Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study
Authors: Lönnrot Maria , Lynch Kristian F. , Rewers Marian , Lernmark Åke , Vehik Kendra , Akolkar Beena , Hagopian William , Krischer Jeffrey , McIndoe Rickhard A. , Toppari Jorma , Ziegler Anette-G. , Petrosino Joseph F. , Lloyd Richard , Hyöty Heikki ,   TEDDY Study Group, Rewers Marian , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Frohnert Brigitte I. , Stahl Marisa , Flores Garcia Isabel , Gesualdo Patricia , Hays Sierra , Hoffman Michelle , Karban Rachel , Liu Edwin , Loaiza Leila , Norris Jill , O’Donnell Holly , Thorndahl Loana , Steck Andrea , Waugh Kathleen , Toppari Jorma , Simell Olli G. , Adamsson Annika , Ahonen Suvi , Åkerlund Mari , Anttila Sirpa , Hakola Leena , Hekkala Anne , Honkanen Tiia , Hyöty Heikki , Ilonen Jorma , Jokipuu Sanna , Karjalainen Taru , Karlsson Leena , Kero Jukka , Koskenniemi Jaakko J. , Kähönen Miia , Knip Mikael , Koivikko Minna-Liisa , Kokkonen Katja , Koskinen Merja , Koreasalo Mirva , Kurppa Kalle , Kuusela Salla , Kytölä Jarita , Laiho Jutta , Latva-aho Tiina , Leisku Siiri , Leppänen Laura , Lindfors Katri , Lönnrot Maria , Mäntymäki Elina , Mattila Markus , Miettinen Maija , Mykkänen Teija , Niininen Tiina , Niisistö Sari , Nurminen Noora , Oikarinen Sami , Oinas Hanna-Leena , Ollikainen Paula , Othmani Zhian , Pohjola Sirpa , Raja-Hanhela Solja , Rautanen Jenna , Riikonen Anne , Romo Minna , Rönkä Juulia , Rönkä Nelli , Simell Satu , Tossavainen Päivi , Vähä-Mäkilä Mari , Varjonen Eeva , Veijola Riitta , Viinikangas Irene , Vilmi Silja , Virtanen Suvi M. , McIndoe Richard , Schatz Desmond , Hopkins Diane , Haller Michael , Bernard Risa , Gardiner Melissa , Sharma Ashok , Jacobsen Laura , Hosford Jennifer , Petty Kennedy , Myers Leah , Salmon Chelsea , Ziegler Anette G. , Bonifacio Ezio , Gezginci Cigdem , Grätz Willi , Heublein Anja , Hohoff Eva , Hummel Sandra , Knopff Annette , Köger Melanie , Koletzko Sibylle , Ramminger Claudia , Roth Roswith , Schmidt Jennifer , Scholz Marlon , Stock Joanna , Warncke Katharina , Wendel Lorena , Winkler Christiane , Lernmark Åke , Agardh Daniel , Andrén Aronsson Carin , Bennet Rasmus , Cilio Corrado , Dahlberg Susanne , Fält Ulla , Goldman Tsubarah Malin , Ericson-Hallström Emelie , Fransson Lina , Halilovic Emina , Holmén Gunilla , Hyberg Susanne , Jonsdottir Berglind , Karimi Naghmeh , Elding Larsson Helena , Lindström Marielle , Lundgren Markus , Maziarz Marlena , Melin Jessica , Nilsson Caroline , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sjöberg Anette , Tekum Amboh Evelyn , Törn Carina , Ulvenhag Ulrika , Wiktorsson Terese , Wimar Åsa , Hagopian William A. , Killian Michael , Cowen Crouch Claire , Skidmore Jennifer , Bender Trevor , Llewellyn Megan , McCall Cody , Meyer Arlene , Meyer Jocelyn , Mulenga Denise , Powell Nole , Radtke Jared , Roy Shreya , Tucker Preston , Becker Dorothy , Franciscus Margaret , Dalmagro-Elias Smith MaryEllen , Daftary Ashi , Klein Mary Beth , Yates Chrystal , Krischer Jeffrey P. , Adusumali Rajesh , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Burkhardt Brant , Butterworth Martha , Cadigan Nicholas , Clasen Joanna , Counts Kevin , Gandolfo Laura , Garmeson Jennifer , Gowda Veena , Karges Christina , Liu Shu , Liu Xian , Lynch Kristian , Malloy Jamie , Mramba Lazarus , McCarthy Cristina , Moreno Jose , Parikh Hemang M. , Remedios Cassandra , Shaffer Chris , Smith Susan , Sulman Noah , Tamura Roy , Tewey Dena , Thuma Henri , Toth Michael , Vehik Kendra , Vijayakandipan Ponni , Wroble Melissa , Yang Jimin , Young Kenneth , Yu Liping , Miao Dongmei , Gillespie Kathleen , Chandler Kyla , Kelland Ilana , Ben Khoud Yassin , Randell Matthew , Rich Stephen S. , Chen Wei-Min , Onengut-Gumuscu Suna , Farber Emily , Roche Pickin Rebecca , Davis Jonathan , Davis Jordan , Gallo Dan , Bonnie Jessica , Campolieto Paul , Petrosino Joseph , Ajami Nadim J. , Lloyd Richard E. , Ross Matthew C. , O’Brien Jacqueline L. , Hutchinson Diane S. , Smith Daniel P. , Wong Matthew C. , Tian Xianjun , Ayvaz Tulin , Tamegnon Auriole , Truong Nguyen , Moreno Hannah , Riley Lauren , Moreno Eduardo , Bauch Tonya , Kusic Lenk , Metcalf Ginger , Muzny Donna , Ardhan Doddapaneni Harsha V. , Gibbs Richard , Deigan Chris , Akolkar Beena , Briese Thomas , Brusko Todd , Buckner Teresa , Bennett Johnson Suzanne , McKinney Eoin , Pastinen Tomi , Ullitz Thorsen Steffen , Triplett Erick 
Published: August 2023

OBJECTIVE
To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort.

RESEARCH DESIGN AND METHODS
GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study.

RESULTS
GIE reports (odds ratio [OR] 2.17 [95% CI 1.39–3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36–23.7]) at &lt;1 year of age were associated with an increased IAA risk at 2–4 years of age. GIEs reported at age 1 to &lt;2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35–0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12–23 months prior [1.41–2.96]). Impacts on GADA risk were limited to GIEs &lt;6 months prior to autoantibody development in children &lt;4 years of age (OR 2.16 [1.54–3.02]).

CONCLUSIONS
Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12–23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.