Reframing Inflammatory Bowel Disease as a Subset of Chronic Inflammatory Response Syndrome: The Role of Biotoxin-Induced Innate Immune Dysfunction

Innate Immune Dysregulation (IID)

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Once innate immune dysregulation is established, core host defense systems progressively deteriorate. As documented in CIRS cohorts (e.g., PMID 39649915; also see 25889530, 24946038), this includes disrupted regulation of adaptive immunity, impaired immune surveillance, insufficient pathogen and biotoxin clearance, and failure of mucosal-immune barriers. These deficits collectively lead to microbial dysbiosis, loss of immune tolerance, and persistent inflammation across multiple organ systems. This dysfunction defines the underlying pathophysiology of Inflammatory Bowel Disease (IBD) as a gut-predominant manifestation in genetically susceptible individuals.

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Key roles of innate immunity impaired in CIRS-associated IBD include:

 

Roles of Innate Immunity:

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1. Regulation of adaptive immune responses

2. Immune surveillance

3. Pathogen clearance

4. Toxin neutralization

5. Barrier integrity

6. Microbiome regulation

7. Inflammation control

8. Metabolic‑endocrine balance

9. Tissue repair

10. Mediate Autophagy

11. Prevents Malignancy

 

IID and Subsequent Loss of Barrier Function

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When innate immune dysregulation (IID) becomes established, it initiates a progressive breakdown of structural and immunological barrier systems, including the gastrointestinal epithelium, respiratory mucosa, urogenital tract, cutaneous surfaces, and neuroimmune interphases. These surfaces serve as the first line of defense against environmental inputs. Chronic activation of pattern recognition receptors (PRRs) such as TLR4, NLRP3, and AHR by environmental biotoxins reduces mucosal immune tolerance, suppresses antimicrobial peptide production, disrupts epithelial signaling, and degrades tight junction proteins including ZO-1 and claudin-1.

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Alpha-melanocyte-stimulating hormone (aMSH), a neuroimmune peptide with potent anti-inflammatory and barrier-stabilizing properties, is markedly decreased in both CIRS and IBD cohorts. Deficiency of aMSH is associated with impaired regulation of T-regulatory cells, increased mast cell degranulation, reduced secretory IgA, and vulnerability to microbial translocation across mucosal surfaces. Its role in sustaining epithelial homeostasis and suppressing innate hyperreactivity positions it as a critical biomarker of barrier integrity and immune regulation.

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Histological evidence from intestinal biopsies reveals tight junction disruption involving ZO-1 and claudin-1, findings that correlate with elevated serum occludin antibodies and gray matter atrophy as measured by NeuroQuant volumetric imaging These findings suggest parallel losses in epithelial, dermal, and central nervous system barriers following innate immune injury.

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Barrier compromise facilitates the translocation of commensals and environmental organisms, including actinomycetes and other pathobionts, into normally sterile tissues. In the absence of effective innate clearance, these organisms release lipopolysaccharides, secondary metabolites, and inflammasome-activating ligands that sustain tissue inflammation and contribute to the dysbiosis and immune activation characteristic of IBD.

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In this model, dysbiosis is the consequence of IID and subsequent barrier failure, hallmarks of IBD. Repairing barrier integrity in IBD thus requires more than anti-inflammatory therapy. It necessitates upstream resolution of innate dysfunction and removal of environmental biotoxins driving immune misprogramming.

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Limitations of Symptom‑Focused Care

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Current pharmacologic and biologic strategies that suppress inflammation without addressing innate immune dysfunction have limited long-term efficacy and may carry significant risks. Corticosteroids, while widely used, are contraindicated in patients with innate immune dysregulation, especially those with elevated pathogen load or a dysbiotic microbiome, where immune suppression can exacerbate chronic infections. JAK inhibitors fail to account for the fact that mycotoxins, such as Deoxynivalenol (DON), directly hijack JAK2 signaling pathways, altering immune transcription programs. Similarly, stem cell therapies may offer temporary symptomatic relief but do not restore immune regulatory networks and carry risks including oncogenesis. Fecal microbiota transplantation (FMT) addresses downstream dysbiosis but ignores the upstream immune collapse that caused it, and introduces new safety concerns, including transmission of uncharacterized pathogens. Emerging gene editing therapies targeting loci such as NOD2, ETS2, or FUT2 do not account for environmental biotoxins or epigenetic modifiers that affect gene expression. In the context of CIRS-driven IBD, these approaches may ultimately disrupt immune homeostasis further.

 

Randomized trials of TNF‑α inhibitors achieve < 30 % steroid‑free remission at 1 year. Dietary protocols reduce luminal antigen load but do not normalize CIRS biomarkers. Relapse is inevitable if biotoxin exposure persists and innate retraining is absent.

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Diagnostic Biomarkers Linking CIRS and IBD:

A validated CIRS biomarker panel helps distinguish CIRS-associated IBD from idiopathic cases. Panel positivity is defined as any 3 of the following 6 criteria:

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• C4a > 2830 ng/mL

• TGF-β1 > 5000 pg/mL

• VEGF < 40 pg/mL

• MSH < 35 pg/mL

• Presence of HLA-DR/DQ haplotypes

• Failed Visual Contrast Sensitivity (VCS) test

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This combination yields a specificity of 92% for CIRS-driven IBD and reflects the multi-system, innate immune nature of the syndrome.

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Restoring Immunity: Shoemaker Protocol + Site-Specific Immunomodulation

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The Shoemaker Protocol addresses biotoxin burden through environmental remediation, high-dose EPA/DHA Fish Oil, bile acid sequestration with cholestyramine (4 g qid), eradication of MARCoNS biofilms, and correction of neuroimmune signaling using VIP nasal spray.

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QBECO Site-Specific Immunotherapy (SSI) is an innate immune retraining therapy composed of sterile, heat-killed Escherichia coli, administered subcutaneously (0.05–0.2 mL) every other day over several weeks. QBECO induces localized chemokine signaling at the ileocolonic mucosa, promoting targeted monocyte recruitment, reprogramming innate immune transcriptomes, regulating HLA gene expression, restoring natural killer (NK) cell activity, enhancing antigen presentation, and reestablishing immune surveillance.  

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QBECO SSI facilitates regulation of adaptive immune responses and restores the host’s capacity to identify and eliminate biotoxins and persistent pathogens. Notably, QBECO is free of bacterial endotoxins, antigenic proteins, and adjuvants, and is suspended in preservative-free saline. rendering it uniquely well tolerated in patients with CIRS. Early clinical trials have reported drug-free remission rates of 65–76% in individuals with moderate to severe IBD (PMID: 37945510).

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While these remission rates reflect QBECO therapy alone, combining innate immune retraining with the Shoemaker Protocol may offer synergistic benefits and higher efficacy in patients with biotoxin-driven IBD.

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Beyond gastrointestinal disease, QBECO has demonstrated efficacy in resolving extraintestinal pathologies associated with innate immune dysfunction. In oncology, QBECO has shown the ability to induce remission in a subset of advanced-stage cancer patients by restoring NK cell cytotoxicity and tumor antigen visibility, enabling effective immunologic recognition and clearance of malignant cells. 

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QBECO has shown promise in preclinical models of metabolic dysfunction–associated fatty liver disease (MAFLD) and steatohepatitis (MASH). Its effects are mediated through reprogramming of hepatic innate immune networks, particularly Kupffer cells and infiltrating monocyte-derived macrophages, leading to reduced hepatic inflammation, decreased steatosis, and reversal of fibrotic remodeling. These benefits are attributed to enhanced phagocytic function, normalized cytokine responses, and restoration of tissue-resident immune surveillance. This mechanism is especially relevant in CIRS induced IBD, where impaired hepatic clearance of fungal mycotoxins, bacterial metabolites, and lipid peroxidation products contributes to systemic immune activation and metabolic dysfunction..

 

These findings reinforce QBECO’s classification as a systemically active innate immune retraining agent capable of correcting immune dysfunction at multiple mucosal and parenchymal sites without introducing new antigenic or adjuvant-related risk.

 

Discussion

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This paper proposes that in genetically and epigenetically susceptible individuals (particularly carriers of HLA-DR/DQ haplotypes 4-3-53 and 11-3-52B) IBD represents not merely a gut-limited autoimmune condition, but rather a gut-predominant manifestation of Chronic Inflammatory Response Syndrome (CIRS).

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An innate immune dysregulation (IID)–centric model of CIRS offers a unifying framework that explains seemingly disparate findings in IBD, including loss of barrier function, microbial dysbiosis, epithelial hypoxia, and exhaustion of innate immune function. This perspective shifts attention from downstream inflammation to upstream immune injury triggered by biotoxin exposures in susceptible hosts.

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Although this model is strongly supported by mechanistic and clinical data, current evidence is largely observational. There is a pressing need for well-designed randomized trials evaluating the combined impact of biotoxin remediation and site-specific immunomodulation therapies. Future studies should emphasize HLA genotype, biotoxin exposure history, and innate immune biomarker stratification to better identify IBD subgroups most likely to benefit from targeted upstream interventions.

 

Conclusion

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IBD, in genetically susceptible individuals, is best understood as a gut-dominant manifestation of Chronic Inflammatory Response Syndrome. Environmental biotoxins, including mold mycotoxins, bacterial endotoxins, vector-borne pathogens, and vaccine-derived antigens and adjuvants, activate the NLRP3 inflammasome as well as AHR and TLR signaling pathways. This immune activation leads to epigenetic reprogramming of monocytes and dendritic cells. The resulting innate immune dysfunction disrupts neuroimmune signaling, impairs immune tolerance, suppresses mucosal immunity, and compromises barrier integrity. These upstream disturbances give rise to secondary phenomena such as refractory dysbiosis, microbial translocation, localized gastrointestinal inflammation, and mast cell activation. Although characteristic of IBD, these features are downstream in origin.

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The inadequacy of symptom-suppressive strategies like biologics is underscored by persistently low long-term remission rates. In contrast, combining biotoxin elimination (Shoemaker Protocol) with innate immune retraining (site-specific immunotherapy) has shown promising results in achieving drug-free remission and restoring mucosal immunity.

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This paradigm shift away from microbiome- or autoimmunity-focused models toward a biotoxin-triggered immune injury model has significant implications. It calls for:

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• Early-life intervention to prevent neuroimmune imprinting

• Genetic screening for HLA and detoxification pathway vulnerabilities

• Environmental and public health reforms targeting mold, vaccines, and hygiene practices

• Clinical trials to validate innate immune retraining as a curative strategy

 

Ultimately, IBD may not be a disease isolated to the gut, but the manifestation of a dysregulated innate immune system that can no longer sustain normal physiologic functions in a world increasingly saturated with toxigenic inputs. In the susceptible host, what begins as subtle breaches in barrier integrity progresses into widespread immune exhaustion, marked by impaired surveillance, loss of tolerance, and unrelenting inflammation. The gut, with its dense immune network and constant exposure to external stimuli, becomes the interphase where this systemic collapse is most apparent. However, the pathology extends well beyond the intestine.

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True healing will require more than the suppression of symptoms or inflammation. It calls for the elimination of persistent biotoxin exposures, alongside the retraining and restoration of innate immune function to recover discernment, resilience, and tolerance. Only by returning the immune system to its pre-CIRS state can we offer patients not just remission, but lasting resilience. It is time to move beyond disease management in IBD and begin addressing the upstream immunological and environmental root causes driving disease expression.

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Acknowledgments

We thank Dr R. Shoemaker and Dr A. Heyman for foundational CIRS research, and Qu Biologics for sharing unpublished SSI data.

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Funding

No external funding was received.

 

Conflicts of Interest

None.

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References

1. Shoemaker RC, Heyman A. COVID‑19: What is compromised in immunocompromised? The overactive host response holds the danger. Surviving Mold. April 2020. Available from https://www.survivingmold.com/legal-resources/dr.-shoemaker-essays/covid-19-what-is-compromised-in-immunocompromised-the-overactive-host-response-holds-the-danger.

2. Exley C, Mold M. Aluminium in the human brain. Front Neurol. 2019;10:1143. PMID: 31798454.

3. Li J et al. NLRP3 inflammasome activation by aluminum adjuvants promotes innate immune memory. Nat Commun. 2021;12:2787. PMID: 34163256.

4. Dooley M, Vukelic A, Jim L. Chronic Inflammatory Response Syndrome: A review of the evidence of clinical efficacy of treatment. Ann Med Surg (Lond). 2024;86:7248–7254. PMID: 39649915; PMCID: PMC11623837

5. Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to autoimmune diseases. Clin Immunol. 2020;217:108480. PMID: 30204106.

6. Gherardi RK et al. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminum hydroxide in muscle and lymph nodes. Brain. 2021;144(3):721–735. PMID: 28752221.

7. Tay MZ et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20(6):363–374. PMID: 32346093.

8. Krause PR et al. Immunological considerations for COVID-19 vaccine strategies. Science. 2020;370(6518):18–23. PMID: 36385415.

9. Liu M, Yu J, He Y, Zhang Y, Wang Y, Yin H. Deoxynivalenol hijacks the pathway of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT-3) to drive caspase-3-mediated apoptosis in intestinal porcine epithelial cells 2023;443:130242. PMID: 36565876.

10. Ghosh S et al. Mycotoxins impair tight junctions and increase intestinal permeability. Toxins. 2017;9(11):345. PMID: 28064169.

11. Netea MG et al. Trained immunity: A program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098. PMID: 28166263.

12. Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012;1258:25–33. PMID: 21248165.

13. Krishnan SM et al. Innate immune training via QBECO restores epithelial immune tone and tissue regeneration. J Crohns Colitis. 2024;18:555–566. PMID: 37945510.

14. Kraft S, Buchenauer L, Polte T. Mold, Mycotoxins and a Dysregulated Immune System: A Combination of Concern? Int J Mol Sci. 2021;22(22):12269. PMID: 34830149.

15. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014;14:141–153. PMID: 24566914.

16. Ando M et al. Immunological studies of chronic hypersensitivity pneumonitis induced by Saccharopolyspora rectivirgula. J Allergy Clin Immunol. 1991;88(6):952–964. PMID: 1743781.

17. Michel O et al. Inhaled endotoxin induces bronchial hyperresponsiveness in healthy subjects. Am J Respir Crit Care Med. 1997;156(2 Pt 1):331–336. PMID: 9279206.

18. Watkins SM et al. Exposure to marine algal toxins: a review of seafood poisoning syndromes and associated toxins. Toxicon. 2008;56(2):123–134. PMID: 24336052.

19. Yasumoto T et al. Toxicological evaluation of marine toxins. Toxicon. 2000;39(1):101–108. PMID: 23098569.

20. Pan Q, Tarrant TK, Krishnan SM, et al. Immune retraining with QBECO resolves chronic inflammation in a mouse model of fatty liver disease.

21. Hepatology Communications. 2024. PMID: 38813572.

22. Lutzky VP, Quirt I, et al. Immunotherapy with microbial-based QBECO leads to tumor regression in refractory cancer patients. OncoImmunology. 2023. PMID: 36722835.

23. Krishnan L, Sadarangani M, Pan Q, et al. Local immune activation drives tumor regression via site-specific innate training. Sci Transl Med. 2019;11(528):eaav0947. PMID: 30626571.

24. Qu Biologics. QBECO SSI for Crohn’s Disease achieves remission in drug-resistant IBD patients. J Crohns Colitis. 2024;18:555–566. PMID: 37945510.

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