What is Leaky Gut Syndrome?
The inner lining or mucosa of the gastrointestinal tract (GI tract) is made up of epithelial cells. The first function of this epithelial lining is to absorb the small micronutrients from digested food that are needed by the body for its various functions like providing fuel for the cells. These digested food particles can be absorbed directly into the epithelial cells (transcellular movement) or they can pass between the cells (paracellular movement).
After passing through or crossing in between the epithelial cells, the digested food particles enter the bloodstream via the gut associated lymphoid tissue (GALT). This GALT, which serves as the immune system of the intestinal system, works like a control station and prevents dangerous substances from crossing into the bloodstream from the intestinal tract.
“A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism.”(1)
The second function of the mucosal epithelial lining of the intestines is to form a defensive barrier and prevent the absorption of larger macromolecules and destructive substances. This function is known as permeability and it is maintained by tight junctions.
Tight junctions seal the spaces between the small epithelial cells that line the intestines. The opening or closure of these tight junctions prevents the paracellular movement of dangerous substances from the GI tract to the blood through the spaces between the cells.
When the tight junctions between the intestinal cells break down, they become larger and permeable to large undigested food compounds, toxins, bacteria, yeasts and parasites. This state of the intestines is referred to as intestinal permeability compromise or leaky gut syndrome.
Once the tight junctions between the cells become dysfunctional, the gut associated lymphoid tissue reacts against the large undigested proteins from food passing through them. This GALT reaction triggers exaggerated immune responsiveness and intestinal inflammation which further destroys the tight junctions.
A vicious cycle is therefore created in which the damaged intestinal barrier and its resultant increased intestinal permeability causes an inflammatory reaction by the immune system which further damages the intestinal barrier leading to the entry of more proteins which continue to trigger intestinal inflammation and more damage to the barrier. (2-5)
Malabsorption of nutrients is another effect of damage to the epithelial lining of the gastrointestinal tract in leaky gut syndrome. This poor absorption develops as a result of the impaired intestinal cells being unable to effectively produce the enzymes that are needed for the digestion and absorption of food.
A leaky gut therefore does the opposite of a normal one since it the absorption by the body of vital nutrients is reduced and the entry of dangerous substances that are usually kept out by healthy intestines is increased.
What are the Symptoms of Leaky Gut Syndrome?
Intestinal permeability compromise is associated with numerous clinical features because the circulation of blood links the GI tract to all other organs in the body. These most common leaky gut syndrome symptoms include:
Gastrointestinal symptoms like bloating and abnormal bowel movements are the most frequently encountered leaky gut syndrome symptoms.
Depression is another symptom of leaky gut syndrome. It can be associated with other symptoms like brain fog and fatigue. (6)
3. Food Sensitivities
Multiple food sensitivities are other common leaky gut symptoms. These food allergies are thought to develop as a result of the immune system’s reaction to the large, undigested proteins from food that cross the intestinal lining as a result of its increased permeability.
“Intestinal permeability is increased in patients with food allergy, suggesting that the uptake of food antigens is elevated in food-allergic patients.”(7)
4. Systemic Inflammation
The development of systemic inflammation after eating certain foods is another symptom of leaky gut syndrome. This systemic inflammation develops after the intestinal barrier is breached since it causes increased inflammatory responses in the intestines and other parts of the body.
Systemic inflammation increases a person’s risk of developing chronic diseases. In fact, some persons with intestinal permeability compromise do not develop intestinal symptoms. They present with inflammatory symptoms like chronic joint pains, muscle aches, bone loss, eczema, cardiovascular disease, neurodegeneration and other degenerative diseases.
Patients with leaky gut syndrome can also develop symptoms related to the nutrient malabsorption that develops as a result of damage to the cells lining the intestines. Symptoms of malabsorption are varied and include bloating, flatulence, weight loss, diarrhea and dry hair.
6. Microbe Overgrowth Syndromes
Chronic yeast and bacterial overgrowth syndromes are common in persons with leaky gut syndrome since these microorganisms can penetrate the intestinal lining by virtue of their greater mass. Symptoms of chronic yeast overgrowth include chronic fatigue, brain fog and muscle aches while those of bacterial overgrowth include diarrhea, flatulence and abdominal pain.
7. Thyroid Problems
A huge problem seen with many Thyroid and IBS sufferers is a leaky gut. Once scoffed at by conventional standard medical practitioners is now widely accepted as a major contributing factor to many disease processes including autoimmune disorders, diabetes, skin conditions, allergies and more.
What Tests are Done for Leaky Gut Syndrome?
The Cyrex intestinal barrier function test is the most accurate and reliable intestinal permeability test available to date. It is also the only laboratory investigation that assesses the immunological response against the intestinal barrier and markers of permeability.
Antibodies that are measured and used as markers of intestinal permeability include
- Actin/Myosin immunoglobulin,
- Occludin/Zonulin immunoglobulins (IgG, IgA, IgM) as well as
- Lipopolysaccharides (LPS) IgG, IgA and IgM.
High levels of occludin/zonulin antibodies are indicative of intestinal barrier breakdown through the tight junctions or paracellular pathways.
Elevated actin/myosin antibodies are indicative of intestinal barrier breakdown through the epithelial cells or transcellular pathways. These high levels may also suggest the presence of autoimmunity against the intestinal epithelium and other tissues in the body that contain actin and myosin fibers.
High levels of lipopolysaccharides (LPS) antibodies are indicative of excessive penetration of LPS into the bloodstream (leakiness).
A common question often asked is “What is the difference between the Lactulose/Mannitol test and Cyrex’s Intestinal Antigenic Permeability Screen™?”
A: Over the last 40 years the Lactulose and Mannitol test have been a useful clinical tool. Lactulose absorption in the past was thought to suggest a tear in the gut barrier and therefore intestinal permeability. However more recent research done through cyrex labs indicated that the passage of Lactulose and Mannitol more accurately indicates a minute leak rather than a tear. Furthermore, Lactulose the sugar, is much smaller than the many dietary proteins we consume on a daily basis.
Cyrex’s Intestinal Antigenic Permeability Screen™ assesses gut barrier damage by measuring antibodies to barrier proteins something Lactulose and Mannitol does not do.
It can therefore detect barrier damage long before there is dysregulation in absorptive function occurs. This makes Cyrex’s Intestinal Antigenic Permeability Screen™ preferential for early detection and preventative care.
These two approaches offer very different perspectives/observations on intestinal tract functionality. Each test realy serves a different purpose and cannot be compared.
Lactulose/Mannitol Test Important Points to Remember
1. Lactulose/Mannitol, is a marker of small-size access through the intestines and was originally designed as a marker of nutrient absorption; however, this test is not indicative of the status of macromolecular (larger proteins) that are transported across the membrane. Gluten and similar proteins are very large when compared to Lactulose and Mannitol.
2. Lactulose and Manitol testing does not evaluate the Trancellular pathway (through the cells).
3. Lactulose and Mannitol does not identify whether or not an immune system response is occurring. This is because Lactulose and Mannitol are inert sugars and these sugars, as we know do not react with the immune system. This is very important.
4. The Dietary proteins that we eat are much larger than Lactulose and Mannitol.
The other, the Intestinal Antigenic Permeability Screen™, identifies an immune response indicating damage to the intestinal mucosal microstructures, including the epithelial cell network and the intercellular tight junctions. Measuring the continuity of the intestinal barrier is accomplished by identifying antibodies against the tight junction proteins (occludin and zonulin) and antibodies to the actomyosin network (a protein complex that regulates intestinal barrier function by maintaining the plasticity of tight junctions).
The increased permeability to antigenic macromolecules across the gut epithelium is identified in Array 2 by measuring an immune response to lipopolysaccharides, and this can have further effects on initiation and/or perpetuation of chronic, systemic inflammation. Thus, one value in identifying antigenic macromolecular permeability is that it acts as a biomarker to follow the success of a healthcare professional’s protocols in reducing a common contributor to systemic inflammation.
What are the Causes of Leaky Gut Syndrome?
Factors that have been identified in the literature and linked to an increased risk or the cause behind the development of leaky gut syndrome include:
1. Gluten Diet
Gluten sensitivity is the factor that is most strongly linked to causing a leaky gut.
Gliadin and its peptides interact with the intestinal epithelium increasing intestinal permeability through the release of zonulin that, in turn, enables paracellular translocation of gliadin and its subsequent interaction with macrophages within the intestinal submucosa (in celiac disease patients).”(8)
In addition to eating gluten containing grains like wheat, other dietary factors that predispose an individual to developing this condition include drinking milk which contains casein.
Low-fiber and high-sugar foods that are typical of fast foods, have also been linked to leaky gut syndrome. Sugar is said to sustain the multiplication of bad bacteria and yeasts in the gut which damage the tight junctions.
Alcohol is thought to cause a leaky gut by virtue of causing inflammation which weakens the tight junctions.
2. Medication Overuse
Overuse of medications like ibuprofen, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) which are used to relieve pain has been linked to the development of leaky gut syndrome. These medications, which are known to irritate the mucosal lining of the gastrointestinal tract, are thought to cause inflammation which damages the tight junctions and consequently causes intestinal hyper-permeability.
Antacids and other acid blockers used to reduce acidity in the stomach are other drugs associated with this condition. Hormones, corticosteroids and antibiotics are also said to predispose an individual to developing a leaky gut.
Infections are thought to cause leaky gut syndrome by breaking the tight junctions. Helicobacter pylori (H. pylori) and intestinal viruses are some of those that have been associated with this condition.
Intestinal dysbiosis, which is the imbalance of beneficial and harmful bacteria in the gut, is another condition linked to a leaky gut. Small intestine bacterial overgrowth (SIBO) is thought to cause this condition by releasing toxins which destroy the tight junctions. Overgrowth of parasites and yeasts like Candida has also been linked to intestinal permeability compromise.
Stress is said to increase a person’s risk for developing a leaky gut since it causes increased levels of cortisol, CRH and catecholamines in the body. Persistently high levels of these stress hormones reduce the immune system’s ability to fight the bad microorganisms that destroy the tight junctions.
5. Hormonal Imbalances
Hormonal imbalances that have been linked to developing intestinal permeability compromise include reduced estradiol, progesterone and testosterone levels as well as decreased thyroid hormones.
6. Neurologic Factors
Neurologic factors thought to increase a person’s risk of developing leaky gut syndrome include brain trauma, stroke and neurodegeneration.
7. Metabolic Factors
Metabolic factors that are associated with developing increased intestinal permeability include glycosylated end products, intestinal inflammation and autoimmunity.
What Conditions are Associated with Leaky Gut Syndrome?
Literature links leaky gut syndrome to conditions that affect numerous organs in the body like the heart, pancreas, liver and brain, bone. These conditions include:
1. Autoimmune Diseases
Intestinal permeability compromise has been shown to be a major factor in the development of autoimmune diseases.
Once these tight junction proteins get compromised, there is such immune zealousness and activation, immune self-tolerance is lost. Any tissue is up for grabs for autoimmune destruction.
“It is now apparent that tight junctions are dynamic structures that are involved in developmental, physiological, and pathological processes. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of several diseases, particularly autoimmune diseases.”(9)
“Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. When the finely-tuned trafficking of macromolecules is dysregulated in individuals, both intestinal and extraintestinal autoimmune disorders can occur.”(10)
“In all cases, increased permeability appears to precede disease and causes an abnormality in antigen delivery that triggers the multiorgan process leading to the autoimmune response.”(11)
“There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases. Therefore, we hypothesize that loss of intestinal barrier function is necessary to develop autoimmunity.”(12)
2. Type 1 Diabetes
Leaky gut syndrome has also been linked to type 1 diabetes.
“These findings indicate the presence of an intestinal permeability associated with type 1 diabetes that is already detectable before clinical onset of the disease. The findings also suggest that the small intestine is an organ participating in the pathogenic process of type 1 diabetes.”(13)
“The origin of beta-cell specific autoimmunity is not known in type 1 diabetes. Several studies of this disease in animal models indicate that the manifestation of autoimmune diabetes can be modified by factors which influence the gut immune system. Some indirect evidence from studies in patients with type 1 diabetes also suggests that aberrant function of the gut immune system may be involved in the development of this disease. These studies have encouraged the search for treatments interfering with mucosal immunity for the prevention of this disease.”(14)
“Increased intestinal permeability has also been observed in animal models of type 1 diabetes as well as in humans with or at increased risk for the disease. Finally, an altered mucosal immune system has been associated with the disease and is likely a major contributor to the failure to form tolerance resulting in autoimmunity. This results in the autoimmunity that underlies type 1 diabetes.”(15)
“Therefore, understanding the interactions between the upregulation of zonulin, increased intestinal permeability, and the development of autoimmune diseases may lead to novel preventative and possibly therapeutic strategies for type 1 diabetes.”(16)
3. Inflammatory Bowel Disorders
Increased intestinal permeability has also been associated with inflammatory bowel disorders like Crohn’s disease and celiac disease.
“A major task of the intestine is to form a defensive barrier to prevent absorption of damaging substances from the external environment. This protective function of the intestinal mucosa is called ‘permeability’. Ample evidence indicates that permeability is increased in most patients with Crohn’s disease and in 10% to 20% of their clinically healthy relatives. Permeability measurements in Crohn’s patients reflect the activity, extent, and distribution of the disease and may allow us to predict the likelihood of recurrence after surgery or medically induced remission. Permeability is also increased in Celiac disease and by trauma, burns and nonsteroidal anti-inflammatory drugs. The major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space.”(17)
“The intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry of inappropriate molecules or substances and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects. These barrier defects exacerbate the underlying immune system, subsequently resulting in tissue damage. The epithelial phenotype in active IBD is very similar in both CD and UC. It is characterized by…increased permeability via both transcellular and paracellular routes and increased apoptosis of epithelial cells. Therapeutic restoration of the mucosal barrier would provide protection and prevent antigenic overload due to intestinal ‘leakiness’.”(18)
4. Autoimmune Hepatitis
The literature also links leaky gut syndrome with the development of autoimmune liver diseases.
“Primary sclerosing cholangitis (PCS) and autoimmune hepatitis are enigmatic chronic inflammatory diseases of the liver, which are frequently associated with chronic inflammatory bowel diseases. In this paper, we review the evidence for microbial infection and leaky gut syndrome that might give rise to chronic hepatic inflammatory disorders with features of autoimmunity.”(19)
5. Cardiovascular Diseases
Studies also suggest that increased intestinal permeability may contribute to cardiovascular conditions like congestive heart failure.
“Chronic heart failure is a multisystem disease with increased sympathetic tone, an anabolic/catabolic imbalance and chronic inflammation. Recent studies suggest an altered morphology, permeability, and absorption of the digestive tract in chronic heart failure…bacterial endotoxin is thought to enter the bloodstream through the hypoperfused edematous gut wall, thereby triggering an inflammatory response. A recent study focused on specific alterations of the gastric, small intestinal and large intestinal region in chronic heart failure. It describes the leaky intestinal barrier with an augmented bacterial biofilm that may contribute to chronic inflammation and malnutrition. Both lack of mucosal integrity with consecutive local and systemic inflammation and dysfunction of transport proteins may worsen the clinical symptoms of chronic heart failure. Therefore, future studies need to address the pathophysiology of the intestinal barrier whose reactivity seems to be crucial for heart function.”(20)
“Chronic heart failure (CHF) is a multi-organ disease with increasing evidence for the involvement of the gastrointestinal system in this syndrome. In recent research, the gut has received very little attention from cardiologists as its role in the pathogenesis of cardiovascular disease is poorly understood. Intestinal ischemia may play an important role in bacterial translocation by increasing bowel permeability. Decreased cardiac function can reduce bowel perfusion and so clearly impairs the function of the intestinal barrier. There is increasing evidence to suggest that a ‘leaky’ bowel wall may lead to translocation of bacterial and/or endotoxin, which may be an important stimulus for inflammatory cytokine activation in CHF.”(21)
6. Chronic Fatigue Syndrome
Chronic fatigue syndrome (CFS) is another condition whose cause has been linked to a leaky gut.
“The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS, and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific natural anti-inflammatory and anti-oxidative substances and a leaky gut diet.”(22)
“…CFS is accompanied by an increased translocation of endotoxins from gram-negative enterobacteria through the gut wall, as demonstrated by increased prevalences and median values for serum IgM and IgA against the endotoxins of gram-negative enterobacteria. This condition can also be described as increased gut permeability or leaky gut and indicates intestinal mucosal dysfunction (IMD).
In one study, they reported a case of a 13-year old girl with CFS who showed very high values for serum IgM against the LPS of some enterobacteria and signs of oxidative and nitrosative stress, activation of the inflammatory response system, and IgG3 subclass deficiency. Upon treatment with specific antioxidants and a leaky gut diet and intravenous immunoglobulins, the increased trasnclocation of the LPS of gram-negative enterobacteria normalized and this normalization was accompanied by a complete remission of the CFS symptoms.”(23)
Studies show that leaky gut syndrome can cause depression.
“The above-mentioned results indicate that both chronic fatigue syndrome and major depressive disorder are accompanied by an increased gut permeability, which has allowed an exaggerated passage of proteins through a compromised epithelial barrier.”(24)
“The results show that intestinal mucosal dysfunction, characterized by an increased translocation of gram-negative bacteria known as leaky gut, plays a role in the inflammatory pathophysiology of depression. It is suggested that patients with major depression should be checked for leaky gut and accordingly, should be treated for leaky gut.”(25)
“Research has found that depression is accompanied by an inflammatory reaction indicated by an increased production of pro-inflammatory cytokines, such as interleukin-1beta (IL-1β), IL-6, TNF-α, and interferon-γ (IFN-γ). These cytokines are stress sensitive and may cause depressive behaviors. This paper hypothesizes that inflammatory, oxidative and nitrosative pathways, and an increased translocation of LPS from gram-negative bacteria from leaky gut are causally related to depression and novel targets for antidepressant development.”(26)
8. Pediatric Diseases
Research reveals that leaky gut syndrome can contribute to the development of multiple diseases in children.
“Tight junctions (TJs) represent the major barrier within the paracellular pathway between intestinal epithelial cells. Disruption of TJs leads to intestinal hyperpermeability (leaky gut) and is implicated in the pathogenesis of several acute and chronic pediatric disease entities that are likely to have their origin during infancy. There is evidence for the role of TJ breakdown in diseases such as systemic inflammatory response syndrome (SIRS), inflammatory bowel disease, type 1 diabetes, allergies, asthma and autism in the pediatric population.”(27)
Autism is another condition that has been associated with leaky gut syndrome.
“Intestinal permeability (IPT) was investigated in patients with autism as well as in their first-degree relatives to investigate leaky gut hypothesis. IPT results, assessed by means of the lactulose/mannitol test, were compared with adult and child controls and with FC values. The results demonstrated that a high percentage of abnormal IPT values were found among patients with autism (36.7%) and their relatives (21.2%) compared with normal subjects (4.8%). Patients with autism on a reported gluten-casein-free diet had significantly lower IPT values compared with those who were on an unrestricted diet and controls. The researchers concluded that the results obtained support the leaky gut hypothesis and indicate that measuring IPT could help to identify a subgroup of patients with autism who could benefit from a gluten-free diet. The IPT alterations found in first-degree relatives suggest the presence of an intestinal (tight-junction linked) hereditary factor in the families of subjects with autism.”(28)
Leaky gut syndrome has also been associated with obesity.
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