‘Leaky Gut’ & The Stress Matrix.

leaky If you believe whatever you read on Wikipedia, you probably think ‘Leaky Gut Syndrome’ is a bunch of pseudo-science woo woo, promoted by alternative health zealots with silver foil wrapped around their heads. And in some ways, you’d be right.

Intestinal barrier dysfunction however, is an experimentally verified biological phenomenon – relevant to the development of many disease conditions or symptoms – often arising as a result of exposure to stress and interference with proper metabolic function.

“The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens…intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection.”

“The intestinal barrier is a layer that constitutes the most important barrier against the external environment. It can be partially disrupted…leading to autoimmune and inflammatory diseases…Disruption of the intestinal barrier may induce local and systemic injuries and may play a role in inflammatory bowel disease, liver diseases, the aging process and in the systemic inflammatory response syndrome, including lung, heart and brain dysfunctions.”

Is ‘leaky gut’ a real concern? If so, how is it related to increased exposure to, and progression of, disease?

Leaky gut and intestinal permeability are basically one and the same, but rather than trying to justify what is often referred to as a hypothetical, medically unrecognized condition or ‘syndrome’, it’s probably more helpful to simply examine the physiological factors which tend to promote intestinal barrier dysfunction (or permeability), and look at the effect this can have on the overall system, and different ways to potentially reduce any impact on long term health.

The intestinal barrier isn’t a wall that one day just ‘springs a leak’. The gut barrier exists as an important part of organismic survival, and functions in fluctuating degrees of effectiveness, depending on a variety of external and internal circumstances, influencing (and influenced by) metabolism.

“The gastrointestinal tract constitutes one of the largest sites of exposure to the outside environment. The function of the gastrointestinal tract in monitoring and sealing the host interior from intruders is called the gut barrier…Ample evidence links gut barrier dysfunction to multiorgan system failure in sepsis and immune dysregulation…evidence for the role of gut barrier dysfunction in disorders such as Crohn’s disease, celiac disease, food allergy, acute pancreatitis, non-alcoholic fatty liver disease, and alcoholic liver disease…”

You don’t either have a leaky gut, or not have a leaky gut. Certain things need to get through and other things need to be prevented from getting past as much as possible. From a general perspective, anything which inhibits cellular energy metabolism, can impede intestinal barrier capability, and this can then lead to greater quantities of toxic, inflammatory and harmful substances, passing through to the liver, and potentially into the main system.

“Blood and stool samples were collected before and after STRESS to measure inflammation…IP [intestinal permeability] increased…during STRESS…and was associated with increased inflammation…Military training, a unique model for studying temporal dynamics of intestinal barrier and intestinal microbiota responses to stress, resulted in increased intestinal permeability concomitant with changes in intestinal microbiota composition and metabolism.”

Stress of any kind, can lead to interference with thyroid energy systems, and inhibit digestive function, increasing ‘leaky gut’ potential. Metabolic stress can be the result of exposure to psychological, dietary, as well as environmental and other stressors.

“…stress-induced increases in intestinal permeability, in combination with modern life-style factors, raise the possibility of translocation of bacteria and/or their toxins across the more permeable gut barrier.”

“Prolonged exposure to stress can induce low-grade inflammation, cause ultrastructural epithelial abnormalities, and alter bacterial-host interactions allowing greater microbial translocation.”

When metabolic issues cause digestion to be sluggish, bacteria are more likely to grow in number, and move further up into the small intestine where they are not intended to be, causing further interference with metabolic performance.

“In healthy individuals normal small GI motility prevents the overgrowth of bacterial microorganisms….It has been reported that SIBO (small intestinal bacterial overgrowth) may be present in more than half of patients with hypothyroidism…”

The overgrowth of bacteria in the intestine can cause a rise in levels of the inflammatory, stress substances (such as endotoxin, nitric oxide, serotonin, histamine and estrogen), and excessive exposure to these and other biochemical materials, can promote further suppression of metabolism, and are involved in the processes which reduce intestinal barrier capability.

“…CD14 expression on Kupffer cells is increased by estriol, thereby increasing toxic mediator production by mechanisms involving gut-derived endotoxin….Our working hypothesis is that estriol increases gut permeability, leading to elevated portal endotoxin.”

“Females have a higher prevalence of most autoimmune diseases…celiac disease, type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, are characterized by increased intestinal permeability…and inflammation…The fact that the expression of ZO-1 is inhibited by estrogen indicates estrogen may increase gut permeability and as a consequence of systemic microbial translocation and its associated inflammation.”

“…changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability…”

“Serotonin, another biogenic amine besides histamine, produced by enterochromaffin cells in the gut, is another endogenous trigger of pain, inflammation and increased permeability in IBS.”

“…increased…histamine levels…were temporally associated with increased gut permeability and bacterial translocation…antihistamine treatment reduced bacterial translocation and gut permeability in mice with malaria…”

“…a brief exposure to circulating endotoxin increases the permeability of the normal gut…during critical illness, prolonged or repeated exposure to systemic endotoxins or associated cytokines may significantly compromise the integrity of the gastrointestinal mucosal barrier.”

When intestinal barrier function is reduced, higher than optimal levels of the inflammation and stress related things, are able to pass into the main system and promote the development of many different disease conditions, effecting a variety of organ systems. Bacterial endotoxin entering into circulation in the main system has been shown to be directly inflammatory.

“Compromised gut barrier function because of alterations in the gut microbiota or intestinal inflammation can lead to translocation of microbial substances and the development of systemic inflammation with potential consequences for patients prone to cachexia. Efforts to preserve the integrity of the gut epithelial barrier and/or limit intestinal inflammation in cancer patients may help avoid the serious metabolic alterations associated with cachexia.”

Stress redirects energy away from digestion, immediately interfering with intestinal barrier function, allowing for greater amounts of endotoxin (and other metabolism interfering substances) to pass through into circulation.

“During exertional heat stress, blood flow is preferentially distributed away from the intestinal area to supply the muscles and brain with oxygen….the gastrointestinal barrier becomes increasingly permeable, resulting in the release of lipopolysaccharides (LPS, endotoxin) into the circulation. LPS leakage stimulates an acute-phase inflammatory response…”

When the environment of the intestine is overburdened with bacteria (and the intestinal lining becomes more permeable) it can become harder for the liver to properly carry out detoxification functions. This can result in an increase in flow throughout the system, of the stress substances which worsen conditions, promoting inflammation and degeneration.

“Increased intestinal permeability to endotoxin leads to increased transfer of endotoxin from the intestine to…the liver where it…initiates a cascade of events leading to…liver injury. Endotoxin that escapes to general circulation may induce injury to other organs.”

“…many studies report increased circulating endotoxin levels and increased gut permeability in patients…The resulting, long lasting, endotoxemia should be considered much more than just a risk factor for chronic disease; it could be a cause…evidence indicates that a disrupted barrier function in parallel with elevated circulating endotoxin levels may underlie disease onset and progression.”

The consumption (and storage in the tissue over time) of the polyunsaturated fats (PUFAs), can influence whether or not the intestinal barrier functions normally, or whether it becomes something fueling a larger problem. PUFAs interfere with metabolic energy system function in many different ways.

“…we investigated the effects of saturated fat (MCT enriched) and unsaturated fat (corn oil/linoleic acid enriched) diets on intestinal tight junction (TJ) integrity and permeability…We demonstrate the protective effect of SF (saturated fat)…USF (unsaturated fat) by itself induces dysregulation of intestinal TJ integrity…”

“…dietary unsaturated fat exacerbates alcohol-mediated intestinal permeability, liver steatosis, inflammation, and injuryThese pathologic effects were prevented or blunted by dietary saturated fat, suggesting a significant contribution of specific dietary lipids in ALD [alcoholic liver disease] development and progression…”

When stress is high – and the supply of sugar, protein and nutrients is inadequate – cortisol and adrenalin tend to rise, and more PUFAs are released out of storage, interfering with thyroid activity, and exacerbating inflammation.

Chronic exposure to stress, can cause cortisol (and related stress substances) to be continuously raised, suppressing intestinal barrier capability.

“Intestinal permeability and psychological stress have been implicated in the pathophysiology of IBD and IBS…the effect of public speech on permeability was only present in subjects with a significant elevation of cortisol.”

“…elevation in serum corticosterone mediates chronic stress induced decrease in specific intestinal epithelial tight junction proteins…associated with an increase in epithelial paracellular permeability…”

“Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor.”

Ongoing stress increases exposure to fatty acids released out of storage, and this (as well as increased consumption of fat) can directly increase the permeability of the ‘intestinal wall’, encouraging a vicious circle of inflammation and oxidative stress (resulting in part from interactions between PUFAs and other stress promoting substances). This can create difficult to deal with metabolic conditions, which can eventually lead to a variety of degenerative illnesses.

“We…demonstrated that the mechanisms of high-fat diet–induced inflammation and metabolic disorders were clearly linked to LPS(endotoxin)…the intestinal epithelium acts as a continuous barrier to avoid LPS translocation…high-fat feeding strongly increased intestinal permeability…”

“HFD [high-fat diets] induced oxidative stress and endotoxemia, leading to disruption of intestinal barrier…HFD increased both oxidative stress and LPS-related markers…results indicate that increased intestinal permeability allows entrance of bacterial pathogens and may cause chronic inflammation which accelerates the formation of intestinal polyps…HFD influences intestinal tumorigenesis by increasing intestinal permeability via oxidative stress and endotoxemia.”

The breakdown products of PUFAs consumed (or released from storage under conditions of stress), cause inflammation and interference with proper blood sugar regulation, and this has been shown to increase the ‘leakiness’ of the intestine, increasing inflammatory issues.

“Recently it was shown that DM2 (Type 2 diabetes) is accompanied by significant alterations in…intestinal permeability…promoting endotoxin-induced low-grade inflammation…”

“Intestinal permeability was positively correlated with intestinal mitochondrial injury indicated as the level of malondialdehyde (breakdown product of PUFA) in ileum mitochondria…”

Sugar restriction and stress, can lead to greater exposure to free fatty acids, which (especially when made up of PUFAs), interfere with the ability of cells to properly use sugar for energy, leading to many of the symptoms of diabetes, including chronic hyperglycemia.

Chronic hyperglycemia has been shown to be a factor increasing intestinal permeability or ‘leakiness’, allowing inflammatory substances (endotoxin for example) to enter into the main system, causing further interference with energy systems and a worsening of inflammatory conditions, potentially creating a downward spiral of degeneration.

“…we have identified glucose as an orchestrator of intestinal barrier function. Hyperglycemia markedly interfered with homeostatic epithelial integrity, leading to abnormal influx of immune-stimulatory microbial products and a propensity for systemic spread of enteric pathogens…findings provide a potential molecular explanation for altered barrier function in the context of the metabolic syndrome and the resultant enhanced mucosal infection noted in patients suffering from obesity and diabetes mellitus…”

The biggest problem with many popular approaches attempting to deal with ‘leaky gut syndrome’ or intestinal barrier dysfunction, arises from the dietary (as well as other) treatment recommendations commonly made to try to fix it. This is where I believe you will find most of the woo woo.

It has become customary to suggest the removal of grains (whichever happen to be considered the bad ones at the time), the restriction of dairy products, and of course the avoidance of white sugar.

The list of ‘healing’ things being promoted have included sprouted grains and seeds, fermented vegetables, probiotics to support ‘beneficial’ bacteria, and plenty of omega-3 PUFAs for their so called anti-inflammatory effects.

Unfortunately there is good evidence indicating that some of these recommendations can potentially promote the worsening of intestinal barrier related issues, rather than necessarily helping to resolve what is causing them.

“Loss of intestinal barrier function…remains a serious clinical problem leading to hypoperfusion, anastomotic leakage, bacterial translocation, and inflammatory mediator liberation…Our data suggest that augmented intestinal barrier permeability…is a possible side effect of (n-3) FA-rich diet supplementation.”

“…the intake of high doses of polyunsaturated fatty acids can promote lipid peroxidation…DHA [docosahexaenoic acid] supplementation…enhances cellular lipid peroxidation and the redistribution of tight junction proteins, which increases paracellular permeability.”

Difficult to digest grains, beans and too many under cooked and overly fibrous foods, have been shown to be able to interfere with metabolism and digestion and promote bacterial overgrowth, increasing the release of endotoxin (and the stress substances like nitric oxide and serotonin), which can then further interfere with metabolism and digestive function.

“…studies have confirmed the importance of NO (nitric oxide) homeostasis in liver injury…Increased NO production has been described in intestinal inflammation associated with hyperpermeability…strategies designed to target iNOS could lead to therapeutic agents for the treatment and prevention of…diseases associated with NO overproduction and intestinal hyperpermeability.”

There isn’t anything terribly new about the idea of intestinal leakiness – apart from perhaps the name ‘leaky gut syndrome’, which has managed to help spawn a whole range of new treatments, and the products that often go with them.

The intestine is always going to be permeable to some degree. It’s intended to be that way. But when energy systems are impaired and nutritional deficiencies exist, the syndrome which is actually real, is the ‘stress matrix syndrome’.

“Chronic non-communicable diseases (NCDs) are the leading causes of work absence, disability, and mortality worldwide…One way of triggering low-grade inflammation is by increasing intestinal barrier permeability through activation of various components of the stress system. Although beneficial to meet the demands necessary during stress, increased intestinal barrier permeability also raises the possibility of the translocation of bacteria and their toxins across the intestinal lumen into the blood circulation.”

One approach to improving gut barrier performance involves play, rest and sleep, exposure to daylight, as well as stress reduction techniques of many kinds.  It might also include a diet avoiding PUFAs, reducing intake of grains, seeds, nuts, legumes, under cooked vegetables, and too many difficult to digest starchy and fibrous foods, whilst getting enough protein and nutrients from milk, cheese and gelatin, and plenty of sugar from sweet ripe fruits and juices, white sugar and honey.

Suppression of intestinal barrier capability (and increased exposure to the things which are then able to pass through into the main system), can probably be demonstrated to be involved with the promotion of every kind of disease or condition.

Obesity, diabetes 1 and 2, cirrhosis of the liver, IBS, Parkinson’s, fibromyalgia, malaria, chronic fatigue, pancreatitis, immunodeficiency, cancer and fatty liver disease, have all been connected to ‘leaky gut’.

“It is more compelling to consider that increased intestinal permeability (leaky gut) and translocation of these substances is the critical factor for intestinal neuronal oxidative injury. Several lines of evidence strongly suggest that endotoxins are plausible neuroinflammatory triggers in PD (Parkinson’s)…”

“A wide collection of studies demonstrate synergism between microbiota dysbiosis, increased intestinal permeability, altered mucosal immunity and pathogenesis of T1D [type 1 diabetes]…”

“The pain intensity of patients with FM (fibromyalgia) has recently been reported to be correlated with the degree of small intestinal bacterial overgrowth (SIBO). SIBO is often associated with an increased intestinal permeability…”

“…manifest steatosis and steatohepatitis with and without beginning fibrosis are frequently associated with increased bacterial endotoxin levels in peripheral blood suggesting that intestinal barrier dysfunction may be critical in patients with NAFLD…even in juvenile patients with beginning NAFLD…plasma endotoxin…levels are significantly higher than in controls.”

“Severe acute pancreatitis (SAP) is a serious systemic disease with a sustained high mortality rate. Extensive evidence has shown that gut barrier dysfunction plays a critical role in the pathophysiology of SAP.”

Excessive exercise, sugar restriction, radiation exposure, fish oil and other PUFAs, and alcohol, can impede barrier function. Red light, activated charcoal, methylene blue, penicillin, niacinamide, taurine, coconut oil, certain antihistamines, and coffee, can all be protective.

Even though I’m not a doctor or a scientist, I know better than to automatically trust what I read on the internet, or anywhere else for that matter. When it comes to metabolism, there rarely are black and white answers, but over time it’s possible to improve your understanding of the way things fit together in the big picture.

The body responds to stress in a variety of ways for the sake of protection and survival. Unfortunately there is a cost associated with this, and the longer the stress goes on, the more expensive it can be. Environmental poisons and toxins – many of which have become far more common in recent times – can make the stress response dysfunctional.

See More Here

The Type of Dietary Fat Modulates Intestinal Tight Junction Integrity, Gut Permeability, and Hepatic Toll-Like Receptor Expression in a Mouse Model of Alcoholic Liver Disease

Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice

Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium.

A Single Dose of Endotoxin Increases Intestinal Permeability in Healthy Humans

Intestinal permeability in liver cirrhosis.

Intestinal permeability in patients with viral and alcoholic liver disease.

Intestinal permeability in liver cirrhosis: relationship with severe septic complications.

Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation?

Pathophysiological mechanisms of stress-induced intestinal damage.

Hepatoprotective, antinociceptive and antioxidant activities of cimetidine, ranitidine and famotidine as histamine H2 receptor antagonists.

Methylene Blue inhibits the inflammatory process of the acetic acid-induced colitis in the rat colonic mucosa.

Tumor-resident macrophages modulate intestinal barrier function through sialylation of Mucin 1 in IBD and colitis-associated cancer.

Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice.

Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism.

Intestinal permeability – a new target for disease prevention and therapy

Diquat-induced oxidative stress increases intestinal permeability, impairs mitochondrial function, and triggers mitophagy in piglets.

Epithelia: Understanding the Cell Biology of Intestinal Barrier Dysfunction

High-fat Diet Accelerates Intestinal Tumorigenesis Through Disrupting Intestinal Cell Membrane Integrity

Saturated and Unsaturated Dietary Fats Differentially Modulate Ethanol-Induced Changes in Gut Microbiome and Metabolome in a Mouse Model of Alcoholic Liver Disease

Stress and intestinal barrier function

Chlorogenic acid decreased intestinal permeability and ameliorated intestinal injury in rats via amelioration of mitochondrial respiratory chain dysfunction

Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome.

Markers of intestinal permeability are already altered in early stages of non-alcoholic fatty liver disease: Studies in children

Chronic social stress in pigs impairs intestinal barrier and nutrient transporter function, and alters neuro-immune mediator and receptor expression

Ingestion of (n-3) fatty acids augments basal and platelet activating factor-induced permeability to dextran in the rat mesenteric vascular bed.

Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer

Lipid peroxidation induced by DHA enrichment modifies paracellular permeability in Caco-2 cells: protective role of taurine.

Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiological stress.

Intestinal permeation and gastrointestinal disease.

Endotoxin in the gut and chylomicrons: translocation or transportation?

Stress Induces Endotoxemia and Low-Grade Inflammation by Increasing Barrier Permeability

Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide

Estriol sensitizes rat Kupffer cells via gut-derived endotoxin.

Human Intestinal Barrier Function in Health and Disease

Dietary niacin supplementation ameliorates ethanol-induced liver injury in rats through sealing the leaky gut

Intestinal Barrier Dysfunction in Human Pathology and Aging.

Effects of histamine and histamine antagonists on intestinal capillary permeability.

Thyroid disorders and gastrointestinal and liver dysfunction: A state of the art review.

Gut–Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease

The Impact of a 24-h Ultra-Marathon on Circulatory Endotoxin and Cytokine Profile.

Isolated ascites revealing a hypothyroidism. Study of 2 cases.

The role of intestinal mucosa oxidative stress in gut barrier dysfunction of severe acute pancreatitis.

Nitric oxide mediated intestinal injury is required for alcohol-induced gut leakiness and liver damage

Protective effects of medium-chain triglycerides on the liver and gut in rats administered endotoxin.

Effects of Alpinetin on Intestinal Barrier Function, Inflammation and Oxidative Stress in Dextran Sulfate Sodium-Induced Ulcerative Colitis Mice.

Intestinal permeability and autoimmune diseases

Mast cells and histamine alter intestinal permeability during malaria parasite infection

Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson’s Disease

Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation

Altered intestinal permeability in patients with primary fibromyalgia and in patients with complex regional pain syndrome.

Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats

Saturated dietary fat prevented unsaturated fat and alcohol-mediated alterations in gut microbiota resulting in attenuation of intestinal barrier disruption and liver injury in an animal model of alcoholic liver disease.

Gut inflammation in chronic fatigue syndrome

Jejunal bacterial overgrowth and intestinal permeability in children with immunodeficiency syndromes.

Progression of Intestinal Permeability Changes and Alpha-Synuclein Expression in a Mouse Model of Parkinson’s Disease


Ferulic acid protects against heat stress-induced intestinal epithelial barrier dysfunction in IEC-6 cells via the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway

Gut barrier dysfunction and microbial translocation in cancer cachexia: a new therapeutic target

The Gut Microbiota, Intestinal Permeability, Bacterial Translocation, and Nonalcoholic Fatty Liver Disease: What Comes First?

The intestinal barrier as an emerging target in the toxicological assessment of mycotoxins

Link between hypothyroidism and small intestinal bacterial overgrowth

Leaky guts: intestinal permeability and NASH

Intestinal permeability in humans is increased after radiation therapy.

Inflammation and Immunity in Radiation Damage to the Gut Mucosa

Chronic stress and intestinal barrier dysfunction: Glucocorticoid receptor and transcription repressor HES1 regulate tight junction protein Claudin-1 promoter

Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat

Alterations in intestinal permeability

Intestinal permeability and oxidative stress in patients with alcoholic pellagra.

Estrogen decreases tight junction protein ZO-1 expression in human primary gut tissues

Intestinal barrier dysfunction: implications for chronic inflammatory conditions of the bowel.

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

Stress-related modulation of inflammation in experimental models of bowel disease and post-infectious irritable bowel syndrome: role of corticotropin releasing factor receptors

Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.

The Role for Gut Permeability in the Pathogenesis of Type 1 Diabetes – A Solid or Leaky Concept?

Heat stress, gastrointestinal permeability and interleukin-6 signaling — Implications for exercise performance and fatigue

Small Intestinal Alterations in Severely Obese Hyperglycemic Subjects


Image: Neo Stops Bullets, The Matrix

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