When Gluten Causes Symptoms but It’s Not Celiac Disease
- Adriano dos Santos
- 1 day ago
- 6 min read
Sometimes the lab results are normal but the symptoms are not. For many people, gluten causes real fatigue, brain fog, and gut issues, even without celiac disease. It’s time we take those stories seriously.
Table of Contents:
It Started with a Familiar Story
What Is Non-Celiac Gluten Sensitivity (NCGS)
How Common Is It
The Genetic Layer: What NCGS Shares (and Doesn’t) with Celiac Disease
The Immune Profile: Distinct but Inflammatory
Gut Permeability and the Leaky Gut Link
NCGS or IBS? Why the Difference Matters
Can You Test for NCGS
What I Do Clinically
The Bottom Line: Your Symptoms Are Valid
It Started with a Familiar Story
I met a patient recently. Let us call her Julia. She had come to me after several years of frustration. Her symptoms included bloating, brain fog, fatigue, and intermittent joint pain. Standard laboratory results were unremarkable, and celiac disease had already been ruled out. Her gastroenterologist had diagnosed her with “IBS” and recommended stress management.
However, something did not quite add up. Julia had initiated a gluten-free diet on her own, and each time she attempted to reintroduce even a small portion of bread or pasta, her symptoms returned. I have observed this clinical pattern repeatedly, where the patient’s lived experience offers clearer insights than conventional diagnostics.
Today, emerging research is beginning to validate these observations.
What Is Non-Celiac Gluten Sensitivity (NCGS)?
Non-celiac gluten sensitivity is a clinical syndrome defined by gastrointestinal and extraintestinal symptoms that occur in response to gluten ingestion, without the serological markers of celiac disease or evidence of wheat allergy (Cárdenas-Torres F. et al., 2021). Unlike celiac disease, NCGS does not cause intestinal villous atrophy, nor does it activate an IgE-mediated allergic response.
Yet the symptoms are very real. Clinically, I most often see:
Bloating
Abdominal pain
Brain fog
Fatigue
Diarrhea or constipation
Headaches
Joint and muscle aches
Dermatologic flare-ups (Cárdenas-Torres F. et al., 2021)
Diagnosis remains challenging. Without reliable biomarkers, we rely on clinical exclusion, ruling out celiac disease and wheat allergy, followed by response to a gluten-free diet and, if tolerated, a gluten reintroduction (Cárdenas-Torres F. et al., 2021). In practice, many patients self-identify based on symptom patterns, often years before receiving professional validation.
How Common Is It?
Prevalence data vary widely. Depending on the population studied and diagnostic criteria used, rates of self-reported NCGS range from 0.49% to as high as 14.9% (Cárdenas-Torres F. et al., 2021). These discrepancies reflect a lack of standardised testing, cultural dietary patterns, and patient awareness.
Still, conservative estimates suggest NCGS may affect 1 to 2 percent of the population, similar to or even exceeding rates of celiac disease (Waffle V. 2020). That represents millions of individuals worldwide whose symptoms remain overlooked, misunderstood, or misattributed.
The Genetic Layer: What NCGS Shares (and Doesn’t) with Celiac Disease
Celiac disease is strongly associated with HLA-DQ2 and DQ8 haplotypes. Over 98 percent of patients carry one or both (Cecilio Arantes L. & Bonatto M. 2015). However, these genes are also found in up to 40% of the general population, most of whom never develop celiac disease (Cecilio Arantes L. & Bonatto M. 2015).
What about NCGS? HLA-DQ2/8 is not required for diagnosis, but evidence suggests that individuals who carry these genes may be more likely to experience immune or gut changes in response to gluten. In one clinical trial, patients with IBS-D who were HLA-DQ2/8 positive experienced measurable improvements on a gluten-free diet, while also exhibiting increased intestinal permeability and tight junction gene dysregulation after gluten exposure (Vazquez-Roque M. et al., 2014).
In practice, when I see IBS symptoms coupled with these genetic patterns, I consider gluten sensitivity a strong possibility, especially if extraintestinal symptoms are also present.
The Immune Profile: Distinct but Inflammatory
Unlike celiac disease, which is marked by an IgG1 and IgG3 dominant response and extensive villous damage, NCGS appears to engage a more modulated immune profile. Research shows that affected individuals exhibit elevated IgG2 and IgG4 levels, which reflect a more mature but still active immune response (Waffle V. 2020).
One biomarker that appears in both conditions is FABP2 (intestinal fatty acid binding protein), which indicates damage to the intestinal lining. However, in NCGS, FABP2 correlates with IgG4 rather than the more inflammatory IgG3 (Waffle V. 2020).
We also see elevations in innate immune markers like IL-10, TNF-α, and CXCL10 in NCGS patients, pointing to both innate and adaptive pathways being involved (Cárdenas-Torres F. et al., 2021). Clinically, this may explain why patients often report diffuse symptoms, ranging from cognitive issues to systemic fatigue, even without overt gut inflammation.
Gut Permeability and the Leaky Gut Link
In my clinical work focused on the microbiome and mucosal integrity, I often assess whether the intestinal lining can maintain its barrier function under physiological stress. In patients with non-celiac gluten sensitivity (NCGS), this barrier is frequently compromised (Cárdenas-Torres F. et al., 2021; Waffle V. 2020).
A Mayo Clinic trial demonstrated that gluten ingestion significantly increased intestinal permeability in HLA-DQ2/8-positive IBS-D patients. This was measured by elevated mannitol excretion and increased lactulose to mannitol ratios, both reliable markers of tight junction disruption (Vazquez-Roque M. et al., 2014). Additional studies have confirmed that gluten can impair tight junction protein expression, even in individuals without celiac disease (Cárdenas-Torres F. et al., 2021).
What is particularly notable is that these effects appear to be reversible. When gluten was removed from the diet, intestinal permeability normalised and symptoms improved (Vazquez-Roque M. et al., 2014; Waffle V. 2020). Clinically, this reinforces an important insight: when patients report rapid improvement after eliminating gluten, impaired barrier function may be the underlying driver.
NCGS or IBS? Why the Difference Matters
Clinically, many NCGS patients are initially diagnosed with IBS. The overlap is significant, particularly with diarrhea-predominant IBS (IBS-D), but there are key distinctions.
Research shows that up to 37 percent of IBS-D patients carry HLA-DQ2 or DQ8 and may exhibit immune changes after gluten exposure, including altered cytokine levels and increased gut permeability (Vazquez-Roque M. et al., 2014). Unlike IBS, however, NCGS often involves extraintestinal symptoms such as headaches, joint pain, or skin irritation (Cárdenas-Torres F. et al., 2021).
That distinction matters. If a patient’s IBS symptoms worsen after gluten ingestion and improve rapidly on a gluten-free diet, it may not be IBS at all.
Can You Test for NCGS?
This remains the most challenging part. At present, there is no gold-standard diagnostic test for NCGS. The Salerno criteria remain the best available framework:
Exclude celiac disease and wheat allergy
Initiate a strict gluten-free diet for six weeks
Reintroduce gluten in a double-blinded, placebo-controlled challenge (Cárdenas-Torres F. et al., 2021)
In reality, few patients are willing to reintroduce gluten once they feel better, especially after years of symptoms. Add to this the high nocebo rate (up to 40% react to placebo), and diagnosis becomes even murkier.
Still, some promising biomarkers are emerging. Elevated IgG4 and FABP2 may support a diagnosis of NCGS once celiac has been ruled out (Waffle V. 2020). These are not yet widely used, but they can support a clinical hypothesis when interpreted alongside the patient’s history and symptoms.
What I Do Clinically
When I suspect NCGS, especially in patients with IBS-like symptoms and fatigue, I often:
Review HLA-DQ2/8 status
Assess markers of gut permeability (e.g., lactulose: mannitol ratio, FABP2)
Consider IgG subclasses to gluten
Trial a six-week elimination and reintroduction protocol, using symptom tracking
Support mucosal integrity with glutamine, zinc carnosine, and butyrate
Address circadian misalignment, which can amplify gut permeability and inflammation
Personalised strategies are essential. For patients with mitochondrial dysfunction, dysbiosis, or stress-related barrier disruption, gluten reactivity is often just one piece of a larger puzzle.
The Bottom Line: Your Symptoms Are Valid
Non-celiac gluten sensitivity is not “in your head.” It is a biologically distinct condition that involves real immune changes, real barrier dysfunction, and real patient stories, such as Julia’s.
If your lab results have been normal but your symptoms persist, you are not alone. Gluten sensitivity without celiac disease is increasingly recognised, and you deserve thoughtful, science-informed care.
Let’s Stay Connected
If this article resonated with your experience, consider sharing it. Someone else may be looking for the answers it offers.
Subscribe to my monthly newsletter for insights on gut health, immunity, circadian rhythms, and clinical strategies you can apply.
Click here to receive the next issue.
References:
Cárdenas-Torres F., Cabrera-Chávez F., Figueroa-Salcido O., Ontiveros N. (2021). Non-Celiac Gluten Sensitivity: An Update. MDPI. Medicina. doi: 10.3390/medicina57060526
Cecilio Arantes L., Bonatto M. (2015). THE PREVALENCE OF HLA DQ2 AND DQ8 IN PATIENTS WITH CELIAC DISEASE, IN FAMILY AND IN GENERAL POPULATION. ABCD. Arquivos Brasileiros de Cirurgia Digestiva. doi: 10.1590/S0102-67202015000300009
Vazquez-Roque M., Camilleri M., Smyrk T., Murray J., Marietta E., O’Neill J., Carlson P., Lamsam J., Janzow D., Eckert D., Burton D., Zinsmeister A. (2014). A Controlled Trial of Gluten-Free Diet in Patients with Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function. Gastroenterology aga. doi: 10.1053/j.gastro.2013.01.049
Waffle V. (2020). Non-Celiac Gluten Sensitivity Shows Distinct Immune Response. Celiac Disease Foundation.