Integrated multiomics of host-bacteria interactions during C. elegans gut infections.

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When one realises that we carry ten times more microbial cells than human cells, it is no surprise that maintaining a good relationship with our gut microbes is essential for our health. Perhaps less evident is the fact that our gut microbes not only determine our propension to obesity and cardiovascular health, they also determine our risk of developing cancers, diabetes, neurodegenerative, and auto-immune diseases. They also condition how we age, how well we recover from illnesses, surgeries or aggressive therapies, and they can even influence our moods!Understanding how we communicate with our gut microbes has thus become a key challenge, and a potentially unlimited source of new therapies to tackle very complex disease states, and help all of us live and age much better. Yet, it is in itself a very difficult endeavor. We host thousands of microbial species organised in dynamically evolving communities. Moreover, no two microbiotas are identical, not even in twins. At the moment, despite amazing advances in biotechnology and computer sciences, it is simply too expensive and too big to solve.Fortunately, as we did before with genome sequencing or brain mapping, we can turn to a simpler system first: C. elegans, a 1mm-long bacterium-eating roundworm that already enabled several Nobel Prize-winning discoveries. If we can solve the problem at a smaller scale, we can uncover essential principles that apply at a larger scale, and accelerate discovery of new drugs and therapies.Like us, C. elegans has a gut microbiota, but it only colonizes its intestine during adulthood. In the laboratory, this allows us to precisely control which and how many bacteria colonize the worm gut. Because C. elegans is transparent, we can also directly look at these bacteria as they divide and move in the worm gut. To watch together different bacteria in the gut of live worms, we can further color-code them and film them by fluorescence microscopy. C. elegans is actually the most intimately known animal. We can know in real-time how active its genes and cells are, and how healthy it is. We can also switch off worm genes at will using RNA interference. We can even tell precisely when a worm dies, as it emits blue fluorescence at death. Lastly, we can make worm sick by giving them human diseases. Thanks to all this, we can use simple worm models to study complex human diseases.This is exactly what we will do in our project. We will give the worms bacteria that are responsible for human urinary tract and lung infections. This will emulate gut dysbiosis in worms: a state where the relationship with our gut microbes goes awry, and which is frequent in ill-health and ageing. Then, combining all the approaches evolved earlier (using microscopy imaging, modifying and looking at gene activities, assessing worm and bacterial health), we will investigate and elucidate how all relevant worm and bacterial genes interact, and how it explains disease states. Knowing that, we will then test if known drugs can be used to improve worm health when dysbiosis happens.Because worms share a lot of physiological functions, genes and diseases with other animals and humans, knowing how dysbiosis works in worms and how to prevent or correct it, will teach us a lot about our own human experience of gut dysbiosis. Hence, it will quick-start the development of new therapies, including new antibiotics and treatments to promote gut health and healthy ageing.