Mushrooms and Trained Immunity: The New Frontier

Mushrooms & Trained Immunity

Bone Marrow

Case et al. (2024) found that oral powdered button mushroom products drive trained immunity in mouse bone marrow: the first evidence a dietary mushroom product, not a pharmaceutical extract, reaches hematopoietic stem cells and reprograms innate immune memory at its source.

Case et al., Frontiers in Nutrition, 2024

2011

year Netea et al. coined 'trained immunity' and proposed beta-glucans as key inducers

Weeks to months

duration of trained immunity depending on whether peripheral or central (bone marrow) cells are affected

Non-specific

beta-glucan trained immunity protected mice against bacterial Mtb infection, not just fungal pathogens

Case et al., Frontiers in Nutrition, 2024

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In 2024, researchers gave mice powdered button mushrooms by mouth, the way a person might take a supplement, and then looked at the bone marrow. What they found was unexpected: the mushroom products had reached the hematopoietic stem and progenitor cells (HSPCs, the bone marrow cells that generate every blood and immune cell in the body) and triggered a process called trained immunity.^[1] Trained immunity is a form of immune memory in innate immune cells, achieved through epigenetic changes rather than the T and B cell expansion that underlies classical vaccine memory. Prior research had established trained immunity with purified beta-glucan extracts and injection models. This was the first time common button mushrooms, consumed by mouth, drove it in bone marrow.

That finding puts a more specific answer on the question of why medicinal mushrooms affect immunity. The mushrooms trained immunity research base now offers a mechanistically characterized pathway, not a vague "immune boost." This article covers what trained immunity is, how mushroom beta-glucans trigger it, what the 2024 oral mushroom evidence shows, and where the clinical evidence still needs to catch up. For a comparison of trained immunity with classical adaptive immune memory, see Beta-Glucans and Innate Immune Memory: Beyond Adaptive Immunity. For the complete beta-glucan immunity research overview, see Mushroom Beta-Glucans and Immunity: The Complete Research Guide.

Trained Immunity Explained: How Mushrooms Create Immune Memory Without T or B Cells

For most of modern immunology, immune memory was the exclusive property of the adaptive immune system. T cells and B cells, the slow-but-specific branch of immunity, were the cells that remembered. After an infection or vaccination, these cells expanded into long-lived memory populations that responded rapidly to future encounters with the same pathogen. The protection from vaccines works this way. The reason you don't get chickenpox twice works this way.

Innate immunity, the immune system's fast-response branch, was considered a non-memorizing system. Macrophages (the frontline immune cells that engulf and destroy pathogens), monocytes (their circulating precursors), and natural killer cells were thought to respond the same way to every threat, every time, with no enhancement from prior exposure.

In 2011, Mihai Netea and colleagues published a paper in Cell Host & Microbe that challenged this view.^[2] They proposed that innate immune cells develop adaptive-like memory through epigenetic reprogramming. Epigenetic here means changes to how genes are expressed, specifically which genes can be activated quickly, without any change to the underlying DNA sequence. They called this "trained immunity."

The core idea: an innate immune cell that encounters a training stimulus (like a beta-glucan from a mushroom) undergoes chemical changes to the proteins its DNA wraps around. These changes make certain immune response genes easier to activate in the future. When a trained cell later encounters any new threat, it responds faster and produces more alarm signals than an untrained cell would.

Beta-glucans were identified as potent trained immunity inducers from the concept's introduction. They were the training stimulus Netea and colleagues initially proposed alongside other microbial products. From the beginning, mushroom cell wall components were part of the trained immunity picture.

The Signal Chain: From Beta-Glucan to a Reprogrammed Immune Cell

The process starts at a receptor on the surface of macrophages and monocytes called Dectin-1. Dectin-1 is tuned specifically to recognize the structural pattern of beta-glucans, including those found in mushroom cell walls.

When a beta-glucan from a mushroom product binds to Dectin-1, it activates a signaling cascade inside the immune cell. The cascade runs through Syk kinase (an enzyme that phosphorylates and activates downstream proteins), reaches a central metabolic switch called mTOR (mechanistic target of rapamycin), and activates two proteins called Akt and Hif1α. The practical result of this cascade is a metabolic shift: the immune cell switches from its usual energy-production process to a faster, glucose-burning method called aerobic glycolysis, which is normally associated with rapidly growing cells. This metabolic shift was identified by Netea and colleagues in 2016 as one of the three core components of trained immunity.^[3]

The epigenetic endpoint of this signaling cascade is chemical tags deposited on the DNA-packaging proteins at the start sites of immune gene sequences. Trained macrophages show two specific tag types, called H3K4me3 and H3K27ac, at the promoters of cytokine genes including those for TNF-α, IL-6, and IL-1β. Cytokines are the signaling proteins immune cells use to alert and coordinate the broader immune response. The Netea 2016 framework incorporated this epigenetic reprogramming as the defining feature of trained immunity.^[3]

Think of these tags as bookmarks in the genome. The most frequently needed cytokine genes stay bookmarked and open. When a new threat arrives, a trained macrophage doesn't have to find and open the relevant immune genes from scratch. It responds faster and produces more.

For the detailed molecular walkthrough of this cascade, including the Dectin-1 receptor biology that initiates it, see The Dectin-1 Receptor: How Your Body Recognizes Mushroom Beta-Glucans and How Beta-Glucans Epigenetically Reprogram Immune Cells.

The Case 2024 Finding: Oral Mushroom Products Reach Bone Marrow and Train Stem Cells

Most trained immunity research used purified beta-glucan extracts or delivered beta-glucan by injection, not as an oral food product. The assumption was that beta-glucans, being large polysaccharide molecules, might not survive digestion or cross the gut barrier in quantities sufficient to train immune cells elsewhere in the body. Prior studies established the trained immunity mechanism in cultured cells and injection models. Whether eating mushrooms could do the same thing was an open question.

Case and colleagues' 2024 study, published in Frontiers in Nutrition, addressed this directly.^[1] They gave mice powdered products made from Agaricus bisporus, common button mushrooms available in any grocery store, orally, not as a pharmaceutical extract but as a food-derived powder. Then they examined what happened in the bone marrow.

The bone marrow is where hematopoietic stem and progenitor cells (HSPCs) live. HSPCs are long-lived stem cells that continuously generate all blood and immune cells, including the monocytes that circulate in blood and the macrophages that reside in tissues. If HSPCs themselves become trained, rather than just the short-lived monocytes already in circulation, the training could cascade into every new immune cell produced for weeks or months.

Case et al. found that oral button mushroom products drove trained immunity in mouse bone marrow. HSPCs and the mature macrophages derived from them showed the hallmarks of trained immunity. This was the first published evidence that a dietary mushroom product, administered the way a supplement would be taken, can reach hematopoietic progenitors and reprogram innate immune memory at its origin.

The limitation: this is a mouse study. How directly these findings apply to human physiology at typical supplement doses is unknown. The significance is in the specificity of what was shown: common grocery store mushroom powder, given by mouth, reached and trained the immune system's foundational cells.

What Beta-Glucan Trained Immunity Protects Against: Not Just Fungal Infections

One of the more striking features of trained immunity is that the protection is non-specific. Training the immune system against one type of threat enhances responses against unrelated threats.

Moorlag and colleagues demonstrated this in a 2020 study published in Cell Reports Medicine.^[4] They trained human monocytes with beta-glucan in culture, then exposed the trained cells to Mycobacterium tuberculosis, the bacterium that causes tuberculosis. The trained monocytes produced an IL-1-dominated signaling signature with measurable anti-mycobacterial properties. In mice, beta-glucan pretraining significantly reduced the bacterial burden following Mtb infection.

The beta-glucan training was initiated by a fungal cell wall component, but the resulting protection extended to a bacterium. The immune cells weren't remembering a specific pathogen and recognizing it again. They had been placed in a generally more responsive state, and that enhanced responsiveness applied to whatever came next.

Vuscan and colleagues published complementary findings in 2024, demonstrating that beta-glucans from Saccharomyces cerevisiae (baker's yeast) are potent trained immunity inducers, with the protection confirmed across pathogen types.^[5] Mushroom beta-glucans share the beta-1,3/1,6 structural pattern that Dectin-1 recognizes; the yeast findings establish that this structural class broadly induces trained immunity, not just specific species.

The non-specific protection is part of why trained immunity is being studied as a basis for vaccine adjuvancy and as an explanation for the documented non-specific beneficial effects of certain vaccines on unrelated infections. For the potential application to vaccination, see Mushroom Supplements Before Vaccination: Immune Priming Evidence.

Why Trained Immunity From Mushrooms May Last Weeks to Months

If the cells that acquire trained immunity are monocytes with a half-life of roughly seven days, a natural question arises: when those monocytes die, does the trained immunity disappear?

Netea and colleagues addressed this in their 2020 paper in Nature Reviews Immunology, introducing the distinction between peripheral and central trained immunity.^[6]

Peripheral trained immunity occurs in circulating monocytes and tissue-resident macrophages. Because monocytes turn over in days, peripheral training persists for weeks but not substantially longer.

Central trained immunity occurs in hematopoietic stem and progenitor cells in the bone marrow. HSPCs are long-lived and continuously produce new monocytes and macrophages. If HSPCs are trained, they generate trained monocytes continuously, extending the enhanced immune response for months rather than weeks.

The Case 2024 finding is significant in this context. Oral button mushroom products drove trained immunity at the central level, in bone marrow HSPCs, not only in circulating monocytes. This is a mechanistic basis for trained immunity of extended duration from dietary mushroom consumption. How long this actually lasts in humans at supplement doses has not been measured, but the mechanistic pathway now has a demonstrated route.

For a dedicated look at the duration question and what the research says about persistence of mushroom immune benefits, see Trained Immunity: Why Mushroom Benefits May Be Long-Lasting.

Mushrooms and Trained Immunity: What the Evidence Shows and What's Still Unknown

The trained immunity research base is scientifically rigorous but largely preclinical. The foundational papers from the Netea group (2011, 2016, 2020) define the mechanism at the molecular and cellular level, and the epigenetic signatures of trained immunity have been confirmed in human cells in culture. The mechanism itself is not theoretical; it is a characterized biological process established across multiple research groups.

The evidence by tier:

Established in human cells in vitro: beta-glucans reprogram monocytes via H3K4me3 and H3K27ac histone marks at cytokine gene promoters. Netea 2016 incorporates this as the defining epigenetic component of trained immunity.^[3]

Established in animal models: beta-glucan trained immunity provides broad-spectrum infection protection, including against bacterial pathogens (Moorlag 2020).^[4] Oral mushroom products drive central trained immunity in bone marrow (Case 2024).^[1]

Not yet established in human clinical trials: trained immunity endpoints measured after mushroom supplementation at food-relevant doses, in humans, with adequate follow-up intervals. That data does not yet exist.

No randomized clinical trial has enrolled human participants, administered mushroom products orally, and then measured trained immunity markers at follow-up. The questions of whether, at what doses, and for how long trained immunity is induced by mushroom supplementation in humans remain unanswered in controlled research.

The mechanistic picture is compelling. The clinical translation is an open question. Both are worth stating clearly.

The Bottom Line

Trained immunity is a form of immune memory in innate immune cells, achieved through epigenetic reprogramming rather than T and B cell expansion. Mushroom beta-glucans were proposed as trained immunity inducers from the concept's introduction by Netea et al. in 2011. In 2024, Case et al. published the first evidence that oral powdered button mushroom products drive trained immunity in mouse bone marrow, reaching the hematopoietic progenitors that generate all immune cells. Moorlag et al.'s 2020 data showed that beta-glucan trained immunity protects against bacterial infection, not just fungal pathogens. The mechanistic foundation is established across multiple research groups. Human clinical trial evidence measuring trained immunity after mushroom supplementation does not yet exist.

Frequently Asked Questions

What is trained immunity in mushrooms?

Trained immunity is a form of immune memory in innate immune cells (monocytes and macrophages) achieved through epigenetic reprogramming of gene expression. Mushroom beta-glucans trigger it by binding to Dectin-1 receptors on immune cells, initiating a signaling cascade that deposits chemical tags at cytokine gene promoters, priming those cells to respond faster and more robustly to future threats. Netea et al. coined the term in 2011 and identified beta-glucans as potent inducers from the start.^[2]

Can eating mushrooms improve long-term immune response?

A 2024 study by Case et al. found that oral powdered Agaricus bisporus (button mushroom) products drove trained immunity in mouse bone marrow, reaching the hematopoietic stem cells that continuously produce all new immune cells.^[1] If central trained immunity is induced in bone marrow stem cells, the enhanced response could persist for months as trained stem cells keep producing trained monocytes. This is a documented mechanistic basis for a lasting immune effect from dietary mushroom consumption, though it has not been measured in human clinical trials.

How do medicinal mushrooms train the immune system?

Beta-glucans in mushroom cell walls bind to Dectin-1 receptors on macrophages and monocytes, activating a signaling cascade through Syk kinase and mTOR that produces a metabolic shift in the immune cell and results in epigenetic marks (H3K4me3 and H3K27ac) at the promoters of cytokine genes including those for TNF-α, IL-6, and IL-1β.^[3] These marks keep immune response genes primed for fast activation. When a trained cell later encounters a new pathogen, it responds more rapidly and produces more cytokines than an untrained cell.

Is trained immunity the reason mushrooms boost immunity?

Trained immunity is a documented mechanism through which mushroom beta-glucans enhance innate immune function, but it is probably not the only mechanism. Mushrooms also stimulate natural killer cell activity, activate complement pathways, and modulate cytokine production through other routes. Trained immunity specifically explains how a period of mushroom consumption could produce immune benefits that outlast the supplementation, because the epigenetic changes persist even after the beta-glucan stimulus is removed. Moorlag et al.'s 2020 data showing protection against bacterial infection is the clearest functional evidence for what the training actually accomplishes in a living organism.^[4]

Sources & References

1. 1RTHM-00867·Case, Sarah et al. (2024). “β-glucans from Agaricus bisporus mushroom products drive Trained Immunity..” Frontiers in nutrition.Study breakdown →PubMed →↩
2. 2RTHM-00423·Netea, Mihai G et al. (2011). “Trained immunity: a memory for innate host defense..” Cell host & microbe.Study breakdown →PubMed →↩
3. 3RTHM-00810·Netea, Mihai G et al. (2016). “Trained immunity: A program of innate immune memory in health and disease..” Science (New York.Study breakdown →PubMed →↩
4. 4RTHM-01255·Moorlag, Simone J C F M et al. (2020). “β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1..” Cell reports.Study breakdown →PubMed →↩
5. 5RTHM-02009·Vuscan, Patricia et al. (2024). “Potent induction of trained immunity by Saccharomyces cerevisiae β-glucans..” Frontiers in immunology.Study breakdown →PubMed →↩
6. 6RTHM-01263·Netea, Mihai G et al. (2020). “Defining trained immunity and its role in health and disease..” Nature reviews. Immunology.Study breakdown →PubMed →↩