Original article: 2016 Romilly Hodges MS CNS IFMCP
Updated: Sept 2020 by Jessica Kovalchik, DC MSACN and Josette Herdell MS CNS to include additional symptoms associated with leaky gut, and recently-published factors that decrease and increase intestinal permeability. Approved by Romilly Hodges.
What’s in your leaky gut protocol? Perhaps it’s time to expand beyond basic diet and 4/5-R supplements… did you know that many more factors influence permeability, including specific food bioactive compounds, hormones, microbes, antigens, additives, pesticides, mold, and lifestyle practices? Read on for our extensive list of intestinal barrier modulators, and find out why we don’t think of leaky gut as an ON or OFF state.
For practitioners of functional medicine, one of the core principles for optimizing health is supporting the gut. The health of our gastrointestinal system is intricately connected to systemic health since it alters nutrient availability, immune activity (more than 60% of our immune system resides in the gut), levels of inflammation, elimination of toxins and wastes, and more. Restoring intestinal barrier integrity is obviously a key goal where increased intestinal permeability is indicated, and is commonly addressed with the use of supplements such as glutamine, zinc carnosine, DGL, marshmallow and aloe.
Selected symptoms and conditions associated with leaky gut:
Abdominal distention (A)
Abdominal pain (H)
Acne (H)
Allergies (R)
Amyotrophic lateral sclerosis (R)
Ankylosing spondylitis (A)
Autoimmune disease (H, A)
Brain fog
Celiac disease (H)
Crohn’s disease (R)
Constipation (H)
Depression (H)
Diabetes-type 2 (H)
Diarrhea (H)
Dysbiosis (A, H)
Eczema (H)
Elevated histamine (H)
Fatigue (R)
Food intolerance (H)
Gastroenteritis (H)
Hives (H)
Hypochlorhydria (H)
Irritable bowel syndrome (H)
Inflammation (H, V, V, V)
Inflammatory bowel disease (A, H)
Migraine headaches (R)
Non-alcoholic fatty liver disease (H)
Obesity (independent of diet) (A)
Obstructive jaundice (H)
Obstructive sleep apnea (H)
Psoriasis (H)
Rosacea (H)
SIBO (H)
Ulcerative colitis (H)
Yeast (candida) (V)
References (A: animal study; H: human study; R: review; V: in vitro)
However, there is more to know when it comes to supporting the health of the intestinal barrier. Yes, those interventions are helpful and restorative, but there are other factors, including non-nutraceuticals, that we can consider as well. In addition, we have to recognize that intestinal permeability is naturally dynamic and that ‘leakiness’ is rather more a sliding scale than binary state.
Regulating the Intestinal Barrier
The intestinal barrier is actually incredibly thin—just a single layer of epithelial cells separates the intestinal lumen from the underlying tissue. These cells are primarily absorptive enterocytes, but also consist of specialized cells with secretive, hormonal and immune functions. All these cells are held together by junctions that play a crucial role in regulating what is allowed to cross the intestinal barrier.
One particular type of junction is the ‘tight junction,’ which form complexes with the cell cytoskeleton. This is facilitated by transmembrane proteins including occludin, claudin and JAM proteins that provide the physical connections between cells. Plaque proteins, such as zonula-family proteins (Z01/2 and Z01/2/3 in the figure below) anchor the transmembrane proteins to the actin cytoskeleton.
Figure 1: Structure of Tight Junctions (from Ulluwishewa et al, 2011)
Various signaling pathways, both internally and externally-driven, alter the function and expression of these proteins leading to either increased or decreased barrier permeability. Any disruption to the cytoskeleton or the transmembrane proteins is associated with reduced barrier integrity. For instance, gliadin causes the release of zonulin and loss of tight junction integrity, even in non-celiac, non-gluten-sensitive individuals. But is this always a concern?
A Barrier in Flux
We have a tendency to talk about leaky gut like an ON/OFF switch; either you have it or you don’t. The reality is that gut permeability is shifting continually depending on regulatory factors and environmental inputs. Externally-driven, transient shifts in permeability are something that drug manufacturers and researchers pay attention to, and even take advantage of, to enhance drug delivery across the GI mucosa.
Likely not all of these shifts in barrier integrity should be considered pathological. Phytic acid, for example, has been shown to transiently increase intestinal permeability, allowing for greater absorption of beneficial phytonutrients such as quercetin and kaempferol. Rather a different view of a compound that has been maligned for its mineral-chelation (antinutrient) properties! Perhaps small amounts of gluten in a non-sensitive person with an otherwise healthy gut isn’t a big concern (although it’s all-too-easy to end up with bagel for breakfast, sandwich for lunch and pasta dinner, all of which adds up to rather too much gluten!).
In today’s environment, our gut is continually exposed to substances that undermine its integrity. Pesticides, food additives, excess sugar, NSAIDs and antibiotics are just some of the culprits in promoting widespread loss of healthy barrier function. If there is significant gut damage, fluctuations may not be getting into a healthy, regulated range at all, and that needs our attention. Even a transient shift towards increased permeability in someone who, say, has an autoimmune condition, might exacerbate the underlying disease pathophysiology. Gluten is certainly worth avoiding in these circumstances.
Extending our View of Intestinal Barrier Modulators
We have compiled an expanded list of factors (with references) that have been shown to affect intestinal permeability.
As we’ve argued, not all factors that increase permeability should be automatically considered pathological in every situation. Dose, chronicity of exposure, and ability to recover normal permeability may determine the extent of clinically-relevant damage. However, some factors may be especially useful to avoid when working to restore a healthy level of gut integrity from a low baseline.
Of course, this is a work-in-progress as the research in this area only continues to come forth.
DIETARY COMPONENTS
- Antioxidant polyphenols (V)
- Butyrate (ghee, prebiotics) (A, A, A, A)
- Casein (A)
- Colostrum (H, H, A)
- Conjugated linoleic acid (A)
- Cruciferous vegetables (A)
- Fermented foods (V)
- Fiber (R, A)
- Fruits (R)
- Garlic (A)
- Ginger (A)
- Laminaria japonica extract (edible brown seaweed) (V)
- Lactoferrin (in breast milk) (V)
- Oats (A)
- Olive oil (A)
- Whey (A, A, A)
NUTRIENTS AND NUTRACEUTICALS
- Amino acids (R)
- Arginine (V)
- Berberine (A)
- Calcium (A)
- DGLA (V)
- DHA (A)
- Elemental diet (A)
- EPA (A)
- Folate (H)
- Citrulline (A)
- Glutamine (H, R)
- Glycine (V)
- Lipoic acid (A)
- N-acetyl cysteine (NAC) (A)
- Phosphatidylcholine (V)
- Prebiotic galacto-oligosaccharides (GOS & BMO – Bovine milk oligosaccharides) (A, A)
- Psyllium fiber (A)
- Resveratrol (V, A)
- Selenium (A, A, A)
- Tryptophan (H)
- Vitamin A (as retinoic acid) (H, V)
- Vitamin C (H) – see also ‘factors that increase…’
- Vitamin D (H, V, V)
- Vitamin E (A, A)
- Zinc carnosine (H, V)
BOTANICALS AND FOOD BIOACTIVES
- Agaricus mushroom (selenium enriched) (A)
- Aloe (V)
- Anthocyanins (V)
- Apple polysaccharides (A)
- Astragaloside IV (from Astragalus membranaceus root) (A)
- Berberine (Goldenseal) (A)
- Boswellia serrata (Frankincense) (V)
- Chitosan (type of fiber) (V)
- Cinnamomum japonicum (V)
- Curcumin (turmeric) (A, A)
- EGCG (green tea) (V)
- Flavonoids (V)
- Ginkgo biloba (A)
- Ginseng (Panax ginseng oligopeptides GOP) (A)
- Grape seed extract (A)
- Hesperidin (V)
- Licorice (DGL) (V)
- Marshmallow (H)
- Moxibustion (dried mugwort) (A)
- Naringenin (citrus) (A)
- Oregano (A)
- Polysaccharides (rhamnogalacturonan) (V)
- Quercetin (apples, onion, parsley, and many more plant foods) (R)
- Rhubarb (H)
- Sinensetin (found in citrus peel) (V)
- Slippery elm (H)
- Thymol (thyme) (A)
- Triphala (A)
- Vanillin (vanilla) (A)
LIFESTYLE
- Avoidance of toxins (inferred)
- Judicious use of pharmaceuticals (avoidance where possible, inferred)
- Moderate exercise (inferred)
- Regular sleep/circadian cycles (inferred)
- Stress management (inferred)
REGULATORY SUFFICIENCY
MICROBES (COMMENSAL)
- Akkermansia (A)
- Bifidobacterium animalis (A)
- Bifidobacterium infantis (V, V)
- Bifidobacterium lactis (H, V)
- Bifidobacterium longum (H)
- Clostridium tyrobutyricum (V)
- Eschericia coli nissle (not to be confused with pathological E. coli strains) (V)
- Faecalibacterium (H)
- Lactobacillus acidophilus (H, V, V)
- Lactobacillus bulgaricus (H)
- Lactobacillus plantarum (H)
- Lactobacillus reuteri (H, V)
- Lactobacillus rhamnosus (H)
- Odoribacter (H)
- Rikenellaceae (H)
- Ruminococcaceae (H)
- Saccharomyces boulardii (H)
- Streptococcus thermophilus (V)
MEDICATIONS
DIETARY COMPONENTS
- Alcohol (V)
- Fast foods and processed foods (H)
- Food additives (A, H)
- Food antigens (IgE-mediated allergy) (R, H)
- Gliadin (gluten) (R)
- Lectins (A, V)
- Palmitic acid (A, V)
- Phytic acid (V)
- Saccharin (A, V)
- Sugar (H)
NUTRIENTS AND NUTRICEUTICALS
- Ascorbic acid (vitamin C) (H) – see also ‘factors that decrease…’
- Proteases (trypsin, chymotrypsin, proteolytic enzymes important for protein digestion) (V)
- Zinc deficiency (A, H)
BOTANICALS AND FOOD BIOACTIVES
- Capsianoside (paprika, Cayenne, peppers) (V)
- Genistein (soy, non-fermented) (A, A)
- Proteolytic enzymes papain and bromelain (V)
- Senna (V)
LIFESTYLE
- Concussion (A)
- Exercise (high intensity) (H, H)
- Exercise-induced splanchnic hypoperfusion (H)
- Night shift work (coupled with alcohol) (H)
- Stress (including subacute/chronic) (A, A, A, A)
REGULATORY
- Cortisol (H)
- Histamine (H)
- Inflammation (via NFkB, TNFalpha, IL-23) (V, V, V)
- MMP-9 (an enzyme that’s involved in degradation of extracellular matrix) (A)
MICROBES (PATHOLOGICAL)
XENOBIOTICS
- Arsenic (A)
- Acrolein (V)
- Bisphenol-A (A)
- Chlorpyrifos (pesticide) (A)
- Glyphosate (pesticide) (V)
- Mercury in food (V)
- Mycotoxins (V)
- Titanium dioxide (E171) in food (V)
- Polychlorinated biphenols (V)
MEDICATIONS
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As alway a great review. DrKF is a leading interpreter of science for us consumers of science on the front line of pt care. Thank you.
Great article!
Thank you so much!
Laurie Love
Thank for this thorough compilation of research. It’s a handy resource!
Wonderful helpful summary – thank you!
Would you consider chemotherapy as a contributing factor to leaky gut?
http://www.naturalmedicinejournal.com/journal/2014-02/leaky-gut-and-chemo
absolutely- chemo can be a contributing factor to leaky gut. Glad you liked the blog! DrKF
Hi, thanks for the information! I am in the process of healing my gut (a period of unusually high stress was the cause, I believe), and have been having some steady success with certain supplements and dietary changes, as well as meditation and qi-gong.
However, I recently was cautioned against continuing to take glutamine. A Dr. Blaylock has been saying that he does not recommend it for healing leaky gut. Are you familiar with his research and if so, what are your thoughts?
Here is a snippet of a response he gave to someone:
Dr. Blaylock’s Answer:
Yes, the glutamine you are taking is the same I mentioned. I do not recommend supplementing with glutamine because it is converted to the excitotoxin glutamate and has been shown to worsen certain neurodegenerative diseases. Though it has become a popular supplement for gastrointestinal repair, many studies do not support this indication.
Thanks for your time!
Vanessa
While glutamine does convert to glutamate, all of our other amino acids do, too. And the bulk of glutamine is used locally- right in the gut. So for that reason, I don’t think you need to be too concerned. I do respect Dr. B’s work, however- so if he suspects you’re sensitive, then follow his suggestions. I agree with him that long term glutamine probably isn’t such a great idea, however. It can be converted to glucose more readily than other amino acids. DrKF
Great article Dr. Kara! Thank you for being such a great resource to clinicians and patients alike.
Thanks, Artemis!! Great to hear from you 🙂
Great article, thank you. Would you also add histamine to the factors that increase leaky gut?
Hi Jane,
Welcome! For sure! Histamine should definitely be on there – we will update accordingly.
Take care,
Dr. KF
Thank you for putting this together – it is a great resource!
You’re welcome! Check back for updates intermittently, we’re going continue to build it out. – DrKF
I’m confused – you mentioned marshmallow as one of the key ingredients for addressing increased gut permeability and then listed TiO2 (titanium dioxide) as a chemical which increases gut permeability. Marshmallows ordinarily contain TiO2 as an ingredient so it seems a little paradoxical to have it listed as both cause and treatment for gut permeability.
If you could better explain this to me, I would be very grateful.
Thanks for bringing this up – this is actually an important point to clarify. The herb referenced in the article was for marshmallow root (an herb that has terrific mucus-forming properties useful for healing leaky gut). You’re correct, marshmallows the confectionary food, have been measure and shown to contain TiO2 – however the processed food is unrelated and has an unfortunately similar name.
You can learn more about marshmallow root here: https://www.mountainroseherbs.com/products/marshmallow-root/profile
Excellent article! Not as simple as on or off!
Why is Vitamin C in both columns?
Vitamin C has been found to both increase and decrease intestinal permeability. You can think of gut permeability as dynamic, expanding and contract in response to various factors. The problem typically arises from excessive permeability, or hyperpermeability. As we learn more about the mechanisms, we may gain a better understanding of how certain nutrients play a duel role.
I have been suffering form acid for 18 months. I had the camera down into my stomach 13 months ago, it came back as a nervous sphincter do to anxiety. I am really struggling. My doctor as me on pentaprozil, but this in turn is giving me joint problems. I have often wondered if all of my symptoms could be hormonal. I’m am 56. Any advice would be much appreciate.
Hi Debbie! Thanks for reaching out. Unfortunately I can’t give medical advice over the internet. If you would like to make an appointment, please click here: https://www.drkarafitzgerald.com/contact-2/
Great article! Given how often digestive enzymes are suggested to assist digestion, yet they are listed as leaky gut instigators, should they be avoided during gut treatment?
I absolutely love this consolidated list, thank you for the work you are doing!
Excellent resource, especially the list of things that increase and decrease gut permeability. Thank you for these wonderful articles!
I have consistently had low bifidus in microbiome testing despite my best efforts. I suffer from 23 years of chronic illness and despite my best efforts with functional medicine, integrative medicine, diet and lifestyle have not been able to stop progression. Neurodegenerative symptoms similar to MS with no diagnosis, fibro etc. long complex history. Have you been able to increase bifidus in gut samples? If so, how?
That’s certainly frustrating that you’ve not had success so far. We have seen success in improving Bifido species (and general balance). Some cases are more challenging than others – and individual variation, environment, infections, and stress all impact success. In some cases, fecal transplant might offer the most significant solution. Best of luck!
That’s certainly frustrating that you’ve not had success so far. We have seen success in improving Bifido species (and general balance). Some cases are more challenging than others – and individual variation, environment, infections, and stress all impact success. In some cases, fecal transplant might offer the most significant solution. Best of luck!