Research
The gut microbiome is composed of trillions of bacterial and archaeal cells, as well as fungi, micro-eukaryotes and viruses. This assemblage of microbiota, or microbiome, is adapted to life in the gut, where together they perform services for the host ranging from food digestion to protection against pathogens. The microbiome is assembled from birth onwards and shaped by the diet, lifestyle and health of the host, as well as by the genetic make-up of the host. By adulthood each of us harbors a unique, individualized microbiome that performs similar tasks across individuals. Differences in microbiome composition and function are emerging as important for various health and disease states, raising questions about how the microbiome interacts with its host to impact health and other aspects of host biology. In the Department of Microbiome Science, we ask fundamental questions about the evolutionary origins of the human gut microbiome and how it influences human physiology and evolution. We combine population-level analyses of gut microbiomes with species-level mechanistic approaches to reveal how gut microbes have evolved with, and affect, their human hosts.
Contributions and ongoing research:
The Ley lab was the first to report links between the the genetic make-up of individuals and the composition of their gut microbiota (Goodrich et al., Cell 2014)(Goodrich et al. 2016)(Goodrich et al., 2017). We identified types of gut microbes for which people are genetically predisposed to have more or less of. These include the family Christensenellaceae, which is also associated with health in people across the world (Ruaud et al., mBio 2020)(Waters and Ley BMC Bio 2019). In our current work we seek to understand how the Christensenellaceae interact with other members of the microbiome and inlfuence host health.
Our work linking host genotype to microbiome composition has led us to ask about the interplay of the microbiome and people in the process of human genetic adaptation to new environments (Suzuki and Ley, Science 2020). We had shown how the human microbiota relates to the microbiota of other animals (Ley et al., 2008) and that gut bacteria and archaea share an evolutionary history with certain mammals (Youngblut et al. Nat Comm 2020)(Youngblut et al., Nat Micro 2021). Now our recent work has revealed specific types of bacteria and archaea that share an evolutionary history with human populations (Suzuki, Fitzstevens et al., Science 2022). By sharing gut microbes between related individuals over hundreds to thousands of generations, people have carried certain species with them as they spread around the globe. These co-diversified species have characteristics of host-associated symbionts, such as reduced genome size, loss of non-essential genes, and reduced tolerance to oxygen and to below-body temperatures; this all points to dependence on body and reduced survivability in the environment.
We are interested broadly in how gut microbiota are adapting to life in the human body. One area of interest is how gut bacteria interact with the innate immune system, specifically the interaction of flagellated bacteria with the innate immune receptor Toll-like receptor 5 (TLR5). Our previous work showed how mice lacking TLR5 have microbiomes very similar in composition to those of wild-type mice, but the the load of flagellin (the protein compoent of flagella) is far higher (Cullender et al., Cell Host & Microbe 2013). This flagellin-rich microbiome causes metabolic inflammation (Vijay-Kumar et al., Science 2010). Thus, a dysregulation in the interations between the immune system and the microbiota can lead the microbiome to be pro-inflammatory. Our recent work has revealed that commensal bacteria produce a type of flagellin that evades the immune system in a novel way we termed 'silent recognition' (Clasen et al., Science Immunology 2023). We are exploring this new evasion strategy in greater detail.
Another area of interest for exploring how the gut microbiota are adapted to life in the gut is to characterize the lipids produced in the gut by bacteria, and how these lipids affect the host. We have shown that sphingolipid production by gut Bacteroides can impact levels of this bioactive lipid class in the liver (Johnson et al., Nat Comm 2020). This led us to characterize how these prevalent gut bacteria synthesize another important lipid type: inositol lipids (Heaver et al. Nat Micro 2022). Our current work explores the bacterial lipodome in the gut and its role in host-microbial interactions.
Probing deeper into these and other questions necessitates tool development, such as the development of new bioinformatics tools and new model genetic systems. These activities form an integral part of the work in the lab.
See our full publication list for more information.
Representative publications:
Clasen SJ, Bell MEW, Borbón A, Lee DH, Henseler ZM, de la Cuesta-Zuluaga J, Parys K, Zou J, Wang Y, Altmannova V, Youngblut ND, Weir JR, Gewirtz AT, Belkhadir Y, Ley RE. Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5. Science Immunology eabq7001. (2023)
Suzuki TA, Fitzstevens JL, Schmidt VT, Enav H, Huus KE, Mbong Ngwese M, Grießhammer A, Pfleiderer A, Adegbite BR, Zinsou JF, Esen M, Velavan TP, Adegnika AA, Song LH, Spector TD, Muehlbauer AL, Marchi N, Kang H, Maier L, Blekhman R, Ségurel L, Ko G, Youngblut ND, Kremsner P, Ley RE. Codiversification of gut microbiota with humans. Science: 16;377(6612):1328-1332.(2022)
Heaver, S. L., H H. Le, P. Tang, A. Baslé, C. Mirretta Barone, D. Long Vu, J. L. Waters, J. Marles-Wright, E. L. Johnson, D. J. Campopiano & R. E. Ley. Characterization of inositol lipid metabolism in gut-associated Bacteroidetes. Nature Microbiology: https://doi.org/10.1038/s41564-022-01152-6 (2022)
Youngblut ND, Reischer GH, Dauser S, Maisch S, Walzer C, Stalder G, Farnleitner AH, Ley RE. Strong influence of vertebrate host phylogeny on gut archaeal diversity. Nature Microbiology. Oct 26. doi: 10.1038/s41564-021-00980-2. (2021)
Suzuki T and Ley RE. The role of the microbiota in human genetic adaptation. Science 370 eaaz6827 (2020).