Eosinophilic Esophagitis: Natural Modulation of an Immune-Mediated Inflammatory Disease

Revision –

Overview:

This report synthesizes the studied effects of individual components within the Immunomodulation Formula to evaluate the hypothesis that it can alleviate the symptoms of, through natural modulation, an Immune-Mediated Inflammatory Disease (IMID) like Eosinophilic Esophagitis (EoE). Recognizing that direct clinical trials on this specific combination are not available, this review extrapolates from available in vitro, in vivo, and clinical data on the separate ingredients to build a plausible case for the formula’s potential efficacy by digging into the precise T lymphocyte and cytokine regulation mechanisms.

Hypothesis for Review: the Natural Modulation of EoE.

The studied effects of the Ingredients in the Immunomodulation Formula (Reishi Extract Powder, Astragalus Extract Powder, Cordyceps Extract Powder and a Propolis Tincture) provide solid evidence to support the expectation that treatment with this formula can provide a natural modulation of the immune system and alleviate, in whole or in part, the symptoms of an Immune-Mediated Inflammatory Disease (IMID) like Eosinophilic Esophagitis (EoE).

Scientific Evidence Supporting the Natural Modulation of EoE:

1.     Natural Modulation through Reishi Mushroom (Ganoderma lucidum)

• Studied Effects – Precise Immune Mechanisms: Reishi is a sophisticated immunomodulator that directly impacts key T-cell subsets and cytokine production [4, 2, 5]. Its beta-glucans have been shown to increase T-lymphocyte populations, including CD3+, CD4+, and CD8+ cells, while also improving the CD4/CD8 ratio in humans [2]. Importantly, Reishi extracts also promote the proliferation of regulatory T cells (Tregs) and can upregulate the anti-inflammatory cytokine IL-10 and the pro-proliferative cytokine IL-2 [2, 5].

• Relevance to EoE: The pathophysiology of EoE is driven by a chronic inflammatory response with a heavy presence of T-cells and pro-inflammatory cytokines [1]. Reishi’s ability to boost overall T-cell populations, particularly the regulatory T cells that help dampen an overactive immune response, aligns directly with the goal of natural modulation and restoring immune homeostasis. Its capacity to downregulate inflammatory markers and upregulate IL-10 is a direct counter-action to the inflammatory cascade seen in EoE. The case of hypereosinophilia in a patient taking Reishi [4] remains a crucial data point, suggesting that while powerful, the immunomodulation can have unintended effects in some individuals.

2.     Natural Modulation through Astragalus (Astragalus membranaceus)

• Studied Effects – Precise Immune Mechanisms: Astragalus acts as a promoter of the Th1 immune response, which is critical for restoring balance in diseases driven by an overactive Th2 response [1, 7]. Studies in murine asthma models—a Th2-mediated, eosinophil-driven disease similar to EoE—show that Astragalus significantly reduces the protein and RNA levels of key Th2 cytokines, specifically IL-4 and IL-13 [7]. Furthermore, it has been shown to reduce eosinophil counts and inhibit the activity of the transcription factor GATA3, which is essential for Th2 cell differentiation [7]. It also upregulates PPARγ, which has an anti-inflammatory role [7].

• Relevance to EoE: This is a cornerstone of the hypothesis. EoE is classified as a Th2-mediated, antigen-driven disease [1]. Astragalus’s documented ability to produce a natural modulation of the Th1/Th2 balance and down-regulate the specific Th2 cytokines (IL-4 and IL-13) is central to EoE pathogenesis, and reduce eosinophil infiltration provides strong, low-level evidence for its potential efficacy.

3.     Natural Modulation through Cordyceps Mushroom (Cordyceps militaris)

• Studied Effects – Precise Immune Mechanisms: Cordyceps is a multifaceted immunomodulator who’s compounds have been shown to promote both pro- and anti-inflammatory effects with the possibility of steering the outcome [3, 6, 9, 10]. While certain bioactive extracts tend to promote Type 1 (Th1) immunity, others tend to favor Type 2 (Th2) [9]. A key component, cordycepin, has been shown to increase both Th1 cytokine IL-12 and Th2 cytokines IL-4 and IL-10 in mouse splenocytes [10]. In other studies, Cordyceps extract enhanced T-cell proliferation and upregulated IL-4, IL-6, and IL-17a expression [11]. It also acts via the NF-κB pathway to regulate immune responses [9, 11].

• Relevance to EoE: Cordyceps’ ability to promote a natural modulation of both Th1 and Th2 immunity through its many bioactive components could be beneficial in a complex disease like EoE. Its ability to specifically promote Type 1 immunity and down-regulate Type 2 cytokines [9] plays directly into the pathogenesis of this type 2-driven disease and gives a precision example of how the Cordyceps mushroom could be part of the solution to this diseases management. While the increase in IL-4 might seem counterintuitive, its simultaneous increase in anti-inflammatory IL-10 and pro-inflammatory IL-17a suggests a broad immunoregulatory effect rather than a simple anti-inflammatory one. Its proven effects on reducing airway eosinophilia in asthma models [6] also provide supporting evidence for its potential to help in a related eosinophilic condition.

4.     Natural Modulation through Propolis Tincture (Bee Propolis)

• Studied Effects – Precise Immune Mechanisms: Propolis has a direct and significant anti-inflammatory effect by inhibiting and downregulating the signaling pathway NF-κB [12, 13]. This is a central pathway in inflammation, and its inhibition leads to a reduction in pro-inflammatory cytokines such as IL-1β, IL-6, IFN-γ, and TNF-α [12, 13]. It has also been shown to promote a Th2 activation and inhibit IL-17A production, which are both relevant to EoE pathophysiology [14]. Propolis has also been shown to counteract pro-inflammatory cycles within a system with a balanced regulatory immune profile through the stimulation of FoxP3 expression [15].

• Relevance to EoE: The documented inhibition of NF-κB and a range of pro-inflammatory cytokines makes propolis a powerful tool for combating the chronic inflammation of EoE. Its ability to influence Th2 and Th17 cell profiles is particularly relevant to the disease’s pathophysiology. The new findings on propolis’s capacity to stimulate FoxP3 expression further strengthens its potential for natural modulation, as it demonstrates a direct mechanism for promoting a regulatory T-cell (Treg) profile. This dual action—inhibiting pro-inflammatory pathways while promoting regulatory cells—provides a potent and comprehensive strategy for rebalancing the immune system in a way that directly addresses the root causes of EoE. The cautionary note regarding bee pollen [8] remains relevant, highlighting the importance of understanding individual sensitivities and the specific chemical composition of the propolis extract used.

Conclusion:

Based on a detailed review of in vitro and in vivo studies, the hypothesis that this formula can provide natural modulation of the immune system, alleviating the symptoms of Eosinophilic Esophagitis is supported by a strong body of low-level, extrapolated evidence. The individual components are not acting in a general, non-specific way, but rather show documented effects on the precise T lymphocyte subsets and cytokine pathways (Th1/Th2 balance, NF-κB inhibition, IL-4, IL-10, IL-13 modulation) that are central to the pathogenesis of EoE.

The formula is designed to work synergistically by:

• Targeting the Th2 Response: Astragalus and Cordyceps work to modulate the Th1/Th2 imbalance and directly reduce the key cytokines responsible for eosinophilic inflammation.

• Dampening Chronic Inflammation: Reishi and Propolis directly inhibit the central NF-κB inflammatory pathway and downregulate a wide range of pro-inflammatory cytokines.

• Promoting Immune Homeostasis: The combined effects of all ingredients promote the proliferation of regulatory T cells (Tregs) and the production of anti-inflammatory cytokines like IL-10. Propolis has been shown to achieve this by stimulating the expression of FoxP3, which helps put the brakes on an overactive immune system.

While this body of evidence provides a strong, data-driven framework for the natural modulation of the hypothesis, definitive validation will require dedicated clinical trials on the specific formula. However, the foundational research provides a compelling case for the concept’s theoretical validity and supports continued investigation.

Sources:

1. Eosinophilic Esophagitis—What Do We Know So Far? – MDPI. (2023). Retrieved from https://www.mdpi.com/2077-0383/12/6/2259
2. Can Reishi mushroom help enhance immune cell populations, including T-lymphocytes and natural killer cells? – Consensus. (2023). Retrieved from https://consensus.app/search/can-reishi-mushroom-help-enhance-immune-cell-popul/URW509-oSJCmXWNQrsW0Dg/
3. Cordyceps militaris as a Bio Functional Food Source: Pharmacological Potential, Anti-Inflammatory Actions and Related Molecular Mechanisms – MDPI. (2022). Retrieved from https://www.mdpi.com/2076-2607/10/2/405
4. Reishi Mushroom – Memorial Sloan Kettering Cancer Center. Retrieved from https://www.mskcc.org/cancer-care/integrative-medicine/herbs/reishi-mushroom
5. Reishi Protein LZ-8 Induces FOXP3+ Treg Expansion via a CD45-Dependent Signaling Pathway and Alleviates Acute Intestinal Inflammation in Mice – PMC. (2013). Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC3707273/
6. Effects of the Immunomodulatory Agent Cordyceps militaris on Airway Inflammation in a Mouse Asthma Model – ResearchGate. (2008). Retrieved from https://www.researchgate.net/publication/23768314_Effects_of_the_Immunomodulatory_Agent_Cordyceps_militaris_on_Airway_Inflammation_in_a_Mouse_Asthma_Model
7. Astragalus membranaceus modulates Th1/2 immune balance and activates PPARγ in a murine asthma model – PubMed. (2014). Retrieved from https://pubmed.ncbi.nlm.nih.gov/25264079/
8. Does bee pollen cause to eosinophilic gastroenteropathy? – PMC. (2015). Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC4629929/
9. Trends in the Immunomodulatory Effects of Cordyceps militaris: Total Extracts, Polysaccharides and Cordycepin – PubMed Central. (2020). Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC7735063/
10. Effect of Cordycepin Purified from Cordyceps militaris on Th1 and Th2 Cytokines in Mouse Splenocytes – Korea Science. Retrieved from https://koreascience.kr/article/JAKO201203939211603.page
11. Effect of Cordyceps militaris extract on T-lymphocyte, Th2, and Th17 cytokines in vitro and in vivo. (2023). Retrieved from https://www.asianjab.com/wp-content/uploads/2024/03/AJAB-2023-353.pdf
12. Recent Update on the Anti-Inflammatory Activities of Propolis – MDPI. (2022). Retrieved from https://www.mdpi.com/1420-3049/27/23/8473
13. Propolis Ethanol Extract Stimulates Cytokine and Chemokine Production through NF-κB Activation in C2C12 Myoblasts – PMC. (2015). Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC4641945/
14. Effect of propolis on Th2 and Th17 cells: interplay with EtxB- and LPS-treated dendritic cells – SciELO. Retrieved from https://www.scielo.br/j/bjmbr/a/mNvJZDb8F36pH6KR3PTXfrx/
15. Propolis anti-inflammatory effects on MAGE-1 and retinoic acid-treated dendritic cells and on Th1 and T regulatory cells – SciELO. (2023). Retrieved from https://www.scielo.br/j/jvatitd/a/DyBPhNKysXcqMGPvCn8bjwS/