When we talk about an increase in intestinal permeability or ‘leaky gut’ – this means that the gaps in between the cells in the small intestine, remain open when they shouldn’t—allowing substances such as pathogens, undigested food and toxins, to pass through into the blood stream. This can happen due to excessive use of certain medications (e.g Ibuprofen & other painkillers), excess alcohol, eating foods that are causing inflammation or antibiotic use.
Once in the blood stream these substances trigger more inflammation and become an underlying driver for inflammatory conditions. Although this concept remains controversial in mainstream medicine, there is much published research linking increased gut permeability with autoimmune diseases: Rheumatoid Arthritis, MS, Celiac and Crohn’s Disease. Not as the original cause, but a factor that keeps the dysregulated immune response going. There is growing research now also around Hashimoto’s and other autoimmune conditions.
In mainstream medicine, leaky gut is usually seen as a feature of another condition such as Crohn’s disease or Coeliac disease and is not considered as a ‘stand-alone’ diagnosis. Whereas in Functional Medicine is recognised as a driving force of a number of different chronic inflammatory conditions and something that can be treated.
There are tests available to investigate this issue, however it is difficult to find a test that looks directly at the permeability of the gut lining and, as is often the way in functional medicine, it is more about putting together pieces of the puzzle – combining several different markers alongside the patient’s symptoms and history to form logical conclusions and a pathway for healing.
It is possible to get information around gut permeability from stool, urine and blood assessment:
Analysis via Stool and Microbiome
Several laboratories offer microbiome tests (looking at gut bacteria) via stool analysis which include some kind of assessment for ‘leaky gut’.
What they are actually looking at is certain bacteria, whose presence at lower (or higher levels) can be an indication of poor gut lining health. For example, there is a bacterial species called Akkermansia Muciniphila bacteria which live in the gut mucosa (lining), this bacteria has been shown to strengthen mucosal layers, improve tightness of gaps between cells, and reduce inflammation, reducing permeability. Studies have shown that reduced levels of A.Muciniphila leads to increased movement of inflammatory toxins (LPS) into the bloodstream from the gut (Mo et al 2024). Another bacteria called Roseburia supports the health of the gut lining by producing butyrate (the primary fuel for the cells of the gut lining) (Nie et al 2021). This bacteria reduces inflammation and supports barrier function. Microbiome stool tests assess groups of these bacteria and then calculate, depending on the levels of these species, how likely it is that the gut barrier is strong. Although these markers are now fairly well supported in the literature, they are not measuring the permeability directly, so can only give us clues around whether or not the gut is permeable and the extent of the problem.
Larger, more comprehensive stool tests also include inflammatory markers such as secretory IgA (SIgA). This marker is giving us a more direct assessment of a triggered immune system (inflammation) in the gut lining, which can indicate potential damage. This type of inflammation is usually caused by a food sensitivity or an immune system reaction to a microbe in the gut. SIgA move up and down a lot, it can be elevated one week, but normal the next, depending on exposures in the environment, for example if you have eaten gluten and had an immune response, this marker may stay elevated for a while but then drop down if there are no more exposures. If SigA is elevated, it is an indication that there is inflammation and potentially increased risk of permeability.
Stool Zonulin is a separate marker that can be elevated if there is leaky gut present. however, if it is not raised then it does not rule out IP. It is often included in the larger stool panels and advocated as a marker of leaky gut, however, the literature around this marker is controversial with some studies showing this marker as being misleading (Power et al 2021, Massier et al 2020). Personally, I don’t find this marker very helpful.
Analysis via Urine
The Lactulose / mannitol test is the one that looks more directly at the permeability of the gut lining and has been a more standadised method of testing (Sequeira 2014). It involves the patient drinking a solution containing sugars of different sized particles (lactulose and mannitol) and then measuring them in the urine to give an answer of how much of each particle got through the gut lining. This test has been documented in the literature for use with Crohn’s disease and Coeliac (Gan et al 2022), however there is discrepancy in how the test is conducted and in the values of the Lactulose: Mannitol obtained. This test is not widely available in the UK and currently seems ‘out of stock’ from the main providers, I’m not sure the reason for this lack of availability.
Analysis via Blood / Serum
The third way is via blood analysis – looking at antibodies to Zonulin in the blood. Zonulin is a protein that controls the tight junctions / gaps between the cells, it decides what can pass through into the blood stream and what should stay in the gut). You can also test antibodies to a structural protein in the gut lining called Occludin. However, it is possible to still have intestinal permeability and not have elevations in these markers as there are other pathways such as inflammation, mucosal damage and microbial imbalance.
Other blood markers can assess levels of LPS – this is an inflammatory substance or ‘endotoxin’ which comes from bacteria and should remain in the gut. Higher levels of LPS in the blood can indicate an issue with the barrier function and can be used as a marker of increased intestinal permeability. Because higher levels of LPS activate the immune system, even small amounts may promote inflammation. But again, high LPS does not necessarily prove intestinal permeability because LPS levels can also be affected by diet, liver clearance, infections & bile acid function. But again, it can be an indicator used alongside other markers.
There are some laboratories that offer a test including blood zonulin, occludin, LPS and also Candida (yeast found it the gut lining, if detected in the blood at higher levels this can be an indicator of microbes translocating through a gut lining that is too permeable)
These blood tests are not looking directly at gut permeability. But we are saying – the immune system appears reactive to the gut barrier / structure / endotoxins.
In conclusion : There are several different methods of assessing for gut permeability and the type of test would depend on your budget and also the wider picture of your health. A comprehensive stool analsis, aswell as looking for markers around intestinal permeability, will also give a range of other indicators on gut health that maybe linked with bloating, constipation, diarrhea, infection. The blood markers, whilst more specific to intestinal permeability, tend to be cheaper but miss out on some of the larger picture. If you want to chat more about whether one of these tests might be helpful for you, you can book a free consultation here: www.gutinsight.co.uk/book
Available Tests
KBMO laboratory : ‘Gut Barrier Panel’ (£150) which is a blood – finger prick, dried blood test. Asssess serum zonulin and occluding, plus also Candida and LPS.
Cyrex Laboratories: The Cyrex Array 2 from the US lab (£260) measures antibodies to zonulin, occludin and Actomyosin which is a structural protein of the gut lining. It also measures antibodies to LPS – the inflammatory particles produced by certain types of bacteria, that should stay sealed in the gut. The Cyrex Array 2 requires a phlebotomy draw which adds another £50 to the price.
Genova Diagnostics: GI Effects Comprehensive (£375) includes SIgA, Butyrate and panel of microbes including Akkermansia Muciniphila.
Microba: Microbiome Explorer (£400) Includes a whole group of markers pulled together to assess ‘intestinal barrier’ including SIgA, Zonulin, Butyrate producing microbes & LPS producing microbes.
References
Sequeira et al 20214. Standardising the lactulose mannitol test of gut permeability to minimise error and promote comparability
https://pubmed.ncbi.nlm.nih.gov/24901524
Gan et al 2022. A case for improved assessment of gut permeability: a meta-analysis quantifying the lactulose:mannitol ratio in celiac and Crohn’s disease.
https://pubmed.ncbi.nlm.nih.gov/35012471
Mo et al 2024. The influence of Akkermansia muciniphila on Intestinal Barrier Function
https://link.springer.com/article/10.1186/s13099-024-00635-7
Nie et al 2021. Roseburia intestinalis: A Beneficial Gut Organism From the Discoveries in Genus to the Applications.
https://pubmed.ncbi.nlm.nih.gov/34881193
Massier et al 2020. Blurring the picture in leaky gut research: how shortcomings of zonulin as a biomarker mislead the field of intestinal permeability.
https://pubmed.ncbi.nlm.nih.gov/33037053
Power et al 2021. Serum Zonulin Measured by Commercial Kit Fails to Correlate With Physiologic Measures of Altered Gut Permeability in First Degree Relatives of Crohn’s Disease Patients
