Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications,Gastroenterology

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Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications
Gastroenterology ( IF 29.4 ) Pub Date : 2022-09-23 , DOI: 10.1053/j.gastro.2022.09.024
Naoyoshi Nagata ₁ , Tadashi Takeuchi ₂ , Hiroaki Masuoka ₃ , Ryo Aoki ₄ , Masahiro Ishikane ₅ , Noriko Iwamoto ₅ , Masaya Sugiyama ₆ , Wataru Suda ₃ , Yumiko Nakanishi ₂ , Junko Terada-Hirashima ₇ , Moto Kimura ₈ , Tomohiko Nishijima ₄ , Hiroshi Inooka ₄ , Tohru Miyoshi-Akiyama ₉ , Yasushi Kojima ₁₀ , Chikako Shimokawa ₁₁ , Hajime Hisaeda ₁₁ , Fen Zhang ₁₂ , Yun Kit Yeoh ₁₂ , Siew C Ng ₁₂ , Naomi Uemura ₁₃ , Takao Itoi ₁₄ , Masashi Mizokami ₁₅ , Takashi Kawai ₁₆ , Haruhito Sugiyama ₇ , Norio Ohmagari ₅ , Hiroshi Ohno ₁₇

Affiliation

Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan; Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Mechanism-based Research Laboratory, Ezaki Glico Co, Ltd, Osaka, Japan.
Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.
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.
Division of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan.
Department of Clinical Research Strategic Planning Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.
Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan.
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.
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.
Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan.
Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan.
Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan.
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

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, the Japanese 4D (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.

更新日期：2022-09-23

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