Carnegie Science | Spring 2019 5 The interactions among the species of microbes in the gastrointestinal system can have large and unpredicted effects on health, according to new work from a team* led by Carnegie’s Will Ludington. Proceedings of the National Academy of Sciences published their findings. The gut microbiome is an ecosystem of hundreds to thousands of microbial species. The diversity within the human gut presents a challenge to cataloging and understanding the effect it has on our health. It has long been known from fruit fly studies that populations of gut bacteria can affect their host’s development, fertility, and longevity. In 1927, Helen Steinfeld of U.C.- Berkeley found that by simply removing the gut bacteria from her laboratory’s fruit flies she could extend their life spans by 14%. Today, biologists are particularly interested in determining whether the microbiome as a whole is greater than the sum of its parts. Specifically, to what extent do individual species influence our health and physiology, and to what degree are these impacts determined by interactions among the different species? Ludington and his team used the naturally simple microbiome of fruit flies to determine the gut ecosystem. They repeated the 1927 Steinfeld experiment and found a 23% life span extension when they removed their flies’ particular microbiomes. But it was unclear how much of this influence was due to the individual species versus the overall microbial ecology. “The classic way we think about bacterial species is in a black-and-white context as agents of disease—either you have it, or you don’t,” Ludington said. “Our work shows that isn’t the case for the microbiome. The effects of a particular species depend on the context of which other species are also present.” Ludington’s team then built off Steinfeld’s work to dissect the fruit fly gut microbiome and better understand how these microorganisms shape the lives of their insect hosts. They developed a mapping system of all the possible interactions between the five species of bacteria found in the fly gut to see how they affected an insect’s development, production of offspring, and life span. The analysis required developing new mathematical approaches, which are based on the geometry of a five-dimensional cube, where each species is a new dimension. The team found that the interactions among microbial populations are as important to the fly’s physiology as the individual species present. In terms of the 23% change in life span, individual species can account for only one quarter of the effect, while interactions account for the rest. These interactions are highly influential to some, but not all, of the factors that determine a fly’s likelihood of passing its genetic material on to a new generation. “As we examined the total of what we call a fly’s fitness—its chances of surviving and creating offspring—we found that there was a trade-off between having a short life span with lots of offspring, versus having a long life span with few offspring,” Ludington explained. “This trade-off was mediated by microbiome interactions. That means that if we want to understand how the microbiome impacts our health, we need to develop a predictive understanding of how combinations of bacteria affect the host, not just the individual species.” Additionally, the measurement and analysis tools they developed demonstrate that the fruit fly is a good model for understanding more complex microbiome interactions in humans and other animals, important for future work.  Interacting Gut Microbes Shape our Lives This super-resolution image shows fly gut crypts that are colonized by the native Lactobacillus (red) and Acetobacter (green) bacteria. Fly cell nuclei appear blue. Image courtesy Benjamin Obadia Lead author Will Ludington joined the Carnegie staff in June 2018. Image courtesy Navid Marvi, Carnegie Institution for Science “The effects of a particular species depend on the context of which other species are also present.” SUPPORT AND COLLABORATORS: Other team members included molecular biologists Alison Gould, Vivian Zhang, and Benjamin Obadia of U.C.-Berkeley; physicists Eric Jones and Jean Carlson of U.C.-Santa Barbara; mathematicians Lisa Lamberti, Nikolaos Korasidis, and Niko Beerenwinkel of ETH Zurich; and Alex Gavryushkin of University of Otago. A National Science Foundation Graduate Research Fellowship, the Royal Society of New Zealand Rutherford Discovery Fellowship, the David and Lucile Packard Foundation, the Institute for Collaborative Biotechnologies and U.S. Army Research Office, the NIH Early Independence Award, and the U.C.-Berkeley William Bowes Research Fellowship supported this research. Carnegie Science | Spring 2019 5