The Leaky Gut

This short essay by Dr Janice Joneja on the ‘leaky gut’ forms part of a longer article on autism which will appear in December. It was written in the context of autism, but ‘leaky gut syndrome’ is also relevant for a wide range of conditions, especially those related to allergy and intolerance.

The “leaky gut” and its relation to food-related reactions has been the subject of research and debate for some time. The term leaky gut was coined to describe food molecules passing more readily than normal through the lining of the digestive tract and into circulation. It has often been suggested that children with autism have this condition.

In early infancy, the digestive tract lining tends to be permeable to food molecules, possibly because components of the mother’s breastmilk need to pass easily into the infant’s circulation. Such components include active immune cells, hormones, and maturation factors that need to remain intact in order to exert their effects. After infancy, these molecules are not essential, and the digestive tract lining starts to “close up” in order to filter out materials that may be detrimental to the body. The gut lining becomes less permeable as the child ages, until at adulthood only the smaller molecular weight nutrients pass through after food has been broken down in the lumen of the digestive tract.

The digestive tract is lined by simple column-shaped (columnar) epithelial cells along its length. The epithelial cells are linked together by tight junction complexes. The epithelial cells as well as the tight junctional complexes are the principal barriers to the free movement into the blood of dietary foods and the products released during their break down (digestion) by digestive enzymes in the lumen of the intestine. This is called the intestinal luminal barrier.

Certain conditions can compromise the intestinal luminal barrier and cause the digestive lining to become less permeable. Inflammation in the digestive tract may damage the epithelial cells and allow food molecules through the non-intact epithelium. Infection, food allergy, and autoimmune disease are some of the insults that may cause inflammation and cell damage and cause the tight junctions to separate. This allows free movement of food molecules into circulation as they bypass the normal processing by the gut-associated lymphoid tissue (GALT). As a result, they encounter immune cells as “foreign material” and cause a variety of problems.

Identification of the Leaky Gut

A useful method of assessing the physical integrity of the luminal barrier is the sugar permeability test. This test measures the ability of small sugar molecules, taken by mouth, to gain entry into the blood and, eventually, to be excreted into the urine. The patient is given a measured quantity of two sugars to drink, dissolved in water. (1) Usually mannitol and lactulose are used. 

Mannitol is a monosaccharide sugar that is poorly absorbed by the human intestine, because it has no affinity for the glucose-galactose carrier protein molecules in the apical (luminal) brush border membrane of small intestinal cells (the enterocytes) that carry sugars across the membrane into circulation. The mannitol molecules pass through the luminal membrane by way of aqueous pores in the brush border membrane. So the larger and more numerous the pores, the more mannitol passes through.

Lactulose, a larger disaccharide molecule, also lacks affinity for the carrier and is too large to pass through the pores. Lactulose molecules, which do reach the blood, do so by passing between the epithelial cells—that is, through the tight junctions. Therefore, if the tight junctions are weakened, lactulose molecules gain access to the blood in circulation.
When these sugars gain access to blood, they are carried to the kidneys and excreted in urine. The ratio of mannitol to lactulose is measured in the patient’s urine. The quantity of each sugar in the urine shows the degree of permeability of the intestinal membranes, and whether the tight junctions are weakened. Passage through weakened tight junctions is also presumed to be the way that peptides such as gliadin pass through a damaged intestinal membrane in coeliac disease.

Method for Conducting the Lactulose/Mannitol Test (2)

The patient drinks a mixture of 5g each of the sugars lactulose and mannitol (referred to as compound in the formula here) dissolved in water. Since these sugars are not metabolized, any absorbed sugar is fully excreted in the urine within 6 hours. The urine is collected, and concentrations of the two sugars are measured. Percent absorptions are calculated using the following formula:
Percentage Absorption = Compound concentration (mg/mL) × Urine volume (mL) × 100  - divided by - Amount of Compound Administered (mL)

In the healthy intestine, the mean absorption of mannitol is 14% of the administered dose, whereas the mean absorption of lactulose is less than 1%. The normal ratio of lactulose to mannitol recovered in urine is less than 0.03. A ratio higher than 0.03 indicates that excessive lactulose was absorbed, indicating that it passed through a hyperpermeable barrier, and thus indicates a leaky gut.


  1. Uil JJ, van Elburg RM, van Overbeek FM, Mulder CJ, VanBerge-Henegouwen GP, Heymans HS. Clinical implications of the sugar absorption test: intestinal permeability test to assess mucosal barrier function. Scand J Gastroenterol Suppl. 1997;223:70–78.
  2. Paroni R, Fermo I, Molteni L, et al. Lactulose and mannitol intestinal permeability detected by capillary electrophoresis. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;834(1–2):183–187.

First published November 2014

You can buy all of Dr Joneja's books here or here in the US.

See also:
Intestinal permeability - a new target for disease prevention and therapy. Review summarising the data that are accumulating emphasizing the important role of the intestinal barrier and intestinal permeability for health and disease. Stephan Bischoff and colleagues in BMC Gastroenterology. November 2014


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