Suchergebnisse

The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment. ; This work was partially supported by Instituto de Salud Carlos III (Madrid, Spain) through the research grants PI15/01934, PI18/01022, and PI21/01361 to J.M.F.-R. and PI20/01090 (co-funded by the European Regional Development Fund. "A way to make Europe") to J.M.-P.; the Catalan Government (AGAUR, #SGR2017-0734, ICREA Academia Award 2021) to J.M.F.-R.; the Spanish Ministry of Science, Innovation and Universities (PID2019-105969GB-I00); Generalitat Valenciana (Prometeo/2018/133), Spain; and Fondo Europeo de Desarrollo Regional (FEDER) funds to A.M. This work was also supported by the European Commission (FP7, NeuroPain #2013-602891); the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2020) to R.M.; the Spanish Instituto ...

[Background]: The chaperone ClpB, a bacterial protein, is a conformational antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH) implicated in body weight regulation in mice. We here investigated the potential associations of gut bacterial ClpB-like gene function with obesity status and gut microbiota in humans. ; [Results]: Gut microbiota ClpB KEGG function was negatively associated with body mass index, waist circumference, and total fat mass (DEXA). The relative abundance (RA) of several phyla and families directly associated with ClpB was decreased in subjects with obesity. Specifically, the RA of Rikenellaceae, Clostridiaceae and not assigned Firmicutes were lower in subjects with obesity and positively associated with gut bacterial ClpB-like gene function (not assigned Firmicutes (r = 0.405, FDR = 2.93 × 10−2), Rikenellaceae (r = 0.217, FDR = 0.031), and Clostridiaceae (r = 0.239, FDR = 0.017)). The gut bacterial ClpB-like gene function was also linked to specific plasma metabolites (hippuric acid and 3-indolepropionic acid) and fecal lupeol. The α-MSH-like epitope similar to that of Escherichia coli ClpB was also identified in some sequences of those bacterial families. After fecal transplantation from humans to mice, the families that more contributed to ClpB-like gene function in humans were also associated with ClpB-like gene function in mice after adjusting for the donor's body mass index (not assigned Firmicutes (r = 0.621, p = 0.003), Prevotellaceae (r = 0.725, p = 4.1 × 10−7), Rikenellaceae (r = 0.702, p = 3.9 × 10−4), and Ruminococcaceae (r = 0.526, p = 0.014)). Clostridiaceae (r = − 0.445, p = 0.038) and Prevotellaceae RA (r = − 0.479, p = 0.024) and were also negatively associated with weight gain in mice. The absolute abundance (AA) of Prevotellaceae in mice was also positively associated with the gut bacterial ClpB-like gene function in mice. DESeq2 identified species of Prevotellaceae, both negatively associated with mice' weight gain and positively with gut bacterial ClpB-like gene function. ; [Conclusions]: In summary, gut bacterial ClpB-like gene function is associated with obesity status, a specific gut microbiota composition and a plasma metabolomics profile in humans that could be partially transplanted to mice. ; This work was partially supported by research grants FIS (PI15/01934) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R 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 Instituto de Salud Carlos III (RTA, #RD16/0017/0020), and the European Regional Development Fund (No. 01.2.2-LMT-K-718-02-0014). María Arnoriaga-Rodríguez is funded by Instituto de Salud Carlos III, Río Hortega (CP19/00190). Jordi Mayneris-Perxachs is funded by Instituto de Salud Carlos III, Miguel Servet (CP18/00009). The project has also been 65% cofinanced by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). POCTEFA aims to reinforce the economic and social integration of the French–Spanish–Andorran border. Its support is focused on developing economic, social and environmental cross-border activities through joint strategies favouring sustainable territorial development. ; Peer reviewed

Background The chaperone ClpB, a bacterial protein, is a conformational antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH) implicated in body weight regulation in mice. We here investigated the potential associations of gut bacterial ClpB-like gene function with obesity status and gut microbiota in humans. Results Gut microbiota ClpB KEGG function was negatively associated with body mass index, waist circumference, and total fat mass (DEXA). The relative abundance (RA) of several phyla and families directly associated with ClpB was decreased in subjects with obesity. Specifically, the RA of Rikenellaceae, Clostridiaceae and not assigned Firmicutes were lower in subjects with obesity and positively associated with gut bacterial ClpB-like gene function (not assigned Firmicutes (r = 0.405, FDR = 2.93 × 10−2), Rikenellaceae (r = 0.217, FDR = 0.031), and Clostridiaceae (r = 0.239, FDR = 0.017)). The gut bacterial ClpB-like gene function was also linked to specific plasma metabolites (hippuric acid and 3-indolepropionic acid) and fecal lupeol. The α-MSH-like epitope similar to that of Escherichia coli ClpB was also identified in some sequences of those bacterial families. After fecal transplantation from humans to mice, the families that more contributed to ClpB-like gene function in humans were also associated with ClpB-like gene function in mice after adjusting for the donor's body mass index (not assigned Firmicutes (r = 0.621, p = 0.003), Prevotellaceae (r = 0.725, p = 4.1 × 10−7), Rikenellaceae (r = 0.702, p = 3.9 × 10−4), and Ruminococcaceae (r = 0.526, p = 0.014)). Clostridiaceae (r = − 0.445, p = 0.038) and Prevotellaceae RA (r = − 0.479, p = 0.024) and were also negatively associated with weight gain in mice. The absolute abundance (AA) of Prevotellaceae in mice was also positively associated with the gut bacterial ClpB-like gene function in mice. DESeq2 identified species of Prevotellaceae, both negatively associated with mice' weight gain and positively with gut bacterial ClpB-like gene function. Conclusions In summary, gut bacterial ClpB-like gene function is associated with obesity status, a specific gut microbiota composition and a plasma metabolomics profile in humans that could be partially transplanted to mice. ; This work was partially supported by research grants FIS (PI15/01934) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R 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 Instituto de Salud Carlos III (RTA, #RD16/0017/0020), and the European Regional Development Fund (No. 01.2.2-LMT-K-718-02-0014). María Arnoriaga-Rodríguez is funded by Instituto de Salud Carlos III, Río Hortega (CP19/00190). Jordi Mayneris-Perxachs is funded by Instituto de Salud Carlos III, Miguel Servet (CP18/00009). The project has also been 65% cofinanced by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). POCTEFA aims to reinforce the economic and social integration of the French–Spanish–Andorran border. Its support is focused on developing economic, social and environmental cross-border activities through joint strategies favouring sustainable territorial development.

[Background]: Gonadal steroid hormones have been suggested as the underlying mechanism responsible for the sexual dimorphism observed in metabolic diseases. Animal studies have also evidenced a causal role of the gut microbiome and metabolic health. However, the role of sexual dimorphism in the gut microbiota and the potential role of the microbiome in influencing sex steroid hormones and shaping sexually dimorphic susceptibility to disease have been largely overlooked. Although there is some evidence of sex-specific differences in the gut microbiota diversity, composition, and functionality, the results are inconsistent. Importantly, most of these studies have not taken into account the gonadal steroid status. Therefore, we investigated the gut microbiome composition and functionality in relation to sex, menopausal status, and circulating sex steroids. ; [Results]: No significant differences were found in alpha diversity indices among pre- and post-menopausal women and men, but beta diversity differed among groups. The gut microbiota from post-menopausal women was more similar to men than to pre-menopausal women. Metagenome functional analyses revealed no significant differences between post-menopausal women and men. Gonadal steroids were specifically associated with these differences. Hence, the gut microbiota of pre-menopausal women was more enriched in genes from the steroid biosynthesis and degradation pathways, with the former having the strongest fold change among all associated pathways. Microbial steroid pathways also had significant associations with the plasma levels of testosterone and progesterone. In addition, a specific microbiome signature was able to predict the circulating testosterone levels at baseline and after 1-year follow-up. In addition, this microbiome signature could be transmitted from humans to antibiotic-induced microbiome-depleted male mice, being able to predict donor's testosterone levels 4 weeks later, implying that the microbiota profile of the recipient mouse was influenced by the donor's gender. Finally, obesity eliminated most of the differences observed among non-obese pre-menopausal women, post-menopausal women, and men in the gut microbiota composition (Bray-Curtis and weighted unifrac beta diversity), functionality, and the gonadal steroid status. ; [Conclusions]: The present findings evidence clear differences in the gut microbial composition and functionality between men and women, which is eliminated by both menopausal and obesity status. We also reveal a tight link between the gut microbiota composition and the circulating levels of gonadal steroids, particularly testosterone. ; This work was partially supported by research grants FIS (PI15/01934) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R and AEI-SAF2017-84060-R from Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain, and also by European Commission (FP7, NeuroPain #2013-602891; #H2020-SC1-2019-2-RTD-848099 (PAINFACT)), the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2015), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), the Fondo Europeo de Desarrollo Regional (FEDER) through the Programa Interreg V-A España-Francia-Andorra (POCTEFA 2014-2020), and 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). 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. Jordi Mayneris-Perxachs 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". ; Peer reviewed

Background: The chaperone ClpB, a bacterial protein, is a conformational antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH) implicated in body weight regulation in mice. We here investigated the potential associations of gut bacterial ClpB-like gene function with obesity status and gut microbiota in humans. Results: Gut microbiota ClpB KEGG function was negatively associated with body mass index, waist circumference, and total fat mass (DEXA). The relative abundance (RA) of several phyla and families directly associated with ClpB was decreased in subjects with obesity. Specifically, the RA of Rikenellaceae, Clostridiaceae and not assigned Firmicutes were lower in subjects with obesity and positively associated with gut bacterial ClpB-like gene function (not assigned Firmicutes (r = 0.405, FDR = 2.93 × 10-2), Rikenellaceae (r = 0.217, FDR = 0.031), and Clostridiaceae (r = 0.239, FDR = 0.017)). The gut bacterial ClpB-like gene function was also linked to specific plasma metabolites (hippuric acid and 3-indolepropionic acid) and fecal lupeol. The α-MSH-like epitope similar to that of Escherichia coli ClpB was also identified in some sequences of those bacterial families. After fecal transplantation from humans to mice, the families that more contributed to ClpB-like gene function in humans were also associated with ClpB-like gene function in mice after adjusting for the donor's body mass index (not assigned Firmicutes (r = 0.621, p = 0.003), Prevotellaceae (r = 0.725, p = 4.1 × 10-7), Rikenellaceae (r = 0.702, p = 3.9 × 10-4), and Ruminococcaceae (r = 0.526, p = 0.014)). Clostridiaceae (r = - 0.445, p = 0.038) and Prevotellaceae RA (r = - 0.479, p = 0.024) and were also negatively associated with weight gain in mice. The absolute abundance (AA) of Prevotellaceae in mice was also positively associated with the gut bacterial ClpB-like gene function in mice. DESeq2 identified species of Prevotellaceae, both negatively associated with mice' weight gain and positively with gut bacterial ClpB-like gene function. Conclusions: In summary, gut bacterial ClpB-like gene function is associated with obesity status, a specific gut microbiota composition and a plasma metabolomics profile in humans that could be partially transplanted to mice. Video Abstract. ; This work was partially supported by research grants FIS (PI15/01934) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R 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 Instituto de Salud Carlos III (RTA, #RD16/0017/0020), and the European Regional Development Fund (No. 01.2.2-LMT-K-718-02-0014). María Arnoriaga-Rodríguez is funded by Instituto de Salud Carlos III, Río Hortega (CP19/00190). Jordi Mayneris-Perxachs is funded by Instituto de Salud Carlos III, Miguel Servet (CP18/00009). The project has also been 65% cofinanced by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). POCTEFA aims to reinforce the economic and social integration of the French–Spanish–Andorran border. Its support is focused on developing economic, social and environmental cross-border activities through joint strategies favouring sustainable territorial development.

Microbioma gastrointestinal; Ferro; Obesitat ; Microbioma gastrointestinal; Hierro; Obesidad ; Gastrointestinal microbiome; Iron; Obesity ; 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-TALENTDUMAS), 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)

Background: Gonadal steroid hormones have been suggested as the underlying mechanism responsible for the sexual dimorphism observed in metabolic diseases. Animal studies have also evidenced a causal role of the gut microbiome and metabolic health. However, the role of sexual dimorphism in the gut microbiota and the potential role of the microbiome in influencing sex steroid hormones and shaping sexually dimorphic susceptibility to disease have been largely overlooked. Although there is some evidence of sex-specific differences in the gut microbiota diversity, composition, and functionality, the results are inconsistent. Importantly, most of these studies have not taken into account the gonadal steroid status. Therefore, we investigated the gut microbiome composition and functionality in relation to sex, menopausal status, and circulating sex steroids. Results: No significant differences were found in alpha diversity indices among pre- and post-menopausal women and men, but beta diversity differed among groups. The gut microbiota from post-menopausal women was more similar to men than to pre-menopausal women. Metagenome functional analyses revealed no significant differences between post-menopausal women and men. Gonadal steroids were specifically associated with these differences. Hence, the gut microbiota of pre-menopausal women was more enriched in genes from the steroid biosynthesis and degradation pathways, with the former having the strongest fold change among all associated pathways. Microbial steroid pathways also had significant associations with the plasma levels of testosterone and progesterone. In addition, a specific microbiome signature was able to predict the circulating testosterone levels at baseline and after 1-year follow-up. In addition, this microbiome signature could be transmitted from humans to antibiotic-induced microbiome-depleted male mice, being able to predict donor's testosterone levels 4 weeks later, implying that the microbiota profile of the recipient mouse was influenced by the donor's gender. Finally, obesity eliminated most of the differences observed among non-obese pre-menopausal women, post-menopausal women, and men in the gut microbiota composition (Bray-Curtis and weighted unifrac beta diversity), functionality, and the gonadal steroid status. Conclusions: The present findings evidence clear differences in the gut microbial composition and functionality between men and women, which is eliminated by both menopausal and obesity status. We also reveal a tight link between the gut microbiota composition and the circulating levels of gonadal steroids, particularly testosterone. Video Abstract. ; This work was partially supported by research grants FIS (PI15/01934) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R and AEI-SAF2017-84060-R from Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain, and also by European Commission (FP7, NeuroPain #2013-602891; #H2020-SC1-2019-2-RTD-848099 (PAINFACT)), the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2015), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), the Fondo Europeo de Desarrollo Regional (FEDER) through the Programa Interreg V-A España-Francia-Andorra (POCTEFA 2014-2020), and 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). 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. Jordi Mayneris-Perxachs 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".

Growing evidence implicates the gut microbiome in cognition. Viruses, the most abundant life entities on the planet, are a commonly overlooked component of the gut virome, dominated by the Caudovirales and Microviridae bacteriophages. Here, we show in a discovery (n = 114) and a validation cohort (n = 942) that subjects with increased Caudovirales and Siphoviridae levels in the gut microbiome had better performance in executive processes and verbal memory. Conversely, increased Microviridae levels were linked to a greater impairment in executive abilities. Microbiota transplantation from human donors with increased specific Caudovirales (>90% from the Siphoviridae family) levels led to increased scores in the novel object recognition test in mice and up-regulated memory-promoting immediate early genes in the prefrontal cortex. Supplementation of the Drosophila diet with the 936 group of lactococcal Siphoviridae bacteriophages resulted in increased memory scores and upregulation of memory-involved brain genes. Thus, bacteriophages warrant consideration as novel actors in the microbiome-brain axis. ; This work was partially funded by the Instituto de Salud Carlos III (Madrid, Spain) through the project PI15/01934, PI18/01022, PI21/01361) to J.M.F.-R. and the project PI20/01090 (co-funded by the European Regional Development Fund. "A way to make Europe") to J.M.-P., the grants SAF2015-65878-R from the Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain and also by the Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669, #2017 SGR- 734, ICREA Academia Award 2015 to R.M. and ICREA Academia Award 2022 to J.M.F.R.), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), 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 Spain-France-Andorra programme (POCTEFA 2014-2020). CIBERobn is also co-funded by the European Regional Development Fund. We also acknowledge the funding from the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), and the Generalitat of Catalonia (Agency for Management of University and Research grants (2017SGR696) and Department of Health (SLT002/16/00250)) to R.M M.A.-R. is funded by the Instituto de Salud Carlos III, Río Hortega (CM19/00190). 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." A.C.-N. is funded by the Instituto de Salud Carlos III, Sara Borrell. MMG was funded by the Spanish Ministry of Science, Innovation and Universities RTI2018-094248-B-I00.

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).

Growing evidence implicates the gut microbiome in cognition. Viruses, the most abundant life entities on the planet, are a commonly overlooked component of the gut virome, dominated by the Caudovirales and Microviridae bacteriophages. Here, we show in a discovery (n = 114) and a validation cohort (n = 942) that subjects with increased Caudovirales and Siphoviridae levels in the gut microbiome had better performance in executive processes and verbal memory. Conversely, increased Microviridae levels were linked to a greater impairment in executive abilities. Microbiota transplantation from human donors with increased specific Caudovirales (>90% from the Siphoviridae family) levels led to increased scores in the novel object recognition test in mice and up-regulated memory-promoting immediate early genes in the prefrontal cortex. Supplementation of the Drosophila diet with the 936 group of lactococcal Siphoviridae bacteriophages resulted in increased memory scores and upregulation of memory-involved brain genes. Thus, bacteriophages warrant consideration as novel actors in the microbiome-brain axis. ; This work was partially funded by the Instituto de Salud Carlos III (Madrid, Spain) through the project PI15/01934, PI18/01022, PI21/01361) to J.M.F.-R. and the project PI20/01090 (co-funded by the European Regional Development Fund . "A way to make Europe") to J.M.-P., the grants SAF2015-65878-R from the Ministry of Economy and Competitiveness , Prometeo/2018/A/133 from Generalitat Valenciana, Spain and also by the Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013- 602891 ), the Catalan Government (AGAUR, #SGR2017-669 , #2017 SGR- 734, ICREA Academia Award 2015 to R.M. and ICREA Academia Award 2022 to J.M.F.R.), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020 ), 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 Spain-France-Andorra programme (POCTEFA 2014-2020). CIBERobn is also co-funded by the European Regional Development Fund. We also acknowledge the funding from the Spanish Ministry of Science, Innovation and Universities ( RTI2018-099200-B-I00 ), and the Generalitat of Catalonia (Agency for Management of University and Research grants ( 2017SGR696 ) and Department of Health (SLT002/16/00250)) to R.M M.A.-R. is funded by the Instituto de Salud Carlos III , Río Hortega ( CM19/00190 ). 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." A.C.-N. is funded by the Instituto de Salud Carlos III , Sara Borrell. MMG was funded by the Spanish Ministry of Science, Innovation and Universities RTI2018-094248-B-I00.

[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).