Increased gut permeability

- What is it, and can something be done about it?

Increased gut permeability means that certain substances can enter the body that do not belong there. Increased gut permeability appears to play a role in a raft of health conditions, varying from diabetes mellitus type 2 to depression. But how does it develop and what can be done about it?

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Gut wall and barrier function

Increased gut permeability means that the gut’s natural barrier function has been compromised. For that reason, the condition is also referred to as “leaky gut”. The gut barrier is made up of more than the gut wall alone. On both the inside and the outside, the gut wall is sheathed in various layers that protect the body from intruders. First of all, bacteria and antigens are broken down in the lumen by digestive juices, the chemical barrier. The physical barrier behind it is made up of a layer of bacteria (the gut microbiota), a mucosal layer and the gut wall itself. (1) The gut wall is the largest bodily surface in contact with the outside world. It is made up of a single layer of epithelial cells, the enterocytes. In between these cells are protein structures that act as a kind of cement to hold the cells together. The best known of these are the tight junctions. (2,3)  Immediately behind the enterocyte layer is the lamina propia. This contains countless numbers of immune cells, including macrophages, T-cells and dendritic cells. (4) This is the immunological barrier. 

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Intestinal permeability, or "leaky gut". Source; Nature Reviews

 

 

 

 

Gut microbiota and the barrier function

The barrier function is affected by the interaction between the microbiota and the immune system on the one hand and microbiota and the brain on the other. (6,7) Changes in the composition of the microbiota affect the immune system’s response, which, in turn, influences the permeability of the gut wall. (8,9) The microbiota and the nervous system communicate via the so-called “gut-brain axis”. (8,10) Stress, for instance, can cause  increased gut permeability by promoting the synthesis of corticotropin-releasing factor (CRF) and changes in the microbiota. (8) In addition, the microbiota produces metabolites, including specific short-chain fatty acids (SCFAs). SCFAs play a key role in maintaining the gut barrier, for instance by providing an important energy source for the enterocytes and tight junctions. (8)

     

 

"Low-grade inflammation could start a vicious cycle resulting in chronically increased gut permeability." 

     

 

Impaired barrier function in disease

Gut permeability can be impaired by various factors, including (physical) stress, medication, disease, toxins and alcohol. This can involve damage to both the enterocytes and the tight junctions. (7,8,12,13) If this line of defence is breached, greater numbers of immunomodulating substances, such as lipopolysaccharides (LPS), are able to enter into the body. When the body’s internal environment is exposed to an unwelcome substance, it will respond by developing an acute inflammation. Chronic exposure to such substances, due to increased gut permeability or other factors, will cause the immune system to continuously produce small quantities of inflammatory substances. This is referred to as low-grade inflammation. (14) As a knock-on effect, the immune system’s inflammatory response will cause additional damage to the gut wall. This could start a vicious cycle resulting in chronically increased gut permeability. (15) Increased gut permeability and the accompanying low-grade inflammation is associated with a range of health conditions, including a number of inflammatory bowel diseases, but also diabetes mellitus type 2 and chronic liver diseases. (8,16–18) These diseases are often associated with depression (diabetics are 10-30% more prone to depression than non-diabetics), which suggests depression may be associated with impaired gut barrier function. (19) The reverse has also been demonstrated: many people with psychological and psychiatric conditions, including depression, schizophrenia, autism, ADD and Parkinson’s disease suffer from gut disorders, which can only partially be explained by drug side effects. (20)

   

 

Microbiota management

Research has shown that certain probiotic bacteria are capable of improving gut barrier function, for instance by influencing the immune system. (21–23) Potential effects include suppression of immune cell replication or activation in the mucosa and other tissues. Some bacterial strains also release substances that have a protective effect on the epithelial cells. (21) In addition, probiotic bacteria or their metabolites (such as SCFAs) can improve the structure of tight junctions. (24,25) Probiotics also seem to be capable of improving certain conditions associated with increased gut permeability. One example is an RCT in which it was demonstrated that probiotics can improve gut barrier function and low-grade inflammation following physical exertion. (25) Other studies have shown that probiotics aimed at improving gut barrier function can help relieve Crohn’s disease (26,27), in treating obesity and metabolic disorders (28), and in cases of non-alcoholic fatty liver disease. (29)  There is also a new, up-and-coming group of probiotics, known as psychobiotics, that appear to be capable of modulating the gut-brain axis and thereby influencing mood. (30) A recent meta-analysis of the effect of probiotics on depression concluded that a significant decrease in depressive feelings can be seen in people who used probiotics compared to a placebo. (31) The effect of probiotics on migraine is not yet clear: the results of migraine research are contradictory, but there is reason to assume that certain subgroups could benefit from probiotics. 

 

 

There has been a sharp increase in research focusing on the mechanisms of action of probiotics in cases of increased gut permeability, and on identifying subgroups that would benefit the most from probiotics treatment. What has already become clear is that probiotics seem capable of positively influencing gut barrier function, resulting in improvement of conditions associated with impaired barrier function. 

  

  

  

Sources

1.           Quigley, E. M. M. Leaky gut – concept or clinical entity? doi:10.1097/MOG.0000000000000243

2.           Anderson, J. M. & Van Itallie, C. M. Physiology and function of the tight junction. Cold Spring Harb. Perspect. Biol. 1, a002584 (2009).

3.           Assimakopoulos, S. F., Papageorgiou, I. & Charonis, A. Enterocytes’ tight junctions: From molecules to diseases. World J. Gastrointest. Pathophysiol. 2, 123–37 (2011).

4.           Mowat, A. M. & Agace, W. W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14, 667–685 (2014).

5.           Bredenoord, A., Tack, J. & Smout, A. in Functiestoornissen van het maag-darmkanaal 11–22 (Bohn Stafleu van Loghum, 2010). doi:10.1007/978-90-313-7840-1_1

6.           Caricilli, A. M., Castoldi, A., Olsen, N. & Câmara, S. Intestinal barrier: A gentlemen’s agreement between microbiota and immunity. World J Gastrointest Pathophysiol 5, (2014).

7.           Camilleri, M., Madsen, K., Spiller, R., Van Meerveld, B. G. & Verne, G. N. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol. Motil. 24, 503–512 (2012).

8.           Kelly, J. R. et al. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 9, 392 (2015).

9.           Caricilli, A. M., Castoldi, A. & Câmara, N. O. S. Intestinal barrier: A gentlemen’s agreement between microbiota and immunity. World J. Gastrointest. Pathophysiol. 5, 18–32 (2014).

10.        Umbrello, G. & Esposito, S. Microbiota and neurologic diseases: potential effects of probiotics. J. Transl. Med. 14, 298 (2016).

11.        Snoeck, V., Goddeeris, B. & Cox, E. The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes Infect. 7, 997–1004 (2005).

12.        Keshavarzian, A. et al. Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J. Hepatol. 50, 538–547 (2009).

13.        Groschwitz, K. R. & Hogan, S. P. Intestinal barrier function: Molecular regulation and disease pathogenesis. J. Allergy Clin. Immunol. 124, 3–20 (2009).

14.        de Punder, K. & Pruimboom, L. Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability. Front. Immunol. 6, 223 (2015).

15.        Xi, W. G. & Jin, L. Z. A novel method for the recovery of Toxocara canis in mice. J Helminthol 72, 183–184 (1998).

16.        Moss, A. C. The meaning of low-grade inflammation in clinically quiescent inflammatory bowel disease. Curr. Opin. Gastroenterol. 30, 365–369 (2014).

17.        Pitsavos, C. et al. Association Between Low-Grade Systemic Inflammation and Type 2 Diabetes Mellitus Among Men and Women from the ATTICA Study. Rev Diabet Stud 4, 98–104 (2007).

18.        Ilan, Y. & Frider, B. Leaky gut and the liver: A role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol 18, 2609–2618 (2012).

19.        Slyepchenko, A. et al. Intestinal dysbiosis, gut hyperpermeability and bacterial translocation: missing links between depression, obesity and type 2 diabetes? Curr. Pharm. Des. 22, 1–1 (2016).

20.        de Groot, Mary PhD; Anderson, Ryan BA; Freedland, Kenneth E. PhD; Clouse, Ray E. MD; Lustman, P. J. P. Association of Depression and Diabetes Complications: A Meta-Analysis. Psychosom. Med. 63, 619–630 (2001). 21.        Klaenhammer, T. R., Kleerebezem, M., Kopp, M. V. & Rescigno, M. The impact of probiotics and prebiotics on the immune system. Nat. Rev. Immunol. 12, 728–734 (2012).

22.        Tomasik, J., Yolken, R. H., Bahn, S. & Dickerson, F. B. Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. Biomark Insights 10, 47–54 (2015).

23.        Ohland, C. L. & Macnaughton, W. K. Probiotic bacteria and intestinal epithelial barrier function. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G807–G819 (2010).

24.        Ulluwishewa, D. et al. Regulation of tight junction permeability by intestinal bacteria and dietary components. J. Nutr. 141, 769–776 (2011).

25.        Lamprecht, M. et al. Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial. J. Int. Soc. Sports Nutr. 9, 45 (2012).

26.        Gupta, P., Andrew, H., Kirschner, B. S. & Guandalini, S. Is lactobacillus GG helpful in children with Crohn’s disease? Results of a preliminary, open-label study. J Pediatr Gastroenterol Nutr 31, 453–457 (2000).

27.        Malin, M., Suomalainen, H., Saxelin, M. & Isolauri, E. Promotion of IgA immune response in patients with Crohn’s disease by oral bacteriotherapy with Lactobacillus GG. Ann. Nutr. Metab. 40, 137–45 (1996).

28.        Le Barz, M. et al. Probiotics as Complementary Treatment for Metabolic Disorders. Diabetes Metab. J. 39, 291–303 (2015).

29.        Paolella, G. et al. Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease. World J. Gastroenterol. 20, 15518–31 (2014).

30.        Dinan, T. G., Stanton, C. & Cryan, J. F. Psychobiotics: A novel class of psychotropic. Biol. Psychiatry 74, 720–726 (2013).

31.        Huang, R., Wang, K. & Hu, J. Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients 8, 483 (2016).

32.        de Roos, N. M. et al. The effects of the multispecies probiotic mixture Ecologic®Barrier on migraine: results of an open-label pilot study. Benef. Microbes 1, 1–6 (2015).

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