BSCB Science Writing Prize 2009

The Gut Barrier: Protecting You From Invasion | Back

By Caroline Weight, Institute of Food Research, University of East Anglia.

A delicate balance exists within the gut through a rich diversity of gut microbes and the activation status of the gut immune system. Researchers are becoming increasingly aware that this balance is affected by a combination of diet, environmental and genetic factors. Therefore the integrity of the gut barrier is vital in maintaining controlled interactions between microbes and pathogens from the gut immune system and the rest of the body.

The contents of the gut are separated from the rest of the body by just a single layer of cells held together by cellular junctions. These junctions control not only the amount of minerals and ions that are absorbed, but also prevent the passage of microbes from entering the body. Therefore, the integrity of the gut barrier is crucial in protecting from invasion.

The gut barrier is comprised of a collection of proteins that work to hold the cells together. This process occurs very early during foetal development and continues throughout life. The cells that make up the gut only live for a few days and are then shed from the barrier. This occurs to limit the amount of microbial colonisation which also means that the cellular junctions have to be dynamic in structure to ensure that the barrier remains intact. 

A number of clinical disorders have been associated with breakdowns in the gut barrier, such as eczema, food allergies, celiac disease, asthma, type 1 diabetes, multiple sclerosis and various cancers1, thus the importance of understanding the physiology of cellular junctions is imperative. 

It is estimated that there are over 100 trillion microbes that reside in the human gut encompassing a rich diversity of bacterial species2. Some of these microbes are beneficial to us (referred to as commensal microbes) and it is important that our gut immune system responds in the best way towards them. A state of inactivation or tolerance has evolved which means that when immune cells present microbial antigens to other immune cells, no attack is mounted and the presence of these microbes are tolerated.

The gut immune system has to keep these microbes in check because if microbial replication increases or microbial behaviour changes, then an active immune response is necessary to restore the balance. There are many factors that can influence the stability of the gut environment. For example, a diet rich in red meat can alter the community of commensal microbes resulting in a domination of numbers in one species (niche exclusion). This increases the probability of microbial infection by chance, referred to in the literature as an opportunistic infection. These events can activate an immune response, leading to a recruitment of immune cells, inflammation, leaky cell junctions and therefore increased permeability. There is evidence to suggest that events such as these increase the risk of developing colon cancer and Inflammatory Bowel Disease (IBD)3 ,4. IBD affects 1 in every 400 people in the UK5 and is highest in Northern Europe, the UK and North America6. The exact sequence of events that result in the development of IBD is currently unknown, but both environmental and genetic factors are thought to contribute to the pathology of the disease.
Commensal microbes can also help to prevent the colonisation of harmful microbes (pathogens) in the gut. They do this by competing for space and nutrients (competitive exclusion), but can also secrete factors that inhibit the growth of pathogens. Pathogens can enter your body through contaminated food or water consumption and pose a significant impact to human health; over 76 million cases of food borne illnesses are reported every year in the USA and 2 million in the UK (World Health Organisation). Pathogens that cause these illnesses include microbes like E. coli and V.cholera,which take advantage of infecting the body when the integrity of the gut barrier is compromised and when cell junction integrity is weakened.

There are some pathogens that have evolved to directly target the cellular junctions as a mechanism for invading the body and, therefore, overcome the presence of commensal microbes. Our aim is to understand in greater detail how cellular junctions form and how they can be affected during and after infection. By looking at individual proteins that make up the tight junction complex and the barrier itself, we can assess the effects of infection caused by pathogens that directly target junctions and identify key roles of signalling cascades in the regulation of different proteins. This information can be used to develop novel therapies that will target and stimulate the production and presence of specific proteins and pathways that regulate cellular junctions, to increase the strength of the barrier and prevent infection.

1. Feldman, G. J., Mullin, J. M., and Ryan, M. P., Occludin: structure, function and regulation. Adv Drug Deliv Rev 57 (6), 883 (2005).
2. O'Keefe, S. J., Nutrition and colonic health: the critical role of the microbiota. Curr Opin Gastroenterol 24 (1), 51 (2008).
3. Gassler, N. et al., Inflammatory bowel disease is associated with changes of enterocytic junctions. Am J Physiol Gastrointest Liver Physiol 281 (1), G216 (2001).
4. Santarelli, R. L., Pierre, F., and Corpet, D. E., Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence. Nutr Cancer 60 (2), 131 (2008).
5. Economou, M. and Pappas, G., New global map of Crohn's disease: Genetic, environmental, and socioeconomic correlations. Inflamm Bowel Dis 14 (5), 709 (2008).
6. Baumgart, D. C. and Carding, S. R., Inflammatory bowel disease: cause and immunobiology. Lancet 369 (9573), 1627 (2007).