Decoding a Gut Commensal Signal: Structural and Immunological Profiling of Segatella copri Lipopolysaccharide

Carone L De Simone; G Barra; R Cirella; M Ziaco; M Mercogliano; F Olmeo; E Andretta; V Mazziotti; C Fusco; G D’Ippolito; Anna K Duda; Freda Farquharson; Petra Louis; A Fontana; A Silipo; A Molinaro; F Chiodo; Flaviana Di Lorenzo

doi:10.1002/anie.202512947

Decoding a Gut Commensal Signal: Structural and Immunological Profiling of Segatella copri Lipopolysaccharide

Carone L De Simone, G Barra, R Cirella, M Ziaco, M Mercogliano, F Olmeo , E Andretta , V Mazziotti , C Fusco, G D’Ippolito, Anna K Duda, Freda Farquharson, Petra Louis, A Fontana, A Silipo, A Molinaro, F Chiodo, Flaviana Di Lorenzo^* (Corresponding Author)

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

University of Naples Federico II

Research output: Contribution to journal › Article › peer-review

Abstract

The immunological effects of lipopolysaccharides (LPSs) from gut microbiota remain poorly explored, overshadowed by the longstanding view of LPS as a prototypical pro-inflammatory molecule. Herein, we report the first comprehensive chemical and immunological characterization of LPS from Segatella copri DSM 18205, a prominent member of the human oral and intestinal microbiota. This LPS features a unique chemical architecture, including a mannose- and glucose-rich oligosaccharide (OS) and a highly heterogeneous, hypo-acylated lipid A domain, as elucidated by advanced mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. Functionally, S. copri LPS displayed attenuated TLR4 activation and weak pro-inflammatory activity. Strikingly, high-dimensional cytometry by time-of-flight (CyTOF) revealed a selective preservation of CD14+CD16+ monocytes, immune subsets typically depleted by canonical enterobacterial LPSs. These findings identify S. copri LPS as a chemically and functionally distinct microbial signature, offering new insights into host-microbiota immune crosstalk and highlighting its potential for microbiome-informed immunomodulatory strategies.

Original language	English
Journal	Angewandte Chemie
Early online date	30 Sept 2025
DOIs	https://doi.org/10.1002/anie.202512947
Publication status	E-pub ahead of print - 30 Sept 2025

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

Funding

This study was supported by the European Research Council (ERC) under the Horizon Europe program under grant agreement No 101039841 (DEBUGGING LPS) to F.D.L. It was also supported by the project “CLariFY” and “GIVING” funded by the Italian Ministry of University and Research, PRIN MUR 2022 (2022SHW3KY) and PRIN MUR PNRR 2022 (P202293ZMC) to F.D.L. and F.C. This work was also supported in part by the Italian Ministry of Foreign Affairs and International Cooperation (Italy-Germany Science and Technology cooperation—Call for joint research proposals for the years 2023–2025) (PGR12361). This research was funded under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3—Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union—NextGenerationEU. Project code PE00000003, Concession Decree No. 1550 of 11 October 2022, adopted by the Italian Ministry of University and Research, CUP E63C22002030007, Project title “ON Foods—Research and innovation network on food and nutrition Sustainability, Safety and Security—Working ON Foods”; POS5 Italian Ministry of Health – Health Operational Plan Trajectory 5—Mediterranean Diet for Human Health Lab “MeDiHealthLab”. F.M.F. and P.L. received funding from the Scottish Government Rural and Environment Science and Analytical Services Division (RESAS). All the authors are grateful to CNR facility “The Mass Spectrometry and Mass Imaging Core” (MyCORE) located at the Department of Biology, University of Naples “Federico II”.

Keywords

cytometry by time of flight
gut microbiota
lipopolysaccharides
segtaella/prevotella
structure to function relationship

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De Simone, C. L., Barra, G., Cirella, R., Ziaco, M., Mercogliano, M., Olmeo , F., Andretta , E., Mazziotti , V., Fusco, C., D’Ippolito, G., Duda, A. K., Farquharson, F., Louis, P., Fontana, A., Silipo, A., Molinaro, A., Chiodo, F., & Di Lorenzo, F. (2025). Decoding a Gut Commensal Signal: Structural and Immunological Profiling of Segatella copri Lipopolysaccharide. Angewandte Chemie. Advance online publication. https://doi.org/10.1002/anie.202512947

De Simone, CL, Barra, G, Cirella, R, Ziaco, M, Mercogliano, M, Olmeo , F, Andretta , E, Mazziotti , V, Fusco, C, D’Ippolito, G, Duda, AK, Farquharson, F, Louis, P, Fontana, A, Silipo, A, Molinaro, A, Chiodo, F & Di Lorenzo, F 2025, 'Decoding a Gut Commensal Signal: Structural and Immunological Profiling of Segatella copri Lipopolysaccharide', Angewandte Chemie. https://doi.org/10.1002/anie.202512947

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abstract = "The immunological effects of lipopolysaccharides (LPSs) from gut microbiota remain poorly explored, overshadowed by the longstanding view of LPS as a prototypical pro-inflammatory molecule. Herein, we report the first comprehensive chemical and immunological characterization of LPS from Segatella copri DSM 18205, a prominent member of the human oral and intestinal microbiota. This LPS features a unique chemical architecture, including a mannose- and glucose-rich oligosaccharide (OS) and a highly heterogeneous, hypo-acylated lipid A domain, as elucidated by advanced mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. Functionally, S. copri LPS displayed attenuated TLR4 activation and weak pro-inflammatory activity. Strikingly, high-dimensional cytometry by time-of-flight (CyTOF) revealed a selective preservation of CD14+CD16+ monocytes, immune subsets typically depleted by canonical enterobacterial LPSs. These findings identify S. copri LPS as a chemically and functionally distinct microbial signature, offering new insights into host-microbiota immune crosstalk and highlighting its potential for microbiome-informed immunomodulatory strategies.",

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AU - De Simone, Carone L

AU - Barra, G

AU - Cirella, R

AU - Ziaco, M

AU - Mercogliano, M

AU - Olmeo , F

AU - Andretta , E

AU - Mazziotti , V

AU - Fusco, C

AU - D’Ippolito, G

AU - Duda, Anna K

AU - Farquharson, Freda

AU - Louis, Petra

AU - Fontana, A

AU - Silipo, A

AU - Molinaro, A

AU - Chiodo, F

AU - Di Lorenzo, Flaviana

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N2 - The immunological effects of lipopolysaccharides (LPSs) from gut microbiota remain poorly explored, overshadowed by the longstanding view of LPS as a prototypical pro-inflammatory molecule. Herein, we report the first comprehensive chemical and immunological characterization of LPS from Segatella copri DSM 18205, a prominent member of the human oral and intestinal microbiota. This LPS features a unique chemical architecture, including a mannose- and glucose-rich oligosaccharide (OS) and a highly heterogeneous, hypo-acylated lipid A domain, as elucidated by advanced mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. Functionally, S. copri LPS displayed attenuated TLR4 activation and weak pro-inflammatory activity. Strikingly, high-dimensional cytometry by time-of-flight (CyTOF) revealed a selective preservation of CD14+CD16+ monocytes, immune subsets typically depleted by canonical enterobacterial LPSs. These findings identify S. copri LPS as a chemically and functionally distinct microbial signature, offering new insights into host-microbiota immune crosstalk and highlighting its potential for microbiome-informed immunomodulatory strategies.

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KW - gut microbiota

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Decoding a Gut Commensal Signal: Structural and Immunological Profiling of Segatella copri Lipopolysaccharide

Abstract

Data Availability Statement

Funding

Keywords

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