{ "abstract": "Background Obesity-related alterations in the gut microbiota have been linked to cognitive decline, yet their relationship with attention remains poorly understood.Objective To evaluate the possible relationships among gut metagenomics, plasma metabolomics and attention.Design We conducted faecal shotgun metagenomics and targeted plasma tryptophan metabolomics across three independent cohorts (n=156, n=124, n=804) with functional validations in preclinical models, including three faecal microbiota transplantation (FMT) experiments in mice and Drosophila melanogaster.Results Obesity was consistently associated with reduced attention. Metagenomics analyses identified Proteobacteria species and microbial functions related to tryptophan biosynthesis from anthranilic acid (AA) as negatively associated with attention in obesity. Plasma tryptophan metabolic profiling and machine learning revealed that 3-hydroxyanthranilic acid (3-HAA) was positively associated with attention, particularly in obesity, while AA showed a negative association. Bariatric surgery improved attention and enriched microbial species linked to attention. In mice, diet-induced obesity (DIO) and microbiota depletion reduced 3-HAA and 5-hydroxy-indole acetic acid (5-HIAA) concentrations in the prefrontal cortex (PFC), which were restored by FMT. Global metabolic profiling (>600 metabolites) of PFC from the FMT group identified 3-HAA and the tryptophan and tyrosine pathways among the most significant in mice receiving microbiota from high-attention donors. A second FMT experiment also revealed a consistent enrichment of the tryptophan and tyrosine metabolism at the transcriptional level in the PFC, with Haao (3-hydroxyantrhanilic acid dioxygenase) and Aox4 (aldehyde oxidase 4), key in 3-HAA and 5-HIAA degradation, among the significantly regulated genes. In a third FMT study, attentional traits were transmitted from humans to mice alongside modulation of serotonergic and dopaminergic pathways. In Drosophila, mono-colonisation with Enterobacter cloacae and DIO induced attention deficit-like behaviours, which were mitigated by 3-HAA supplementation.Conclusions We have identified the microbiota and 3-HAA as potential therapeutic targets to improve attention, especially in obesity.", "authors": [ { "affiliations": [ "Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain", "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain", "Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Salt, Spain", "CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain" ], "name": "Anna Castells-Nobau" }, { "affiliations": [ "Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain", "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain", "Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Salt, Spain", "CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain" ], "name": "Andrea Fumagalli" }, { "affiliations": [ "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain", "Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Salt, Spain", "CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain" ], "name": "Ángela del Castillo-Izquierdo" }, { "affiliations": [ "Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain", "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain", "Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Salt, Spain", "CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain" ], "name": "Marisel Rosell-Díaz" }, { "affiliations": [ "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain" ], "name": "Lisset de la Vega-Correa" }, { "affiliations": [ "Laboratory of Neuropharmacology, Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona, Spain", "Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania" ], "name": "Solveiga Samulėnaitė" }, { "affiliations": [ "Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain", "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain", "CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain" ], "name": "Anna Motger-Albertí" }, { "affiliations": [ "Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain", "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain", "CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain" ], "name": "María Arnoriaga-Rodríguez" }, { "affiliations": [ "Serra-Hunter Programme, Department of Nursing, University of Girona, Girona, Spain", "Girona Biomedial Research Institute (IDIBGI-CERCA), Girona, Spain" ], "name": "Josep Garre-Olmo" }, { "affiliations": [ "Girona Biomedial Research Institute (IDIBGI-CERCA), Girona, Spain", "Department of Radiology (CDI) and IDIBAPS, Hospital Clínic de Barcelona, Barcelona, Spain", "Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain" ], "name": "Josep Puig" }, { "affiliations": [ "Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain", "Vascular Health Research Group of Girona (ISV-Girona), Jordi Gol Institute for Primary Care Research (Institut Universitari per a la Recerca en Atenció Primària Jordi Gol I Gorina-IDIAPJGol), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud-RICAPPS- ISCIII, Girona, Spain", "Research in Vascular Health, Girona Biomedical Research Institute (IDIBGI), Girona, Spain" ], "name": "Rafael Ramos" }, { "affiliations": [ "Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania" ], "name": "Aurelijus Burokas" }, { "affiliations": [ "Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain", "Neurodegeneration and Neuroinflammation Research Group, Institute of Biomedical Research of Girona Dr Josep Trueta, Girona, Spain" ], "name": "Clàudia Coll" }, { "affiliations": [ "Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain", "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain", "Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Salt, Spain" ], "name": "Cristina Zapata-Tona" }, { "affiliations": [ "Foundation for the Promotion of Sanitary and Biomedical Research of Valencian Community (FISABIO), Valencia, Spain", "CIBER in Epidemiology and Public Health (CIBEResp), Madrid, Spain" ], "name": "Vicente Perez-Brocal" }, { "affiliations": [ "Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain", "Neurodegeneration and Neuroinflammation Research Group, Institute of Biomedical Research of Girona Dr Josep Trueta, Girona, Spain" ], "name": "Lluis Ramio" }, { "affiliations": [ "Foundation for the Promotion of Sanitary and Biomedical Research of Valencian Community (FISABIO), Valencia, Spain", "CIBER in Epidemiology and Public Health (CIBEResp), Madrid, Spain", "Institute for Integrative Systems Biology (I2SysBio), University of Valencia and Spanish National Research Council (CSIC), Valencia, Spain" ], "name": "Andres Moya" }, { "affiliations": [ "School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK" ], "name": "Jonathan Swann" }, { "affiliations": [ "Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain", "Laboratory of Neuropharmacology-Neurophar, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain", "Department of Psychobiology and Methodology in Health Sciences, Universitat Autonoma de Barcelona, Bellaterra, Spain" ], "name": "Elena Martín-García" }, { "affiliations": [ "Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain", "Laboratory of Neuropharmacology-Neurophar, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain", "Université de Strasbourg (UNISTRA), INSERM UMR-S 1329, Strasbourg Translational Neuroscience and Psychiatry, Centre de Recherche en Biomédecine de Strasbourg, Strasbourg, France" ], "name": "Rafael Maldonado" }, { "affiliations": [ "Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain", "Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain", "CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain" ], "name": "Jose Manuel Fernández-Real" }, { "affiliations": [ "Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain", "Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Salt, Spain", "CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain" ], "name": "Jordi Mayneris-Perxachs" } ], "title": "Gut microbial modulation of 3-hydroxyanthranilic acid and dopaminergic signalling influences attention in obesity", "uid": "243a449c-4a57-5be9-b8b3-6786d0e09012" }