Last week we talked about how the gut microbiota can impact our health via nutrition and interactions with the gut itself. However, the gut microbiota can also affect our health via its interactions with the immune system. In fact, studies suggest that the gut microbiota may be critical for our immune system to function correctly. Let's talk about the immune system briefly. This will help us understand its interaction with the gut microbiota. The immune system is composed of two main parts. The innate immune system and the adaptive immune system. The innate immune system is non specific. That means it defends us against all pathogens in the same way no matter what they are. The innate immune system is made up of physical barriers like our skin, as well as chemicals in the blood that react against anything deemed foreign. The adaptive immune system on the other hand, is specific. It tests cells to determine if they are foreign or not and mounts a defense against whatever specific type of pathogen it encounters. Cells called helper T-cells do this by testing and sending chemical signals called cytokines that tell the immune system how to respond. Basically the adaptive immune system has to process and recognise all cells that it comes into contact with and then directs special immune cells to attack any pathogens it recognises. It also has a memory which is why it is called adaptive. Once it comes into contact with a pathogen, it remembers it, so that it can react against it more quickly in the future. Vaccines work by training our adaptive immune system. We present it with deactivated forms of common pathogens so that it learns to recognize them and will react more quickly when the real thing comes along. That way you don't get it sick. Within the adaptive immune system, there are two types of responses, humoral immune responses and cell-mediated responses. Humoral immunity targets pathogens found outside of our human cells, in the blood for example. These are things like bacteria, fungus and worms. Humoral immunity involves B cells, which tag pathogenic cells as invaders. This is where the term antibody comes from. Cells called helper T Cells help recognize projections on pathogen cell walls called antigens and direct B-cells to create other proteins, antibodies, that latch onto the antigens and identify the pathogen. This tags pathogens for other immune cells to destroy them. In this video, you can see a tagged pathogen being eaten up by the immune system. Cell-mediated immunity in contrast to humoral immunity, targets pathogens that are found inside of ourselves. These are things like viruses. Cells with pathogens inside of them send signals. As part of cell-mediated immunity colored T cells recognize these cells and incite infected cells to self destruct. Here you can see colored T cell and Macrophage, the same kind of immune cell that ate the pathogen in the video, attacking a cancer cell. The gut microbiota interacts constantly with the adaptive immune system. If you think about it, that makes sense. Microbes are foreign. They are not our own body's cells. And yet, we have them in and on our body. The immune system has to allow them to stay there by recognizing that they are foreign, but not pathogenic. Therefore, the adaptive immune system constantly monitors the gut microbiota using a variety of cells located in the wall of the intestine. These effectively test the gut microbiota to see what's there and stimulate the secretion of antibodies, called immunoglobulin or IGA, in the gut. These antibodies are specific to certain strains of microbes and are used by B cells to tag pathogenic invaders. So, when immune cells in the gut secrete IGA in response to certain strains of microbes in the gut. It influences gut microbiotic composition. And protects beneficial microbiota from post immune attacks. It is actually hypothesized, the reason we even have an adaptive immune system is to be able to recognize and tolerate our microbial residents. However, the gut microbiota doesn't just sit there. It actually incites the host immune system to make IGA antibodies. For example, germ-free animals and newborns have far fewer cells that can secrete IGA compared to individuals with a fully developed gut microbiota. Additionally, studies suggest that the gut microbiota actually stimulates the development of our immune system. In addition to having fewer immune cells like those that secrete IGA, germ free mice lack immune activity as you can see on the left in this image. Only colonization of their guts with specifically selected bacteria can restore it. Mice without a developed gut microbiota are more susceptible to infection by viruses, bacteria and parasites. This is partially because some kinds of beneficial gut microbes create chemicals that attack pathogens, and partially because some kinds of beneficial gut microbes incite T cells to react to pathogens. Gut microbes affect immune function outside of the gut as well. A study by Ichinohe and colleagues suggests that antibiotic use may reduce immune function in response to the influenza virus. Mice were treated with a variety of antibiotics for four weeks or given water with no antibiotics. When the mice were exposed to the influenza virus, those that had been given antibiotics showed a reduced adaptive immunized response. They had fewer influenza specific antibodies and T cells, as seen in the first two graphs, and more influenza virus, as seen in the final graph. So it seems that exposure to microbes during development and avoidance of antibiotics when possible after development, can help keep us healthy in more ways than one. In fact, in humans, the hygiene hypothesis suggests that reduced exposure to micro organisms due to sanitation and antibiotic use suppresses the normal developement of the immune system. Resulting in increased rates of allergies and immune or inflammatory conditions. Basically if you're too clean your immune system doesn't get trained correctly. And it overreacts to non pathogenic foreign cells. Like allergens or even to your own body cells. We'll explore this topic in more detail in the next lecture. So what if you haven't been exposed to the right microbes at birth? Does that mean your immune system will never develop right? We talked about a related topic with Jessica and Maria Gloria Dominguez during week one. There may be ways to get exposed to microbes after birth. Studies with mice suggest that this type of exposure in infant mice can rescue the gut microbiota and immune system development. However, the same studies showed that exposing adult germ free mice to microbes does not rescue immune system development. In mice at least, there is a critical period during which infants must be exposed to microbes to develop a normal immune system. Finally, despite all the good things they do for us, we know that microbes can sometimes do bad things too. Are our gut microbes always beneficial? Like we discussed last week, the answer is no. If something affects the gut microbial community, so that the individual abundances of microbes are changed, that can lead to health problems. However, it is also possible for gut microbes to do damage if they get out of the gut. The intestinal wall has a mucus layer that physically prevents gut bacteria from getting out of the intestine and into the body. And remember that the immune cells in the intestinal wall are constantly monitoring the gut microbes as well. Together these defenses do a great job of keeping our gut bacteria in the gut where their helpful to us. But sometimes gut microbes do manage to get out of the intestine, when this happens they become an infection and are no longer begin helpful. To counteract this our body stages an immune response. The innate immune system will attack anything that crosses into the body from the gut. And the adaptive immune system will target specific bacteria with antibodies to destroy them if they leave the gut as well. But how do these microbes get out of the gut? Sometimes it's just random chance. But many times something changes our gut environment to make it easier for the microbes to get out. For example certain types of foods might cause inflammation in the gut. Inflammation can lead to less mucus on the intestinal wall, or to tiny holes in the gut wall's defenses. Microbes then find these holes and get through, causing infection. This is referred to as leaky gut. We're still learning what causes leaky gut and how to fix it. But it's one of the key factors in determining when our microbes are contained and helpful, and when they are let loose and become a problem. The gut microbe immune system interactions I described today are simplified. If you think about it, our immune system has to be pretty complex to be able to switch from communicating and cooperating with the gut microbiota to attacking them when they cross the line. But the take home message is that in a normal scenario our gut microbes affect much more than just our nutrition. They can affect how our body works, even outside the gut. The next lecture, we'll talk more about some of these effects
