Gut microbiome maturation in early childhood interacts with host genetics to predict type 1 diabetes risk
Abstract
Prospective evidence linking early-life microbiome development and host genetics with type 1 diabetes (T1D) risk is limited. Here, we describe how gut microbiome maturation and host genetics influence T1D risk in the TEDDY study. We analysed 12,151 longitudinal metagenomes and host genetic data from 887 children at high genetic risk for T1D followed for up to 6 years. We identify three microbiome maturational patterns: Early Matured, Late Matured and Early Plateaued, driven primarily by non-linear changes in species from the Bifidobacterium and Ruminococcus genera. The Early Matured pattern is enriched in galactose metabolism and exhibits higher production of aromatic amino acids and B-group vitamins at early follow-ups, whereas the Early Plateaued pattern has increased microbial production of branched-chain amino acids. Notably, the Early Plateaued pattern is associated with a threefold elevated risk of T1D, whereas other patterns are not associated with T1D risk. Furthermore, we find that host genetic variants related to antimicrobial and antiviral immune responses modify the association between the Late Matured pattern and T1D risk. These findings highlight the role of early microbial exposures and host genetics in T1D susceptibility. In the prospective, multicentre TEDDY study, distinct patterns of gut microbiome maturation are associated with differential risk of type 1 diabetes, with host genetics modifying the strength of this association.
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Authors: Danyue Dong, Aaron M. Walsh, Tommi Vatanen, George Weingart, Mondher Khdhiri, Meir J. Stampfer, Kendra Vehik, Eric A. Franzosa, Curtis Huttenhower, Dong D. Wang, The TEDDY Study Group, Marian Rewers, KIMBERLY BAUTISTA, Judith Baxter, Daniel Felipe-Morales, Brigitte I. Frohnert, Marisa Stahl, Patricia Gesualdo, Michelle Hoffman, Randi Johnson, Rachel Karban, Edwin Liu, Jill Norris, Holly O’Donnell, Andrea Steck, Kathleen Waugh, Jorma Toppari, Olli G. Simell, Annika Adamsson, Suvi Ahonen, Mari Åkerlund, Sirpa Anttila, Leena Hakola, Sanni Heikura, Tiia Honkanen, Heikki Hyöty, Jorma Ilonen, Saori Itoshima, Sanna Jokipuu, Taru Karjalainen, Leena Karlsson, Pieta Kemppainen, Jukka Kero, Marika Korpela, Jaakko J. Koskenniemi, Miia Kähönen, Mikael Knip, Minna-Liisa Koivikko, Katja Kokkonen, Merja Koskinen, Mirva Koreasalo, Kalle Kurppa, Salla Kuusela, Jarita Kytölä, Jutta Laiho, Tiina Latva-aho, Siiri Leisku, Laura Leppänen, Katri Lindfors, Maria Lönnrot, Elina Mäntymäki, Markus Mattila, Maija E. Miettinen, Teija Mykkänen, Tiina Niininen, Sari Niinistö, Noora Nurminen, Sami Oikarinen, Hanna-Leena Oinas, Paula Ollikainen, Zhian Othmani, Sirpa Pohjola, Jenna Rautanen, Mia Rein, Minna Romo, Juulia Rönkä, Nelli Rönkä, Noora Ruotsalainen, Satu Simell, Päivi Tossavainen, Mari Vähä-Mäkilä, Eeva Varjonen, Riitta Veijola, Irene Viinikangas, Suvi M. Virtanen, Richard McIndoe, Desmond Schatz, Diane Hopkins, Michael Haller, Melissa Gardiner, Ashok Sharma, Laura Jacobsen, Percy Gordon, Jennifer Hosford, Anette G. Ziegler, Ezio Bonifacio, Cigdem Sanverdi, Anja Heublein, Sandra Hummel, Annette Knopff
Institutions: Brigham and Women's Hospital, University of Florida, University of Colorado Anschutz, Harvard University, University of South Florida, University of Helsinki, Turku University Hospital, Tampere University, University of Turku, University of Oulu, Broad Institute, University of Auckland, Oulu University Hospital, Technische Universität Dresden, Tampere University, Helmholtz Munich, German Center for Diabetes Research, Tampere University Hospital, Finnish Institute for Health and Welfare, Augusta University, Center for Regenerative Therapies Dresden, Northern Ostrobothnia Hospital District