Gut Immunology

To get a better understanding of probiotic function, it’s essential to have a basic understanding of gut immunology. The intestines, besides just being a sheath that absorbs nutrients and water and collects solid waste for disposal, is actually its own microcosm. Cells that make up the walls of the intestines are constantly interacting with the bacteria, yeasts and food particles that collect in the interior. These interactions maintain, to a large extent, your general health.

The Intestines

The intestines form a sheath that surrounds the gut lumen, the space inside of the intestines where the feces are formed. For most of us, the only interaction that we have with intestinal walls is when we eat a natural casing hot dog or a sausage packed in pig intestine. The intestines used to make sausage are the small intestines and they can be up to 32 feet long in humans. The small intestine connects to the stomach at one end and then connects to the cecum, which in humans is the beginning of the large intestine and is the location of the appendix. The colon is much shorter and is the most bacteria rich region of the intestines. It is here that most of the water is reabsorbed from the fecal material.

The Intestinal Wall

In a living intestine, the inside wall is covered with a mucus layer, which is thicker in the large intestine than in the small intestine. Just underneath the mucus lies the outer most protective layer of cells called the epithelial cell layer. This layer consists of epithelial cells and goblet cells that produce mucus. Under the epithelial layer is a space created by a thin muscle layer (muscularis mucosae). This region is called the lamina propria and it contains many immune cells, small blood vessels called capillaries and also glands that secrete mucus. The epithelial layer and the lamina propria are together called the mucosa

probiotics cross-section intestinal wallThe mucosae in the colon and the small intestine are different. In both the colon and the small intestine, the epithelial layer forms a series of pockets, a lot like an egg carton. The pockets are called crypts and when the areas between the crypts extend above the surface, they are called villi. The small intestine has both villi and crypts, while the colon only has crypts. Microbial entrance into the crypts is forbidden and Paneth cells located at the bottoms of the crypts protect them with the secretion of anti-microbial peptides.

Also within the mucosae, scattered about, are lymphoid structures. Lymphoid structures are dense areas filled with immune cells. In the small intestine, they are called Peyer’s patches and in the large intestine they are called colon patches. While many immune cells reside in the mucosa of the intestines, they are not isolated from the rest of the body. Transport of immune cells occurs via the blood circulatory system and also through a part of the circulatory system called the lymphatic system.

lymphaticsThe lymphatic system consists of vessels extending throughout the body and often lying parallel to the blood vessels. This system acts as an immune cell super highway with hubs called lymph nodes. Lymph nodes are lymphoid structures housing many immune cells much like the Peyer’s patches and colon patches. The most important and locally located lymph nodes of the intestines are called the mesenteric lymph nodes.

Underneath the mucosa are two additional layers: the submucosa and the muscle layer. The submucosa contains loose connective tissue and many blood vessels. The muscle layer contains the muscles that control the contractions of the intestines, which are responsible for the transport and compaction of fecal matter.

Immune Cells of the Gut

The main cells of the immune system located within the gut are macrophages, neutrophils, dendritic cells, mast cells, T cells and B cell. These cells all have very different functions but they can be loosely classified into combat, scouting and intelligence functions.

Combat Cells

Macrophages, mast cells and neutrophils function as the foot soldiers of the immune system. These cells are the most capable of dealing with bacterial invaders, and all are capable of phagocytosis – the engulfment and destruction of bacteria. Macrophages are the most renowned for the ability to ingest particles. Another skill, in which macrophages and neutrophils excel, is the respiratory burst. This is the release of harmful oxygen radicals that can also kill invaders. Neutrophils and mast cells have an additional weapon in the form of granules. Granules are actually small vesicles of harmful molecules that can be released by cells. Neutrophil granules contain mainly anti-microbial substances, while mast cell granules contain substances that activate surrounding cells and cause the signs of inflammation. Histamine, one of the main factors that lead to allergic responses, is released by mast cells.

Scouting Cells

Dendritic cells, and to some degree macrophages, function as the scouts of the immune system. Dendritic cells, like macrophages, have the ability to phagocytize bacteria and other particles in the environment. Besides allowing the dendritic cell to kill bacteria, this function also allows the cell to collect information about the pathogen. Using receptors, dendritic cells can recognize patterns associated with good and bad bacteria as well as viruses and fungi, which allows them to conclude the total threat posed by the invader. But, what makes them really good scouts is that they also have the ability to dismantle the engulfed microbe and deliver that information to the cells that are experts at intelligence.

Intelligence Cells

Although, the dendritic cells can dismantle bacteria and collect new clues, it’s not the cell that deals with the information. The cells in charge of the real intelligence functions are the T and B cells. These cells, unlike the others, have the ability to remember invaders from the past (very similar to elders remembering dangers that the younger generation isn’t aware of). When they see signs of the pathogens that they remember, they can alert and organize all of the other immune cells.

Their memory isn’t formed using small brains, but instead uses a complex set of receptors called simply T cell receptors (TCRs) and B cell receptors (BCRs). TCRs and BCRs can recognize small protein molecules. The memory is created when there is recognition of a pathogen-related molecule via the TCR and BCR along with other stimulatory signals from the environment verifying the threat. When these triggers are present, the cells divide and become long-lived memory cells.

T cells

T cells interact primarily with dendritic cells, receiving their information from them about local pathogens. The dendritic cells present pieces of the invader plus other information in the form of cytokines (secreted proteins that the T cell can detect). The cytokines tell the T cell how bad the danger is and, depending on the situation, the T cell will adjust its function and the signals that it sends out.

T cells can be divided into two main types depending on their function and protein markers found on the cell surface. T helper cells are designed to help and activate other cells and cytotoxic T cells are designed to kill infected cells. Cytotoxic T cells are a bit of combat and intelligence rolled into one.

The T helper cells are quite important because they can orchestrate immune responses in the future. After be given information by dendritic cells, they can morph into several types. Th1 cells are associated with internal bacteria and viral infections, Th2 cells are created mainly as consequence of parasite infection and allergy, Th17 cells are formed with there are extracellular bacterial infections and regulatory T cells (Treg) are formed when something is deemed as safe, and the wish is to lower inflammation. During non-dangerous situations, which are the majority of the time in the gut, Treg are formed. It is these Treg that ensure that you are able to tolerate the food that you eat.

B cells

B cells are not dependent on dendritic cells for the information collecting. They are, for the most part, dependent on T helper cells for their information. B cells, using their BCR, pick up soluble molecules floating around in the environment. However, the B cell will not see the molecule as a threat until a T helper cell gives them a signal that it is associated with an invader. The signals are in the form of secreted cytokines and receptor signals. Once a threat is communicated, the B cells will produce antibodies and become long-lived. Antibodies are extremely important weapons against pathogens. They can coat pathogens, neutralizing their function, and they also alert other immune cells to problems.

How Are Some Bacteria Beneficial?

Probiotics can be beneficial at many levels. First, probiotics have the ability to limit the numbers of harmful bacteria in the intestines. They do this through lowering the intestinal pH, the production of antimicrobial substances and by out-competing bad bacteira for resources. Second, they have positive interactions with epithelial cells. It has been noted that when epithelial cells come into contact with probiotics, they improve their barrier function by increasing the production of anti-microbial substances, mucus, and barrier proteins. This prevents the entrance of harmful bacteria into the layers below. The third way that probiotics are helpful is by encouraging anti-inflammatory responses. By interacting with epithelial cells and dendritic cells, they can indirectly instruct B and T cells to function in ways that suppress harmful inflammation.

Examples of Probiotics in Action

To give you an idea of how probiotics might interact with the immune system, we’ll take a look at what is going during two intestinal diseases that just happen to be candidates for probiotic treatments.

Acute diarrhea

Acute diarrhea is usually caused by the ingestion of bacterially contaminated food or water. What causes the symptoms is not always a direct result of the body being overwhelmed by infection, but is often a result of the intense immune response that the bacteria and their products elicit. During Salmonella infection, the epithelial cells and local combat cells (macrophages, neutrophils and mast cells) all recognize and react to the Salmonella and its toxin. As a result, the intestinal wall becomes a battlefield with degranulation, respiratory bursts, phagocytosis and cytokine production. Unfortunately, the epithelial surface becomes a casualty of war in this situation and the water absorbing function of the intestines is disturbed causing diarrhea. The loss of barrier function also allows the leakage of more bacteria (both good and bad) into the intestinal wall and beyond. This causes a systemic inflammation and is the reason why food poisoning makes one feel so bad. Control is restored when the Salmonella is destroyed, the immune cells settle and the epithelium is allowed to heal. Probiotics can help this process by destroying Salmonella directly and by helping encourage regulatory T cell function allowing inflammation to end quickly.

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the intestines. It is unknown precisely how this disease starts, but it is clear that it happens as a consequence of both genetic and environmental factors. Those with IBD have large amounts of immune cells in the inflamed areas of the intestine. Large populations of neutrophils, macrophages, T and B cells are noted in particular. It is suspected that the T and B cells are providing guidance to the neutrophils and macrophages that continually calls them into action. The T helper response is often skewed away from Treg towards Th17. It is speculated that finding ways to increase Treg would bring things back into balance allowing the inflammation to resolve.

Because probiotics have been shown to increase Treg function and numbers, they are now being seriously investigated for treatment of IBD. Besides increasing Treg, probiotics could also help IBD by encouraging better barrier function. Limiting the amounts of bacteria and particles that enter the intestinal wall, would reduce the signals that immune cells need to be activated and continue inflammation.

Conclusion

The use of different probiotics needs to be investigated on a cellular level. By doing so, it would be easier to determine when and where they should be used. An important step right direction would be fully exploring different bacterial strains at a genomic and proteomic level. Simultaneously, steps should be made to investigate how the immune system decides if a strain is beneficial or harmful. Combining these two fields of research would allow probiotics to exit the field of alternative medicine and enter the arena of cutting edge medicine.

If you wish to learn more about immunology, visit the basic immunology page on The IBD Immunologist site.


Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.

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