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
Abdominal pain
Acne
Allergies
Brain fog
Celiac disease
Crohn’s disease
Depression
Diarrhea
Eczema
Fatigue
Food intolerance
Hives
Irritable Bowel Syndrome
Migraine headaches
Overweight/Obesity
Psoriasis
Rosacea
Ulcerative colitis
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, and key below) 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.
Factors that DECREASE Intestinal Permeability
DIETARY COMPONENTS
- Antioxidant polyphenols (V)
- Butyrate (ghee, prebiotics) (A, A, A)
- Casein (A)
- Colostrum (H, H, A)
- Conjugated linoleic acid (A)
- Cruciferous vegetables (A)
- Fermented foods (V)
- Fiber (R)
- Fruits (R)
- Garlic (A)
- Ginger (A)
- Oats (A)
- Olive oil (A)
- Whey (A, A)
NUTRIENTS AND NUTRACEUTICALS
- Amino acids (R)
- Arginine (V)
- Calcium (A)
- DGLA (V)
- DHA (A)
- EPA (A)
- Folate (H)
- Citrulline (A)
- Glutamine (H)
- Lipoic acid (A)
- N-acetyl cysteine (NAC) (A)
- Phosphatidylcholine (V)
- Prebiotic galacto-oligosaccharides (GOS) (A)
- Resveratrol (V)
- Selenium (A, A)
- Tryptophan (H)
- Vitamin A (as retinoic acid) (H, V)
- Vitamin C (H) – see also ‘factors that increase…’
- Vitamin D (H, V)
- Vitamin E (A)
- Zinc carnosine (H)
BOTANICALS AND FOOD BIOACTIVES
- Agaricus mushroom (selenium enriched) (A)
- Aloe (V)
- Berberine (Goldenseal) (A)
- Boswellia serrata (Frankincense) (V)
- Chitosan (type of fiber) (V)
- Curcumin (turmeric) (A, A)
- EGCG (green tea) (V)
- Flavonoids (V)
- Ginkgo biloba (A)
- Grape seed extract (A)
- Licorice (DGL) (V)
- Marshmallow (H)
- Moxibustion (dried mugwort) (A)
- Naringenin (citrus) (A)
- Oregano (A)
- Quercetin (apples, onion, parsley, and many more plant foods) (R)
- Rhubarb (H)
- 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)
- Bifidobacterium lactis (H, V)
- Bifidobacterium longum (H)
- Eschericia coli Nissle (not to be confused with pathological E. coli strains) (V)
- Lactobacillus acidophilus (H, V)
- Lactobacillus bulgaricus (H)
- Lactobacillus plantarum (H)
- Lactobacillus reuteri (H)
- Lactobacillus rhamnosus (H)
- Saccharomyces boulardii (H)
- Streptococcus thermophilus (V)
MEDICATIONS
Factors that INCREASE Intestinal Permeability
DIETARY COMPONENTS
- Alcohol (H)
- Fast foods and processed foods (H)
- Food additives (A, H)
- Food antigens (IgE-mediated allergy) (R, H)
- Gliadin (gluten) (H)
- High fat diets* (H)
- Lectins (A, V)
- Phytic acid (V)
- Sugar (H)
NUTRIENTS AND NUTRACEUTICALS
- Ascorbic acid (vitamin C) (H) – see also ‘factors that decrease…’
- Proteases (trypsin, chymotrypsin) (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)
REGULATORY
MICROBES (PATHOLOGICAL)
- Parasitic infection (A)
XENOBIOTICS
- Bisphenol-A (BPA) (A)
- Chlorpyrifos (pesticide) (A)
- Glyphosate (pesticide) (V)
- Mercury in food (V)
- Titanium dioxide (E171) in food (V)
- Mycotoxins (A, V)
- Polychlorinated biphenols (PCBs) (V)
MEDICATIONS
COMORBIDITY
When Do Fermented Foods Outperform Probiotic Supplements?