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Guardians of the Gut

Credit: freshidea/adobe

Credit: freshidea/adobe

By Lucille Rankin & Gabrielle Belz

The appendix has long been considered an evolutionary relic but new evidence indicates it has an important role in our immune system.

The immune system is a complex network of white blood cells comprising two units. The first encompasses the adaptive immune cells that specifically recognise and respond to foreign bodies, while the second unit comprises innate immune cells that react in a more generic way, utilising alert signals such as the chemical factors that signal inflammation to kickstart their response.

Our body’s largest physical barrier is its epithelial surface. It forms a protective “glove” separating our internal machinery from the outside world. This barrier is formed by the skin on the surface; internally, epithelial cells line the lungs and gut to provide a protective layer.

Lying immediately beneath these barriers is a very intricate network of innate immune cells known as innate lymphoid cells. This family of cells is thought to play important roles in protection of the gut, lungs and skin. Due to the strategic location of these innate lymphoid cells at the body’s protective barriers, they are ideally situated to sense signs of danger or infection.

Bacteria and Immune Cells in the Gut

The intestine performs the important function of digesting the food we eat and converting it to energy. The gut also contains more than 100 trillion bacteria from an estimated 500–1000 species that together weigh1.3 kg. Although we often think of microorganisms as harmful, most of the bugs that inhabit our body’s surfaces are essential for our health.

About 70% of our immune cells are localised to the gut. This is unlikely to be coincidental – the close proximity of each of these different elements suggests that the immune system and microbiota might co-regulate each other.

When a pathogen breaches a body’s surface it generally damages or disrupts the epithelial cells. This results in the release of chemical mediators that activate innate immune cells. These then recruit adaptive immune cells that mount a full assault to eliminate the pathogen.

The adaptive immune cells are distinct from the innate cells as they can distinguish different types of pathogens or threats that need to be eliminated while leaving our own cells protected from attack by the immune system. They do this by essentially recognising the “signature” of these pathogens. The adaptive immune cells can then mount an immune response that is specifically tailored towards destroying the invading organism and eliminating it from the body.

Over the past few years, immunologists have discovered a number of novel populations of immune cells that have blown apart some of our conventional views on how the immune system works. We think it’s very unlikely that the innate lymphoid cells are simply left over from evolutionary shifts, and believe instead that they perform important and specific functions.

We wanted to try and discover what these roles might be and how they contribute to health. This led us to establish a mouse model of infection with the murine pathogen Citrobacter rodentium, which first colonises the caecum before infecting the rest of the gastrointestinal tract. This infection strongly resembles infections that cause severe cases of diarrhoea in people.

Gut Specialisation

Although the gut is essentially a single continuous tube, it is divided into specialised segments that are involved in different parts of the digestion process. For example, 90% of digestion and absorption of nutrients takes place in the human small intestine with the remaining 10% taking place in the stomach and large intestine.

The caecum is a small pouch at the beginning of the large intestine that intriguingly contains a large patch of immune cells near its tip. In large animals such as cows, horses and even koalas, the caecum is home to bacteria that digest the tough plant components in the diet.

In humans, however, this part of the gut is much reduced in size and the part that contains the immune cell patch is found in what is now a smaller appendage to the caecum, the appendix. This immune cell patch is important for initiating immune responses and is sometimes a target for the colonisation of various pathogenic microbes.

The appendix is not required for digestive functions in humans but normally houses symbiotic bacteria that are important for overall gut health. Randall Bollinger and Bill Parker at Duke University have suggested that these symbiotic bacteria play a more prominent role following gut infections that can result in diarrhoea. Such an infection effectively cleans out the gut, not only of fluids and nutrients but also of good bacteria. Bollinger and Parker proposed that the good bacteria harboured in the appendix provide a site where the body’s own microbial culture is sequestered so that it can repopulate the gut after the infection is over.

Our group was able to create mice in which we manipulated or deleted the innate lymphoid cells and/or the adaptive immune cells to test how each of these populations are involved in the development of intestinal disease following C. rodentium infection. The worst outcome occurred when both innate and adaptive cell subsets were depleted. To our surprise, the caecum was quite shrunken and clearly not performing its usual function of processing food as it moves towards the colon.

We found that altering the balance of the different types of immune cells significantly affected what was happening in the caecum. It made us wonder if a similar effect might occur in humans in the appendix. Could it be that this organ, which is often considered irrelevant, may indeed play a very important role?

We found that although innate lymphoid cells are found throughout the intestine, they seem to perform specific roles that are critical for caecal health. It’s already known that innate lymphoid cells produce a number of signalling molecules that are very important for regulating inflammation and tissue repair. Some of these pathways could be involved in this protective circuit. Unlike humans, mice don’t themselves have an appendix, but this system now provides a model in which we can systematically start to investigate what is happening in the different parts of the gut, in particular the caecum.

The Future

The genomics revolution has ushered in a very exciting phase in understanding how the gut works, how immune cells impact on its function, and how man and microbes coexist to maintain the health of the body. These technological advances will allow us to assemble a much more complete picture of how immune cells interact with the different compartments of the digestive tract. Importantly we hope to understand how this affects the health of an animal and how we might manage a number of health problems associated with disorders of the intestine, including inflammatory disease, allergy, obesity and diabetes.

Lucille Rankin is now a Postdoctoral Fellow at Weill Cornell Medical College. Gabrielle Belz is a Laboratory Head at the Walter and Eliza Hall Institute of Medical Research.