Intestinal Permeability —
The Leaky Gut Explained
Intestinal permeability is a measurable physiological state — not a speculative concept. When the gut lining is compromised, it drives food sensitivity, systemic inflammation, immune dysregulation, and symptoms that appear far removed from the gut. Here is what it is, what causes it, what it drives, and how it is assessed in UK clinical practice.
What Intestinal Permeability Actually Is
The gut lining is a single cell layer thick — roughly the surface area of a tennis court — held together by tight junction proteins that act as gatekeepers between the gut contents and the bloodstream. These proteins — including occludin, claudin, and zonulin-regulated junctions — control what passes through: nutrients in, everything else out.
When this barrier is compromised, the tight junctions open beyond their normal parameters. Partially digested food particles, bacterial fragments, lipopolysaccharides (LPS) from gram-negative bacteria, and other substances cross into circulation that should not. The immune system — 70-80% of which is located in the gut — encounters these substances and mounts a response. Over time, this drives chronic low-grade inflammation that can manifest as symptoms far removed from the gut itself.
The term "leaky gut" is informal, but the physiology is not speculative. The measurement of it is where this page used to be wrong, and the correction is worth stating before anything else. An earlier version of this page told you zonulin is measurable in blood and that elevated levels indicate an open barrier. That is not supportable. The biology of tight junction regulation stands; the blood test sold to assess it does not measure what it claims to. The section on testing, below, sets out why in full.
So the honest framing is this: barrier dysfunction is real, it matters clinically, and measuring it in routine practice is genuinely hard. Everything that follows is written to that standard rather than to the standard of a test we would like to sell.
The mainstream medical hesitation around leaky gut is not about the physiology — intestinal permeability as a measurable state is well established. The hesitation is about causation: whether increased permeability is a driver of systemic disease or a consequence of it, and whether treating it as a primary clinical target produces meaningful outcomes. The functional medicine position is that it is a clinically significant modifiable factor — one piece of a picture that also includes the microbiome, the immune system, the neuroendocrine axis, and the person's full history. It is not treated as a single cause. It is investigated as one component of a systemic pattern.
Symptoms Associated with Increased Permeability
The symptoms associated with intestinal permeability are often diffuse and non-specific — which is part of why it goes unrecognised through conventional routes. The common thread is systemic immune activation: the body responding to substances that have crossed a barrier they should not have crossed.
- Bloating and distension
- Alternating bowel habits
- Food reactions and intolerances
- Nausea after eating
- Abdominal discomfort
- Chronic fatigue
- Recurrent infections
- Autoimmune flares
- Joint pain and inflammation
- Skin conditions — eczema, psoriasis, rosacea
- Brain fog and poor concentration
- Anxiety and mood dysregulation
- Headaches
- Poor sleep quality
- Low motivation
These symptoms overlap significantly with many other conditions — which is precisely why intestinal permeability requires testing rather than assumption, and why a positive finding in isolation never tells the whole clinical story.
The Causes of Leaky Gut
Intestinal permeability is rarely the result of a single cause. In clinical practice it typically reflects the accumulated effect of multiple factors operating simultaneously — which is why it responds best to an approach that addresses the full picture rather than a single intervention.
Cortisol affects tight junction protein expression, and acute stress raises measured permeability in human studies. Grade: mechanism established; the chronic-stress-to-clinical-outcome step is inference. The gut–brain axis is described as running both ways — stress compromising the barrier, the barrier driving neuroinflammation — and the return leg is the less evidenced half.
An imbalanced microbiome — depleted beneficial bacteria, overgrowth of opportunistic bacteria or Candida — produces metabolites and toxins that damage the epithelial lining and disrupt tight junction integrity. H. pylori, SIBO, and Candida are all associated with increased permeability.
Gliadin triggers zonulin release in tissue models, and that pathway is often extended to people without coeliac disease. Grade: mechanistic, largely ex vivo — not outcome data in humans. Ultra-processed foods, emulsifiers, and food additives disrupt the mucus layer and microbiome composition that protect the epithelium.
Non-steroidal anti-inflammatory drugs increase gut permeability through prostaglandin inhibition — a well-documented effect even with short-term use. Antibiotics disrupt the microbiome that supports barrier integrity, with permeability effects that can persist long after the course is complete.
Alcohol and its metabolite acetaldehyde directly damage tight junction proteins and the intestinal mucosa. Regular alcohol consumption — even at moderate levels — is associated with measurably increased gut permeability and elevated LPS in circulation.
Zinc, vitamin D, and glutamine are essential for tight junction maintenance and epithelial repair. Deficiencies — common in the context of poor diet, stress, and chronic inflammation — impair the gut's capacity to maintain and restore barrier integrity.
How Intestinal Permeability is Actually Measured
This section used to recommend a blood panel built on serum zonulin. It no longer does, and the reason is not a change of opinion.
In 2018 a group including Alessio Fasano — the researcher who discovered zonulin and built the first assay for it — tested the widely used commercial ELISA against 376 samples. It did not correlate with haptoglobin genotype, which it must if it is measuring pre-haptoglobin 2. Antibody capture, mass spectrometry and Western blot followed: the kit did not detect recombinant pre-haptoglobin 2 at any concentration. A second group replicated it independently by a different route in 2019 and found the kits were binding haptoglobin and complement C3, concluding that the community should exercise caution until the methodology improves.
There is a second problem that settles it on its own. Haptoglobin has two alleles, and roughly 15% of people carry a genotype that cannot express pre-haptoglobin 2 at all. They cannot have zonulin. The assay returns a number for them anyway. A 2022 study using a newer kit found 27% of 217 people tested negative for serum zonulin entirely, with no relationship to sex, age or disease status.
And even granting that the kit measures something real, that something does not do the job. Tested head-to-head in the same people against the urinary lactulose-rhamnose ratio, serum zonulin showed no relationship at all (r = −0.016, p = 0.929). It correlated instead with waist circumference and hs-CRP. In a cohort of 363, neither gastrointestinal symptoms nor gastrointestinal disease had any influence on zonulin levels, while waist circumference, blood pressure and glucose did. The assay appears to read adiposity and inflammation, not gut barrier state.
The normative study of 13C-mannitol found a median interindividual coefficient of variation of 76.5% — which is the number that should govern how anyone talks about a permeability result. Cut-offs do not transfer between conditions or methods: 0.022 in Crohn's, 0.018 in cirrhosis, 0.030 for predicting Crohn's relapse, below 0.044 as a normal limit in children. And in 29 coeliac patients found by population screening, 16 had a lactulose/mannitol ratio within normal limits. These tests are real and imprecise. Neither statement cancels the other.
So what do we actually use? A stool panel, symptom history, dietary and medication review, and the rest of the five-test picture. That combination gives a reading consistent with barrier dysfunction and a clear sense of what is driving it — dysbiosis, inflammation, NSAIDs, alcohol, stress load. It is not a measurement of permeability, and this page will not describe it as one. If that seems like a weaker offer than a panel with a number on it, consider that the number was not measuring the thing.
The GI-MAP stool test provides additional permeability-relevant markers within the context of the full microbiome and pathogen picture:
| Marker | What it Indicates | Source |
|---|---|---|
|
Secretory IgA (sIgA)
|
Mucosal immune defence — low sIgA indicates depleted gut immune capacity; high sIgA indicates active immune challenge at the mucosal surface | GI-MAP |
|
Calprotectin
|
Neutrophil-derived inflammatory marker — elevated in active intestinal inflammation; used to monitor IBD and distinguish inflammatory from functional gut disorders | GI-MAP |
|
Zonulin (stool)
|
Not the same analyte as the blood test above. Tested against the sugar ratio, faecal zonulin was associated with permeability in overweight and obese cohorts only — better than the serum version, and not a general-purpose barrier measure. Grade: mixed, cohort-dependent. | GI-MAP |
|
Occult Blood
|
Presence of blood in stool — may indicate mucosal damage requiring investigation; contextualises other inflammatory findings | GI-MAP |
Addressing Leaky Gut — The Clinical Approach
Restoring gut barrier integrity requires addressing both the drivers that are maintaining permeability and the conditions needed for repair. This is not a supplement protocol — it is a multi-system intervention guided by what the test data shows rather than what is assumed.
Find What Is Driving It — Without Pretending to Measure It
GI-MAP stool analysis, food sensitivity testing, the DUTCH hormone panel, organic acids and blood chemistry make up the TDG Five-Test System. Together they show what is inflaming, irritating or depleting the gut and what to do about it. That is a different claim from measuring barrier permeability, and it is one the evidence actually supports.