So, while it may sound obvious, a varied and balanced diet that provides adequate nutrients is the foundation of a healthy immune system.  However, some nutrients receive particular attention for their role in immune health, including vitamins A, C and D, as well as the minerals such as zinc and selenium¹.

There is also evidence for the immune benefits of other nutrients and ingredients, such as long-chain omega-3 fatty acids, probiotics and beta-glucans².

Immunonutrition

Read how each of the nutrients listed below support the immune system.  It is important to bear in mind that micronutrients have additional health benefits to immune health.  Click on each nutrient/non-nutrient below to learn more:

• Vitamin A
• Vitamin C
• Vitamin D
• Selenium
• Zinc
• Probiotics
• Beta Glucans

How the Immune System Works?

The immune system is the body’s way of protecting itself from infection by foreign invaders like bacteria and viruses.  It helps the body stay healthy and recover when illness does occur and is made up of the innate (general) and adaptive (specialised) immune system³.

The innate immune system is the body’s first line of defence.  When pathogens like infectious bacteria or viruses get into the respiratory tract or gastrointestinal system, the innate immune system responds by sending cells like neutrophils or macrophages to remove the threat.  These cells try to engulf the invading pathogen or create enzymes to destroy it.

The adaptive immune system specifically targets the pathogen and takes over from the innate immune system.  It is often described as the ‘memory’ of the immune system.  Once exposed to a pathogen, the immune system can remember the identity of that pathogen for the future and quickly mount a defence specific to that pathogen.

Impact of Age and Physical Activity on Immune Health

Immune health becomes especially important in vulnerable age groups like infants and the elderly. Both physical and psychological stress can also compromise the immune system.  Examples include over-exercising, emotional stress and surgery.

This article was published in March 2022 and updated on June 15, 2026.

Some selenoproteins, called glutathione peroxidases, are important for the body’s antioxidant system, which protects DNA and cells from oxidative damage.  This includes protecting the body’s immune cells from damage^{1, 2}.

Selenium also plays a role in activating immune cells ¹ and helping them function, such as assisting macrophages to more effectively destroy or engulf pathogens.  The role of selenium in the response to vaccines continues to be investigated³.

Figure 1. A summary of selenium and immune responses¹.   © 2018 by the authors ¹. Licensee MDPI, Basel, Switzerland.  Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Recommended Intakes

The recommended daily intake of selenium varies around the world².  The Chinese Nutrition Society⁴ set a Reference Nutrient Intake (RNI) of 60mg per day for adults.  Similarly, in the US the Institute of Medicine has set a Recommended Dily Allowance of 55mg per day⁵.  In addition, the European Food Safety Authority set an adequate intake (AI) of 70mg per day for adults⁶.

Dietary Sources

Meats, eggs, nuts, seeds, seafood and whole grains are good sources of selenium.  The selenium content of foods is linked to the selenium content of the soil (see ‘Deficiency’ section below).

Table 1. Selenium content of common foods in the diet⁷

Deficiency

Selenium deficiency is expected to affect up to 1 billion people worldwide.  This deficiency primarily affects people in areas where the soil is low in selenium⁷ and, as a result, the foods that grow in that soil are low in selenium.

The distribution of selenium in the soil is extremely uneven, with significant differences even within countries.  Regions with lower selenium intakes⁸ include certain areas of New Zealand, China and Italy, among many others.

In areas where the soil is rich in the soil, selenium deficiency is rare.  For example, the average daily intake of selenium in the US is almost twice the daily recommendation.  Certain regions of China, where selenium is plentiful in the soil, also have high intakes of selenium⁹.

Excess Intakes

Selenium has a narrow window between adequate and toxic levels.  Getting too much selenium can lead to symptoms like gastrointestinal or neurological symptoms, hair loss, nausea and fatigue, among others⁷.

For this reason, in the US a tolerable upper limit of selenium has been set at 400mg per day for adults³ .  The EFSA recently revised their upper limit to 255mg per day for adults including pregnant and lactating women¹⁰.  Lower limits are recommended for younger groups.

Selenium Supplementation

People who are deficient in selenium are shown to have impaired immune responses² and studies show that reinstating selenium status through supplementation can improve the body’s ability to fight infection.

Those with adequate selenium intake through their diet are unlikely to see additional benefits.  A recent meta-analysis of selenium¹¹ supplementation trials showed a very mixed picture of effects but no conclusive evidence of an beneficial effect on the immune system beyond the recommended dietary intake.

This article was publishing in March 2020 and updated on April 07, 2026.

Zinc is a popular nutrient in winter supplements.  It is an essential nutrient and the second most abundant trace element in the body, after iron¹.

It is found in every cell in the body and involved in many bodily processes.  It is required by cells from both the innate (general) and adaptive (specialised) immune system².

The innate immune system is the body’s first line of defence.  When pathogens like infectious bacteria or viruses get into the respiratory tract or gastrointestinal system, the innate immune system responds by sending cells like neutrophils or macrophages to remove the threat.  These cells try to engulf the invading pathogen or create enzymes to destroy it.

The adaptive immune system specifically targets the pathogen and takes over from the innate immune system.  It is often described as the ‘memory’ of our immune system.  Once exposed to a pathogen, the immune system can remember the identity of that pathogen for the future and quickly mount a defence specific to that pathogen.

The role of Zinc in the immune system includes:

• • helping to maintain the integrity of the skin and muscular membranes, preventing pathogen entry into the body.
  • supporting the growth and differentiation of immune cells.
  • supporting the phagocytic activity of monocytes and help regulate cytokine release.
  • antibody production, particularly IgG and helping the immune system distinguish between “self” and “non-self”³.

This role has been recognised in an approved European Union health claim for zinc stating that it “contributes to the normal function of the immune system” and is available to foods that meet defined criteria within the EU⁴.

Are there Recommended Intakes for Zinc?

Zinc recommendations range from 5 to 11mg per day for adults, varying by each global region⁵.  In the US, the Institute of Medicine (IOM) recommendations are 11mg per day for men and 8mg per day for women⁶.

Similarly, the Chinese Nutrition Society Reference intake (RNI) is 12mg per day for adult men and 8.5 mg per day for women⁸.  In Europe, the European Food Safety Authority has established a Population Reference Intake of 9.4 to 16.3mg per day for men with low to higher intakes of dietary phytate and 7.5 to 12.7mg per day for adults women with low to higher intakes of phytate⁷.

Most people in developed countries get enough zinc through their diet, meaning their immune system isn’t missing the zinc it needs.  For example, in the US around 18% of people do not meet the Estimated Average Requirement (EAR) of zinc per day.

This means most people are not zinc deficient, but  certain people may still benefit from eating more zinc in their diet.

Where can Zinc be Sourced in Dietary Sources

Zinc is mostly found in seafood, beef, poultry, beans, nuts or fortified cereal.  Phytic acid, found in cereals, legumes and nuts, is known to decrease zinc bioavailability¹.  Evidence shows that the biofortification of varieties of staple crops may be useful in improving the zinc status of an individual⁵.

Table 1. Zinc content of common foods in the diet⁹

What Happens with a Zinc Deficiency?

Zinc deficiency is a widespread global health issue, particularly prevalent in low- and middle-income countries.  About 17.3% of the world’s population¹⁰ is at risk of inadequate zinc intake.  When the body doesn’t have enough zinc, it does not develop a strong immune response.

Zinc deficiency affects many different organs and tissues in the body with signs and symptoms varying by age⁹.  For example, zinc deficiency can delay growth and cause diarrhoea and alopecia in children and it can alter cognitive and psychological function in older adults.

Most people in developed countries get enough zinc through their diet but it can affect more vulnerable groups.  For example, the percentage of people in the US that do not meet the  Estimated Average Requirement (EAR) of zinc varies from 16% in households with full food security to 27% in those with very low food security¹¹.

In Europe, the average intake of zinc is above the recommended amount.  However, certain vulnerable populations may benefit from including more zinc rich foods or supplements in their diet e.g. those on plant-based diets with little animal foods and the elderly⁵.

Are there Health Risk of Excess Intakes?

Excessive amounts of zinc can cause nausea, dizziness, headaches, gastric distress, vomiting and loss of appetite and chronic large doses of 50mg of zinc or more can inhibit copper absorption and reduce immune function⁹.

Excessive intakes from food sources are unlikely but may occur with excessive supplementation.  The IOM Tolerable Upper Intake Level for zinc is 40mg per day for adults.  EFSA has set the Tolerable Upper Intake Level (UL) for total daily zinc intake from all sources (diet and supplements) at 25mg per day for adults.

This level is based on the reduction of copper status¹².  Lower limits are recommended for younger groups.

Is Zinc Supplementation Effective?

A 2024 Cochrane review ¹³ based on 34 randomised controlled trials in children and adults (15 prevention, 19 treatment) showed that compared with placebo, taking zinc preventatively may make little to no difference to whether a person catches a cold or to the duration or severity of the cold.

Taking zinc for treatment of an existing cold may reduce the duration but the authors were not confident of the quality of the result which they describe as low to very low.

The most common negative sides effects were irregularities in taste and stomach upset.  A recent review however supports a preventive role of zinc supplementation in reducing the incidence and burden of respiratory infections, particularly in children with recurrent disease and in zinc-deficient populations¹⁴.

This article was published in March 2020 and updated on March 31, 2026.

Vitamin C is one of the most common nutrients that comes to mind when thinking about immune health.  It is a water-soluble vitamin that serves as a cellular antioxidant, which means it protects cells from reactive oxygen species and cellular damage¹.

By protecting both skin barriers and immune cells from damage, vitamin C enables them to function properly.  It is required by cells from both the innate (general) and adaptive (specialised) immune system².

The innate immune system is the body’s first line of defence.  When pathogens like infectious bacteria or viruses get into the respiratory tract or gastrointestinal system, the innate immune system responds by sending cells like neutrophils or macrophages to remove the threat.  These cells try to engulf the invading pathogen or create enzymes to destroy it.

The adaptive immune system specifically targets the pathogen and takes over from the innate immune system.  It is often described as the ‘memory’ of the immune system.  Once exposed to a pathogen, the immune system can remember the identity of that pathogen for the future and quickly mount a defence specific to that pathogen.

Vitamin C promotes barrier function, supports the function of neutrophils, monocytes and macrophages and the activity of NK cells.  It also has a role in the differentiation and function of T cells, especially cytotoxic T cells and in antibody production¹.

This role has been recognised in an approved European Union health claim for vitamin C, stating that it “contributes to the normal function of the immune system” and is available to foods subject to condition within the EU³.

Are there Recommended Intakes for Vitamin C?

Global daily vitamin C intake recommendations range from 40 to 110mg per day, depending on region⁴.  In the US, the Institute of Medicine’s (IoM) recommendations are 90mg per day for men and 75mg per day for women⁵.

In the EU, the European Food Safety Authority has established a Population Reference Intake of 110mg per day for adult men and 95mg per day for adult women⁶.  Similarly, the Chinese Nutrition Society Reference Nutrient intake is 100mg per day for adult men and women⁷.

What are the Dietary Sources of Vitamin C?

Vitamin C can be found in many fruits and vegetables, such as kiwis, oranges, peppers and broccoli.  The table below shows amounts of vitamin C found in commonly consumed foods.

Source: National Institutes of Health Vitamin C Fact Sheet for Health Professionals ⁸

What Happens with Vitamin C Deficiency?

About 53% of the global population have an inadequate intake of vitamin C ⁹, but the exact number varies depending on global region.  Inadequate intakes were more prevalent in men than women and in areas like South Asia.

Scurvy is a nutritional disorder caused by low vitamin C levels which manifests with varied symptoms affecting multiple organ system due to its role in connective tissue synthesis.  Although it is rarely seen, sporadic cases still occur.

In developed countries, it is mainly diagnosed in the elderly and malnourished individuals and is associated with alcoholism and poor dietary habits¹⁰.

People who smoke or are exposed to second-hand smoke need more vitamin C in their diets because smoke increases the amount of vitamin C that the body needs to repair damage caused by free radicals⁵.

Are there and Risks with Excess Intakes of Vitamin C?

In general, vitamin C has low toxicity and high intakes of vitamin C do not cause serious adverse effects.  However, high doses of vitamin C can lead to diarrhoea, nausea, abdominal cramps and other gastrointestinal disturbances⁵.

There are some concerns surrounding high vitamin C intakes, such as the formation of kidney stones and excess iron absorption, but these are not generally considered a risk in healthy individuals.

While EFSA did not establish an upper limit, the IoM Tolerable Upper Intake Level for vitamin C ranges from 400 to 2,000mg per day, depending on age⁵.

What about Vitamin C Supplementation?

There is some evidence that vitamin C doses exceeding recommended daily values could have potential benefit.

A Cochrane review¹¹ of clinical trials testing vitamin C’s effect on immune health found that regular supplementation (>200mg per day) did not influence how often participants got common colds but reduced the duration of cold symptoms.

A recent meta-analysis¹² of trials which used doses of Vitamin C above 1g per day found a greater benefit on more severe measures of the common cold.

Severe Acute Respiratory Syndrome Coronavirus, which is a respiratory condition, is marked by significant oxidative stress and an excessive inflammatory response that results in tissue damage of the respiratory system.

For this reason, there has been interest in combining antioxidants like vitamin C with antiviral and anti-inflammatory treatments to improve patient outcomes.  However, a recent review¹³ suggests that further trials are necessary to determine optimal doses and conditions of use.

This article was first published in May 2022 and updated on March 24, 2026.

The ‘gut microbiota’ refers to the microorganisms (which may include bacteria, fungi and viruses) living in our intestines and they play a vital role in gut health and the management of several gastrointestinal disorders.

The term ‘microbiome’ refers to both microorganisms along with their collective genomes and metabolites (the molecules they produce)¹.

The composition of gut microbiota can be affected by a wide variety of dietary components including carbohydrates, dietary fibres, fat, polyphenols, plant extracts and by ingredients such as fermented foods, prebiotics and probiotics².

What are Probiotics?

Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”³.  Usually, this benefit is exerted in the gastrointestinal tract.

Probiotics influence health through non-specific, species-specific and strain-specific mechanisms.  Non-specific effects—varying across strains and species—include inhibiting pathogenic microbes in the gut, producing bioactive compounds like short-chain fatty acids and lowering colonic pH.

Species-specific actions may involve vitamin synthesis, strengthening the gut barrier, bile salt metabolism, enzymatic functions and toxin neutralisation. Together, these mechanisms can broadly affect human health and disease⁴.

It is key to remember that the health benefits of probiotics are considered to be strain specific.

For more information on how probiotics work see this section.

How do Probiotics Impact the Immune System?

Immune health is one of the more commonly studied health outcomes of probiotics and the following mechanisms have been proposed^{4, 5}:

1. Probiotics have been shown to help protect against infection by improving the strength of the intestinal barrier.  This reduces the ability of infectious microbes to enter the body via the gastrointestinal tract.
2. Enhancing phagocytic activity (the process of engulfing and ingesting solid particles, such as bacteria by the cell membrane).
3. Some probiotics, or the products they produce, can interact with immune cells of the human body to influence their effectiveness.  For example, some probiotics can increase the production of cytokines (e.g. Interleukin-1 (IL-1), IL-2, IL-10, IL-12, tumour necrosis factor alpha (TNF-α)) in the intestine.  These cytokines act as chemical messengers to regulate immune responses.

When it comes to researching aspects of immunity, studies often measure the frequency of the common cold or upper respiratory tract infections (URTIs) and the duration and severity of symptoms among study participants.

A 2022 Cochrane Review⁵ titled “Probiotics for Preventing Acute Upper Respiratory Tract Infections”, which included 23 randomised controlled trials, found that probiotics were significantly better than placebo or no treatment  for reducing the number and duration of URTIs.

They also reduced the number of participants who used antibiotics for URTIs.  This means that probiotics are likely working with the immune system to have a protective effect against the pathogens that cause URTIs.

Because studies have shown that probiotics may have an impact on upper respiratory tract infections (URTIs), there was significant interest in their potential role during the COVID-19 pandemic.

However, the International Scientific Association for Probiotics and Prebiotics (ISAPP)  stated that no probiotics or prebiotics have been shown to prevent or treat COVID-19 or to inhibit the growth of SARS-CoV-2⁶.

In the post-pandemic period, probiotics continue to be studied for their possible role in areas such as vaccine effectiveness and support for individuals experiencing post-COVID-19 syndrome⁷.

Antibiotics can disturb gastrointestinal microbiota and lead to reduced resistance to pathogens such as Clostridioides difficile and associated diarrhoea (CDAD).  The use of probiotics for the prevention of Clostridioides difficile infection has been researched for many years.

A recent Cochrane meta-analysis concluded that probiotics may be effective for preventing CDAD in those receiving an antibiotic for any reason, suggesting that for every 65 people taking probiotics, one case of CDAD may be prevented⁸.

Large trials comparing probiotics with placebo in people with a low risk of CDAD are needed.  This will be an interesting area to keep an eye on as the science progresses.

How to Choose a Probiotic

Resources from the International Scientific Association for Probiotics and Prebiotics (ISAPP)

The probiotic marketplace can be confusing for consumers.  See  for some basic information on how to choose a probiotic for healthy people.  There is also useful information about how to read a US and hypothetical European probiotic label.

Here are some basic principles to guide your search:

• • There is no one strain or one dose that is best.  Sometimes lower dose products or products with fewer strains have the best evidence.
  • Any health benefit claim made should be substantiated with a human trial.  The types of claims allowed in the US on foods and dietary supplements are restricted by law.  Contact the manufacturer to get information on what studies have been conducted, or consult Clinical Guide for Probiotic Products Available in the United States⁹ or the  Guide to Probiotic Products Available in the United Kingdom¹⁰.
  • One of the biggest challenges in the probiotic market is keeping the probiotic strain alive.  Responsible manufactures go to great lengths to be sure their probiotics retain viability and deliver an efficacious dose through the end of the product’s shelf-life.  Unfortunately, not all products on the market are responsibly formulated so consumers should buy products from companies they trust.

Resources for Healthcare Professionals
In addition to resources from ISAPP, in 2023, the  World Gastroenterology Organisation published a resource for professionals working specifically in gastroenterology “WGO Practice Guideline. Probiotics and Prebiotics”¹¹.

Resources for Researchers
Health benefits of probiotics can be strain-specific and meta-analysis may not represent the ‘gold standard’ for evidence in this area.  This paper identifies common mistakes and offers expert panel recommendations for conducting meta-analysis for probiotic studies¹².

This perspective literature review describes state-of-the-art tools for harnessing the microbiome for precision health and a corresponding future vision of healthcare¹³.

This article was first published in April 2020 and updated on March 11, 2026.

Decades later, this observation was noticed again, where vaccinated children in high-mortality areas of West Africa had a significantly lower mortality rate¹.

In 2012, the mystery behind these observations was finally solved and a new type of immune protection was identified, which is now called trained immunity².

The understanding of immune memory has been centred around the idea of targeted disease-specific approaches.  The aim of a vaccine is to induce a disease specific memory in the adaptive immune system (memory T and B cells), which then can spring into action if an individual is exposed to that disease.

However, trained immunity research has been ground-breaking within the field of immunology due to its differences in immune memory.

It revealed that cells of the innate immune system also have a kind of memory, although this memory works in a very different way and results in defence against a broad range of threats.

With the discovery of trained immunity, we now know that it is possible to also increase protection against multiple, unrelated diseases.

This important discovery has therefore presented new opportunities to bolster immune defences against a myriad of threats in a non-targeted manner; a new method to protect ourselves from future disease.

Moreover, research has recently shown that it is possible to induce trained immunity through food³.

How Does Innate Training Occur?

A growing body of research over the past decade has helped identify key mechanisms which explain how innate training occurs.

Innate training agents, such as the BCG vaccine^2,4 and the adenoviral ChAdOx1 nCoV-19 vaccine⁵ are able to induce trained immunity via metabolic reprogramming and epigenetic modifications⁶.

Epigenetic Changes – Placing a Bookmark

DNA contains instructions for making proteins, including proteins crucial for launching immune responses.  However, DNA is a very tightly coiled structure where gaining access to the instructions required can take precious time.

Training stimuli, such as the BCG vaccine, in essence creates bookmarks in this instruction manual to be placed on crucial pages for launching immune responses.

This act of “placing the bookmark” is done via epigenetic changes; reversible chemical modifications to the DNA structure that loosen the DNA at certain sites, making the genes/instructions at those sites more easily accessible.

These epigenetic changes are made possible due to altered metabolism within the cell, which provides the materials for these chemical modifications to occur.

Consequently, when a subsequent danger is detected in future, the relevant pages/genes are more easily read, allowing an immune response that is more rapid and potent, compared with non-trained immune cells.

This more potent response is also possible due to metabolic reprogramming.

Metabolic Reprogramming – Meeting Energy Requirements

When an immune cell is activated as part of launching an immune response, processes engage which require a lot of energy and the production of numerous compounds, such as immune messenger signals.

These energy and production demands are met by metabolic machinery.

Innate training stimuli initiate metabolic reprogramming, which not only provides the necessary building blocks for epigenetic changes to occur to the DNA (“placing the bookmark”), but also increases the metabolic machinery available to the cell, to meet future energy and production requirements.

This could be seen as the trained cell building up its energy infrastructure to be better prepared for future challenges.

When a subsequent danger is detected, the innate immune cells can immediately spring into action, as this enhanced metabolic machinery is ready to meet the required energy and production needs, facilitating a rapid and robust immune response ⁷.

Is Trained Immunity Long Lasting?

A hallmark of the adaptive immune response is the induction of long-lived memory cells, which mobilise should a “memorised” danger appear again.

This is the type of memory targeted with a vaccine, to induce long-lived protection.  Trained immunity has also been shown to last for several months, despite innate immune cells not living for very long.

Innate immune cells are replaced regularly, both by cell division and by influx of new cells, coming from hematopoietic stem cells in bone marrow.

These stem cells divide and mature into different types of immune cells, replenishing the body’s immune cells as needed.

The explanation of innate training above has focused on individual innate immune cells coming across training stimuli and thus having a more efficient responses against subsequent dangers.

This type of trained immunity is known as peripheral trained immunity and is thought to be maintained, at least to a degree, by cell division – where epigenetic modifications (bookmarks) can be passed on to daughter cells⁸.

Although this is believed to contribute to the longevity of trained immunity, the core component is due to training of hematopoietic stem cells in the bone marrow, as identified by epigenetic changes therein.  This is known as central trained immunity⁹.

How this training occurs is not fully understood, although certain immune messenger signals have been identified to contribute to this phenomenon.

It has also been postulated that stem cells may be able to detect danger signals, in a similar manner as innate immune cells, possibly leading to similar metabolic and epigenetic outcomes.

Because stem cells divide and become lots of different immune cells, their training can result in altered amounts of certain immune cells, as well as affect their responses.

For instance, central trained immunity induced by BCG vaccination, has been shown to result in a higher number of innate immune cells that are more effective at fighting off infections up to five months post vaccination, due to altered gene expression¹⁰.

Although studies have shown that innate training can be long lasting, there is an important aspect of this phenomenon that needs to be highlighted: it is reversible.

Epigenetic changes, placing bookmarks at relevant pages, are a core component of trained immunity, which are caused by chemical modification to the DNA.

However, these modifications can be reversed and the bookmarks consequently removed^11,12.  This is a highly dynamic feedback system, where the innate immune response is adapting to new information all the time.

Can The Immune Response Be Trained?

There are numerous substances and challenges that have been shown to cause trained immunity, such as the earlier mentioned BCG and adenovirus COVID-19 vaccines and more are being discovered all the time.

However, most identified innate trainers need to be either administered by medical staff or occur as the result of an infection/being sick, neither of which is ideal for day-to-day protection.

To both induce and maintain trained immunity, the most desirable approach is something an individual can eat or drink.

Fortunately, research suggests that certain functional/bioactive ingredients found in everyday food, beverages and dietary supplements may be able to induce and maintain this process of trained immunity.

For instance,  food-safe whole beta glucan particles (WGPs) not only induce trained immunity in isolated innate immune cells (peripheral trained immunity) but also resulted in central trained immunity when ingested by mice³.

This discovery has opened new dietary possibilities to bolster defences against immune challenges.

Summary

There is growing enthusiasm in understanding the influence of diet and supplementation on the immune system.

These approaches include the use of probiotics to support balanced gut flora and the inclusion of essential nutrients, such as vitamin C, to maintain regular immune function.

What is exciting about the discovery of trained immunity and the possibility to induce it through diet, is that it enables next level immune protection.

As discussed herein, it is a recently discovered, natural enhancement of the innate immune defence, enabling the immune system to be at the ready for future challenges.

As consumers continue to seek more natural, holistic health solutions and as the area of prevention over cure grows, traditional botanical and herbal ingredients have emerged as a key area of interest^2,3.

While botanical extracts have been used in ancient Chinese and India medicine for centuries, this growing popularity has been spurred on by consumer desire for cleaner labels, more sustainable nutrition and ingredients that provide a halo effect⁴.

Globally, immune support has been outlined by consumers as the number one reason for purchasing healthy lifestyle products⁵, therefore making it unsurprising that botanical and herbal ingredients that are thought to support immune health have seen a growth spurt over the last number of years.

Elderberry is one of the most well-known botanicals that falls under this category, with a compound growth rate of over 25% observed in supplement launches with elderberry over the last 5 years⁶.

With over 50% of global consumers associating elderberry with improving immune health⁷, we look to explore the origins of the use of elderberry in immune health and the potential mechanism of action which mediates its suggested benefits.

Background and Potential Health Benefits

Elderberry is a plant native to both northern and southern hemisphere sub-tropical areas⁸.

With over 10 species within the genus, research into the structure and function of the species has assessed their effect, if any, on human health⁹.

Sambucus Nigra or black elder is one such species of elderberry commonly used in supplements. Sambucus Nigra has been found to be a natural source of bioactive compounds and therefore have a high antioxidant activity¹⁰.

In addition to the proposed anti-oxidant activity of elderberry, Mlynarczyk et al., 2017 have proposed other potential benefits of the plant and the way in which these are mediated through bioactive compounds (Figure 1)¹¹.

Figure 1. Proposed Potential Health Benefits of Elderberry¹¹

While all parts of the plant (flower, bark, leaf and fruit) are a rich source of these bioactive compounds, the fruits and flowers of the elderberry plants are the most commonly used components in elderberry extracts¹².

Extracts can concentrate the flavour, colour, nutritional value and active components of a fruit or plant into a smaller essence while maintaining these desired qualities.

The fruit and flowers from black elder have traditionally been used to prevent or reduce the effects of illnesses such as those relating to the respiratory tract and therefore elderberry and elderberry extract are thought to support immune health.

How Is This Health Benefit Modulated?

Elderberry extract has been shown to have antibacterial and antiviral properties in both in-vitro and in-vivo models, further positioning this as an immune modulating ingredient¹³.

These immune benefits are thought to be modulated through its unique composition, consisting of bioactive compounds such as phenolic compounds like anthocyanins and a variety of vitamins and minerals including vitamin C and Zinc¹⁰.

These compounds and nutrients have been shown to have antioxidant activity, demonstrating anti-inflammatory, antiviral and immunostimulatory effects in the research.

Overall, the research has shown elderberry to reduce the severity or delay the onset of oxidative stress and inflammation mediated chronic health conditions¹⁴.

In addition to this, clinical studies investigating the effectiveness of elderberry on the common cold and flu have resulted in a reduction in symptoms or reduction in the duration of illness¹⁵.

A study by Tiralongo et. al.¹⁴ found elderberry extract supplementation to reduce ‘common cold’ episode days in passengers of long-haul flights.

Passengers were given either elderberry extract or placebo, consuming this 10 days before travel until 5 days after arriving at their destination.

Those in the placebo group had a duration of 177 cold episode days collectively, versus 57 in the elderberry extract group, while over 580 symptoms were identified across the placebo group on these days versus 327 in the elderberry extract group (Figure 2).

On an individual level, this resulted in on average, a 2-day reduction in duration of the cold and decreased symptom load for those supplementing with elderberry extract versus placebo¹⁴.

This is just one study which highlights the potential effects of elderberry in immune health and improving quality of life.

Figure 2. Cold episode days (A) and cold symptom score (B) of participants with a well-defined cold established from Jackson Score¹⁴

While future studies  will be needed to further confirm its efficacy and clarify the way in which elderberry mediates immune benefits, the research has shown, that at a minimum, elderberry is a safe option with the botanical showing no evidence of over stimulating the immune system¹⁶.

In addition to this, organizations such as the German Commission E have approved the flower of Sambucus Nigra for cold and flu¹⁷, with the European Committee on Herbal Medicinal Products also concluding that Sambucus Nigra can be used in the relief of early symptoms of the common cold ¹⁸.

As consumer interest in more natural, proactive health solutions continues to grow, science-backed, botanical ingredients, such as elderberry have an opportunity to take a further foothold in this market and become the solution of choice when preventing common immune health conditions such as cold and flu.

What are immunomodulators?

An immunomodulatory compound, also called a biological response modifier or BRM in the pharmaceutical industry, is one that has the capacity to interact with the immune system in a specific way, altering the outcome of specific immune processes.  The resulting changes could be either an increase or decrease in function depending on how much of the immunomodulator was consumed or administered as well as how that specific immunomodulator interacts with the immune system. Immunomodulatory compounds can be produced either endogenously (inside the body) or exogenously (outside of the body).  Endogenous immunomodulators are compounds normally found within our body such as cytokines, hormones and growth factors.  Exogenous immunomodulators can be synthetic (many prescription medications) or naturally occurring such as ingredients in our foods and nutritional supplements. Some of these ingredients are familiar, such as vitamins and minerals which are commonly understood to be necessary for the proper functioning of our bodies.¹ For example, zinc helps activate and regulate immune cells so they can perform their job in the body.²

Examples of immunomodulators

• Omega-3 and omega-6 polyunsaturated fatty acids
• Carbohydrates such as glucans, mannans, fucoidans, fructans, xylans, and pectins
  • Yeast beta-glucans
  • Plant components such as astragalus root or echinacea flower, to varying degrees

There are many other types of naturally occurring compounds found in the foods and supplements we consume which have at least some scientific evidence that they have immunomodulatory activity. Many of these ingredients are plant-sourced and can be easily consumed in foods and nutritional supplements.  Examples include omega-3 and omega-6 polyunsaturated fatty acids (PUFA) such as linoleic acid and oleic acid which are proposed to have anti-inflammatory effects in humans.³  The more familiar fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been studied for a wide range of biological effects, including immunomodulation but are sourced mainly from marine animals.⁴ Plant-derived polyphenols such as curcumin and quercetin have been tested in human clinical trials for immunomodulatory (generally anti-inflammatory) activity as well as other biological effects.⁵

Some of the most well-studied immunomodulatory food ingredients are polysaccharides, a type of carbohydrate. Polysaccharides that have been examined for immunomodulatory activity mainly fall into six types: glucans, mannans, fucoidans, fructans, xlyans and pectins and galactans.⁶  Some of these polysaccharide ingredients are well known such as pectins, glucans and inulin (a fructan) for being dietary fibers. Others, such as carrageenan (a galactan), have been used as emulsifiers and texturants in foods for decades. Many of these polysaccharides seem to have immunomodulatory properties that have been examined with various degrees of scientific rigor.⁷

How do immunomodulators work?

A case study with beta glucan

A polysaccharide of particular interest due to the observed positive effects on health, more than 75-year history of scientific study and overall robust scientific data portfolio is beta glucan. Beta glucan occurs naturally in many different types of organisms ranging from yeast to mushrooms to bacteria and plants such as algae and cereal grains.

The beta glucans produced by these different organisms vary in chemical structure depending on which organism made it, and science shows that the biological activity a beta glucan has in the human body is linked to its specific structure.⁸ Because of this structure-activity relationship inherent in beta glucan biology, it is essential to clearly identify the source and chemical structure of a beta glucan when seeking out an immunomodulator food ingredient since not all beta glucans have immunomodulatory properties.⁹

Breaking down the structure

Beta glucans are long chains of sugar molecules linked by one of three types of chemical bonds from which they derive their name (β-(beta)1,3; -1,6 or β-1,4).  You will see beta glucans commonly described based on their chemical linkage patterns. Yeast beta glucan (called β-1,3/1,6 glucan) is one of the most well studied types of immunomodulatory beta glucans. It has a linear β-1,3-linked backbone with long β-1,3-linked branches connected through β-1,6 linkages. It was identified as the primary immunomodulatory component of yeast in laboratory experiments approximately 80 years ago ¹⁰ and has been characterized in increasing detail through subsequent decades. Once scientists discovered the receptors that recognize yeast beta glucan in our body and allow it to bring about its effects on health, called CR3¹¹ and Dectin-1¹², great progress has been made toward a detailed understanding of how yeast beta glucan exerts its immunomodulatory effects.

Innate immune training and yeast beta glucan

Experts in the field currently understand that yeast beta glucan modulates the immune system partially through a phenomenon referred to as innate immune training.¹³ Innate immune training is the term used to describe the priming of the innate immune system by some types of immunomodulators.  This concept can be understood by comparing it with the more familiar concept of immune memory.  Immune memory occurs when we are infected with or vaccinated against a pathogenic organism (eg measles or whooping cough). Our immune system recognizes the challenge and fights it off, making antibodies in the process.  The cells that make these specific antibodies stay in the body long-term and will respond quickly to that same pathogen if it were to enter the body again, which typically prevents further symptomatic infections from that pathogen.

In contrast, the innate immune system works on a shorter time frame but can still be trained by that same encounter with the pathogen described above. Instead of “remembering” that specific pathogen for a lifetime, innate immune cells become primed for an extended period of time (months to a year), or ready to respond to the next threat (of any type) more effectively than when the cells were not primed. In this case, the pathogen would have modulated the immune system to be more effective at fighting off a specific pathogen.  This training effect has been shown to have real impact on human health, for example reducing all-cause mortality in the first two years of life for infants vaccinated with the tuberculosis vaccine.¹⁴ Encouragingly, in the last decade it has been recognized that the innate immune system can also be trained by encountering compounds that are not from pathogenic organisms such as beta glucan from baker’s yeast.^15,16  This means we could experience a similar training effect from consuming food instead of being infected by a pathogen.

Innate immune training could be compared to a recreational athlete training for a more intense event such as a marathon. Imagine you are the athlete. You don’t know specifically what kind of weather and race conditions you will encounter on the day of the race but you have a set of skills that will get you through the race (running pace, mental strength, breathing techniques, etc.). You can prepare yourself to use these skills most effectively on the day of the race by training generally to run the distance in varied weather or terrain conditions. The goal of the regular training is to ready (prime) all your skills to perform at your best and complete the race to the best of your ability no matter what race conditions you encounter (challenge).

Ways yeast beta glucans can act as immunomodulators

Immune training by certain yeast beta glucans works in a similar way. The immune system cannot predict what the next challenge encountered will be, but when the innate immune system is trained by yeast beta glucan, innate immune cells are primed to activate the defense skills they possess (similar to run pacing, mental strength and breathing techniques for the athlete) more efficiently in order to combat the threat. Think of primed cells as ready for action but not yet acting in the absence of a threat.

There are a plethora of scientific studies describing the effects of yeast beta glucan on the immune system.  A few highlights include studies reporting

• • increased potential for producing the innate immune system’s chemical weapons (reactive oxygen species)¹⁷
  • increased capacity to produce cytokines important for an effective immune response^15,18
  • increased speed and directionality of innate cells migrating toward a pathogenic challenge^19-21
  • enhanced engulfment ability (phagocytosis) of foreign challenges²²
  • reversal of experimentally-induced immune suppression²³
  • enhancing the body’s ability to make more innate immune cells.²⁴

This increased readiness of multiple immune defense functions likely results in the effects observed in numerous clinical trials, showing improved outcomes in upper respiratory tract infections, an indicator of immune system efficacy. ²⁵ 

Constant research is being done to understand the mechanisms of action of immunomodulators, so expect to see more studies in the future describing how these components of food can support immune health.

In this interview, he shares his perspective on the role of food in supporting health and how Japanese and Asian tradition influence his experience.

“As the Greek physician Hippocrates said ‘Let food be thy medicine and let medicine be thy food’; this is a very fundamental idea for me. We have some nice treasures in nutrition.”

Dr. Watanabe, you are a Medical Doctor with deep experience in the area of functional food, ingredients and health benefits – what led you to researching and working in this area and why do you find this interesting?

Treatments for most of diseases can not be covered using by only medicines and surgical technology, unfortunately. It is very important to reduce the medical expenses in each country by establishing the disease prevention using good integrated practice between Pharm and Food. Particularly, the use of traditional Japanese foods that contain materials such as beta-glucans, tea-catechins, fucoidan, ginger, etc, can be used as a basis of healthy longevity.

Consumers are looking for immune health benefits from their food and beverages – what guidance would you give them?

I always focus on active health for aging persons. For keeping good immune health, the link to the digestive system is key – we have to consider the chewing, swallowing, digesting through the intestine and the activation of enteric bacteria. The digestive system’s role in immunity is one reason why it’s important for functional foods and materials to be taken by the oral administration rather than injection. Some ingredients in food, like beta glucans, can stimulate the Peyer’s patch, while others are absorbed through the small intestine. Through this path, they can boost immune health.

What ingredients do you think have the strongest evidence and potential in terms of health benefits in the arena of immune health?  Now and in the near future?  

Of course, 1,3 -1,6 beta-glucans can be expected to keep or strengthen healthy longevity. And also the tea -catechin, extracts from typical Japanese food materials, coriander leaf and seed extract, Japanese plum, curcumin, mucopolysaccharide and matsutake-mushroom help the protection of decreases of immune activities.

What learnings from your research are you finding to be the most relevant in a society looking more and more to functional food for health benefits?

The ability of foods and ingredients like green tea or fibers to improve cognition or even potentially reduce the risk of chronic disease will become more important as society looks more toward preventing health conditions with diet. The research on green tea is especially interesting and convincing and an area of science to keep an eye on.

Probiotics were defined by the World Health Organisation as live microorganisms that when applied in sufficient amounts confer a health benefit on the host.  The probiotic definition is intentionally broad because it is intended to cover the use of probiotics on different body sites and for different health conditions.  Yet, in all applications, the term probiotic should only be used to describe the presence of living microorganisms that have been proven to result in a health benefit.  Those microorganisms should be defined at the strain level and have genome sequences which are known.

What do Probiotics do?

Human studies have shown that probiotics can be useful for improving and sustaining health in a number of ways.  Strong evidence for probiotic use is available for the prevention and management of digestive disorders and infectious and antibiotic-associated diarrhoea.  Beyond the digestive tract, probiotics may lower the frequency and duration of upper respiratory infections, diminish weight gain and insulin resistance, and reduce feelings of depression and anxiety.

With this broad array of beneficial health outcomes, it is reasonable to ask how this could be possible.  How could the exposure to certain microorganisms as probiotics result in benefiting our health in so many ways? The answer to this question lies within our own microbiome.  Our bodies are home to trillions of microorganisms that reside on the skin, mouth, digestive tract, and many other body sites.  Also known as the human microbiome, these microorganisms are increasingly understood for affecting metabolism as well as our immune and nervous systems.

The presence of certain microorganisms in our microbiome are known to be good for us, while others are either associated with or known to cause harm.  For example, some beneficial intestinal microorganisms can breakdown fibres that are otherwise non-digestible and convert them into short chain fatty acids that can be used by our colonic tissues for energy and also prime the immune system towards a healthy equilibrium.  Other microorganisms that are more associated with harm, produce endotoxin, a compound that causes inflammation.

So with this in mind, it may be expected that certain microorganisms consumed or applied as probiotics can have significant effects on our body and that some microorganisms are more suited to be better for us than others.  Even though there are far fewer microorganisms in probiotic foods or dietary supplements than the number of microorganisms in our microbiome, probiotics can cause a measurable response and potentially a lasting change at their site of action.

How do Probiotics Work in the Body?

You might be wondering what happens in your body when you use a probiotic, and how they actually generate a health benefit.  Probiotics can improve health through any of several specific mechanisms:

• • Interact with other microorganisms in our microbiome
  • Stimulate growth of beneficial bacteria in our microbiome
  • Inhibit growth of harmful bacteria in our microbiome
  • Interact directly with our body’s organs, such as the intestine
  • Produce compounds that reduce inflammation or alleviate leaky gut
  • Modulate our immune system

One way some probiotics work is through modulating our microbiome.  Probiotics can affect the growth and activity of bacteria in our microbiome to change what they make and do. Studies have shown that these changes are possible even when the probiotic does not colonise for long periods of time.  The consequences of probiotic-induced alterations to the human microbiome may be to then change how the microbiome affects organ function.  For example, some probiotic strains of Bifiobacterium and Lactobacilus make antimicrobial compounds and organic acids that inhibit, endotoxin containing, potentially harmful bacteria in the intestine.  Reductions in the numbers of those harmful bacteria results in reduced inflammation and disruptions to barrier integrity.  This mechanism is indirect because probiotic efficacy is dependent on the resident microbiome at that particular body site.

Alternatively, probiotics and the secreted metabolites and other compounds that they make are also directly recognised by immune, endocrine, and epithelial cells.  Once recognised, a series of downstream events are activated, such as the reduction of inflammatory responses or alleviation of a leaky gut.  Just as for probiotic induced changes to the gut microbiome, these direct effects of probiotics may result in sustained changes at local site where they are applied (for example, the digestive tract) as well as other sites on the body.

Importantly, any single probiotic is not expected to be universally efficacious for all conditions.  Microorganisms are genetically diverse and even different strains of the same species can cause a variety of non-overlapping, physiological responses.  For example, different strains of the species Lactiplantibacillus plantarum (formerly known as Lactobacillus plantarum) can elicit the production of cytokines over a physiologically-relevant range comparable to ranges observed for different bacterial species and genera.

Applications in Food and Beverages

Although it is currently yet not possible to predict which strains work best, research efforts are underway to understand exactly the specific features of probiotics that are necessary for the observed health outcomes.  Whether a probiotic works directly on mucosal tissues or indirectly through modulation of the human microbiome, or some combination of both, knowledge on the molecular mechanisms of probiotic function will ultimately improve the probiotic selection process and guidelines for use.  Until then, it is always a good idea to read the label of your probiotic products to find out which species and strains of those species are included.

When using probiotics in foods or beverages, the ability of the microbes you select to withstand different conditions can also be important to consider.  Strains like Lactobacillus or Bifidobacterium species typically need to be refrigerated in order to remain alive.  These microbes are therefore appropriate for products which will be refrigerated throughout their distribution and shelf life.  These species unlikely to survive certain processing conditions like high temperature or acid environments.  Endospore-forming strains can withstand a wider range of temperatures and pH ranges because of their hardy spore coat.  These strains stay dormant until ideal conditions (e.g. water activity, pH, temperature) are met, similar to a seed for a plant.  As a result, it’s important to consider the science, strain characteristics, and application you plan to use a probiotic in when working in foods and beverages.