Are Most People Harmed by Grains?
and the damage that stays below the clinical threshold
Fasano's research established that gliadin triggers zonulin — the master regulator of tight junction opening — release in all human gut epithelium. Not just in coeliacs. Not just in the genetically susceptible. Every person who eats wheat experiences some degree of tight junction opening.
The CXCR3 receptor that gliadin binds to is not a genetic variant — it is standard human gut architecture. Similarly, the glycaemic response to white rice is not person-specific in its mechanism; the insulin demand is universal. So at a mechanistic level, nobody is truly immune. The question is what determines why some people eat bread daily for 80 years and appear to suffer no obvious consequence.
Where Resilience Enters
Several factors determine how much damage accumulates and how quickly it becomes clinically visible:
Probably the biggest variable. A diverse, robust microbiome produces short-chain fatty acids — particularly butyrate — that actively reinforce tight junction integrity and counteract zonulin-driven permeability. Someone with excellent microbial diversity may be continuously repairing the barrier that gliadin is loosening, maintaining rough equilibrium. Someone with dysbiosis has lost that repair capacity, and the same gliadin exposure tips them into net permeability.
These variants determine whether the immune system mounts an adaptive response to gliadin peptides once they cross the permeable gut wall. Roughly 30–40% of the population carries them, though only ~1% develop full coeliac disease. But this is not binary: HLA-DQ2/8 carriers without coeliac disease still mount a subclinical immune response that is absent in non-carriers.
Someone with a HOMA-IR of 0.8 has insulin receptors that are highly responsive — the metabolic hit from a grain meal is absorbed and cleared efficiently. Someone already at HOMA-IR 2.5 is adding grain-driven insulin spikes onto a system already struggling, accelerating receptor down-regulation much faster.
High cortisol independently increases gut permeability, interacting directly with zonulin pathways. A stressed person eating the same grain as a calm person experiences greater combined barrier disruption — two inputs driving the same mechanism simultaneously.
The more accurate framing is not "some people are fine with grains" but rather "some people have sufficient resilience that the damage remains subclinical for longer, or manifests in ways that aren't obviously connected to grain consumption."
The person who eats sourdough every day and appears healthy at 70 may simply have had excellent microbial diversity, low stress load, and sufficient insulin sensitivity to stay below the threshold where the cumulative damage becomes symptomatic — or they may be carrying silent arterial stiffness, a HOMA-IR of 1.8, or early cognitive decline that hasn't yet crossed a diagnostic threshold.
"But my grandfather ate bread every day and lived to 90." The answer is that the grandfather probably also had a genuinely different microbiome — less antibiotic exposure, more fermented foods, more physical labour — ate far less refined grain than his grandchildren, and likely had the constitutional resilience that kept him subclinical. It doesn't mean the mechanism wasn't operating. It means he stayed below the damage threshold long enough. The mechanism was always present.
The Three Foundational Fasano Papers
Fasano identified zonulin as the only known physiological modulator of intercellular tight junctions, involved in the trafficking of macromolecules between the environment and the host. The paper established that zonulin controls the equilibrium between tolerance and immune response to non-self antigens — laying the foundation for all subsequent research connecting dietary triggers, gut permeability, and systemic disease.
pubmed.ncbi.nlm.nih.gov/10801176Fasano's group established that gliadin induces a MyD88-dependent zonulin release leading to increased intestinal permeability. Gliadin was shown to bind to the CXCR3 receptor, triggering zonulin release and tight junction opening in wild-type but not CXCR3-deficient mice. This is the definitive mechanistic paper establishing exactly how gliadin opens the tight junctions.
pubmed.ncbi.nlm.nih.gov/18485912Fasano expanded the zonulin framework beyond coeliac disease, demonstrating that luminal zonulin release is stimulated by gliadin exposure or microbiome imbalance. Zonulin then binds epidermal growth factor receptor and activates protein kinase C-α, causing cytoskeletal rearrangement and displacement of tight junction proteins ZO-1 and occludin. This is his magnum opus — connecting gut permeability to the full spectrum of inflammatory and autoimmune conditions.
journals.physiology.org/doi/full/10.1152/physrev.00003.2008This document is for educational purposes only.