Friend or foe? How the immune system copes with the gut microbiotica

The job of the human immune system is to destroy pathogens. Using a combination of quick, immediate responses (the innate immune system) and long-term memory (the adaptive immune system) in humans the cells of the immune system are perfectly primed to seek out any cells that are Other (i.e not Self) and kill them.

Which leads to a slight problem, because rather a lot of the cells within your body are 'Other' cells, and their existence is vital to your health. Within your stomach, and your respiratory tract, live a number of commensal bacteria, friendly and harmless bugs that can survive quite happily inside you and help to fight against incoming pathogenic bacteria. Stripping away the bacteria in the gut (i.e by going on a course of very strong antibiotics) leads to all kinds of problems including digestive problems and, once the antibiotics have finished, increased risk of disease-causing bacteria invading the now bacteria-free stomach.

In fact several notable yoghurt making companies are making a lot of money by selling you drinks with bacteria in them. They reassure you that the bacteria aren't dangerous, which is all well and good, but they never quite explain why the ingestion of many bacteria doesn't cause your immune system to have a panic attack.

A new review in Nature looks at the interactions between the gut microbiome and the immune system. The 'gut microbiome' is the collection of bacteria that start colonising the inside of your intestines soon after birth, both from your mother, and from the general environment. It's helpful here to remember that technically your intestinal tract isn't actually inside your body. There's an open tube right the way from your mouth to your arse (for want of a better word...) so the body has a tendency to treat bacteria living there in similar ways to the bacteria living on your skin, by using barriers to keep them out.

However there still is a trade off. The cells that make up the intestinal walls still need to be able to respond to bacteria, and the commensal bacteria still need to be contained. A non-regulated population of bacteria will simply keep growing until all available space is filled (and all nutrients eaten), and this does not happen within the gut.

Starting with the innate immune system which works by recognising molecules found in all pathogens (called PAMPs) these are recognised by human cells using receptors called TLRs (Toll-like receptors - long story) and lead to a signalling cascade that result in a huge number of cytokines and other inflammatory agents being released to kill the bacteria. In the gut this wouldn't just lead to the massive slaughter of the microbiome, but also to a huge amount of damage to the surrounding human cells. Enough exposure to microbial elements such as lipopolysacharrides can downregulate this response; the lipopolysacharrides (which are in the bacteria cell wall) down-regulate one of the key components of the signalling system, a molecule called IRAK1. This prevents the cell from mounting a response to the bacteria. For those that want scientific details, check out the diagram below (image from the reference):


The adaptive immune system is more complex. In normal situations it works by taking a small sample of the bacteria back to the lymph nodes and preparing a specific immune response against it. Special immune cells (B cells) are then made which will kill the specific bacteria, with the help of T cells, which also act as a memory of the threat and the correct response. The B cells are then sent to the point of infection and secrete antibodies which clump the bacteria into groups and recruit other factors to kill them.

This still mostly happens in the case of the gut microbiome, the B cells release the antibody IgA which diffuses out into the intestinal tract and traps the bacteria in the mucus layer. However the bacteria are able to strike back, not by targeting the B cells, but the T cells. There are many different forms of T cells, and by secreting certain chemicals the bacteria can encourage the formation of T-regulatory cells which encourage tolerance towards both commensal bacteria and molecules in food.

So it seems to be not so much a relationship of mututal tolerence and understanding, but more like a sort of uneasy standoff. Bacteria are still being killed to stop them spreading, but are holding off the immune systeme enough to maintain a steady population. In return, the immune system is still there and active, but not active enough to cause any serious damage to either the microbiotica or the surrounding human cells.

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Cerf-Bensussan N, & Gaboriau-Routhiau V (2010). The immune system and the gut microbiota: friends or foes? Nature reviews. Immunology, 10 (10), 735-44 PMID: 20865020

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