The Reseach
Reframing Inflammatory Bowel Disease as a Subset of Chronic Inflammatory Response Syndrome: The Role of Biotoxin-Induced Innate Immune Dysfunction
Author: Alli Manzella, CIRS-Literate FNTP, Environmental Health Specialist
Co-Founder, Root Cause for Crohn’s & Colitis
Date: June 2025
Abstract
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Background: Inflammatory Bowel Disease (IBD) is traditionally framed as a chronic, idiopathic autoimmune disorder. Despite advancements in therapeutics, unmedicated remission remains elusive, suggesting an incomplete pathophysiologic model.
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Objective: To synthesize clinical and molecular evidence supporting that a subset of IBD represents a manifestation of Chronic Inflammatory Response Syndrome (CIRS), precipitated by environmental biotoxins in HLA-susceptible hosts. This process culminates in innate immune dysregulation (IID), loss of barrier function, mucosal immune suppression, and microbiome destabilization.
Rethinking CIRS: Innate Immune Dysregulation as the Upstream Driver Beyond Inflammation and Genetic Susceptibility
Author: Alli Manzella, CIRS-Literate FNTP, Environmental Health Specialist
Co-Founder, Root Cause for Crohn’s & Colitis
Date: May 2025
Abstract
Chronic Inflammatory Response Syndrome (CIRS) has been defined by a specific clinical phenotype and lab profile following biotoxin exposure in genetically susceptible individuals. While the Shoemaker Protocol laid critical groundwork in establishing a reproducible diagnostic and therapeutic framework, a deeper look at a specific subgroup within the CIRS population reveals a more defined root cause. This paper proposes that innate immune dysregulation (IID) is an upstream mechanism in individuals carrying the HLA-DR4-3-53 and DR11-3-52B haplotypes, which differ mechanistically from other CIRS-susceptible types by impairing antigen presentation, promoting immune misrecognition, and failing to resolve innate inflammatory responses. These haplotypes predispose the host to chronic immune dysfunction, making them uniquely vulnerable to persistent biotoxin sensitivity and multisystem involvement. In these patients, inflammation, immune exhaustion, and persistent susceptibility to biotoxins arise from a primary loss of regulation in innate immune signaling and resolution. This insight may also help explain the immune dysfunction seen in a subset of patients with Inflammatory Bowel Disease (IBD), carrying these specific HLA haplotypes.
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