Definition of Intestinal Permeability
Intestinal permeability also known as ‘leaky gut’ has gained researchers attention in recent years, with the overwhelming amount of evidence linking the integrity of the intestine to health and disease. The exact definition of intestinal permeability remains poorly understood. However, the current definition describes intestinal permeability as the loss of integrity between the cells of the small intestine caused by the disassembling of the transmembrane proteins.
The classification of intestinal permeability can be divided into two major categories, namely acute intestinal permeability and low-grade chronic intestinal permeability. Firstly, acute intestinal permeability is more common within a hospital setting where pathogenic bacteria trigger a change in intestinal integrity, resulting in sepsis. Acute intestinal permeability is seen in conditions such as pancreatitis and burn injuries. Whereas, low-grade chronic intestinal permeability appears to be more prominent in health conditions found within clinical practice.
A Brief History of Intestinal Permeability
The concept that pore size varies at different levels of intestine was first established in the literature during the early 1960s and collectively referred to as the ‘intestinal-pore hypothesis’. During the early 1970s research emerged surrounding the association between intestinal permeability and coeliac disease, with preliminary data suggesting that the degree of intestinal permeability correlates with the severity of coeliac disease. More recently, the mechanism of action for intestinal permeability development was discovered, strengthening the understanding of the involvement of intestinal permeability in health and disease. However, currently, Intestinal permeability is not officially recognised as a medical condition with the closest diagnosis classified as K59.9 functional intestinal disorder. Intestinal permeability may thereby be considered as an intestinal reaction in response to a stimulus and not a condition nor syndrome.
Measuring Intestinal Permeability
The simple fact is the identification and diagnosis of intestinal permeability is difficult.
Currently there is no gold standard for measuring intestinal permeability. All tests on the market have their limitations. So regardless of the method you use to measure intestinal permeability, it is always advised to incorporate symptoms and other biomarkers into the differential diagnosis.
Lactulose and Mannitol
The dual sugar test involves the oral consumption of two sugars, namely lactulose and mannitol in roughly 100-300ml of water after an overnight fast. The core principle behind the lactulose and mannitol test is the molecule size of the two sugars. When the intestinal integrity is healthy, the monosaccharide mannitol is readily absorbed while lactulose being a disaccharide remains within the intestine and is poorly absorbed. However, during a loss of intestinal integrity, the ratio of lactulose to mannitol is increased, as lactulose is able to permeate the intestinal mucosa and become present in the urine. Many of the confounding factors such as gastric emptying, renal function and intestinal transit time are controlled for when the dual sugar test is used compared to just using a disaccharide. The most common test used to assess intestinal permeability is the lactulose and mannitol urine test. This at home urine test involves collecting urine for 6 hours after an overnight fast.
Zonulin is an acute phase protein, meaning it has a relatively short half-life. So the stool zonulin is generally better when intestinal permeability is in its early stages or there is “active intestinal permeability”. The other use of the stool zonulin is in conditions that are situated in the gastrointestinal system (IBS, IBD). Unfortunately, as zonulin is released from adipose tissue someone who has a high BMI or has a metabolic like condition may have a high level of zonulin but not caused by the disassembling of the tight junctions.
So the difference between the two? The stool is more likely to give a false negative whereas the blood is more likely to give a false positive. All other tests on the market (excluding the lactulose and mannitol urine test) have insufficient evidence to use in clinical practice.