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Cited by 666Gut microbiota and healthGenetics, Aging, and Longevity in Model OrganismsProbiotics and Fermented Foods

Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice

Open access
Bárcena, Clea, Valdés-Mas, Rafael, Mayoral, Pablo, Garabaya, Cecilia, Durand, Sylvère, Rodríguez, Francisco, Fernández-García, María Teresa, Salazar, Nuria +9 more·2019·Nature Medicine
DOI 10.1038/s41591-019-0504-5
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Abstract

The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways 1,2. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease and cancer 3-6, but its precise role in aging remains to be elucidated. Here, we find that two different mouse models of progeria are characterized by intestinal dysbiosis with alterations that include an increase in the abundance of Proteobacteria and Cyanobacteria, and a decrease in the abundance of Verrucomicrobia. Consistent with these findings, we found that human progeria patients also display intestinal dysbiosis and that long-lived humans (that is, centenarians) exhibit a substantial increase in Verrucomicrobia and a reduction in Proteobacteria. Fecal microbiota transplantation from wild-type mice enhanced healthspan and lifespan in both progeroid mouse models, and transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. Our results demonstrate that correction of the accelerated aging-associated intestinal dysbiosis is beneficial, suggesting the existence of a link between aging and the gut microbiota that provides a rationale for microbiome-based interventions against age-related diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

Fecal microbiota transplantation from wild-type donors into progeroid mice extends healthspan and lifespan, while progeroid microbiota can induce metabolic alterations in wild-type recipients. The study links progeria-associated gut dysbiosis to loss of Akkermansia and altered bile acid metabolism, with A. muciniphila supplementation modestly extending lifespan in progeroid mice.

Key findings

  • Progeroid mouse models and human progeria patients show intestinal dysbiosis; Lmna G609G/G609G mice at 4 months lose Akkermansia and show increased Enterobacteriaceae, while centenarians have higher Akkermansia, Ruminococcaceae, Christensenellaceae, and Enterobacteriaceae.
  • FMT from WT donors into Lmna G609G/G609G mice improved survival (P = 0.0029), with a 13.5% increase in median lifespan (160 vs 141 days) and 9% extended maximal survival (P = 0.04); FMT from old progeroid donors reduced survival (P = 0.045; median 129 days).
  • FMT from WT donors into Zmpste24−/− mice enhanced survival (P = 0.0092), with a 13.4% median lifespan increase (279 vs 246 days) and almost 8% maximal survival increase (P = 0.09).
  • Oral A. muciniphila supplementation in Lmna G609G/G609G mice modestly extended lifespan (P = 0.016), induced ileal Reg3g and Tff3, thickened intestinal mucosa, and FMT restored depleted secondary bile acids and metabolites including arabinose, ribose, inosine, and PCae(18:0).

Methods

  • Gut metagenomic profiling by 16S rRNA V3–V4 sequencing in Lmna G609G/G609G and Zmpste24−/− mice, human HGPS/NGPS families, centenarians (n = 17) and healthy controls (n = 14), using QIIME 2/DADA2, LEfSe, PICRUSt, and HUMAnN2.
  • FMT experiments: antibiotic cocktail followed by oral gavage of microbiome suspensions from WT or old progeroid donors into progeroid or WT mice, with assessment of survival, body weight/temperature, glucose, histology, and calorimetry.
  • A. muciniphila culture and oral gavage; metabolomic profiling of ileal content by GC-MS and UHPLC-MS; survival analyzed by Kaplan-Meier log-rank tests and maximal survival by Fisher’s exact test at the 80th percentile.

Limitations

  • The paper states that human progeria samples were low in number and that environment may have more influence on the gut microbiome than the pathological condition.
  • The paper states that future work is needed to identify the functional mechanisms by which specific bacterial species and metabolites mediate the healthspan and lifespan extension conferred by FMT, and to explore applicability in normal or accelerated aging.
  • Evident from the text: human progeria analyses included only four HGPS children and one NGPS patient with siblings, and the centenarian cohort was small (17 centenarians vs 14 controls), limiting generalizability; the study also notes a possible beneficial effect of the FMT protocol per se in old-donor transplanted progeroid mice.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41591-019-0504-5

Cites

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Statistics

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Claims the paper makes

0 of 34 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Oral gavage of Akkermansia muciniphila extends the lifespan of progeroid mice.

    “Analysis of centenarians and progeria mouse models point to a beneficial role for the genus Akkermansia, as oral gavage of Akkermansia muciniphila extends the lifespan of progeroid mice.”
    Quote in the paperSubstantial claim
  • Findingnone given

    The microbiota of centenarians is characterized by the presence of both pathological- and health-associated bacterial genera.

    “In turn, the microbiota of centenarians is characterized by the presence of both pathological-and healthassociated bacterial genera.”
    Quote in the paperNot a substantial claim
  • Findingown data

    FMT from progeroid donors to wild-type recipients induces metabolic alterations.

    “We show that fecal microbiota transplantation (FMT) from wild-type (WT) donors to progeroid recipients attenuates the accelerated-aging phenotype and increases survival, whereas FMT from progeroid donors to WT recipients induces metabolic alterations.”
    Quote in the paperSubstantial claim
  • Findingown data

    Lmna G609G/G609G 4mo mice show a loss in Clostridiaceae, Allobaculum, Sutterella, Dehalobacterium, Rikenella and Akkermansia.

    “At a lower taxonomical level, Lmna G609G/G609G 4mo mice showed a loss in Clostridiaceae, Allobaculum, Sutterella, Dehalobacterium, Rikenella and Akkermansia (Fig. 1d).”
    Quote in the paperSubstantial claim
  • Findingown data

    When samples were compared by geographical location (families), a differential clustering was observed at quantitative and qualitative levels.

    “However, when samples were compared by geographical location (i.e., comparing families), a differential clustering was observed at the quantitative (Fig. 2b) and qualitative levels (Extended Data Fig. 4e).”
    Quote in the paperSubstantial claim
  • May combine two claims. 34
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingown data

    WT and Lmna G609G/G609G mice at 1 month of age have a similar gut bacterial profile, with only an increment in Allobaculum, Desulfovibrio, and Clostridiales in Lmna G609G/G609G 1mo.

    “We noted a similar profile for WT and Lmna G609G/G609G mice at 1 month of age (Fig. 1b and Extended Data Fig. 2a), observing solely an increment in the genera Allobaculum from the family Erysipelotrichaceae, Desulfovibrio (class deltaproteobacteria) and Clostridiales of the families Ruminococcaceae and Lachnospiraceae, in Lmna G609G/G609G 1mo (Extended Data Fig. 2b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When comparing progeria patients with their healthy controls, no differences were found in alpha-diversity or beta-diversity indices.

    “When comparing progeria patients with their healthy controls, we found no differences in alpha-diversity (Extended Data Fig. 4b,c) or beta-diversity indices (Fig. 2a and Extended Data Fig. 4d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The gut microbiome of a fraction of WT 22mo exhibited a tendency towards intestinal dysbiosis, but the only significant shift was the loss in Rikenella.

    “The gut microbiome of a fraction of WT 22mo exhibited a tendency towards intestinal dysbiosis (Extended Data Fig. 2a); however, the only significant shift consisted in the loss in Rikenella (Extended Data Fig. 2e), a change also found when comparing Lmna G609G/G609G 4mo to WT 4mo mice (Fig. 1d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Hierarchical clustering grouped Lmna G609G/G609G 4mo mice together and separated them from all other groups.

    “Similar differences were revealed by hierarchical clustering, where Lmna G609G/G609G 4mo mice were grouped together and separated from all other groups (Extended Data Fig. 1e,f).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Zmpste24 -/- mice showed no differences in bacterial diversity but exhibited higher bacterial richness.

    “Although Zmpste24 -/-mice showed no differences in bacterial diversity (Extended Data Fig. 3b), they exhibited higher bacterial richness (Extended Data Fig. 3c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LEfSe analysis detected an increase in KEGG pathways related to pathological bacteria such as 'Bacterial invasion of epithelial cells' (ko05100) and 'Flagellar assembly' (ko02040), and a differential enrichment in multiple metabolic pathways.

    “LEfSe analysis detected an increase in KEGG pathways related to pathological bacteria such as 'Bacterial invasion of epithelial cells' (ko05100) and 'Flagellar assembly' (ko02040), and a differential enrichment in multiple metabolic pathways (Extended Data Fig. 2f and Supplemental Table S3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Zmpste24 -/- animals showed differences in beta diversity at quantitative and qualitative levels, clustering differently from WT mice, and exhibited signs of dysbiosis with high abundance of Proteobacteria and Cyanobacteria.

    “Like Lmna G609G/G609G mice, Zmpste24 -/-animals showed differences in beta diversity at the quantitative (Fig. 1f) and qualitative level (Extended Data Fig. 3d), clustering differently from WT mice, and exhibited signs of dysbiosis (Fig. 1g, Extended Data Fig. 3e) with a high abundance of Proteobacteria (class Alphaproteobacteria) and Cyanobacteria (Fig. 1g, Extended Data Fig. 3e and Supplementary”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Alterations in the gut microbiome occur in progeria patients and long-lived humans.

    “Alterations in the gut microbiome in progeria patients and long-lived humans.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    PCoA of beta-diversity among fecal samples by family showed significant difference (P = 0.001, PERMANOVA).

    “(b) family (P = 0.001, PERMANOVA) (Family A, n = 3; Family B, n = 3; Family C, n = 3; Family D, n = 2; Family E, n = 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Body weight loss and hypoglycemia were avoided in Zmpste24 -/--WTmic mice.

    “Body weight loss (Fig. 3m and Extended Data Fig. 8a) and hypoglycemia (Fig. 3n) were avoided in Zmpste24 -/--WTmic mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Lmna G609G/G609G -WTmic showed improved survival compared to control Lmna G609G/G609G mice, with a 13.5% increase in median lifespan (160 vs 141 days).

    “Most importantly, Lmna G609G/G609G -WTmic showed improved survival compared to control Lmna G609G/G609G mice (P = 0.0029), with a 13.5% increase in median lifespan (160 vs 141 days, respectively) (Fig. 3f).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In beta-diversity PCoA, G609G 4mo mice show statistical differences with each of the other groups (P = 0.001; PERMANOVA).

    “G609G 4mo mice show statistical differences with each of the other groups (see Supplementary Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Intestinal inflammation markers increased in Lmna G609G/G609G mice and were recovered in Lmna G609G/G609G -WTmic.

    “We also noted an increase in intestinal inflammation markers in Lmna G609G/G609G mice that was recovered in Lmna G609G/G609G -WTmic (Extended Data Fig. 6d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Lmna G609G/G609G -oG609Gmic showed reduced survival compared to control Lmna G609G/G609G mice, with a reduction in median lifespan (129 days).

    “In contrast, Lmna G609G/G609G -oG609Gmic showed reduced survival compared to control Lmna G609G/G609G mice (P = 0.045), with a reduction in median lifespan (129 days) (Fig. 3f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Different bile acids were decreased in Lmna G609G/G609G compared to WT mice, and recovered in Lmna G609G/G609G -WTmic.

    “As recently described 28 , different bile acids were decreased in Lmna G609G/G609G compared to WT mice, and recovered in Lmna G609G/G609G -WTmic (Fig. 4e).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Barcena, C. et al. Methionine restriction extends lifespan in progeroid mice and alters lipid and bile acid metabolism. Cell Rep. 24, 2392–2403 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Centenarians showed lower alpha-diversity and considerably lower bacterial richness compared to controls.

    “Centenarians showed lower alpha-diversity compared to their controls (Extended Data Fig. 5b), and a considerably lower bacterial richness (Extended Data Fig. 5c).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    FMT from old Lmna G609G/G609G donors into WT mice caused metabolic alterations, including higher body weight, higher glucose levels, lower O2 consumption, lower CO2 production and reduced energy expenditure.

    “However, this maneuver caused metabolic alterations, including a higher body weight, higher glucose levels, lower O2 consumption, lower CO2 production and reduced energy expenditure (Fig. 3g-k and Extended Data Fig. 7a-d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    qPCR validation showed differences in abundance of E. coli (W = 6, P = 0.0046) and A. muciniphila (W = 52, P = 0.03) between WT (n = 8) and G609G mice (n = 8) at 10 weeks of age.

    “(e) Validation using qPCR of the differences in abundance of E. coli (W = 6, P = 0.0046) and A. muciniphila (W = 52, P = 0.03) between WT (n = 8) and G609G mice (n = 8) at 10 weeks of age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Centenarians were characterized by a lower abundance of Desulfovibrionaceae, Lachnospiraceae and Erysipelotrichaceae and Prevotella, Sutterella, Roseburia, or Butyricicoccus, among other differences.

    “At a lower taxonomic level, centenarians were characterized by a lower abundance of Desulfovibrionaceae, Lachnospiraceae and Erysipelotrichaceaethe last two enriched in progeria patientsand Prevotella, Sutterella, Roseburia, or Butyricicoccus, among other differences (Fig. 2f).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The changes in microbiota from 1 to 4 months were more profound in progeroid mice, displaying a loss in Akkermansia and Dehalobacterium and an enrichment in Parabacteroides, Prevotella and the Enterobacteriaceae.

    “however, the changes from 1 to 4 months were more profound in progeroid mice, displaying a loss in Akkermansia and Dehalobacterium and an enrichment in Parabacteroides, Prevotella and the Enterobacteriaceae, among other differences (Extended Data Fig. 2d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    FMT from WT mice into Zmpste24 -/- mice caused a less pronounced cervicothoracic lordokyphosis, larger body size and maintained grooming.

    “This manipulation caused Zmpste24 -/- mice to manifest a less pronounced cervicothoracic lordokyphosis, larger body size and maintained grooming (Fig. 3l).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spleen weight was similar in Lmna G609G/G609G -WTmic and Lmna G609G/G609G controls, but lower in Lmna G609G/G609G -oG609Gmic.

    “Spleen weight, typically reduced in progeroid mice, was similar in Lmna G609G/G609G -WTmic and Lmna G609G/G609G controls, but lower in Lmna G609G/G609G -oG609Gmic (Extended Data Fig. 6c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LEfSe analysis pointed to a loss in Gemmiger (family Ruminococcaceae) and an enrichment in Clostridium from families Erysipelotrichaceae and Lachnospiraceae in progeria patients.

    “LEfSe analysis pointed to a loss in Gemmiger -family Ruminococcaceae-and an enrichment in Clostridium from families Erysipelotrichaceae and Lachnospiraceae in progeria patients (Fig. 2c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LEfSe analysis showed that centenarians presented less Betaproteobacteria and more Synergistia and Verrucomicrobiae, among others.

    “LEfSe analysis showed that centenarians presented less Betaproteobacteria and more Synergistia and Verrucomicrobiae, among others (Fig. 2e and Supplementary Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Zmpste24 -/--WTmic mice exhibited enhanced survival, with a median lifespan increase of 13.4% (279 vs 246 days).

    “Like Lmna G609G/G609G mice transplanted with WT microbiota, Zmpste24 -/--WTmic mice also exhibited enhanced survival (P = 0.0092), with a median lifespan increase of 13.4% (279 vs 246 days) (Fig. 3o).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Relative expression levels of Reg3g and Tff3 differ between G609G and AKK mice (Reg3g: t = 2.33, df = 13, P = 0.0365; Tff3: t = 2.42, df = 13, P = 0.0306).

    “(b) Relative expression levels of Reg3g and Tff3 in G609G (n = 8) and AKK (n = 7) mice.Differences were analyzed with an unpaired two-tailed Student's t-test.For Reg3g, t = 2.33, df = 13, P = 0.0365; for Tff3, t = 2.42, df = 13, P = 0.0306.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In mammals, the gut microbiota is involved in food processing, activation of satiety pathways, protection against pathogens, and production of metabolites including vitamins, short chain fatty acids and secondary bile acids.

    “In mammals, the gut microbiota is involved in food processing, activation of satiety pathways, protection against pathogens, and production of metabolites including vitamins, short chain fatty acids and secondary bile acids [8][9][10] .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Rios-Covian, D. et al. Intestinal short chain fatty acids and their link with diet and human health. Front. Microbiol. 7, 185 (2016). source

      Not checked in the free run.

    • cites [9] Breton, J. et al. Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab. 23, 324–334 (2016). source

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    • cites [10] Wahlstrom, A., Sayin, S. I., Marschall, H. U. & Backhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016). source

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    Premisecitation

    The gut microbiota has essential metabolic and immunological functions conserved from worms to humans.

    “It is now known that the microbiota has essential metabolic and immunological functions conserved from worms 7 to humans 1,2 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Thaiss, C. A., Zmora, N., Levy, M. & Elinav, E. The microbiome and innate immunity. Nature 535, 65–74 (2016). source

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    • cites [2] Leulier, F. et al. Integrative physiology: at the crossroads of nutrition, microbiota, animal physiology and human health. Cell Metab. 25, 522–534 (2017). source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The gut microbiota signals to distant organs, contributing to the maintenance of host physiology.

    “The gut microbiota also signals to distant organs, contributing to the maintenance of host physiology 11 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Schroeder, B. O. & Backhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat. Med. 22, 1079–1089 (2016). source

      Not checked in the free run.

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    Premisecitation

    Intestinal microbiota alterations are associated with major conditions like obesity, type-2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease, cancer, and the response to antineoplastic therapy.

    “Intestinal microbiota alterations are associated with major conditions like obesity, type-2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease, cancer, and the response to antineoplastic therapy [3][4][5][6] .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] Koeth, R. A. et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013). source

      Not checked in the free run.

    • cites [4] Loomba, R. et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 25, 1054–1062 (2017). source

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    • cites [5] Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The in vivo results suggest that therapeutic interventions on the intestinal microbiome may lead to healthspan and even lifespan improvements.

    “The promising in vivo results obtained in this study suggest that therapeutic interventions on the intestinal microbiome may lead to healthspan end even lifespan improvements.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies reported high levels of Akkermansia and Christensenellaceae and low levels of Roseburia in centenarians.

    “These results are in line with previous studies reporting high levels of Akkermansia and Christensenellaceae and low levels of Roseburia in centenarians 12,24 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016). source

      Not checked in the free run.

    • cites [24] Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Secondary bile acids are produced by the gut microbiota and positively correlate with Akkermansia levels in mice.

    “Of note, secondary bile acids are produced by the gut microbiota 38 and positively correlate with Akkermansia levels in mice 39 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] de Aguiar Vallim, T. Q., Tarling, E. J. & Edwards, P. A. Pleiotropic roles of bile acids in metabolism. Cell Metab. 17, 657–669 (2013). source

      Not checked in the free run.

    • cites [39] Pierre, J. F. et al. Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G286–G304 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Bile acids regulate metabolism and anti-inflammatory signals.

    “Considering that bile acids regulate metabolism and anti-inflammatory signals 40 and that they are depleted in Lmna G609G/G609G mice 28 , the restoration of secondary bile acidsand other metabolites (arabinose, ribose, inosine)by FMT might contribute to extend healthspan and lifespan in progeroid mice (Fig. 4g).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Postler, T. S. & Ghosh, S. Understanding the holobiont: how microbial metabolites affect human health and shape the immune system. Cell Metab. 26, 110–130 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    High abundance of Akkermansia has been associated with improved immunomodulation and metabolic homeostasis, reduced inflammation, and protection against atherosclerosis.

    “Of note, high abundance of Akkermansia has been associated with improved immunomodulation and metabolic homeostasis, reduced inflammation, and protection against atherosclerosis [17][18][19] .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Plovier, H. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23, 107–113 (2017). source

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    • cites [18] Schneeberger, M. et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci. Rep. 5, 16643 (2015). source

      Not checked in the free run.

    • cites [19] Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl Acad. Sci. USA 110, 9066–9071 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Previous studies have described that successful FMT treatment of recurrent infection by C. difficile relies on restoration of correct bile acid metabolism, and that antibiotic-induced microbiome depletion reduces the secondary bile acid pool.

    “Previous studies have described that successful FMT treatment of recurrent infection by C. difficile relies on restoration of correct bile acid metabolism 35,36 , and that antibioticinduced microbiome depletion reduces the secondary bile acid pool 37 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [35] Weingarden, A. R. et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G310–G319 (2014). source

      Not checked in the free run.

    • cites [36] Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015). source

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    • cites [37] Zarrinpar, A. et al. Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism. Nat. Commun. 9, 2872 (2018). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Enterobacteriaceae contains the genus Escherichia and has been associated with dysbiosis and intestinal inflammation.

    “By contrast, Lmna G609G/G609G 4mo exhibited an increment in Mucispirillum, Enterococcus, Acinetobacter, Staphylococcus, Parabacteroides, Bacteroides, Prevotella and Enterobacteriaceae, which contains the genus Escherichia and has been associated with dysbiosis and intestinal inflammation 20 (Fig. 1d).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Maharshak, N. et al. Altered enteric microbiota ecology in interleukin 10-deficient mice during development and progression of intestinal inflammation. Gut Microbes 4, 316–324 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    FMT might modulate obesity and metabolism in humans and mice, ameliorate metabolic syndrome in patients, and contribute to the treatment of refractory immune checkpoint inhibitor (ICI)-associated colitis and recurrent infections by Clostridium difficile.

    “FMT might modulate obesity and metabolism in humans and mice 29,30 , ameliorate metabolic syndrome in patients 31 , and contribute to the treatment of refractory immune checkpoint inhibitor (ICI)-associated colitis 32 and recurrent infections by Clostridium difficile 33 .”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [29] Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013). source

      Not checked in the free run.

    • cites [30] Cox, L. M. et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705–721 (2014). source

      Not checked in the free run.

    • cites [31] Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916 (2012). source

      Not checked in the free run.

    • cites [32] Wang, Y. et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat. Med. 24, 1804–1808 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The QC sample was re-injected in each batch to monitor and correct analytical bias.

    “This QC sample was re-injected in each batch to monitor and correct analytical bias.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Differentially expressed metabolites in each condition were identified using moderate t-statistic implemented in limma, using sex as a covariate.

    “Differentially expressed metabolites in each condition were identified using moderate t-statistic implemented in the R/Bioconductor package limma 46 , using sex as a covariate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Normalization was performed by correcting the area of the MS picks across the batches using the QC pooled samples and by centering their values around the mean of the QC areas.

    “Normalization was performed by correcting the area of the MS picks across the batches using the QC pooled samples and by centering their values around the mean of the QC areas.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Research involving humans was approved by the Ethical Committee of Regional Clinical Research of the Principality of Asturias, project no.105/16.

    “Research involving humans was approved by the Ethical Committee of Regional Clinical Research of the Principality of Asturias, project no.105/16.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Number of mice allocated per group was based on previous experiments and their distribution was randomized.

    “Number of mice allocated per group was based on previous experiments and their distribution was randomized, being indicated in each Figure legend.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All participants read and signed an informed consent.

    “All participants read and signed an informed consent.”
    Quote in the paperNot a substantial claim
44 of 44

  • The paper relies on this without support.

    No alterations in the gut microbiome have been described in accelerated aging syndromes.

    “Although some works have explored the microbiome profile of long-lived humans 12,13 , no alterations have been described in accelerated aging syndromes.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Many studies have shown that Akkermansia can effectively improve symptoms in mouse models of ALS, progeria, and chronic colitis by promoting healing and recovery of intestinal mucosal layer and reducing the expression of proinflammatory cytokines such as TNF-α and IFN-γ in the colon.

    “Many studies have shown that Akkermansia can effectively improve symptoms in mouse models of diseases such as ALS [34], progeria [35], and chronic colitis [36] by promoting healing and recovery of intestinal mucosal layer and reducing the expression of proinflammatory cytokines such as TNF-α and interferon gamma (IFN-γ) in the colon.”

    From Neuroprotective Effect of Ceftriaxone on MPTP‐Induced Parkinson’s Disease Mouse Model by Regulating Inflammation and Intestinal Microbiota (2021) · cites this paper as [35]

  • In aged mice, receiving microbiota from young mice has been reported to extend life span or halt functional decline in the mucosal immune system.

    “Similar beneficial effects have been reported in aged mice receiving microbiota from young mice to extend life span [8, 61] or halt the functional decline in the mucosal immune system [112].”

    From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [8]

  • Members of the Bifidobacteriaceae, Akkermansiaceae, and Eubacteriaceae families are associated with beneficial effects on intestinal and extra-intestinal health in both mice and humans.

    “Members of the Bifidobacteriaceae, Akkermansiaceae, and Eubacteriaceae families that are associated with beneficial effects on intestinal and extra-intestinal health in both mice and humans”

    From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [8]

  • Bifidobacterium animalis and Akkermansia muciniphila are associated with promoting intestinal and extra-intestinal health and healthy aging.

    “and are associated with promoting intestinal and extra-intestinal health and healthy aging.”

    From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [8]

  • In mouse models of accelerated aging, supplementation with A. muciniphila can attenuate age-related decline in colon thickness and immune activation, and exert beneficial effects on lifespan and healthspan.

    “In mouse models of accelerated aging, supplementation with A. muciniphila can also attenuate age-related decline in colon thickness and immune activation [73], and exert beneficial effects on lifespan and healthspan [8].”

    From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [8]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Akkermansia treatment has conflicting start ages

    Major

    The Methods say oral gavage began at 12 weeks of age, whereas the Figure 4 legend says it began at 7-8 weeks. These are different treatment schedules for the same survival experiment.

1 of 1

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Authors
Bárcena, C., Valdés-Mas, R., Mayoral, P., Garabaya, C., Durand, S., Rodríguez, F., Fernández-García, M. T., Salazar, N., Nogacka, A. M., Garatachea, N., Bossut, N., Aprahamian, F., Lucia, A., Kroemer, G., Freije, J. M. P., Quirós, P. M., & López-Otín, C.
Affiliations
  • Universidad de Oviedo (ES)
  • Inserm (FR)
  • Consejo Superior de Investigaciones Científicas (ES)
  • Universidad de Zaragoza (ES)
  • Karolinska University Hospital (SE)
Corresponding author
Quirós, Pedro M.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-07-22
Volume
25
Issue
8
Pages
1234-1242
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-019-0504-5
OpenAlex
W2963531283
Cited by
661
References
49
Citations by year
2026: 78 · 2025: 110 · 2024: 124 · 2023: 90 · 2022: 95 · 2021: 86 · 2020: 65 · 2019: 12
FWCI
22.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc-nd)
  • ABACUS. Repositorio de Producción Científica (Universidad Europea) (submittedVersion)
  • Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Funders
Agence Nationale de la Recherche (ANR-16-ECVD-0008)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
Keywords
fecal microbiota transplantation, gut microbiota, aging, healthspan, lifespan extension, Hutchinson-Gilford progeria syndrome, gut dysbiosis, Akkermansia muciniphila, Verrucomicrobia, Proteobacteria, centenarians, secondary bile acids, microbiota-targeted interventions
MeSH terms
Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Animals, Disease Models, Animal, Female, Humans, Longevity, Male, Mice, Inbred C57BL, Progeria, Mice, Metabolomics, Dysbiosis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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