Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state functional magnetic resonance imaging studies have found significant age-related alterations in functional connectivity across various networks. Nevertheless, most of the studies have focused mainly on static functional connectivity. Studying the dynamics of resting-state brain activity across the whole-brain functional network can provide a better characterization of age-related changes. Here, we employed two data-driven whole-brain approaches based on the phase synchronization of blood-oxygen-level-dependent signals to analyze resting-state fMRI data from 620 subjects divided into two groups (middle-age group (n = 310); age range, 50–64 years versus older group (n = 310); age range, 65–91 years). Applying the intrinsic-ignition framework to assess the effect of spontaneous local activation events on local–global integration, we found that the older group showed higher intrinsic ignition across the whole-brain functional network, but lower metastability. Using Leading Eigenvector Dynamics Analysis, we found that the older group showed reduced ability to access a metastable substate that closely overlaps with the so-called rich club. These findings suggest that functional whole-brain dynamics are altered in aging, probably due to a deficiency in a metastable substate that is key for efficient global communication in the brain. ; A.E. was supported by the Catalan project Imagenoma de L'Envelliment (Aging Imageomics Study). G.D. was supported by the Spanish Ministry of Economy and Competitiveness, Spain (grant agreement number PSI2016- 75688-P, MINECO/AEI/FEDER-EU); European Union's Horizon 2020 FET Flagship Human Brain Project (grant agreement number 785907, HBP SGA2); the Catalan Research Support, Spain (grant agreement number 2017 SGR 1545) and La Marató TV3 2017 (grant agreement 201725.33).
[Background]: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear. ; [Results]: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient's mice. In line with the results in humans, transplantation from 'high ferritin donors' resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient's mice. ; [Conclusions]: Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies. ; This work was supported by EU-FP7 FLORINASH (Health-F2-2009-241913) to R.B., M.F., J.M.F.R., E.H. and J.K.N. Infrastructure support was provided by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC). L.H. was in receipt of an MRC Intermediate Research Fellowship in Data Science (grant number MR/L01632X/1, UK Med-Bio). This work was also partly supported by funding to M.-E.D. (EU METACARDIS under agreement HEALTH-F4-2012-305312, Neuron II under agreement 291840 and the MRC MR/M501797/1) and by grants from the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes]), from the National Center for Precision Diabetic Medicine – PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council (Agreement 20001891/NP0025517) and by the European Metropolis of Lille (MEL, Agreement 2019_ESR_11) and by Isite ULNE (R-002-20-TALENT-DUMAS), also jointly funded by ANR (ANR-16-IDEX-0004-ULNE) the Hauts-de-France Regional Council (Agreement 20002045) and by the European Metropolis of Lille (MEL). J.M.-P. is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund 'Investing in your future'. María Arnoriaga Rodríguez is funded by a predoctoral Río Hortega contract (CM19/00190, co-funded by European Social Fund 'Investing in your future') from the Instituto de Salud Carlos III, Spain. This work was supported by grants to AM from the Spanish Ministry of Science and Innovation (PID2019-105969GB-I00) and Generalitat Valenciana (project Prometeo/2018/133). ; Peer reviewed
Gut: first published. ; [Background]: Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits. ; [Methods]: We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics. ; [Results]: An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism (thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice. ; [Conclusion]: These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts. ; This work was partially supported by research grants FIS (PI15/01934 and PI18/01022) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R and #AEI-SAF2017-84060-R-FEDER from Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain; and also by Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2015), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), the Catalan Goverment (Agency for Management of University and Research Grants [2017SGR696] and Department of Health [STL002/16/00250]; the European Regional Development Fund (project No. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT); and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A SpainFrance-Andorra programme (POCTEFA 2014-2020). MA-R is funded by a predoctoral Río Hortega contract from the Instituto de Salud Carlos III (ISCIII, CM19/00190), co-funded by the European Social Fund "Investing in your future". OC-R is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP20/00165), co-funded by the Europeran Social Fund "Investing in your future". JM-P is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund "Investing in your future". JS is funded by a predoctoral PERIS contract (SLT002/16/00250) from the Catalan Government. MJ is a professor under the "Serra Hunter" programme (Generalitat de Catalunya). ; Peer reviewed
Background Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits. Methods We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics. Results An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism (thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice. Conclusion These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts. ; This work was partially supported by research grants FIS (PI15/01934 and PI18/01022) from the Instituto de Salud Carlos III from Spain, SAF2015- 65878-R and #AEI-SAF2017-84060-R-FEDER from Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain; and also by Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award ...
Background Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits. Methods We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics. Results An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism (thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice. Conclusion These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts. ; This work was partially supported by research grants FIS (PI15/01934 and PI18/01022) from the Instituto de Salud Carlos III from Spain, SAF2015- 65878-R and #AEI-SAF2017-84060-R-FEDER from Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain; and also by Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2015), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), the Catalan Goverment (Agency for Management of University and Research Grants [2017SGR696] and Department of Health [STL002/16/00250]; the European Regional Development Fund (project No. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT); and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A SpainFrance-Andorra programme (POCTEFA 2014-2020). MA-R is funded by a predoctoral Río Hortega contract from the Instituto de Salud Carlos III (ISCIII, CM19/00190), co-funded by the European Social Fund "Investing in your future". OC-R is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP20/00165), co-funded by the Europeran Social Fund "Investing in your future". JM-P is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund "Investing in your future". JS is funded by a predoctoral PERIS contract (SLT002/16/00250) from the Catalan Government. MJ is a professor under the "Serra Hunter" programme (Generalitat de Catalunya).
