Microbial dysbiosis fuels STING-driven autoinflammation through cyclic dinucleotides

Takayuki Shibahara¹, Burcu Temizoz², Shiori Egashira³, Koji Hosomi⁴, Jonguk Park⁵, Naz Surucu⁶, Albin Björk⁷, Erdal Sag⁸, Takehiko Doi⁹, Rabia Miray Kisla Ekinci¹⁰, Sibel Balci¹⁰, Marjan A Versnel¹¹, Jun Kunisawa⁴, Masahiro Yamamoto¹², Tomoya Hayashi², Shuichi Ito¹³, Yuji Kamiyama¹³, Kouji Kobiyama², Peter D Katsikis¹¹, Cevayir Coban¹⁴, Mayda Gursel¹⁵, Seza Ozen⁸, Sumiyuki Nishida¹⁶, Atsushi Kumanogoh¹⁷, Ken J Ishii¹⁸

Affiliations

¹ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
² Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan.
³ Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
⁴ Laboratory of Vaccine Materials, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
⁵ Laboratory of Bioinformatics, Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
⁶ Department of Biological Sciences, Middle East Technical University (METU), Ankara, Turkey.
⁷ Division of Rheumatology, Department of Medicine, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden; Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸ Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
⁹ Department of Pediatrics, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
¹⁰ Department of Pediatric Rheumatology, Cukurova University, Adana, Turkey.
¹¹ Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
¹² Department of Immunoparasitology, Division of Infectious Disease, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
¹³ Department of Pediatrics, School of Medicine, Yokohama City University, Kanagawa, Japan.
¹⁴ Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Immunopathology, WPI, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan; International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan.
¹⁵ Izmir Biomedicine and Genome Center, Izmir, Turkey.
¹⁶ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
¹⁷ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Immunopathology, WPI, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan; Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Suita, Osaka, Japan.
¹⁸ Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan. Electronic address: kenishii@ims.u-tokyo.ac.jp.

PMID: 40334619
DOI: 10.1016/j.jaut.2025.103434

Free article

Microbial dysbiosis fuels STING-driven autoinflammation through cyclic dinucleotides

Takayuki Shibahara et al. J Autoimmun. 2025 Jun.

Free article

. 2025 Jun:154:103434.

doi: 10.1016/j.jaut.2025.103434. Epub 2025 May 6.

Authors

Affiliations

¹ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
² Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan.
³ Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
⁴ Laboratory of Vaccine Materials, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
⁵ Laboratory of Bioinformatics, Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.
⁶ Department of Biological Sciences, Middle East Technical University (METU), Ankara, Turkey.
⁷ Division of Rheumatology, Department of Medicine, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden; Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸ Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
⁹ Department of Pediatrics, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
¹⁰ Department of Pediatric Rheumatology, Cukurova University, Adana, Turkey.
¹¹ Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
¹² Department of Immunoparasitology, Division of Infectious Disease, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
¹³ Department of Pediatrics, School of Medicine, Yokohama City University, Kanagawa, Japan.
¹⁴ Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Immunopathology, WPI, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan; International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan.
¹⁵ Izmir Biomedicine and Genome Center, Izmir, Turkey.
¹⁶ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
¹⁷ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Immunopathology, WPI, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan; Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Suita, Osaka, Japan.
¹⁸ Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan. Electronic address: kenishii@ims.u-tokyo.ac.jp.

PMID: 40334619
DOI: 10.1016/j.jaut.2025.103434

Abstract

Aberrant activation of the stimulator of interferon genes (STING) pathway is a hallmark of autoinflammatory disorders such as STING-associated vasculopathy with onset in infancy (SAVI), characterized by systemic inflammation affecting blood vessels, skin, and lungs. Despite its clinical significance, the mechanisms linking STING activation to disease pathology remain poorly defined. In this study, we demonstrated that SAVI mice harboring the N153S STING mutation exhibit diverse disease phenotypes, with a subset developing severe colitis and diarrhea alongside exacerbated systemic inflammation. These diarrheal SAVI mice showed pronounced dysbiosis, marked by reduced short-chain fatty acid-producing bacteria and an enrichment of segmented filamentous bacteria. This microbial imbalance was accompanied by elevated levels of both microbial and host-derived cyclic dinucleotides (CDNs), potent activators of the STING pathway. Notably, antibiotic treatment ameliorated inflammation, underscoring the role of dysbiosis in driving STING-mediated autoinflammation. Furthermore, in SAVI patients, elevated systemic microbial and host-derived CDNs were observed. In conditions such as systemic lupus erythematosus (SLE)-a heterogeneous autoimmune disease with potential STING involvement-systemic microbial CDNs were significantly correlated with disease biomarkers, including type I interferon scores and anti-dsDNA antibodies. In contrast, no such correlations were observed in STING-independent conditions like rheumatoid arthritis (RA). Importantly, this study highlights that both microbial and host-derived CDNs are key drivers of STING activation, suggesting that personalized treatment strategies could target cGAS or the microbiome based on a patient's specific CDN profile. These findings position systemic CDNs as valuable biomarkers and therapeutic targets for STING-driven diseases.

Keywords: Autoinflammation; Cyclic dinucleotides; Dysbiosis; Microbiome; SAVI; STING.

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Conflict of interest statement

Declaration of competing interest BT, TS, TH, AK, SN and KJI are currently applying for a patent related to the use of cyclic dinucleotides for diagnostic purposes, based on the findings presented in this manuscript. The authors declare no other competing interests.

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Microbial dysbiosis fuels STING-driven autoinflammation through cyclic dinucleotides

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Microbial dysbiosis fuels STING-driven autoinflammation through cyclic dinucleotides

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