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Cited by 371Gut microbiota and healthGenetics, Aging, and Longevity in Model OrganismsGastrointestinal motility and disorders

Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

Open access
Parker, Aimée, Romano, Stefano, Ansorge, Rebecca, Aboelnour, Asmaa, Le Gall, Gwenaelle, Savva, George M., Pontifex, Matthew G., Telatin, Andrea +7 more·2022·Microbiome
DOI 10.1186/s40168-022-01243-wPMC PMC9063061
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Abstract

Background: Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Methods: Using fecal microbiota transplantation, we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing. Results: We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota. Conclusions: These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut–brain and gut–retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life. Graphical abstract:

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Written from the paper’s full text.

TL;DR

Heterochronic fecal microbiota transfer (FMT) between young (3-month), old (18-month), and aged (24-month) C57BL/6 mice showed that aged donor microbiota transferred into young mice increased CNS microglial activation, retinal inflammation, and intestinal barrier permeability, while young donor microbiota transferred into aged mice reversed these changes. The findings support a causal role for the aging gut microbiota in gut–brain and gut–retina axes.

Key findings

  • FMT shifted recipient microbiota toward donor-age profiles: aged donor microbiota into young mice enriched *Prevotella* sp. MGM2, *Lactobacillus intestinalis*, and *L. johnsonii*; young donor microbiota into aged mice enriched *Bifidobacterium animalis*, *Akkermansia muciniphila*, *Eubacterium* sp14–2, and *T. muris*. Time point accounted for 50% of data variance (R²adj = 50%; permutational ANOVA on dbRDA F = 55.8, df = 3, P < .01).
  • Aged donor FMT into young mice increased Iba-1+ microglia in cortex and corpus callosum to aged-like levels; young donor FMT into aged mice decreased them. Baseline PBS young vs. aged: cortex P = .005, corpus callosum P < .001.
  • In retina, aged donor FMT into young mice increased complement C3 at the RPE/BM interface, while young donor FMT into aged mice reduced C3 and restored RPE65 to young-like levels; young donor FMT into aged mice reduced retinal CCL11, CXCL11, and IL-1β and most increased IL-13.
  • Barrier/systemic markers: serum I-FABP increased ∼30% in young mice receiving aged donor microbiota and decreased ∼30% in aged mice receiving young donor microbiota; LBP was approximately two times higher in aged than young mice and moved toward donor-age levels after FMT; serum IL-6 was approximately twice as high in young mice receiving aged donor microbiota; intestinal TNF was reduced by around 40% in aged mice receiving young donor microbiota. Y-maze and novel object recognition showed no significant improvement in aged mice receiving young donor microbiota.

Methods

  • Male C57BL/6J mice aged 3, 18, or 24 months from the same colony were antibiotic-depleted, then received heterochronic or coeval FMT via oral gavage and soiled bedding; controls received PBS or antibiotics only. Fecal pellets were collected at Pre-Abx, Post-Abx, Post-FMT (7 days), and end (18 days).
  • Whole metagenomic shotgun sequencing (MetaPhlAn3, HUMAnN3), 1H-NMR fecal metabolomics, ELISAs/Luminex, immunohistology for Iba-1, complement C3, and RPE65, retinal cytokine array, and Y-maze/novel object recognition were used. Analyses included linear mixed models, PERMANOVA/dbRDA, PLS-DA, and Kruskal–Wallis tests.
  • Sample sizes included groups of seven mice sub-housed as three or four; Iba-1 counts n = 5–7 mice/group; retinal staining n = 5 mice/group; retinal cytokine array n = 8 mice/group; behavior n = 10 aged FMT, n = 10 aged control, n = 11 young baseline.

Limitations

  • Stated: the old (18-month) group had inter-individual variation and did not form a discrete cluster, so further metagenomic analysis focused on young and aged mice; limited availability of 24-month mice meant only heterochronic FMT and no-transfer controls were possible for that age group.
  • Stated: by 18 days post-FMT, transplanted microbiota more closely resembled baseline pre-antibiotic profiles (Procrustes correlation = 25%, P = .05), raising questions about long-term persistence; behavioral tests showed no significant improvement; procedures were optimized for the bacterial fraction, so fungal, viral, and archaeal contributions cannot be excluded; antibiotics may penetrate the blood–brain barrier and theoretically affect microglial reactivity; and it is difficult to distinguish changes in microglial cell number from changes in Iba-1 expression.
  • Evident from design: the endpoint was short-term (18 days), no germ-free or single-species colonization experiments were performed, and extrapolation to elderly humans would require comparable FMT studies.

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

Integrity signals

Registry

Crossref · 10.1186/s40168-022-01243-w

Cites

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Statistics

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Claims the paper makes

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  • Findingown data

    Transfer of aged donor microbiota into young mice promotes loss of key functional protein in the eye.

    “and promotes loss of key functional protein in the eye”
    Quote in the paperSubstantial claim
  • Findingown data

    Transfer of young donor microbiota reverses detrimental effects of aged donor microbiota in aged mice.

    “Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota.”
    • Also stated in: § Background · plain
      “age-associated inflammatory changes were reversed in aged mice by transfer of young donor microbiota”
    Quote in the paperSubstantial claim
  • Findingown data

    Effects of aged donor microbiota transfer into young mice are coincident with increased intestinal barrier permeability.

    “effects which are coincident with increased intestinal barrier permeability”
    Quote in the paperSubstantial claim
  • Findingown data

    FMT between young and aged mice successfully transfers microbiota composition profiles and key species enriched in young or aged mice.

    “We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice”
    • Also stated in: § Background · plain
      “We show that FMT from between young and aged mice replaced the recipient microbiota composition with a composition resembling the donor, enriched for particular bacterial species”
    Quote in the paperSubstantial claim
  • Findingown data

    Transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation.

    “The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation”
    Quote in the paperSubstantial claim
  • May combine two claims. 43
  • Classified as probably not a substantial claim. 38

  • May combine two claims.

    Findingown data

    FMT modulates the resulting metabolic pathway profiles and alters the metabolic potential of the resulting gut microbial composition.

    “and that FMT modulates resulting metabolic pathway profiles”
    • Also stated in: § Background · plain
      “and altered the metabolic potential of the resulting gut microbial composition”
    Quote in the paperSubstantial claim

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

    Findingown data

    IL-12, IL-17, IL-1β, and IL-27 were not above the assay threshold of detection in any group.

    “Our cytokine analysis also included IL-12, IL-17, IL-1β, and IL-27, but none of these was above the assay threshold of detection in any group”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    FMT induced significant alterations in the fecal microbiota of recipients (permutational ANOVA on dbRDA F = 55.8, df = 3, P < .01) with experimental time point accounting for 50% of the data variance (R2adj = 50%).

    “The FMT induced significant alterations in the fecal microbiota of recipients (Fig. 5C, D, Figs. S7 and S8, permutational ANOVA on dbRDA F = 55.8, df = 3, P < .01) with experimental time point accounting for 50% of the data variance (R2adj = 50%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transfer of aged donor microbiota into young mice dramatically altered the recipients' fecal microbiota composition (pairwise PERMANOVA P = .01, after BH correction) and resulted in a microbiota profile resembling that of aged mice at baseline.

    “Transfer of aged donor microbiota into young mice dramatically altered the recipients’ fecal microbiota composition (pairwise PERMANOVA P = .01, after BH correction) and resulted in a microbiota profile resembling that of aged mice at baseline”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In aged mice receiving young donor microbiota, the altered profile was distinct from that of young baseline mice, with the observed shifts following those of young mice transplanted with a young donor microbiota.

    “In this case, the altered profile was distinct from that of young baseline mice, with the observed shifts following those of young mice transplanted with a young donor microbiota”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The young (3 months) and aged (24 months) groups formed separate clusters in the ordination; the old (18 months) group did not form a separate cluster and shared features with both young and aged mice.

    “The young (3 months) and aged (24 months) groups formed separate clusters in the ordination; however, the old (18 months) group did not form a separate cluster and shared features with both young and aged mice”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The old (18 months) group had significant inter-individual variation in microbiota composition and did not form a discrete cluster in the ordination.

    “The old (18 months) group of animals had significant inter-individual variation in the microbiota composition and did not form a discrete cluster in the ordination”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The most significantly enriched species in aged mice receiving young donor microbiota (Bifidobacterium animalis, Eubacterium sp. 14-2, A. muciniphila, and Clostridium cocleatum) were also enriched in young mice recolonized with young donor microbiota, although others (Parabacteroides distasonis, Lachnospiraceae 28-4, Clostridium ASF356) were only enriched in the aged recipients.

    “The most significantly enriched species in aged mice receiving young donor microbiota (Bifidobacterium animalis, Eubacterium sp. 14–2, A. muciniphila, and Clostridium cocleatum) were also enriched in young mice recolonized with young donor microbiota, although others (Parabacteroides distasonis, Lachnospiraceae 28–4, Clostridium ASF356) were only enriched in the aged recipients”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    dbRDA showed high inter-individual variation with only 24% of variance explained by treatment groupings (4% of variance was explained by cage groupings).

    “Distance-based redundancy analysis (dbRDA) showed high inter-individual variation with only 24% of variance explained by treatment groupings (4% of variance was explained by cage groupings).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Changes in the aging intestinal microbiota can adversely affect host metabolism and immunity and are associated with development of cardiovascular, autoimmune, metabolic, and neurodegenerative disorders.

    “These changes can adversely affect the host metabolism and immunity [25–27, 40, 64, 86, 110, 112, 118] and are associated with the development of cardiovascular, autoimmune, metabolic, and neurodegenerative disorders [17, 90, 122, 132].”
    Quote in the paperSubstantial claim0 of 10 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Young flies fed homogenates from aged flies had significantly decreased lifespan and increased incidence of intestinal barrier dysfunction compared with flies fed homogenates from young animals.

    “Young flies fed homogenates from aged flies had significantly decreased lifespan and increased incidence of intestinal barrier dysfunction, compared with flies fed homogenates from young animals [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Clark RI, Salazar A, Yamada R, Fitz-Gibbon S, Morselli M, Alcaraz J, et al. Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep. 2015;12(10):1656–67. https://doi.org/10.1016/j.celrep.2015.08.004. source

      Not checked in the free run.

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

    Premisecitation

    Altered microbial composition has been associated with neovascularization and immune cell activation in retinal disease models.

    “The altered microbial composition has also been associated with neovascularization and immune cell activation in retinal disease models [4, 50, 99].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Declining immune cell function and immunosenescence, together with increased epithelial barrier permeability, promotes elevated systemic inflammation termed inflammaging, contributing to functional decline in the intestine and CNS in old age.

    “This, together with declining immune cell function and immunosenescence, promotes a state of elevated systemic inflammation termed “inflammaging” [39, 40, 118], contributing to the functional decline in the intestine and CNS in old age [10, 13, 48].”
    Quote in the paperSubstantial claim0 of 6 sources checked
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      Not checked in the free run.

    • cites [118] Thevaranjan N, Puchta A, Schulz C, Avee Naidoo JC, Szamosi CP, Verschoor DL, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21(4):455–466.e4. https://doi.org/10.1016/j.chom.2017.03.002. source

      Not checked in the free run.

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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand S, Rodríguez F, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med. 2019;25(8):1234–42. https://doi.org/10.1038/s41591-019-0504-5. source

      Not checked in the free run.

    • cites [61] Kundu P, Lee HU, Garcia-Perez I, Tay EXY, Kim H, Faylon LE, et al. Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice. Sci Transl Med. 2019;11(518). https://doi.org/10.1126/scitranslmed.aau4760. source

      Not checked in the free run.

    • cites [112] Stebegg M, Silva-Cayetano A, Innocentin S, Jenkins TP, Cantacessi C, Gilbert C, et al. Heterochronic faecal transplantation boosts gut germinal centres in aged mice. Nat Commun. 2019;10(1). https://doi.org/10.1038/s41467-019-10430-7. source

      Not checked in the free run.

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

    Premisecitation

    In the short-lived African killifish, transfer of young donor microbiota to aged individuals ameliorated behavioral decline and extended lifespan.

    “In the short-lived African killifish, the transfer of young donor microbiota to aged individuals ameliorated behavioral decline and extended lifespan [110].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Smith P, Willemsen D, Popkes M, Metge F, Gandiwa E, Reichard M, et al. Regulation of life span by the gut microbiota in the short-lived African turquoise killifish. ELife. 2017;6(August). https://doi.org/10.7554/eLife.27014. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-related macular degeneration is associated with chronic inflammation and altered fecal microbial metabolite profiles.

    “Age-related macular degeneration (AMD) is associated with chronic inflammation [29, 65] and altered fecal microbial metabolite profiles [100].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Combadière C, Feumi C, Raoul W, Keller N, Rodéro M, Pézard A, et al. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Investig. 2007;117(10):2920–8. https://doi.org/10.1172/JCI31692. source

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    • cites [65] Langmann T. Microglia activation in retinal degeneration. J Leukoc Biol. 2007;81(6):1345–51. https://doi.org/10.1189/jlb.0207114. source

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    • cites [100] Rowan S, Taylor A. The role of microbiota in retinal disease. Adv Exp Med Biol. 2018;1074:429–35. https://doi.org/10.1007/978-3-319-75402-4_53. source

      Not checked in the free run.

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

    Study design and conductown data

    For differential abundance analyses, linear mixed models and transformations were selected only when residuals were roughly random and normally distributed.

    “We selected all lmm-transformation combinations that had roughly random and normally distributed residuals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The data support a causal role for the gut microbiota-retina axis in regulating retinal inflammation and age-related cytokine signaling, along with expression of a key functional visual protein (RPE65).

    “Together, our data support a causal role for the gut microbiota–retina axis in regulating retinal inflammation and age-related cytokine signaling, along with the expression of a key functional visual protein (RPE65).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    One sample from the aged Pre-Abx group was removed as an outlier in the ordination.

    “One sample from the aged Pre-Abx group was removed as it clearly represented an outlier in the ordination.”
    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 conductnone given

    Animals not achieving a cumulative 10 s with the familiar object or total object exploration were excluded from behavioral analysis.

    “Animals not achieving 10 s were excluded from the analysis. Similarly, animals not achieving a cumulative 10 s with the familiar object were excluded.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The aged microbiota promotes breakdown of epithelial barrier integrity, translocation of bacterial products, and elevated serum levels of pro-inflammatory cytokines, all of which were reversed by transplantation with young donor microbiota.

    “Together, these data demonstrate that the aged microbiota promotes the breakdown of epithelial barrier integrity, the translocation of bacterial products, and the elevated serum levels of pro-inflammatory cytokines, all of which were reversed by transplantation with young donor microbiota.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Mice were randomly re-assigned to experimental cages 2 weeks prior to the start of the experiment.

    “Groups of young (3 months), old (18 months), or aged (24 months) male mice were randomly re-assigned to experimental cages 2 weeks prior to the start of the experiment.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All experiments were approved by the UEA Animal Welfare and Ethical Review Body.

    “All experiments were approved by the UEA Animal Welfare and Ethical Review Body”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Chronic inflammation and microglial overactivation in the brain contribute to neurodegenerative pathology, which in turn can lead to cognitive decline.

    “Chronic inflammation and microglial overactivation in the brain contribute to neurodegenerative pathology, which in turn can lead to cognitive decline”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Heneka MT. Microglia take Centre stage in neurodegenerative disease. Nat Rev Immunol. 2019;19(2):79–80. https://doi.org/10.1038/s41577-018-0112-5. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The study used mice of three different ages from the same colony, bred and maintained in the same environment for their entire lifespan, to avoid confounding vendor influences on the microbiota.

    “To avoid confounding impacts of vendor influences on the microbiota of different age groups, our study used mice of three different ages from the same colony, which were all bred and maintained in the same environment for their entire lifespan.”
    • Also stated in: § Experimental model details · plain
      “Male C57BL/6J mice aged 3, 18, or 24 months were used in this study and were all bred and housed in the same room.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    Fecal pellets, blood, and tissue collections and FMT interventions were performed at the same time of day across all cages to account for circadian rhythm variability.

    “Fecal pellets, blood, and tissue collections and FMT interventions were all performed at the same time of day across all cages to account for circadian rhythm variability in feeding and microbiota/metabolite composition.”
    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

    The study accounted for potential inter-cage variability by randomizing housing before FMT and factoring inter-cage variation into statistical analyses of the metagenomic data.

    “we accounted for potential inter-cage variability, both before FMT by randomizing housing in the weeks prior to the start of the experiment and post-FMT by factoring inter-cage variation into our statistical analyses of the metagenomic data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The intestinal microbiota strongly influences microglia activation and heterochronic FMT modulates levels of Iba-1+ microglia, increasing them in young adult mice transplanted with an aged donor microbiota and reducing them in the CNS of aged animals receiving a young donor microbiota.

    “Collectively, these data demonstrate that the intestinal microbiota strongly influences microglia activation and that heterochronic FMT modulates levels of Iba-1+ microglia, increasing the levels in young adult mice transplanted with an aged donor microbiota and reducing them in the CNS of aged animals receiving a young donor microbiota.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The analyses accounted for potential cage grouping or housing effects.

    “Importantly, we also accounted for any potential cage grouping or housing effects in our analyses.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    The increase in Bifidobacterium shunt pathway is in keeping with the increase in proportional abundance of Bifidobacterium spp. in this group.

    “the latter in keeping with the increase in proportional abundance of Bifidobacterium spp. in this group”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The adaptation over time did not limit the impact of the transplanted microbiota on tissues, in which changes in key functional cell types and biomarkers of health were apparent at 18 days post-FMT, the point of tissue collection.

    “This adaptation over time however did not limit the impact of the transplanted microbiota on tissues, in which changes in key functional cell types and biomarkers of health were apparent at 18 days post-FMT, the point of tissue collection.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In mammalian models, altered microglial morphology and function, and elevated expression of microglial activation markers are seen with advancing age.

    “In mammalian models, altered microglial morphology and function, and elevated expression of microglial activation markers are seen with advancing age [82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Mosher KI, Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol. 2014. https://doi.org/10.1016/j.bcp.2014.01.008. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The data support the suggestion that altered gut microbiota in old age contributes to intestinal and systemic inflammation, and so may contribute to driving inflammatory pathologies of aged organs.

    “Our data support the suggestion that altered gut microbiota in old age contributes to intestinal and systemic inflammation, and so may contribute to driving inflammatory pathologies of aged organs.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Prevotella species associated with detrimental impacts on intestinal barrier integrity are enriched in IBS patients and in models of intestinal inflammation and may promote inflammatory arthritis.

    “Prevotella species associated with detrimental impacts on intestinal barrier integrity are enriched in IBS patients and in models of intestinal inflammation [52, 113] and may promote inflammatory arthritis [3, 104, 126].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [52] Iljazovic A, Roy U, Gálvez EJCC, Lesker TR, Zhao B, Gronow A, et al. Perturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation. Mucosal Immunol. 2020;May:1–12. https://doi.org/10.1038/s41385-020-0296-4. source

      Not checked in the free run.

    • cites [113] Su T, Liu R, Lee A, Long Y, Lijun D, Lai S, et al. Altered intestinal microbiota with increased abundance of Prevotella is associated with high risk of diarrhea-predominant irritable bowel syndrome. Gastroenterol Res Pract. 2018;2018. https://doi.org/10.1155/2018/6961783. source

      Not checked in the free run.

    • cites [3] Alpizar-Rodriguez D, Lesker TR, Gronow A, Gilbert B, Raemy E, Lamacchia C, et al. Prevotella copri in individuals at risk for rheumatoid arthritis. Ann Rheum Dis. 2019;78(5):590–3. https://doi.org/10.1136/annrheumdis-2018-214514. source

      Not checked in the free run.

    • cites [104] Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. ELife. 2013;2013(2):1202. https://doi.org/10.7554/eLife.01202.001. source

      Not checked in the free run.

    • cites [126] Wells PM, Adebayo AS, Bowyer RCE, Freidin MB, Finckh A, Strowig T, et al. Associations between gut microbiota and genetic risk for rheumatoid arthritis in the absence of disease: a cross-sectional study. Lancet Rheumatol. 2020;2(7):e418–27. https://doi.org/10.1016/S2665-9913(20)30064-3. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Heterochronic FMT resulted in significant shifts in lipid and vitamin metabolism pathways, increasing their proportional abundance in aged mice transplanted with the microbiota of young donors and decreasing their abundance in young mice receiving aged donor microbiota.

    “In summary, heterochronic FMT resulted in significant shifts in lipid and vitamin metabolism pathways, increasing their proportional abundance in aged mice transplanted with the microbiota of young donors and decreasing their abundance in young mice receiving aged donor microbiota.”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    The reduction in methanogenesis is suggestive of some impact on gut archaea.

    “There was also a reduction in methanogenesis suggestive of some impact on gut archaea”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Aged donor microbiota transfer to young mice drives inflammation and loss of integrity in the intestinal epithelial barrier, elevated systemic and tissue markers of inflammaging, and upregulated inflammation in the retina and brain.

    “We show that aged donor microbiota transfer to young mice drives inflammation and loss of integrity in the intestinal epithelial barrier elevated systemic and tissue markers of inflammaging, and upregulated inflammation in the retina and brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066–71. https://doi.org/10.1073/pnas.1219451110. source

      Not checked in the free run.

    • cites [73] van der Lugt B, van Beek AA, Aalvink S, Meijer B, Sovran B, Vermeij WP, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Immun Ageing. 2019;16:6. https://doi.org/10.1186/s12979-019-0145-z. source

      Not checked in the free run.

    • cites [8] Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand S, Rodríguez F, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med. 2019;25(8):1234–42. https://doi.org/10.1038/s41591-019-0504-5. source

      Not checked in the free run.

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

    Premisecitation

    Tauro-conjugated bile acids, acetate, putrescine, and ornithine are metabolites previously associated with beneficial effects in aging.

    “metabolites previously associated with beneficial effects in aging [74, 94]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] Ma J, Hong Y, Zheng N, Xie G, Yuanzhi Lyu YG, Xi C, et al. Gut microbiota remodeling reverses aging-associated inflammation and dysregulation of systemic bile acid homeostasis in mice sex-specifically. Gut Microbes. 2020;11(5):1450–74. https://doi.org/10.1080/19490976.2020.1763770. source

      Not checked in the free run.

    • cites [94] Ramos-Molina B, Queipo-Ortuño MI, Lambertos A, Tinahones FJ, Peñafiel R. Dietary and gut microbiota polyamines in obesity- and age-related diseases. Front Nutr. 2019. https://doi.org/10.3389/fnut.2019.00024. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The transferred aged microbiota and resulting recipient microbiota composition were distinguished by enrichment for Prevotella, Lacnospiraceae, and Facecalibaculum species and depletion of long-chain fatty acid synthesis.

    “The transferred aged microbiota and resulting recipient microbiota composition were distinguished by enrichment for Prevotella, Lacnospiraceae, and Facecalibaculum species and depletion of long-chain fatty acid synthesis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A. muciniphila is depleted in models of inflammation and metabolic disorders and displays probiotic potential, by regulating mucus production and epithelial barrier integrity and by reducing serum LPS.

    “Furthermore, A. muciniphila is depleted in models of inflammation and metabolic disorders and displays probiotic potential, by regulating mucus production and epithelial barrier integrity and by reducing serum LPS [38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066–71. https://doi.org/10.1073/pnas.1219451110. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Transplanting an aged donor microbiota into young recipients results in elevated intestinal concentrations of TNF, and elevated surrogate biomarkers of altered epithelial barrier permeability (I-FABP, LBP), supporting a driving role for the age-associated microbiota in the breakdown of barrier integrity and promotion of systemic inflammatory responses.

    “Our data show that transplanting an aged donor microbiota into young recipients results in elevated intestinal concentrations of TNF, and elevated surrogate biomarkers of altered epithelial barrier permeability (I-FABP, LBP), supporting a driving role for the age-associated microbiota in the breakdown of barrier integrity and promotion of systemic inflammatory responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Heterochronic FMT resulted in significant alteration of the recipient microbiota structure, enriching for bacterial species distinctive of the donor age group, and both donor and recipient were influential in the resulting microbiota composition.

    “Collectively, our results showed that heterochronic FMT resulted in significant alteration of the recipient microbiota structure, enriching for bacterial species distinctive of the donor age group, and that both donor and recipient were influential in the resulting microbiota composition.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Some species within the Eubacteriaceae family are currently thought to modulate cholesterol and bile acid metabolism and are considered potential therapeutics.

    “However, some species are currently thought to modulate cholesterol and bile acid metabolism and are considered potential therapeutics [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Ghosh TS, Das M, Jeffery IB, O’Toole PW, O’Toole PW. Adjusting for age improves identification of gut microbiome alterations in multiple diseases. ELife. 2020;9(March). https://doi.org/10.7554/eLife.50240. source

      Not checked in the free run.

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

    Premisecitation

    B. animalis is a probiotic species positively associated with longevity in mice and negatively correlated with inflammation and human obesity.

    “B. animalis, a probiotic species positively associated with longevity in mice [78] and negatively correlated with inflammation and human obesity [81]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Matsumoto M, Kurihara S, Kibe R, Ashida H, Benno Y. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS One. 2011;6(8). https://doi.org/10.1371/journal.pone.0023652. source

      Not checked in the free run.

    • cites [81] Million M, Angelakis E, Maraninchi M, Henry M, Giorgi R, Valero R, et al. Correlation between body mass index and gut concentrations of lactobacillus reuteri, Bifidobacterium animalis, Methanobrevibacter smithii and Escherichia coli. Int J Obes. 2013;37(11):1460–6. https://doi.org/10.1038/ijo.2013.20. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] van der Lugt B, van Beek AA, Aalvink S, Meijer B, Sovran B, Vermeij WP, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Immun Ageing. 2019;16:6. https://doi.org/10.1186/s12979-019-0145-z. source

      Not checked in the free run.

    • cites [8] Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand S, Rodríguez F, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med. 2019;25(8):1234–42. https://doi.org/10.1038/s41591-019-0504-5. source

      Not checked in the free run.

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

    Study design and conductreasoning

    The study's procedures were optimized to assess the bacterial fraction of the intestinal microbiota, and as such, the study cannot exclude potential contributions from other microbial constituents in the effects described.

    “Our procedures were optimized to assess the bacterial fraction of the intestinal microbiota, and as such, we cannot exclude potential contributions from other microbial constituents in the effects we describe.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The aged donor microbiota engraftment was strongest in the young recipients, while the transfer of young donor microbiota was more susceptible to modification by the FMT procedure, the recipient intestinal environment, or both.

    “This suggests that the aged donor microbiota engraftment was strongest in the young recipients, while the transfer of young donor microbiota was more susceptible to modification by the influence of the FMT procedure, or the recipient intestinal environment, or both.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The observation that microbiota from aged donors exacerbates paracellular permeability and inflammation in germ-free mice is in agreement with the study's findings and interpretation.

    “In agreement with our findings and interpretation is the observation that the microbiota from aged donors exacerbates paracellular permeability and inflammation in germ-free mice [40, 118].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Fransen F, van Beek AA, Borghuis T, El Aidy S, Hugenholtz F, van der Gaast-de Jongh C, et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. 2017;8(NOV):1385. https://doi.org/10.3389/fimmu.2017.01385. source

      Not checked in the free run.

    • cites [118] Thevaranjan N, Puchta A, Schulz C, Avee Naidoo JC, Szamosi CP, Verschoor DL, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21(4):455–466.e4. https://doi.org/10.1016/j.chom.2017.03.002. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The reversal of these effects in aged recipients of young donor microbiota supports the hypothesis, suggesting a positive impact of the microbiota of young mice on barrier integrity, or that removal of age-associated microbiota allows for barrier recovery.

    “That these effects are reversed in aged recipients of young donor microbiota supports this hypothesis, suggesting a positive impact of the microbiota of young mice on barrier integrity, or that removal of age-associated microbiota allows for barrier recovery.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Transfer of aged mice with young donor microbiota, which was distinguished by enrichment Bifidobacteria, Eubacteria, and Akkermansia species, and enrichment for B vitamin biosynthesis and lipid synthesis pathways, reversed inflammatory changes in the aged gut, brain, and retina.

    “Conversely, transfer of aged mice with young donor microbiota, which was distinguished by enrichment Bifidobacteria, Eubacteria, and Akkermansia species, and enrichment for B vitamin biosynthesis and lipid synthesis pathways reversed inflammatory changes in the aged gut, brain, and retina.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    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”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [8] Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand S, Rodríguez F, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med. 2019;25(8):1234–42. https://doi.org/10.1038/s41591-019-0504-5. source

      Not checked in the free run.

    • cites [38] Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066–71. https://doi.org/10.1073/pnas.1219451110. source

      Not checked in the free run.

    • cites [43] Ghosh TS, Das M, Jeffery IB, O’Toole PW, O’Toole PW. Adjusting for age improves identification of gut microbiome alterations in multiple diseases. ELife. 2020;9(March). https://doi.org/10.7554/eLife.50240. source

      Not checked in the free run.

    • cites [73] van der Lugt B, van Beek AA, Aalvink S, Meijer B, Sovran B, Vermeij WP, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Immun Ageing. 2019;16:6. https://doi.org/10.1186/s12979-019-0145-z. source

      Not checked in the free run.

    • cites [78] Matsumoto M, Kurihara S, Kibe R, Ashida H, Benno Y. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS One. 2011;6(8). https://doi.org/10.1371/journal.pone.0023652. source

      Not checked in the free run.

    • cites [81] Million M, Angelakis E, Maraninchi M, Henry M, Giorgi R, Valero R, et al. Correlation between body mass index and gut concentrations of lactobacillus reuteri, Bifidobacterium animalis, Methanobrevibacter smithii and Escherichia coli. Int J Obes. 2013;37(11):1460–6. https://doi.org/10.1038/ijo.2013.20. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CNS microglial populations constantly and rapidly remodel, making it difficult to discriminate between changes in cell number versus changes in Iba-1 expression in the setting of FMT.

    “CNS microglial populations constantly and rapidly remodel [6], making it difficult to discriminate between changes in cell number versus changes in Iba-1 expression in the setting of FMT.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 2017;18(2):391–405. https://doi.org/10.1016/j.celrep.2016.12.041. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCL11, CXCL11, and IL-1β are elevated in aged mouse retinae.

    “Transfer of young donor microbiota results in a decrease in aged mice of cytokines involved in inflammatory immune cell recruitment and pro-inflammatory signaling, including CCL11 (eotaxin), CXCL11, and IL-1β [23, 62, 84], all of which are elevated in aged mouse retinae [108].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Shinhmar H, Hogg C, Jeffery G. Long wavelength light that improves aged mitochondrial function selectively increases cytokine expression in serum and the retina. BioRxiv. 2021:10.468030. https://doi.org/10.1101/2021.11.10.468030. source

      Not checked in the free run.

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

    Premisecitation

    Deficiencies in B vitamins are implicated in retinitis pigmentosa and glaucoma.

    “Deficiencies in B vitamins are implicated in retinitis pigmentosa and glaucoma, for which improved outcomes can be achieved by dietary supplementation [24, 114].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Chou T-H, Romano GL, Amato R, Porciatti V. Nicotinamide-rich diet in DBA/2J mice preserves retinal ganglion cell metabolic function as assessed by PERG adaptation to flicker. Nutrients. 2020;12(7):1910. https://doi.org/10.3390/nu12071910. source

      Not checked in the free run.

    • cites [114] Sugano E, Tabata K, Takezawa T, Shiraiwa R, Muraoka H, Metoki T, et al. N-methyl-N-nitrosourea-induced photoreceptor degeneration is inhibited by nicotinamide via the blockade of upstream events before the phosphorylation of signalling proteins. Biomed Res Int. 2019;2019. https://doi.org/10.1155/2019/3238719. source

      Not checked in the free run.

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

    Premisecitation

    There is some evidence for improved cognition with probiotic use in those with pre-existing cognitive impairment.

    “There is some evidence for improved cognition with probiotic use in those with pre-existing cognitive impairment [31]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Coutts L, Ibrahim K, Tan QY, Lim SER, Cox NJ, Roberts HC. Can probiotics, prebiotics and synbiotics improve functional outcomes for older people: a systematic review. Eur Geriatr Med. 2020. https://doi.org/10.1007/s41999-020-00396-x Springer Science and Business Media Deutschland GmbH. source

      Not checked in the free run.

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

    Premisecitation

    Polymorphisms in human complement regulatory factor H (CFH) predispose individuals to AMD.

    “Polymorphisms in human complement regulatory factor H (CFH) predispose individuals to AMD [35, 46, 59]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–4. https://doi.org/10.1126/science.1110189. source

      Not checked in the free run.

    • cites [46] Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102(20):7227–32. https://doi.org/10.1073/pnas.0501536102. source

      Not checked in the free run.

    • cites [59] Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–9. https://doi.org/10.1126/science.1109557. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of intestinal barrier integrity and elevated circulating pro-inflammatory cytokine concentrations are linked with the polarization of CNS microglia toward a pro-inflammatory phenotype and promote neurodegenerative disease.

    “Loss of intestinal barrier integrity and elevated circulating pro-inflammatory cytokine concentrations are linked with the polarization of CNS microglia toward a pro-inflammatory phenotype [11, 73, 109] and promote neurodegenerative disease [10, 13, 48].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [11] van Beek AA, Van Bossche J, Mastroberardino PG, de Winther MPJ, Leenen PJM. Metabolic alterations in aging macrophages: ingredients for inflammaging? Trends Immunol. 2019a. https://doi.org/10.1016/j.it.2018.12.007. source

      Not checked in the free run.

    • cites [73] van der Lugt B, van Beek AA, Aalvink S, Meijer B, Sovran B, Vermeij WP, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Immun Ageing. 2019;16:6. https://doi.org/10.1186/s12979-019-0145-z. source

      Not checked in the free run.

    • cites [109] Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia. 2007;55(4):412–24. https://doi.org/10.1002/glia.20468. source

      Not checked in the free run.

    • cites [10] Becker L, Nguyen L, Gill J, Kulkarni S, Pasricha PJ, Habtezion A. Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut. 2018;67(5):827–36. https://doi.org/10.1136/gutjnl-2016-312940. source

      Not checked in the free run.

    • cites [13] Bevan-Jones WR, Cope TE, Simon Jones P, Kaalund SS, Passamonti L, Allinson K, et al. Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain J Neurol. 2020;143(3):1010–26. https://doi.org/10.1093/brain/awaa033. source

      Not checked in the free run.

    • cites [48] Heneka MT. Microglia take Centre stage in neurodegenerative disease. Nat Rev Immunol. 2019;19(2):79–80. https://doi.org/10.1038/s41577-018-0112-5. source

      Not checked in the free run.

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

    Premisecitation

    Upregulation of CXCL11 is seen in RPE cells adjacent to drusen deposits in AMD.

    “Upregulation of CXCL11 is seen in RPE cells adjacent to drusen deposits in AMD [62], and its secretion can be triggered by proinflammatory cytokines including TNF and IL-1β.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Kutty RK, Samuel W, Abay R, Cherukuri A, Nagineni CN, Duncan T, et al. Resveratrol attenuates CXCL11 expression induced by proinflammatory cytokines in retinal pigment epithelial cells. Cytokine. 2015;74(2):335. https://doi.org/10.1016/J.CYTO.2015.03.016. source

      Not checked in the free run.

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

    Premisecitation

    Association studies have linked intestinal microbial products with the development and progression of age-related choroidal neovascularization (CNV) and age-related macular degeneration (AMD).

    “Association studies have linked intestinal microbial products with the development and progression of age-related choroidal neovascularization (CNV) and age-related macular degeneration (AMD) [4, 131, 133].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Andriessen EMMAMA, Wilson AM, Mawambo G, Dejda A, Miloudi K, Sennlaub F, et al. Gut microbiota influences pathological angiogenesis in obesity-driven choroidal neovascularization. EMBO Mol Med. 2016;8(12):1366–79. https://doi.org/10.15252/emmm.201606531. source

      Not checked in the free run.

    • cites [131] Zinkernagel MS, Zysset-Burri DC, Keller I, Berger LE, Leichtle AB, Largiadèr CR, et al. Association of the intestinal microbiome with the development of neovascular age-related macular degeneration. Sci Rep. 2017;7(1):1–9. https://doi.org/10.1038/srep40826. source

      Not checked in the free run.

    • cites [133] Zysset-Burri DC, Keller I, Berger LE, Largiadèr CR, Wittwer M, Wolf S, et al. Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration. Npj Genom Med. 2020;5(1):34. https://doi.org/10.1038/s41525-020-00141-0. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The antibiotics used in this study are, to varying degrees, able to penetrate the blood-brain barrier and cerebrospinal fluid.

    “The antibiotics used in this study are, to varying degrees, able to penetrate the blood–brain barrier and cerebrospinal fluid.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    RPE65 is vital for maintaining normal photoreceptor function via trans-retinol conversion.

    “RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion; mutations or loss of function are associated with retinitis pigmentosa and are implicated in AMD [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Cai X, Conley SM, Naash MI. RPE65: role in the visual cycle, human retinal disease, and gene therapy. Ophthalmic Genet. 2009. https://doi.org/10.1080/13816810802626399 NIH Public Access. source

      Not checked in the free run.

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

    Premisecitation

    CXCL11 secretion can be triggered by proinflammatory cytokines including TNF and IL-1β.

    “Upregulation of CXCL11 is seen in RPE cells adjacent to drusen deposits in AMD [62], and its secretion can be triggered by proinflammatory cytokines including TNF and IL-1β.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Kutty RK, Samuel W, Abay R, Cherukuri A, Nagineni CN, Duncan T, et al. Resveratrol attenuates CXCL11 expression induced by proinflammatory cytokines in retinal pigment epithelial cells. Cytokine. 2015;74(2):335. https://doi.org/10.1016/J.CYTO.2015.03.016. source

      Not checked in the free run.

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

    Premisecitation

    Evidence for unsaturated, mono-, and poly-unsaturated fatty acids impacting microglial function comes from both in vitro and in vivo studies.

    “Evidence for unsaturated, mono-, and poly-unsaturated fatty acids impacting microglial function comes from both in vitro and in vivo studies [70].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Leyrolle Q, Layé S, Nadjar A. Direct and indirect effects of lipids on microglia function. Neurosci Lett. 2019. https://doi.org/10.1016/j.neulet.2019.134348 Elsevier Ireland Ltd. source

      Not checked in the free run.

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

    Premisecitation

    Mutations or loss of function of RPE65 are associated with retinitis pigmentosa and are implicated in AMD.

    “RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion; mutations or loss of function are associated with retinitis pigmentosa and are implicated in AMD [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Cai X, Conley SM, Naash MI. RPE65: role in the visual cycle, human retinal disease, and gene therapy. Ophthalmic Genet. 2009. https://doi.org/10.1080/13816810802626399 NIH Public Access. source

      Not checked in the free run.

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

    Premisecitation

    CFH deficiency in mice causes retinal abnormalities, including accumulation of complement C3, resulting in significant visual dysfunction.

    “CFH deficiency in mice causes retinal abnormalities, including accumulation of complement C3, resulting in significant visual dysfunction [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Coffey PJ, Gias C, McDermott CJ, Lundh P, Pickering MC, Sethi C, et al. Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proc Natl Acad Sci U S A. 2007;104(42):16651–6. https://doi.org/10.1073/pnas.0705079104. source

      Not checked in the free run.

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

    Premisecitation

    Retinal degeneration induces upregulation of a cytokine and chemokine production whose expression is coordinated by Müller cells, microglia, and RPE.

    “Retinal degeneration induces upregulation of a cytokine and chemokine production whose expression is coordinated by Müller cells, microglia, and RPE [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Rutar, Matt, Riccardo Natoli, RX Chia, Krisztina Valter, and Jan M Provis. 2015. “Chemokine-mediated inflammation in the degenerating retina is coordinated by Müller cells, activated microglia, and retinal pigment epithelium.” J Neuroinflammation 12 (1): 1–15. https://doi.org/10.1186/S12974-014-0224-1. source

      Not checked in the free run.

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

    Premisecitation

    Elevated CCL11 may contribute to driving neovascularisation in AMD via interaction with CCR3.

    “Elevated CCL11 in the plasma and cerebrospinal fluid seen in aging mice and humans are associated with declining neurogenesis, neurodegenerative disease, and cognitive decline and may contribute to driving neovascularisation in AMD via interaction with CCR3 [1, 93, 123].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Takeda A, Baffi JZ, Kleinman ME, Cho WG, Nozaki M, Yamada K, et al. CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature. 2009;460(7252):225–30. https://doi.org/10.1038/NATURE08151. source

      Not checked in the free run.

    • cites [93] Leung R, Proitsi P, Simmons A, Lunnon K, Güntert A, Kronenberg D, et al. Inflammatory proteins in plasma are associated with severity of Alzheimer’s disease. PLoS One. 2013;8(6). https://doi.org/10.1371/JOURNAL.PONE.0064971. source

      Not checked in the free run.

    • cites [123] Villeda LJ, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–6. https://doi.org/10.1038/nature10357. source

      Not checked in the free run.

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

    Premisecitation

    IL-1β is associated with the progression of retinal pathologies, including AMD.

    “In addition, IL-1β is associated with the progression of retinal pathologies, including AMD [130].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Zhao BY, Xie W, Shi X, Li F, Yang F, Sun Y, et al. Interleukin-1β level is increased in vitreous of patients with neovascular age-related macular degeneration (NAMD) and polypoidal choroidal vasculopathy (PCV). PLoS One. 2015;10(5). https://doi.org/10.1371/JOURNAL.PONE.0125150. source

      Not checked in the free run.

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

    Premisecitation

    Improved outcomes in retinitis pigmentosa and glaucoma can be achieved by dietary supplementation.

    “Deficiencies in B vitamins are implicated in retinitis pigmentosa and glaucoma, for which improved outcomes can be achieved by dietary supplementation [24, 114].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Chou T-H, Romano GL, Amato R, Porciatti V. Nicotinamide-rich diet in DBA/2J mice preserves retinal ganglion cell metabolic function as assessed by PERG adaptation to flicker. Nutrients. 2020;12(7):1910. https://doi.org/10.3390/nu12071910. source

      Not checked in the free run.

    • cites [114] Sugano E, Tabata K, Takezawa T, Shiraiwa R, Muraoka H, Metoki T, et al. N-methyl-N-nitrosourea-induced photoreceptor degeneration is inhibited by nicotinamide via the blockade of upstream events before the phosphorylation of signalling proteins. Biomed Res Int. 2019;2019. https://doi.org/10.1155/2019/3238719. source

      Not checked in the free run.

70 of 70

  • The paper relies on this without support.

    Findings in mice can be translated to humans for therapeutic benefit in later life.

    “suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life”

  • The paper relies on this without support.

    The 3-, 18-, and 24-month-old mice model human aging stages relevant to inflammaging and age-associated tissue decline.

    “we used young (3 months), old (18 months), and aged (24 months) mice”

  • The paper relies on this without support.

    During aging, the intestinal microbiota undergoes changes in community structure and function, with elderly individuals showing altered taxa proportions, increased inter-individual variability, and altered diversity.

    “During aging, the intestinal microbiota undergoes changes in the community structure and function, with samples from elderly individuals showing changes in the proportions of different taxa, increased inter-individual variability, and altered diversity.”

  • The authors state this as an assumption.

    Whether age-associated changes in the diversity, composition, or function of the gut microbiota are causal in disease etiology remains largely unknown.

    “However, whether age-associated changes in the diversity, composition, or function of the gut microbiota are causal in disease etiology remains largely unknown.”

  • The paper relies on this without support.

    Altered intestinal microbiota composition in old age is associated with chronic low-grade inflammation and increasing susceptibility to age-associated chronic diseases.

    “Altered intestinal microbiota composition in old age is associated with chronic low-grade inflammation and increasing susceptibility to age-associated chronic diseases.”

  • The paper relies on this without support.

    Inflammaging and pathological inflammation in the CNS have been associated with loss of intestinal epithelial barrier integrity, so-called leaky gut.

    “Inflammaging and pathological inflammation in the CNS have been associated with loss of intestinal epithelial barrier integrity, so-called leaky gut.”

  • The authors state this as an assumption.

    It is unclear whether age and absolute numbers of activated microglia in different regions of the brain are positively associated.

    “However, it is unclear whether age and absolute numbers of activated microglia in different regions of the brain are positively associated.”
7 of 7

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?

  • FMT from young mice to aged mice restored intestinal epithelial barrier integrity and attenuated microglial activation in aged mice.

    “FMT from young mice to aged mice restored the intestinal epithelial barrier integrity and attenuated microglial activation in the aged mice.”

    From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [632]

  • Transplantation of gut microbiota from young mice to aged mice reverses immunosenescence and neuroinflammation and improves hippocampal neurogenesis, behaviour and cognition.

    “Transplantation of the gut microbiota from young mice to aged mice reverses immunosenescence and neuroinflammation and improves hippocampal neurogenesis, behaviour and cognition.75,459”

    From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [459]

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.

  • Discussion claims a young-mouse TNF increase despite a nonsignificant result

    Major

    The results report no significant intestinal TNF difference for young mice receiving aged microbiota, but the discussion presents elevated intestinal TNF as an effect of that transfer.

  • Aged donor pool conflicts with the stated two-mice-per-cage rule

    Minor

    The method says fecal material was pooled from two mice per cage for each age group, but the aged pool included all 16 mice across four cages-an average of four mice per cage.

2 of 2

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Oksanen J, Blanchet FG, Friendly M, Kindt R, Legendre P, Mcglinn D, et al. Package ‘vegan’ title community ecology package version 2.5-7; 2020.

Cited by

Sorted by citations

Related

Authors
Parker, A., Romano, S., Ansorge, R., Aboelnour, A., Le Gall, G., Savva, G. M., Pontifex, M. G., Telatin, A., Baker, D., Jones, E., Vauzour, D., Rudder, S., Blackshaw, L. A., Jeffery, G., & Carding, S. R.
Affiliations
  • Quadram Institute (GB)
  • University College London (GB)
  • University of East Anglia (GB)
Corresponding author
Parker, Aimée
ORCID
Venue
Microbiome
Publisher
Springer Science and Business Media LLC
Published
2022-04-29
Volume
10
Issue
1
Pages
68-68
ISSN
2049-2618 (ISSN-L)
DOI
10.1186/s40168-022-01243-w
PMC
PMC9063061
OpenAlex
W4225316232
Semantic Scholar
d8741fdf8834b11999b9de7067487b00b947a0c6
Cited by
368
References
129
Citations by year
2026: 90 · 2025: 91 · 2024: 96 · 2023: 66 · 2022: 25
FWCI
22.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Microbiome (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UEA Digital Repository (University of East Anglia) (acceptedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Biotechnology and Biological Sciences Research Council
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
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
fecal microbiota transplantation, aging, gut microbiota, inflammaging, gut-brain axis, gut-retina axis, retinal inflammation, neuroinflammation, intestinal permeability, cytokine signaling, neurodegeneration
MeSH terms
Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Aging, Animals, Brain, Inflammation, Mice

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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