Beyond Leaky Gut Investigating Barrier Integrity: Leaky Gut, Leaky Brain and Leaky Vessels

ARTICLE Jul 6, 2023 250 Add to Reading List

Beyond Leaky Gut

Investigating Barrier Integrity: Leaky Gut, Leaky Brain, and Leaky Vessels

It is our barriers that divide and separate us from the outside world, providing an interface between us and our environment. Our physical and chemical barriers are what protect us from potentially invasive microorganisms, viruses, and other threats to our system. Insults that occur at the level of the gut barrier, for example, can be the trigger for the systemic inflammatory response that is a root cause of just about every chronic disease.. It is well understood that viruses are a major trigger for the onset of autoimmune disease in susceptible individuals (1). And it isn’t just the gut barrier that we need to consider - the nasal barrier also provides an important first line of defence against inhaled pathogens, and the skin barrier provides a large network of tight junctions and antimicrobial peptides to ward off invaders.

The evidence clearly shows us that the interplay between our barriers and the environment can have an enormous effect on future health outcomes. So what happens when these barriers become compromised, and what can we do about it?

Hyper-Permeability

When a barrier becomes challenged, the integrity of the barrier can become altered. Research over the past decade has highlighted that the loss of mucosal barrier function, particularly in the GI tract, likely plays a key pathogenic role in the development of chronic inflammatory diseases. As a result of this loss of barrier function, the bidirectional relationship between the gut microbiome and the immune system may be influenced by changes in antigen trafficking. The downstream consequence of these changes is a shift from genetic predisposition to clinical outcome (2). In other words, this is how the environment ‘pulls the trigger’ on a genetic predisposition, turning it into a patient’s reality. Our barriers are the site where these epigenetic changes are initiated, so it is important that we focus on interventions to repair the integrity of these barriers. Such interventions can affect mucosal homeostasis and therefore play a primary role in the pathogenesis of many conditions.

Beyond Leaky Gut Syndrome

The role that the process of hyper-permeability has in the development and progression of disease highlights an opportunity to investigate, modulate and preserve barrier function when it comes to supporting those with chronic inflammatory conditions. Whilst the gut is often a good starting point when it comes to addressing barrier integrity, we need to keep in mind that the impairment of one barrier can lead to a deterioration of other barriers, or it can be partly compensated by the upregulation of other barriers. For example, Leaky Gut Syndrome is often a root cause of a leaky blood-brain barrier - circulating LPS as a result of leaky gut can contribute to neuroinflammation. So, in addressing barrier health, we need to consider then the relationship between different barrier systems in the body and the order in which to address them.

As practitioners, we’re all very familiar with the potential issues with gut barrier function and how intestinal hyper-permeability plays a role in almost all chronic diseases, but what about our other barriers?

Leaky Brain

Research shows us that an inflammatory challenge can lead to a compromised Blood Brain Barrier (BBB). Just like the intestinal barrier, the BBB is comprised of endothelial cells and tight junctions. This barrier selectively allows nutrients in and lets toxins and metabolites out. Increased BBB permeability is thought to be a key feature of neurological diseases including Multiple Sclerosis, Parkinson’s and Alzheimer’s. Recent research on the gut-brain axis shows us that many neurodegenerative disorders appear to have a microbial-driven component in their pathogenesis. This relationship is bidirectional - stress-induced changes in the gut microbiota are also well documented (3). We must also consider those barriers which are a little closer geographically - namely the nasal mucosa and the oral mucosa. Both of these barriers have their own microbial communities, the health of which can directly impact the health of the BBB. Some research has indicated that dysbiosis of the oral microbiota can induce and accelerate the formation of Aβ plaques and neurofibrillary tangles in Alzhimer’s. In addition, oral microbes can spread to the brain through cranial nerves or cellular infections, which has been suggested to increase the risk of developing AD (4).

Leaky Blood Vessels

Research indicates that our blood vessels can also become hyper-permeable. As with the gut and the BBB, these vessels are lined with endothelial cells which can be damaged by endotoxins (for example LPS), free radicals and inflammatory cytokines. This endothelial damage is at the root of the development of cardiovascular disease - you can read more about that here. Dysfunction of the vascular endothelium is a hallmark of other diseases, including diabetes, insulin resistance and chronic kidney failure (5). The health of the gut barrier must be considered when it comes to heart health as changes in the gut microbiota have been linked to the development of cardiovascular disease. Imbalances in host-microbial interaction can activate multiple pathways leading to CVD risk factor progression (6).

Leaky Skin Barrier

Protecting and maintaining the skin barrier is particularly important for those suffering with acne, eczema, psoriasis, ichthyosis and atopic dermatitis. A deficient skin barrier can lead to a higher penetration of allergens through the skin, causing immune system activation. Fillagrin is a protein found in the epidermis that is crucial for a healthy and functional stratum corneum. Filaggrin deficiency as a result of a genetic mutation leads to a ‘leaky’ skin barrier, as observed in some forms of eczema. Research supports the idea that we can feed our filaggrin - for example, L-histidine increases Filaggrin protein formation. One study found that supplementation of l-histidine significantly reduced symptoms in those with atopic dermatitis. (7)

There is an established link between such skin disorders and other chronic conditions including cardiovascular disease, immune-mediated conditions such as food allergies, and mental health conditions such as anxiety and depression, suggesting a need to consider other barriers in the pathogenesis of conditions that have been primarily thought of as skin conditions. Stress and other endocrinological changes may be a common linking factor when it comes to the compromised barrier function of the skin, brain and gut.

Assessing Barrier Function - Markers of Compromised Barrier Function

Here are some of the key tests and markers for assessing barrier function.

Blood-Brain Barrier

MMP-9 is an important marker for those suffering from CIRS and mould or biotoxin exposure. It is also a useful marker for identifying inflammation associated with chronic illnesses, and has been implicated in the pathogenesis of atherosclerosis. When it comes to barrier function, higher MMP-9 levels have been associated with disruption of the blood brain barrier by degrading the tight-junction proteins (8). MMP-9 is available as an add-on, and features on our CIRS panels including the Q100 CIRS Elite (Chronic Inflammatory Response Syndrome) Full Panel and the Q150 CIRS - Lite panel. It also appears on the Bredesen Q500 Bredesen Full ReCODE Panel.

Intestinal Barrier Analysis

Colabs’ IG613 Intestinal Barrier Analysis test includes key markers for intestinal permeability such as Zonulin, LPS and IL-6. IL-6, as well as being a useful marker for Leaky Gut Syndrome, is also implicated in vascular endothelial injury and ‘leaky blood vessels’ (9). The Zonulin-mediated opening of tight junctions in the gut is a known trigger in the development of Leaky Gut Syndrome. Zonulin is also available as an add-on with the DS811 GI-MAP.

The IG613 (NMI) Intestinal Permeability and Barrier Analysis + Food reactivity panel also includes histamine and DAO, the enzyme responsible for breaking down histamine. Gut permeability can increase histamine levels as t-cells are activated which can trigger the degranulation of histamine-containing mast cells.

Vascular Barrier Analysis

The marker Lp-PLA2 is associated with inflammatory processes within the artery wall that can lead to atherosclerosis. This marker is part of our Cardiometabolic panels Q703 CHL Advanced Cardio Profile and C704 CHL Cardio Elite Profile.

OxLDL is another key marker for arterial health. When LDL cholesterol enters the artery wall it becomes oxidised. In an attempt to mediate this, macrophages in our arterial walls then engulf the OxLDL-forming foam cells. It is these foam cells that lead to plaques and damage the lining of the arteries. This marker can be found on our Q702 CHL Metabolic Profile.

We can also look at C3a and C4a, as research links these markers with increased vascular permeability. Finally, myeloperoxidase is a marker that measures active disease activity within the arterial wall. C3a is avaiable as an add-on marker, and C4a features on our Q100 CIRS Full panel and our Q150 CIRS - Lite panel.

Skin Barrier

The EM217 Actinomycetes Skin Swab assesses microbial invasion of skin. This organism can significantly affect the skin barrier. We also offer the EM226 Actinomycetes Plasma test for assessing blood levels of actinomycetes.

Add-On Markers: TNF-a

Tumor necrosis factor (TNF)-α is a key mediator of intestinal inflammation and is known to cause an increase in intestinal epithelial tight junction permeability by activating myosin light chain kinase (10). This marker is available as an add-on to any test panel, and is part of our LM4687 Inflammation Profile (MeGeMIT).

In addition to the LM4687 Inflammation Profile and IG613 Intestinal Barrier Analysis, other tests you may want to consider to evaluate barrier integrity include the DS810 GI MAP and the LMTTF Gluten-Related TTG Reactivity Panel.

We’re always happy to help you choose the most appropriate test for your patient. Drop us an email for a free support call to discuss your options.

References