Successful Aging Part 5: Intestinal Permeability (What is Leaky Gut?)

girl-smiling-red-bandanaIn this issue, we discuss a common clinical condition known as intestinal permeability in the literature, also known as “leaky gut”.  We discuss the most common signs and symptoms associated with this condition, reliable testing methods for this and review the literature on the leaky gut—autoimmune connection.

puzzled-womanIs leaky gut syndrome real?

By now, most people have heard of leaky gut syndrome but are still wondering if this is real or if this is folklore medicine.  Leaky gut syndrome is very real.  The immunological literature is filled with information on leaky gut syndrome.  In the immunological literature, leaky gut syndrome has been linked to autoimmune disease, depression, congestive heart failure and pediatric diseases such as autism.  It is called intestinal permeability compromise in the literature and is much more common than most people and doctors realize. 

tight-junction-intestinal-permeabilityWhat is intestinal permeability (or “leaky gut” syndrome)?

For a more complete discussion of intestinal permeability, click here:  What is Intestinal Permeability or “Leaky Gut”?  The lining of the gastrointestinal (GI) tract is composed of small epithelial cells that lie side-by-side each other forming tight junctions. These tight junctions act as a barrier between the interior of the body (blood/circulatory system) and the exterior of the body (the GI tract).   There are two primary functions of the epithelial lining of the GI tract: the first is to absorb small, micromolecules, such as digested food particles, which are used as fuel sources and other processes for the body. These micronutrients are absorbed directly into the epithelial cells or between the cells and enter the bloodstream after passing through the gut-associated lymphoid tissue (GALT), the underlying intestinal immune system.   The GALT serves as a containment system, preventing potentially harmful antigens from reaching systemic circulation.

LEAKY-GUT-SYNDROME-HEALTHY-UNHEALTHY-EPITHELIAL-CELLS“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 epithelial lining of the GI tract, is to prevent the absorption of larger macromolecules which should not normally penetrate through the intestinal barrier. When tight junctions of the intestinal mucosa are compromised, they become widened and permeable to large undigested food compounds, toxins and bacteria. This is known as intestinal permeability or “leaky gut”. The larger compounds of absorbed yet undigested proteins are reacted against by the GALT (gut-associated lymphoid tissue). This reaction then promotes exaggerated immune responsiveness and intestinal inflammation.

INFLAMMATION-LEAKY-GUTThe Vicious Cycle of Leaky Gut

Once these tight junctions breakdown for whatever reason, the large compounds of undigested proteins that are absorbed are reacted against by the underlying intestinal immune system.  This promotes exaggerated immune responsiveness which causes further destruction of the tight junctions.  So the immune response which results from intestinal permeability actually perpetuates further intestinal barrier destruction.  This creates a vicious cycle of further intestinal inflammation and increased intestinal permeability.(2-5)

Summary of Increased Intestinal Permeability (Leaky Gut)

  • When tight junctions of the intestinal mucosa are compromised, they become widened and permeable to large, undigested compounds, toxins and bacteria, known as “leaky gut”
  • The large compounds of absorbed yet undigested proteins are reacted against by the underlying intestinal immune system
  • This reaction then promotes exaggerated immune responsiveness
  • This creates a vicious cycle of further intestinal inflammation and greater loss of intestinal permeability

LEAKY-GUT-SYNDROME-ABDOMENWhat are the signs and symptoms of intestinal permeability?

For a more complete list of signs and symptoms of intestinal permeability, click here: Symptoms and Common Imbalances Associated with Intestinal Permeability

The most common symptoms of a person suffering from leaky gut syndrome are gastrointestinal symptoms such as bloating, gas, abnormal bowel movements, systemic inflammation and food sensitivities.  Additionally, the development of any inflammatory symptoms after exposure to certain foods or diets may also indicate intestinal permeability dysfunction.  On the other hand, the person with intestinal permeability may not complain of intestinal symptoms but have inflammatory issues such as chronic systemic joint pain, eczema, muscle aches, etc.  Other times, the person will complain only of depression, brain fog or fatigue.(6)

GI-tract-man-blueLeaky Gut Leads to Poor Digestion and Malabsorption

When the intestinal mucosa of the GI tract becomes damaged, the damaged cells become unable to properly produce the enzymes necessary for digestion and absorption.  The other consequence of intestinal permeability is malabsorption of nurients. Many of these leaky gut patients have nutrient malabsorption because of damage to the microvilli of the epithelial cells that occurs in leaky gut.  The microvilli are the finger-like projections on the surface of the epithelial cells where absorption of nutrients takes place.  damaged-intestinal-microvilliYou can think of these microvilli as the shag on a carpet.  Each of these ‘shags’ absorbs a different type of nutrient.  These damaged microvilli are then unable to absorb micronutrients efficiently. The larger molecules are able to penetrate because of their greater mass. So you get leaky gut with poor digestion and malabsorption.  This leads to malnutrition, further intestinal inflammation, further intestinal permeability and the development of food sensitivities and bacterial and yeast overgrowths in the GI tract.

food-allergy-leaky-gut-inflammationFood Sensitivities Are Common in Leaky Gut

The literature shows a close connection between increased food sensitivities and intestinal permeability.    The mechanism is believed to be due to increased penetration of large undigested food peptides through the intestinal lining that are then reacted against by the immune system.  Since these large molecules are foreign to the immune cells of the gut, they become targets of the immune system, leading to food sensitivities.

“Intestinal permeability is increased in patients with food allergy, suggesting that the uptake of food antigens is elevated in food-allergic patients.”(7)

leaky-gut-symptoms-womanMost Common Symptoms Associated with Leaky Gut Syndrome:

  • Bloating and digestive complaints
  • Depression
  • Fatigue
  • Chronic pain/inflammation
  • Multiple food sensitivities
  • Chronic yeast overgrowth syndromes
  • Brain fog

leaky-gut-syndrome-signsIntestinal permeability will cause systemic inflammation

Intestinal permeability will cause systemic inflammation (throughout the circulatory system).  If a person has their barrier system breached, they will have an increase in inflammatory responses which increases risk of all chronic disease, including neurodegeneration, cardiovascular disease, bone loss, etc.  A person’s intestinal barrier integrity will influence their inflammatory load and their potential for deteriorating mechanisms.

Intestinal permeability dysfunction should always be considered and assessed by proper laboratory testing when a person has autoimmune disease, systemic inflammation, depression, fatigue or any other degenerative or inflammatory condition.

intestinal-barrier-integrity-screen Assessment of Intestinal Permeability:   Intestinal Permeability Antigenic Screen

The Cyrex intestinal barrier function test is the most accurate intestinal barrier permeability test available and is currently the only lab that measures the immunological response against the intestinal barrier and accepted markers of permeability.  The profile includes actin/myosin network IgG, occludin/zonulin IgG, IgA, IgM and lipopolysaccharides (LPS) IgG, IgA, and IgM.  Measurements of these antibodies can be used as markers for intestinal permeability.  Elevations of occludin/zonulin antibodies indicate breakdown of the intestinal barrier integrity through paracellular (tight junction) pathways.  Elevations of actomyosin antibodies indicate breakdown of the intestinal barrier integrity through transcellular (across the intestinal cells) pathways and may also suggest possible autoimmunity against mucosal epithelium and other tissues that contain the actomyosin cytoskeleton.  Elevations of LPS antibodies indicate excess penetration of LPS into the bloodstream (leakiness).

leaky-gut-causesWhat Causes Leaky Gut?

Below are the mechanisms that have been identified in the literature to be associated with risk of development of intestinal permeability/leaky gut. For a more complete discussion of the causes of leaky gut, click here:  Intestinal Permeability: Mechanisms Leading to Leaky Gut

Mechanisms of Leaky Gut

dietDiet

  • Alcohol
  • Gluten
  • Casein
  • Processed foods
  • Excess sugar
  • Fast food

NSAIDsMedication

  • Corticosteroids
  • NSAIDs (ie: ibuprofen, aspirin, other anti-inflammatory drugs)
  • Antibiotics
  • Antacids (and acid-supressing medications)
  • Xenobiotics

bacteriaInfections

  • H. pylori
  • Bacterial overgrowth
  • Yeast overgrowth
  • Intestinal virus
  • Parasitic infection

stressStress

  • ↑ Cortisol
  • ↑ CRH
  • ↑ Catecholamines

Hormonal

  • ↓ Thyroid
  • ↓ Progesterone
  • ↓ Estradiol
  • ↓ Testosterone

brainNeurologic

  • Brain trauma
  • Stroke
  • Neurodegeneration

Metabolic

  • Glycosylated end products
  • Intestinal inflammation
  • Autoimmunity

Where-gluten-hidesHow gluten sensitivity leads to intestinal permeability (leaky gut)

All of the above conditions can increase risk of leaky gut.  However, one of the most well-documented cause of leaky gut is gluten sensitivity.  Immune responses to gliadin have been found to initiate intestinal permeability via upregulation of zonulin:  “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)

LEAKY-GUT-PROGRESSION-EPITHELIAL-CELLSThe Leaky Gut—Autoimmune Connection

There is increasing evidence in the literature that intestinal permeability plays a major role in immune dysregulation and the potential for the development of autoimmune disease.  One of the things we need in order to prevent autoimmune disease is immune self-tolerance (tolerance to self-tissue).  The research is showing 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)

pathogenesis-leaky-gut-autoimmune-connectionA recent article published in a well-respected medical journal hypothesized that intestinal permeability is a necessary pre-condition for the development of autoimmunity:

“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)

Leaky Gut Syndrome and Autoimmune Disease

The recent literature shows leaky gut syndrome to be associated with a wide variety of autoimmune diseases affecting multiple organs, including the gastrointestinal system, liver and pancreas.  It has even been associated with heart disease, chronic fatigue, depression, obesity and pediatric conditions such as autism.  Below is a list of health conditions associated with leaky gut syndrome and excerpts from the recent literature supporting this connection.

gut-autoimmune-connectionHealth Conditions Associated with Leaky Gut Syndrome:

  • Type 1 Diabetes
  • Inflammatory bowel Disorders
  • Autoimmune Hepatitis
  • Cardiovascular Disease
  • Chronic Fatigue Syndrome (CFS)
  • Depression
  • Pediatric Disorders
  • Autism

type-1-diabetesLeaky Gut Syndrome and Type1 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)

colon-blue-redLeaky Gut Syndrome and Inflammatory Bowel Disorders (IBD)

“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)

small-large-intestine“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)

liverLeaky Gut Syndrome and Autoimmune Hepatitis

“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)

heartLeaky Gut Syndrome and Cardiovascular Disease

“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)

tired-fatigued-womanLeaky Gut Syndrome and Chronic Fatigue Syndrome

“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)

depression-woman-hand-on-headLeaky Gut Syndrome and 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)

asthma-girl-inhalerLeaky Gut Syndrome and Pediatric Disease

“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)

autsim-boyLeaky Gut Syndrome and Autism

“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)

 In part 6, we will discuss the increasing prevalence of autoimmune disease and how these diseases are related to gluten sensitivity.  We will also discuss the management of intestinal permeability and autoimmune disease with functional medicine.

References

1. NAT CLIN PRAC GASTRO & HEP SEPT 2005 VOL 2 NO 9

2.  Fasano A.  Systemic autoimmune disorders in celiac disease.  Curr Opin Gastroenterol.  2006 Nov;22(6):674-679.

3.  Barton SH, Murray JA.  Celiac disease and autoimmunity in the gut and elsewhere.  Gastroenterol Clin North Am.  2008 Jun;37(2):411-28, vii.

4.  Ventura A, et al.  Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease.  SIGEP Study Group for Autoimmune Disoders in Celiac Disease.  Gastroenterology. 1999 Aug;117(2):297-303.

5.  Cosnes J, et al.  Groupe D’Etude et de Recherche Sur la Maladie Coeliaque.  Incidences of autoimmune diseases in celiac disease : protective effect of the gluten-free diet.  Clin Gastroenterol Hepatol. 2008 Jul;6(7):753-8.

6.  Kharrazian, D.  The Gluten, Leaky Gut, Autoimmune Connection. Apex Energetics lecture. Mar. 16, 2013.

7. GASTROENTEROLOGY 2005;128:1089-1113

8.  The Journal of Immunology, 2006, 176: 2512-2521.

9.  NAT CLIN PRAC GASTRO & HEP SEPT 2005 VOL 2 NO 9

10.  Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointes-tinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol. 2005 Sep;2(9): 416-22

11.  DIABETES, VOL. 55, MAY 2006

12.  Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms.  Ann N Y Acad Sci. 2009 May;1165:195-205

13.  Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia. 2006 Dec;49(12):2824-7. Epub 2006 Oct 7

14.  Vaarala O.  Gut and the induction of immune tolerance in type 1 diabetes.  Diabetes Metab Res Rev. 1999 Sep-Oct;15(5):353-61

15.  Varaala O, Atkinson MA.  The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes. 2008 Oct;57  (10):2555-62

16.  DIABETES, VOL. 55, MAY 2006

17.  Hollander D.  Intestinal permeability, leaky gut and intestinal disorders.  Curr Gastroenterol Rep. 1999 Oct;1(5):410-6

18.  Salim SY, Soderholm JD.  Importance of disrupted intestinal barrier in inflammatory bowel diseases.  Inflamm Bowel Dis. 2011 Jan;17(1):362-81

19.  Terjung B, Spengler U. Atypical p-ANCA in PSC and AIH: a hint towards a “leaky gut”? Clin Rev Allergy Immunol. 2009 Feb;36(1):40-51

20.  Sandek A, et al.  The emerging role of the gut in chronic heart failure. Curr Opin Nutr Metab Care. 2008 Sep;11(5):632-9

21.  Krack A, et al.  The importance of the gastrointestinal system in the pathogenesis of heart failure.  Eur Heart J. 2005 Nov;26(22):2368-74

22.  Maes M. Normalization of leaky gut in chronic fatigue syndrome is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria.  Neuro Endocrinol Lett. 2008 Dec;29(6):902-10

23.  Maes M, et al.  Normalization of the increased translocation of endotoxin from gram-negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome.  Neuro Endocrinol Lett. 2007 Dec;28(3):739-44

24.  Maes M, et al. An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: evidence that nitrosative stress is another factor underpinning the comorbidity between major depression and CFS. Neuro Endocrinol Lett.2008 Jun;29(3):313-9

25.  Maes M, et al. The gut-brain barrier in major depression:  intestinal mucosal dysfunction with an increased translocation of LPS from gram-negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008 Feb;29(1):117:24

26.  Maes M.  The cytokine hypothesis of depression: inflammation, oxidative and nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett. 2008 Jun;29(3):287-91

27.  Liu Z, Li N, Neu J. Tight junctions, leaky intestines, and pediatric diseases.  Acta Paediatr. 2005 Apr;94(4):386-93

28.  de Magistris L, et al.  Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives.  J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24

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