Microbial dysbiosis fuels STING-driven autoinflammation through cyclic dinucleotides

Date

2025-06-01

Author

Shibahara, Takayuki
Temizoz, Burcu
Egashira, Shiori
Hosomi, Koji
Park, Jonguk
Surucu, Naz
Björk, Albin
SAĞ, ERDAL
Doi, Takehiko
Kisla Ekinci, Rabia Miray
Balci, Sibel
Versnel, Marjan A.
Kunisawa, Jun
Yamamoto, Masahiro
Hayashi, Tomoya
Ito, Shuichi
Kamiyama, Yuji
Kobiyama, Kouji
Katsikis, Peter D.
Coban, Cevayir
Gürsel, Mayda
Ozen, Seza
Nishida, Sumiyuki
Kumanogoh, Atsushi
Ishii, Ken J.

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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.

Subject Keywords

Autoinflammation, Cyclic dinucleotides, Dysbiosis, Microbiome, SAVI, STING

URI

https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105004010710&origin=inward
https://hdl.handle.net/11511/114875

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Graduate School of Natural and Applied Sciences, Article