Microviridae bacteriophages influence behavioural hallmarks of food addiction via tryptophan and tyrosine signalling pathways

Food addiction contributes to the obesity pandemic, but the connection between how the gut microbiome is linked to food addiction remains largely unclear. Here we show that Microviridae bacteriophages, particularly Gokushovirus WZ-2015a, are associated with food addiction and obesity across multiple human cohorts. Further analyses reveal that food addiction and Gokushovirus are linked to serotonin and dopamine metabolism. Mice receiving faecal microbiota and viral transplantation from human donors with the highest Gokushovirus load exhibit increased food addiction along with changes in tryptophan, serotonin and dopamine metabolism in different regions of the brain, together with alterations in dopamine receptors. Mechanistically, targeted tryptophan analysis shows lower anthranilic acid (AA) concentrations associated with Gokushovirus. AA supplementation in mice decreases food addiction and alters pathways related to the cycle of neurotransmitter synthesis release. In Drosophila, AA regulates feeding behaviour and addiction-like ethanol preference. In summary, this study proposes that bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism.

This work was partially funded by Instituto de Salud Carlos III (ISCIII, Madrid, Spain) through the project PI15/01934 to J.M.F.-R. and the projects PI20/01090 and PI23/00575 (co-funded by the European Union under the European Regional Development Fund (FEDER) ‘A way to make Europe’) to J.M.-P. (HR22-00737). The Aging Imageomics Study was funded by Pla estratègic de recerca i innovació en salut 2016–2020 from Generalitat de Catalunya (reference no. SLT002/16/00250). Health Imageomics was funded by Health LivingLab operation of the Girona Healthy Region Program, which was granted by the Projectes d’Especialització i Competitivitat Territorial of the RIS3Cat and the Operative Programme of the European Regional Development Fund of Catalonia 2014–2020. This work was also supported by the Spanish ‘Ministerio de Ciencia e Innovación (MICIN), Agencia Estatal de Investigación’ (PID2020-120029GB-I00/MICIN/AEI/10.13039/501100011033, RD21/0009/0019, to R.M.; the ‘Generalitat de Catalunya, AGAUR’ (2017 SGR-669, to R.M.; the ‘ICREA-Acadèmia’ (2020, to R.M.); the ‘European Commission-DG Research’ (PainFact, H2020-SC1-2019-2-RTD-848099, QSPain Relief, H2020-SC1-2019-2-RTD-848068, to R.M.); the Spanish ‘la Caixa’ Foundation under project code LCF/PR/HR22/52420017 to R.M. and J.M.F.-R.; the Spanish ‘Instituto de Salud Carlos III, RETICS-RTA’ (RD16/0017/0020, to R.M.); the Spanish ‘Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional Sobre Drogas’ (PNSD-2021I076, to R.M.; PNSD-2023I040, to E.M.G.; and Ministerio de Ciencia e Innovación (ERA-NET) PCI2021-122073-2A to E.M.G. This study has been co-financed by FEDER funds from the European Union (‘A way to build Europe’) and the Generalitat of Catalonia: Agency for Management of University and Research Grants (2021SGR00990) and Department of Health (SLT002/16/00250) to R.P. IDIBGI is a CERCA Programme/Generalitat de Catalunya. J.M.-P. and A.C.N. are funded by Instituto de Salud Carlos III (Madrid, Spain) through the Miguel Servet Program CP18/00009 and Sara Borrell Program CD20/00051 (co-funded by the European Union under the European Social Fund ‘Investing in Your Future’), respectively. L.V.-C. is funded by the Program for the Promotion of Talent and Employability (Generalitat de Catalunya) SLT017_20_000164. This study was conducted using samples and/or data from the Aging Imageomics Study, supported by the Generalitat de Catalunya through the Strategic Plan for Health Research and Innovation 2016–2020 (SLT002/16/00250). We particularly acknowledge the participants of the IDIBGI Horizontal Aging Program and the IDIBGI Biobank (Biobanc IDIBGI, B.0000872), integrated in the Platform ISCIII Biomodels and Biobanks, for their collaboration. This study was conducted using samples and/or data from the Healthy Imageomics Study, supported by the Specialization and Territorial Competitiveness Projects within the RIS3Cat and the Catalonia European Regional Development Fund (ERDF) Operational Programme 2014–2020. It was co-financed by the ERDF of the European Union under the Catalonia ERDF Operational Programme 2014–2020 and by the Diputació de Girona. Illustrations were created with Biorender.com.