L’analyse isotopique en abondance naturelle est au cœur de l'équipe MIMM depuis sa mise au point dans les années 80 par les Professeurs Martin et Martin, qui ont développé une approche originale basée sur la RMN-FINS pour détecter la chaptalisation des vins.
Depuis, l'équipe a réalisé d’importants développements dans ce domaine, conduisant à une nouvelle approche « isotopomique », définie comme la mesure d’un grand nombre d’informations isotopiques en abondance naturelle, qu’il s’agisse d’informations position-spécifique obtenues par RMN ou d’informations moléculaires moyennes obtenues par spectrométrie de masse de rapports isotopiques (IRMS).
Les développements innovants en RMN isotopique menés au sein de l’équipe, alliés à une expertise reconnue en IRMS de haute précision, permettent à notre équipe de cibler des applications particulièrement originales de l’isotopomique en agroalimentaire, environnement, criminalistique, santé ou métabolisme.
Current team members: Margot Sanchez, Tania Mahnna, Anne-Marie Schiphorst, Mathilde Grand, Gérald Remaud, Maxime Julien, Serge Akoka*.
Past team members: Lenny Haddad, Sophie Renou, Vincent Portaluri, Ghina Hajjar, Sophie Guyader, Noelle Merchack.
Collaborations: J. Bejjani, T. Rizk (Saint-Joseph University, Beirut, Lebanon), F. Thomas, E. Jamin (EUROFINS, Nantes, France), P. Lesot (University of Paris Sud, Paris Saclay).
This project concerns the characterization of complex matrices by the determination of the isotope profiles on targeted molecules using the methods described in the “Methodological Developments and Experimental Validation for NMR Isotope Analysis” section. The interest of position-specific isotope analysis is demonstrated on ethanol and vanillin. Using R2D3, the combined use of 13C and 2H NMR enables the distinction of origins that cannot be distinguished by other methods.
The geographical origins of olive oil or products from animal origin are also separated on basis of relative 13C profiles measured on the whole matrix thank to the capability of modified INEPT or HSQC pulse sequences.
A new methodology was proposed that combines polarization transfer techniques with the concept of intramolecular isotopic referencing. This enables us to determine position-specific values more quickly and accurately, and with greater repeatability, without needing the overall isotopic composition value.
Stable isotopes also hold great potential for investigating the provenance of polymers. Virgin styrene and pyrolysis-recycled samples were analyzed. The detected 13C intramolecular distribution profiles revealed significant differences between the two sources, showing that polystyrene recycling induces an isotope effect. Furthermore, the substantial intramolecular 13C composition variations observed in the samples could potentially enable the quantification of recycled and virgin polymers in composite materials.
Key References:
- N. Merchak, V. Silvestre, D. Loquet, T. Rizk, S. Akoka, J. Bejjani. A strategy for simultaneous determination of fatty acid composition, fatty acid position, and position-specific isotope contents in triacylglycerol matrices by C-13-NMR. Analytical and Bioanalytical Chemistry, 409, 307-3015 (2017).
- V. Joubert, M. Trebuchet, M. Mikic, V. Silvestre, A.-M. Schiphorst, D. Loquet, A. Stemmelen, V. Ladroue, F. Besacier, S. Akoka, G. S. Remaud. Isotopomics by isotope ratio monitoring by 13C Nuclear Magnetic Resonance Spectrometry on cutting agents in heroin: a new approach for illicit drugs trafficking route elucidation. Drug Testing and Analysis, 12, 449-457 (2020).
- G. Hajjar, T. Rizk, J. Bejjani, S. Akoka. Metabisotopomics of triacylglycerols from animal origin: A simultaneous metabolomic and isotopic profiling using 13C INEPT. Food Chemistry, 315, 126325 (2020).
- M. Julien, C. Mejía, M. Grand, A.-M. Schiphorst, E. Martineau, et al. Is it possible to distinguish virgin versus pyrolytic recycled styrene by determining the intramolecular 13C distribution? Analytical Methods (2025).
- T. Mhanna, M. Sanchez, M. Grand, M. Julien, T. Rizk, et al. 13C position-specific isotopic analysis of fatty acid methyl esters using NMR with intramolecular isotopic referencing. Analytical and Bioanalytical Chemistry, 417, 6731-6742 (2025).
Supported by: National Council for Scientific research, University of Nantes National Council for Scientific research of Lebanon and Saint-Joseph University of Beirut, Michelin.
Current team members: Anne-Marie Schiphorst, Mathilde Grand, Gérald Remaud
Past team members: Estelle Martineau, Julie Lalande, Maxime Julien, Richard Robins.
Research axis led by Illa Tea until 2025
Collaborations (past and present): Sophie Barillé-Nion (CRCNA Nantes), Estelle Martineau (CEISAM, Univ Nantes), Anneke Blackburn (JCSMR, ANU, Canberra), Jane Dahlstrom (Canberra Hospital), Mikael Croyal (CRNH Nantes), Guillaume Tcherkez (RSB, ANU Canberra), José Hureaux (CHU Angers, MINT team), Regis Hankard (INSERM, Tours), Arnaud De Lucas (INSERM, Tours), Olivier Mantha (INSERM Tours)
There are important challenges: finding new treatments, improving diagnosis and cancer classification so as to anticipate treatment sub-type and life prognostic, and finding good markers to follow the response of cancer to treatment and anticipate cancer reactivation. Using stable (non-radioactive) isotopes at natural abundance (13C/12C and 15N/14N ratios), we have been the first to show that natural isotope abundance reflects cancer cell metabolism and that the isotope signature is a potential biomarker to differentiate normal and cancer cells and tissues.
Since cancer cells exchange nutrients and waste products with blood, we anticipate that isotopic differences should be detectable in some plasmatic metabolites. Therefore, we intend to carry out a biomarker discovery process by which we will elaborate on our preliminary findings, and identify candidate isotopic biomarkers. The ultimate aim is to find avenues to develop a blood test for cancer detection and thus patient screening, and to monitor cancer patients for the recurrence of disease, detecting it earlier and improving their treatment outcomes.
Recent References
- Mantha, M. Mahé, K. Mahéo, G. Fromont, M. Guéguinou, I. Tea, R. Hankard, A. De Luca. Understanding natural isotopic variations in cultured cancer cells. Rapid.Com. Mass.Spec (2024), 38:e9878
- Mangeon, R. Le Balchb, OL. Mantha, C. Guimaraes-carneiro, M. Pinault, R. Hankard, A. De Luca, I. Tea*, Simultaneous quantification and natural 13C abundance of fatty acids in breast cancer tissues and serum by GC-C-IRMS for tumor characterization. TalantaOpen (2025)
- Tea*, M.P.M. Letertre, J. Boccard, A-M. Schiphorst, S. Blanchet, M. Croyal, J. Dahlstrom, A. Blackburn, G. Tcherkez, Breast cancer metabolism and responsiveness to dichloroacetate: relationships with 15N and 13C natural abundance. (2026), BioRxiV
- Couton, M. Sanchez, V. Fargeas, I. Tea*, Position Specific 15N Isotope Analysis at Natural Abundance by 1H NMR Anal. Chem. (2026), ChemRxiV
- Illa Tea*, Guillaume Tcherkez Nitrogen isotope effects in urea metabolism: from biochemistry to 15N natural abundance in cancer. A review. International Journal of Molecular Sciences MDPI (2026) ChemRxiV
Supported by: INSERM (Interdisciplinary Project), Canberra Hospital (Private Practice Fund), Australian National University ANU, French Funding for international cancer research ‘Fondation de France’, Australian National University ANU, ANR INDEED
Current team members: Anne-Marie Schiphorst, Mathilde Grand, Maxime Julien, Serge Akoka
Collaborations: Julie Lalande (IRMS, Angers), Guillaume Tcherkez (IRMS, Angers and RSB, ANU Canberra)
The natural isotope composition of bulk organic matter or tissues often isn’t detailed enough to uncover key physiological processes, (bio)synthetic pathways, or nutritional sources in biological systems. Metabolic and synthetic reactions create distinct isotope patterns, leading to uneven distributions of ²H, ¹⁸O, ¹³C, and ¹⁵N within organic molecules.
To address this complexity, we focus on compound‑specific isotope analysis (CSIA) and position‑specific isotope analysis (PSIA) - powerful tools that open new possibilities in biological and medical research. Our work extends CSIA to a wide range of molecules, including xanthines, fatty acids, and amino acids.
We are also developing innovative PSIA methods using quantitative NMR and pyrolysis coupled with IRMS. Combined with insights into metabolic pathways, these techniques support applications such as authenticating the origin of sensitive compounds, including vanillin and benzaldehyde, which are frequently subject to counterfeiting.
More recently, we demonstrated the strong potential of ¹³C‑PSIA for tracing the provenance of industrial molecules. This approach has successfully distinguished between virgin and recycled sources of styrene, highlighting its value for sustainability and circular‑economy challenges.
Key References:
- Diomandé, D. et al. Use of the 13C/12C, 15N/14N and 18O/16O isotopic ratios of theobromine and caffeine in the characterization of geographic origin. J. Anal. Chem. (2021) 12, 87.
- Romek, K. M. et al. Human baby hair amino acid natural abundance 15N-isotope values are not related to the 15N-isotope values of amino acids in mother’s breast milk protein. Amino Acids (2013) 45, 1365.
- Mhanna, T. et al. Carbon-13-isotopomics and metabolomics of fatty acids from triacylglycerols: overcoming the limitations of GC-C-IRMS for short- and medium-acyl chains. Bioanal. Chem. (2024) 416, 5557.
- Guyader, S. et al. Combination of 13C and 2H SNIF-NMR isotopic fingerprints of vanillin to control its precursors. Flavour Fragr. J. (2019) 34, 133.
- Julien, M. et al. Is it possible to distinguish virgin versus pyrolytic recycled styrene by determining the intramolecular 13C distribution? Methods (2025) 17, 8533.
Supported by: Australian National University ANU, Nantes University, Région Pays de la Loire and Angers Loire Métropole via the research grant Connect Talent Isoseed, Biogenouest, Corsaire, the CNR Défi Isotop, MetaboHUB-ANR-11-INBS-0010