What you ingest through your mouth pass through the gastro intestinal (GI) tract. GI tract is designed to absorb nutrients, electrolytes most through your gut and allows excrete the unused portion through anus. Your intestine also contains trillions of bacteria including friendly as well as pathogenic that are living like an ecosystem. Intestinal barrier restricts entry of toxins, large food molecules, bacteria or other pathogens from intestine to blood stream. When the intestinal permeability increases or you have leaky gut, it allows entry to those restricted substances into your blood circulation and which further create numerous health problems with a long list.Numbers of lab tests are available to test integrity of intestinal barrier. Those test gives results through varied way. So here I am giving effort to evaluate effectiveness of three leaky gut or Intestinal Hyper-Permeability lab tests.
Effectiveness of three leaky gut or Intestinal Hyper-Permeability lab tests
Sugar Tests
Leaky gut mainly implies passage of molecules with a molecular weight larger than 150 Da across the gut barrier.(1) Transportation of nutrients, electrolytes from intestine to circulation occurs by two pathways
- Paracellular Pathway: Which means passage of molecules through spaces between the cells i.e. through the “tight junctions”
- Transcellular Pathway: Passage through the specialized cells i.e. cells to cells that the line of the intestine
Usually water soluble molecule can’t penetrate the lipid cell membrane of enterocytes and thus use the paracellular pathways through the tight junctions to enter in the circulation. So non-metabolizable water soluble molecules are generally used in testing of increased intestinal permeability.
Lactulose / Mannitol test through urine
This is one old test to perform to test increased intestinal permeability through urine testing. Mannitol is a small sugar molecule that is easily absorbed through intestine where as Lactulose is a larger sugar molecule which is not usually absorbed through intestinal barrier. Both are non metabolized sugar. In normal condition intestinal barrier restrict passage of large molecule. So when large amount of lnon metabolized actulose trespass through intestinal barrier and excrete through urine, indicate increased intestinal permeability. And on the other hand mannitol absorption is used as a measure of normal small bowel function. Initially baseline urine sample is collected and then apply Lactulose and Mannitol solution to the patient for ingesting. And urine collection is performed.
This test easy to perform but consumes time. Can test for small intestinal permeability. Test results depend on factors like time period for urine collection intake of drug like NSAIDs (temporarily elevates permeability) individual patterns of processing as well as excretion. Other factors to be considered refrain from consuming alcohol for three days prior to the test, to avoid exercise on the day prior to and on the morning of the test and to fast overnight before attending the test. (2) However this test unable to detect trespass of larger food proteins, antigenic macromolecule as well as immune response.
This test can’t perform in testing of permeability of large intestine as some colonic bacteria has ability to ferment lactulose. Another sugar testing by using non-fermented sweetener sucralose can perform large intestine permeability test. (3,4)
Zonulin Test
Zonulin a protein, a biomaker released from epithelial cells of intestine controls the opening of intestinal barrier through paracellular space i.e. between cells through tight junction. (5)You need small amount zonulin for opening the gut barrier to allow nutrients to blood stream. However presence of zonulin in large amount can increase the opening to large extent through which large food molecule, toxin, gut bacteria can trespass into the blood stream. Gladin a component of gluten (a protein found in wheat, barley, rye and some oats) and bacterial exposure to small intestine stimulates zonulin secretion as known factor. (6, 7)
As a large protein molecule zonulin should not pass into the blood stream from gut in normal situation. From this aspect higher serum zonulin indicates increased intestinal permeability. But there are some facts to consider.
Zonulin has molecular sizes from 45000-65000 Da. Molecules greater than 5000 Da in size encourages immune cells into action. When such molecules that calls immune actions enters into the circulation immune system, immune cells will take up the molecules or liver Kupffer cells will process them. For that reason zonulin and similar molecules fluctuate from non-detectable to higher level within minutes to hours. Due to fluctuation of zonulin level, a single measurement of zonulin level is not suitable for assessment of intestinal barrier permeability. Although zonulin numbers are very useful in the setting of research analysis, they are insufficiently correlated to be applied to diagnostic medical use. In careful examination of data reveals only 42% of patients with type I diabetes had higher zonulin level. Data from another study had shown only 33% patients with celiac disease had higher blood zonulin level. (8,9)
Antibody Tests
When large proteins, antigens, gut bacteria enter in circulation they initiate immune response. Immune system becomes alerts and so produces antibody against them. With antibody testing it aims to detect antibody against proteins and bacterial endotoxins by testing blood sample. So these type of tests give a better picture along with detection of immune response.
IgG and IgA antibodies tests against zonulin, occludin, and other tight junction proteins. Thus presence of higher serum antibodies against those large proteins indicates deregulation of gut permeability. (8)
Lipopolysaccharides (LPS), an endotoxins a major component of the outer membrane of Gram-negative bacteria can cause inflammation, an increases in intestinal tight junction permeability as well as initiate immune response when high amount in blood.(10)So antibody test against LPS can provide a useful indication about intestinal barrier integrity. Actomyosin a complex protein network holds cell structure and also contributes to muscular contractions. And thus antibody found against actomyosin indicates cell damage to the barrier as well as barrier dysfunction. Antibodies tests can indicate intestinal permeability as well as gut bacterial imbalance. (11)
Bottom line
Asha Mishra and Govind K Makharia, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India concluded that although Intestinal Permeability test is not required for day to day patient’s diagnosis and management, it is an important tool which helps in the study of the early phases of pathophysiology of many autoimmune diseases. (12)
If malfunction of intestinal barrier detects against disease that can be addressed accordingly. But the problem is that these tests are not widely available and also no so budget friendly. Presently only few laboratories are performing these tests.Alternatively signs and symptoms of leaky gut or increased intestinal permeability can help to detect the condition.
Disclaimer:Above article is for informational purpose only.
Reference:
1.Intestinal permeability: functional assessment and significance,
Travis S, Menzies I,Clin Sci (Lond). 1992 May;82(5):471-88
2.Standardising the Lactulose Mannitol Test of Gut Permeability to Minimise
Error and Promote Comparability,Ivana R. Sequeira, Roger G. Lentle, Marlena
C. Kruger,and Roger D. Hurst,PLoS One. 2014; 9(6): e99256
3.The fermentation of lactulose by colonic bacteria,Sahota SS, Bramley PM,
Menzies IS.,J Gen Microbiol. 1982 Feb;128(2):319-25
4.Intestinal permeability – a new target for disease prevention and
therapy, Stephan C Bischoff, Giovanni Barbara, Wim Buurman, Theo Ockhuizen,
Jörg-Dieter Schulzke, Matteo Serino, Herbert Tilg, Alastair Watson, and
Jerry M Wells,BMC Gastroenterol. 2014; 14: 189
5. Fasano A. Physiological, pathological, and therapeutic
implications of zonulin-mediated intestinal barrier modulation: living
life on the edge of the wall. Am J Pathol.2008;173(5):1243-1252
6.Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac
intestinal mucosa and intestinal cell lines,Drago S, El Asmar R, Di Pierro
M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio
A, D'Agate C, Not T, Zampini L, Catassi C, Fasano A., Scand J
Gastroenterol. 2006 Apr;41(4):408-19
7.Host-dependent zonulin secretion causes the impairment of the small
intestine barrier function after bacterial exposure,El Asmar R, Panigrahi
P, Bamford P, Berti I, Not T, Coppa GV, Catassi C, Fasano A.,
Gastroenterology. 2002 Nov;123(5):1607-15
8.Fluctuation of zonulin levels in blood vs stability of antibodies,
Aristo Vojdani, Elroy Vojdani, and Datis Kharrazian,World J Gastroenterol.
2017 Aug 21; 23(31): 5669–5679
9.Host-dependent zonulin secretion causes the impairment of the small
intestine barrier function after bacterial exposure,El Asmar R, Panigrahi
P, Bamford P, Berti I, Not T, Coppa GV, Catassi C, Fasano A.,
Gastroenterology. 2002 Nov;123(5):1607-15
10.Lipopolysaccharides Causes an Increase in Intestinal Tight Junction
Permeability in Vitro and in Vivo by Inducing Enterocyte Membrane
Expression and Localization of TLR-4 and CD14,Shuhong Guo, Rana Al-Sadi,
d M. Said, and Thomas Y. Ma,Am J Pathol. 2013 Feb; 182(2): 375–387
11.The Onset of Enhanced Intestinal Permeability and Food Sensitivity
Triggered by Medication Used in Dental Procedures: A Case Report,
Aristo Vojdani and Jama Lambert,Case Rep Gastrointest Med. 2012; 2012:
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12.Techniques of Functional and Motility Test: How to Perform and Interpret
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2 Responses
Informative. Mannitol in urine is an easily doable test even in small towns. As long as one can assay levels of Mannitol and Lactulose accurately. Question is sensitivity and accuracy of prediction. Antibodies are most likely most sensitive, it will increase cost and may not be possible to do test in small centres.
An informative post. Mannitol and Lactulose in urine can be easily assayed even in less specialised labs. Question is accuracy and sensitivity of prediction. Antibody approach is probably most accurate. It will drive up cost and need expertise.