Naoyoshi Nagata1, Tadashi Takeuchi2, Hiroaki Masuoka3, Ryo Aoki4, Masahiro Ishikane5, Noriko Iwamoto5, Masaya Sugiyama6, Wataru Suda3, Yumiko Nakanishi2, Junko Terada-Hirashima7, Moto Kimura8, Tomohiko Nishijima4, Hiroshi Inooka4, Tohru Miyoshi-Akiyama9, Yasushi Kojima10, Chikako Shimokawa11, Hajime Hisaeda11, Fen Zhang12, Yun Kit Yeoh12, Siew C Ng12, Naomi Uemura13, Takao Itoi14, Masashi Mizokami15, Takashi Kawai16, Haruhito Sugiyama7, Norio Ohmagari5, Hiroshi Ohno17. 1. Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan; Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan. Electronic address: nnagata_ncgm@yahoo.co.jp. 2. Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 3. Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 4. Mechanism-based Research Laboratory, Ezaki Glico Co, Ltd, Osaka, Japan. 5. Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan. 6. Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan; Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Ichikawa, Japan. 7. Division of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan. 8. Department of Clinical Research Strategic Planning Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan. 9. Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. 10. Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan. 11. Department of Parasitology, National Institute of Infectious Diseases. 12. Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Microbiota I-Center, Hong Kong, China; Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 13. Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan; Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Kohnodai Hospital, Tokyo, Japan. 14. Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan. 15. Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan. 16. Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan. 17. Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Electronic address: hiroshi.ohno@riken.jp.
Abstract
BACKGROUND & AIMS: We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and we validate the results with follow-up, a Japanese Disease, Drug, Diet, Daily Life microbiome cohort, and non-Japanese data sets. METHODS: We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non-COVID-19 control individuals matched by important confounders. RESULTS: Multiple correlations were found between COVID-19-related microbes (eg, oral microbes and short-chain fatty acid producers) and gut metabolites (eg, branched-chain and aromatic amino acids, short-chain fatty acids, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (eg, interferon γ, interferon λ3, interleukin 6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia; moderately in the high D-dimer level, kidney dysfunction, and liver dysfunction groups; but rarely in the diarrhea group. We confirmed concordances of altered metabolites (eg, branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional data set were partly concordant with those from the follow-up data set. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan. CONCLUSIONS: Multiomics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19related complications but few in gastrointestinal complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut-lung axis in COVID-19.
BACKGROUND & AIMS: We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and we validate the results with follow-up, a Japanese Disease, Drug, Diet, Daily Life microbiome cohort, and non-Japanese data sets. METHODS: We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non-COVID-19 control individuals matched by important confounders. RESULTS: Multiple correlations were found between COVID-19-related microbes (eg, oral microbes and short-chain fatty acid producers) and gut metabolites (eg, branched-chain and aromatic amino acids, short-chain fatty acids, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (eg, interferon γ, interferon λ3, interleukin 6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia; moderately in the high D-dimer level, kidney dysfunction, and liver dysfunction groups; but rarely in the diarrhea group. We confirmed concordances of altered metabolites (eg, branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional data set were partly concordant with those from the follow-up data set. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan. CONCLUSIONS: Multiomics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19related complications but few in gastrointestinal complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut-lung axis in COVID-19.
Authors: Moritz Rapp; Maximilian W M Wintergerst; Wolfgang G Kunz; Viola K Vetter; Max M L Knott; Dominik Lisowski; Sascha Haubner; Stefan Moder; Raffael Thaler; Stephan Eiber; Bastian Meyer; Natascha Röhrle; Ignazio Piseddu; Simon Grassmann; Patrick Layritz; Benjamin Kühnemuth; Susanne Stutte; Carole Bourquin; Ulrich H von Andrian; Stefan Endres; David Anz Journal: J Exp Med Date: 2019-03-25 Impact factor: 14.307
Authors: Alessio Milanese; Daniel R Mende; Lucas Paoli; Guillem Salazar; Hans-Joachim Ruscheweyh; Miguelangel Cuenca; Pascal Hingamp; Renato Alves; Paul I Costea; Luis Pedro Coelho; Thomas S B Schmidt; Alexandre Almeida; Alex L Mitchell; Robert D Finn; Jaime Huerta-Cepas; Peer Bork; Georg Zeller; Shinichi Sunagawa Journal: Nat Commun Date: 2019-03-04 Impact factor: 14.919
Authors: Graham J Britton; Alice Chen-Liaw; Francesca Cossarini; Alexandra E Livanos; Matthew P Spindler; Tamar Plitt; Joseph Eggers; Ilaria Mogno; Ana S Gonzalez-Reiche; Sophia Siu; Michael Tankelevich; Lauren Tal Grinspan; Rebekah E Dixon; Divya Jha; Adriana van de Guchte; Zenab Khan; Gustavo Martinez-Delgado; Fatima Amanat; Daisy A Hoagland; Benjamin R tenOever; Marla C Dubinsky; Miriam Merad; Harm van Bakel; Florian Krammer; Gerold Bongers; Saurabh Mehandru; Jeremiah J Faith Journal: Sci Rep Date: 2021-06-25 Impact factor: 4.379