal nutrient status from zinc to water and as such, undernourished individuals have a greater risk of adverse immune responses, and immune responses regardless of how mild, place greater nutritional demands on the host. ( to learn more see the book Biochemical Imbalances in Disease– Chapter 8)
Changing View of Barrier Defence
The view, held for many years, that the body surface epithelia contribute to host protection strictly as a physical and chemical barrier is being revised owing to accumulating evidence that epithelial cells can activate tissue-associated lymphocytes and that the epithelial cells’ response to infection, damaged cells and/or stress can strongly influence dendritic cells and subsequent adaptive immune responses. In other words the barriers experiences are not limited to the barrier – the effects are felt everywhere in the body – even the brain.
Cells in complex organisms continually face decisions about differentiation, proliferation, quiescence, stress responses and apoptosis. Decisions triggered by direct signals will always be influenced by indirect factors, such as environmental context, differentiation stage and metabolic state of the cell. Because of the dynamic and interactive nature of the immune system, immune cells constantly ‘decide’ on how to deal best with invading pathogens and other homeostatic challenges in the local and systemic environment.
Most of the immune conditions are the result of interaction of the developing immune system and the environment including food selection, and epigenetics is all about the environmental impact on genetic traits. Exposure to microbes and antigens — whether through the gut or elsewhere can change the epigenetics of immune system cells.
SIgA the Forgotten Antibody
Immunoglobulin A is the dominant antibody produced in humans and it is mostly secreted across mucous membranes especially in the intestine.
IgA secreted in the gut lumen performs a number of key functions.
- It can trap food antigens; this is responsible for immune exclusion of dietary antigens and favours their degradation by pancreatic enzymes.
- It modifies antigens that have been translocated through the epithelial barrier by inducing the synthesis of antigen-specific Secretory IgA, and antigens bound to IgA are then actively transported from the lamina propria back to the lumen.
- SIgA may also exert an immunoregulatory effect.
Epidemiologicalal studies suggest that IgA-deficient individuals are more susceptible to various allergies, including food allergies. Neonates are temporarily deficient in IgA synthesis, but maternal IgA in breast milk can substitute efficiently for this lack production. Mothers deficient in SIgA may have difficulty in transferring suitable oral tolerance to their young babies despite breast feeding, and mothers with defective digestive processes may also limit environmental exposures and so alter oral tolerance development in their baby. Other immunoglobulins apart from IgA are found in the gut including IgE and IgM and IgD and these also modify risk for allergy and atopy as well as other future disease risks.
Breast milk also contains colostrums and gut epithelium growth factors, such as epidermal growth factor and transforming growth factor that stimulate intestinal growth and development, accelerate gut closure, and might affect antigen transfer across the gut wall, limiting it to the size for tolerance rather than reaction.
It is understood that there are gene based risk factors for poor tolerance and allergy development, and whilst gene ‘expression’ can be changed, the hard wired DNA cannot. There exists compelling evidence that modifiable factors such as gut bacterial colonisation and diet have a key role in the maturation of the neonatal immune system and its further susceptibility to tolerance induction through epigenetic influences.
Numerous genes are involved in innate and adaptive immunity and these have been modified over millions of years. During this evolution, the mucosal immune system has developed two key anti-inflammatory strategies:
- Immune exclusion by the use of secretory antibodies to control epithelial colonisation of microorganisms and to inhibit the penetration of potentially harmful agents
- Immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens, such as food proteins. The latter strategy is called oral tolerance when induced via the gut.
The mucosal epithelial barrier and immunoregulatory network are poorly developed in newborns. The perinatal period is, therefore, critical with regard to the induction of food allergy. The development of immune homeostasis depends on windows of opportunity during which innate and adaptive immunity are coordinated by antigen-presenting cells (Dendritic cells). The function of these cells is not only orchestrated by microbial products but also by dietary constituents, including vitamin A and lipids, such as polyunsaturated omega-3 fatty acids. These factors can in various ways, exert beneficial effects on the immunophenotype of the infant.
To date the most convincing effect of a protective microbiota is found in the presence of Bifidobacterium and Lactobacillus species in the gut microbiota along with the observation that the administration of probiotics of these bacteria species has had encouraging results for allergy prevention in infants and mice. Intriguingly, bacteria from mother’s flora are found in the milk of mice and humans confirming that gastric bacteria are able to migrate to the milk ducts.
Bacteria in the gut and exogenously consumed as probiotics also stimulate the epithelial cells and dendritic cells to produce the two most important cytokines required for immune tolerance in the gut. These are called transforming growth factor beta and interleukin 10.
In addition to TGF-β and IL-10, a lot of attention has been paid in recent years to retinoic acid and its precursor vitamin A, and its role in the generation of the tolerogenic Tregs in the gut. Specialised gut dendritic cells convert vitamin A into retinoic acid to encourage the conversion of naive T cells into Treg rather than the potentially damaging TH17 cells.
In addition, retinoic acid favours production of IgA. Thus, the availability of food-derived vitamin A is a unique aspect of the gut mucosal milieu that probably has a major influence on tolerance induction toward orally administered antigen, meaning that people who are vitamin A deficient will find food tolerance harder.
Avoidance or Inclusion?
The recent years have favoured an avoidance strategy for foods that are allergenic or produce an intolerance response. Not only children and adults have followed this strategy but so have babies. Yet the results have been poor, no prospective studies demonstrate a long term reduction in allergies and thousands of people are destined to follow a life in which there may be significant and socially compromising food avoidance strategies in place.
A more contemporary strategy is that of deliberate exposure to dietary and environmental triggers to prevent allergic disease and increase tolerance to foods for later in life called ‘oral immunotherapy’.
People have noted that the exposure to peanuts early in life means that those populations have far less peanut allergy than in the westernised countries.
From a practical perspective the ingestion of potential allergenic foods by the mother during pregnancy and whilst breast feeding will confer some additional reduction of risk. Promoting optimal micronutrient status in the mother as well as regular probiotic and Saccharomyces Boulardii supplementation may enhance this by inducing SIgA, TGF-β and IL-10, as there seems clear indications that the variability of the tolerogenic factors in the maternal milk will complicate outcomes, keeping the mothers relevant immune chemicals at an optimal level will enhance oral tolerance in the baby.
Immune responses induced in early life to environmental and dietary antigens will be decisive for children and their adult response to these antigens, and will also condition development of immune-mediated diseases such as allergies and autoimmunity. The role of the commensal flora is vital in the management of food and environmental antigens, whilst there is much to be learnt as to which species and strain confers the greatest predictable benefits choice of foods, including those that have a prebiotic effect the use of vitamin A, Lactobacillus Rhamnosus GG and Bifido Bifidus as well as Saccharomyces Boulardii has a low risk to benefit and may confer long term significant health benefits. It is reasonable to say that we are well enough informed at this stage to say this is a safe and a suitable recommendation.
|Food Supplement||Paediatric dose to feed mother for breast milk||Paediatric dose in formula or expressed milk||Notes|
|Vitamin Ae Mulsion Forte||12,500 iu (as palmitate) is 2000µgRE||2000iu (as palmitate) is 333µgRE every other day||All supplementation must be considered in context of age, size, diet and response.|
|Bifido Bac T||1 heaped teaspoon||¼ tspn every day|
|LGG||2 per day||½ capsule every other day|
|Saccharomyces Boulardii||3 per day||¼ – ½ capsule daily|
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