Expanding Our View on Leaky Gut: Beyond the ON/OFF Idea

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)

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.

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