A Short History of Trained Innate Immunity
Although certain yeast beta glucans have been recognised as highly efficacious ingredients for immune support for over 20 years, the most recent research exploring the detailed mechanism of action has revealed some surprising findings. The established scientific thinking from the past 75 years has been that only the adaptive immune system has the capacity to “remember” past experiences with infectious and inflammatory challenges and respond more effectively to them upon a future encounter. This dogma has now been dismantled with the discovery of trained innate immunity, thanks in large part of the exploration of how specific yeast beta glucans with unique molecular structures support immune health.
The Quest for Evidence of Innate Immune Training In Vivo
This recent paradigm shift in our understanding of the capabilities of the innate immune system to include trained immunity traces its roots to epidemiologic research in the early 2000’s. This was followed by a set of human clinical trials published starting in 2009 which provided evidence of the physical health benefit resulting from trained innate immunity1-10 . However, most of the published cellular data revealing trained innate immunity has come from experiments in vitro and pre-clinical models11-14, not in human clinical studies.
In the past two years, several clinical reports have now been published describing innate immune training at the cellular level in clinical trials when healthy volunteers consume a particular yeast beta glucan15-17. Previously, the method available to test if the immune system had become trained in human volunteers involved challenging people with physical or lifestyle stressors to provoke an immune response and measuring functional changes that indirectly reflect innate immune training.
The newest publications provide a strong example of direct measurement of innate immune training in humans by measuring changes in gene expression (use) of specific genes that make up cellular innate immune training programs.
Research also demonstrates that consumption of a specific yeast beta glucan with a defined molecular structure trains the innate immune system in healthy volunteers and not just laboratory models. This has revolutionised the study of innate immune training in vivo. Using the proposed gene expression signature, it seems possible to observe and monitor innate immune training in near real time in healthy people without challenging or unnecessarily stimulating the immune system.
The gene use signature includes genes that are known to have critical roles in the innate immune response to foreign challenges. Some of these genes code for proteins that are key parts of cellular signalling pathways used by the yeast beta glucan receptor, Dectin-1. Other genes are part of the innate immune training cellular control program. Identifying and measuring this signature provides strong evidence that innate immune training occurs in healthy people following daily consumption of a specific yeast beta glucan. These studies also provide greater insight into how this well characterised yeast beta glucan supports a healthy immune response. Greater understanding of how this specific type of innate immune training works helps to reassure consumers that this ingredient provides efficacious support for a healthy immune response.
The Importance of Structure–Function Clarity
Although beta glucans are widely recognised, there remains significant confusion in the market about the differences between beta glucan sources such as yeast, cereal and mushroom. What sets certain yeast beta glucans apart is their specific molecular structure, including the configuration of (1,3/1,6) linkages and the tertiary conformation that allows them to interact effectively with innate immune receptors like Dectin-1. These structural features are foundational to whether the body can mount a meaningful trained innate immune response. By highlighting the importance of well-defined structure–function relationships, this emerging research gives both scientists and product developers a clearer framework for evaluating beta glucan quality.
Why This Science Matters Now
Over the past several years, consumers have increasingly shifted toward a more proactive and holistic understanding of immune health—one that emphasises everyday resilience, not just seasonal defence. This shift is reflected in strong ongoing demand for functional foods, beverages and supplements that provide clinically validated benefits and are grounded in credible mechanisms of action. As consumers become more discerning, ingredients supported by emerging scientific insights such as trained innate immunity stand out as particularly relevant. Yeast beta glucans with well characterised structures and robust clinical substantiation are uniquely positioned to meet these expectations, offering an immune support solution that aligns with how consumers now think about “living well” rather than simply managing illness.
What Does the Future Hold?
Training of the innate immune system has been happening long before we were aware of the concept or understood some of its benefits for our everyday health. For nearly two decades research has repeatedly shown that daily consumption of a well-studied yeast beta glucan supports immune health, reducing the severity and incidence of symptoms from upper respiratory challenges1,2,4,7-10. Using the recently proposed gene expression signature of a trained innate immune system in healthy people, future research can finetune interventions such as yeast beta glucans to more effectively optimise support for a healthy lifestyle and immune health.
Additionally, by using powerful new data informatics tools coupled with new results from clinical studies, researchers are very likely to uncover new ways that training the innate immune system leads to other benefits to our everyday health and wellness. We look to the future with great optimism and excitement about what science will teach us about the benefits of training the innate immune system to support our health.
Almost 100 years ago when childhood mortality due to infectious disease was high, Dr. Carl Naslund noticed that Swedish children who received a tuberculosis vaccine not only were protected from tuberculosis but were three times less likely to succumb to any disease compared with children who were not vaccinated.
Decades later, this observation was noticed again, where vaccinated children in high-mortality areas of West Africa had a significantly lower mortality rate 1. In 2012, the mystery behind these observations was finally solved and a new type of immune protection was identified, which is now called trained immunity 2.
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 your 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 food 3.
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 vaccine 5 are able to induce trained immunity via metabolic reprogramming and epigenetic modifications 6.
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 cells 8. 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 immunity 9.
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 expression 10.
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 you Train your Immune Response?
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 mice 3. This discovery has opened new dietary possibilities to bolster defences against immune challenges.
In 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.