Unraveling gut immune system, one microbe at a time
The intestine is probably the most difficult organ for the immune system to deal with. First of all, it’s huge (the surface area of the small intestine alone is about the same as a tennis court). Second, it’s filled with microbes that the immune system would rather not deal with. The vast majority are totally harmless, and they tend to crowd out the ones that would actually be a problem. But on the surface, there’s very little difference between normal, run-of-the-mill E. coli and dangerous, going-to-make-you-sick E. coli. So, how does the immune system tell the difference?
This is a really hard question to address experimentally, but a new paper in Science describes a new tool that might pave the way for more understanding of this crucial immune interface:
The lower intestine of adult mammals is densely colonized with nonpathogenic (commensal) microbes. Gut bacteria induce protective immune responses, which ensure host-microbial mutualism. The continuous presence of commensal intestinal bacteria has made it difficult to study mucosal immune dynamics. Here, we report a reversible germ-free colonization system in mice that is independent of diet or antibiotic manipulation.
It hard to study what happens in the gut because it’s either filled with incredible amounts of bacteria, or it has absolutely no bacteria. Germ-free mice can be made by treating them with tons of antibiotics, and then housing them in special facilities where they are isolated and everything is sterilized before coming near them. Unfortunately, the immune systems (everywhere, but especially in the gut) of these mice are totally messed up. You can then add back particular bacteria (called mono-colonization), but these will get established and are very difficult to remove without giving another round of high-dose antibiotics.
What these guys did is to engineer a strain of E. coli that requires particular nutrients that are not present in the host. The researchers can culture these bacteria by providing the nutrients, and then they could colonize germ-free mice while supplementing their diet with these nutrients. When they want to remove the bacteria, they just stop the supplements, and all the bacteria die off. In this way, they can add or remove gut bacteria at whim, and see exactly what effects they are having on the immune system.
What they found was a bit surprising. Normally, if you get infected with a virus or bacteria, your body makes an immune response and pumps out antibodies. These antibodies persist in your bloodstream for a really long time, and upon re-infection with the same bug, you have greater protection. In fact, the secondary response will usually be much better than the first, because your immune system has “learned” how to deal with it (this is why vaccinations often have several rounds of injections – each one trains the immune system to be better than before). When these mice were colonized multiple times, however, this “prime-boost” effect was not seen. In addition, in order for the antibodies against these bacteria to persist, they need to be constantly re-stimulated. If you were vaccinated against the measles, we could still measure antibodies against the measles in your blood years later. By contrast, antibodies against these gut bacteria were lost after 17 weeks.
There are still many open questions – this study makes it even more clear that we have a lot to learn about the intestinal immune system. But hopefully tools like this bacterial strain will make it possible.