Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J, Lapidus J, Earls JC, Zimmer A, Glusman G, Robinson M, Yurkovich JT, Kado DM, Cauley JA, Zmuda J, Lane NE, Magis AT, Lovejoy JC, Hood L, Gibbons SM, Orwoll ES, Price ND. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021 Feb;3(2):274-286. Epub 2021 Feb 18 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is a fascinating study of gut microbiome in older adulthood. While the investigators did not look at brain health or cognitive outcomes, it is interesting that they found that healthy aging was accompanied by gut microbiomes that became increasingly more unique to each person starting in middle-age.

    This type of divergence in trajectories of aging is something that is also observed in the brain. If you examine groups of older adults they start to “spread out,” with many individuals maintaining good cognitive health, while others showing more decline, and still others progressing to dementia. It would be so interesting to see whether the gut microbiome effects observed in this study track with brain health into older age in longitudinal studies.

    What we don’t know from this study is why the gut microbiome is becoming more unique in older age, particularly among the healthy older adults. Does the gut drive patterns of health and disease, or does the gut microbiome respond to age-related health threats to actually become more supportive of better outcomes? Perhaps the gut microbiomes of some individuals are more readily able to respond to the effects of aging than the gut microbiomes of others. Conversely, the results may reflect the environments and life experiences that contribute to both successful aging and gut composition.

    Additional studies, particularly those that involve longitudinal sample collection, will be needed to address these questions. Kudos to Dr. Rima Kaddurah-Daouk and colleagues for pursuing their large multisite longitudinal studies on gut microbiome, which are critically needed to better determine the link between gut, brain aging, and development of neurodegenerative disease (Alzheimer’s Gut Microbiome Project). 

    View all comments by Barbara Bendlin

  2. This study by Wilmanski et al. provides strong additional support for the idea that alterations in, distinct signatures of, and taxonomic diversity and abundance within the gut microbiome play important roles in physiological versus pathological aging, and even in survival in the oldest-old (over 80 years).

    Using three large, independent cohorts, the authors show that compositional uniqueness is associated with microbial amino acid metabolites in the plasma, including phenylalanine/tyrosine and tryptophan, which have been implicated previously in immune function, aging, and longevity. Healthy aging associated with a drift toward a more unique compositional state, including a depletion of Bacteroides. In contrast, unhealthy aging associated with a decline in the Lachnoclostridium and Rumminococace genera. The drift toward an increasingly unique gut microbiome composition started between 40 and 50 years of age at the genus level, and between 50 and 60 years at the amplicon sequence variant level, and continued to increase with every decade.

    Some of the identified taxa that positively associated with uniqueness, both beneficial (Christensenellaceae) and potentially pathogenic (Methanobrevibacter and Desulfibrio), were previously implicated in human longevity. Based on health heterogenicity, the authors could stratify MrOS study participants based on four measures: medication use, self-perceived health (excellent versus less than excellent), life-space score (LSC) (how often an individual leaves his or her room, house, or neighborhood) and walking speed. For both the LSC and walking speed, the authors compared the top tertile with the bottom two. The correlation between uniqueness and age remained significant in highly medicated (more than eight medications) healthy individuals and was independent of sex. Prescription medication use and alcohol consumption significantly associated with uniqueness but after adjusting for age, only lipid markers remained significantly associated with gut microbiome uniqueness. The direction of association indicated healthier metabolic and lipid profiles, including lower low-density lipoprotein-cholesterol, higher vitamin D and lower triglycerides, in individuals with more unique microbiomes.

    These data are consistent with increasing evidence supporting for a role for alterations in the gut microbiome in brain function. The gut microbiome can communicate with the brain and affect neurobiology and behavioral phenotypes, including stress-related behaviors, anxiety, and depression (Foster et al., 2013; Allen et al., 2017; Kelly et al., 2015; Lynch and Hsiao, 2019; Vuong et al., 2017; Sudo et al., 2004). For example, gut microbiota regulate motor impairments and neuroinflammation in an α-synuclein-based Parkinson’s disease mouse model (Sampson et al., 2016), and we have shown that the effects of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on cognitive performance may be, at least in part, mediated by the gut microbiome (Kundu et al., 2021). MPTP affected the diversity of the gut microbiome and there were significant associations between microbiome α-diversity and sensorimotor performance, as well as microbiome composition and fear learning.

    The gut microbiome might be important in Alzheimer’s disease as well (Magnusson et al., 2015). Microbiome perturbations using an antibiotic cocktail reduced Aβ pathology, astrogliosis, and microglial morphology in male mice overexpressing both human amyloid precursor protein (hAPP) with the Swedish mutation and human presenilin 1, and transplants of fecal microbiota of genotype- and age-matched male mice partially rekindled Aβ pathology and microglial morphology (Dodiya et al., 2019). 

    Our data in hAPP knock-in (KI) mice containing the Swedish and Iberian mutations (AppNL-F), or those variants and the Arctic mutation (AppNL-G-F), further support that alterations in the gut microbiome composition might contribute to AD (Kundu et al., 2021). Behavioral and cognitive performance in 6-month-old AppNL-F, AppNL-G-F, and C57BL/6J wild-type (WT) mice were associated with the gut microbiome. Genotype modulated these relationships, which were also test-dependent, as evidenced by our β diversity analysis, revealing baseline differences in the microbiome based on genotype. For example, the biodiversity of the gut microbiome negatively associated with the amount of time WT mice spent exploring a novel object, which is an indicator of object-recognition memory. However, the biodiversity within AppNL-F and AppNL-G-F mice manifested positive associations with this same measure. The composition of the gut microbiome manifested striking differences as a function of genotype, with all three genotypes eliciting distinct microbiome compositions. Moreover, the association between the composition of the microbiome and the time a mouse spent exploring a novel object differed in a genotype-dependent manner. Accordingly, the APP genotype also affected the relationship between the relative abundance of specific phylotypes in the gut and various behavioral and cognitive measures.

    These genotype-dependent associations involved members of the Lachnospiraceae and Ruminococcaceae families, which in our prior data in the MPTP PD model described above and in B6D2F1 mice exposed to simulated space radiation were linked to behavior and cognitive performance (Magnusson et al., 2015; Raber et al. 2020; Torres et al., 2018). Intriguingly, the Ruminococcaceae families also came up in the current human study. That does not mean that the direction of gut microbiome changes in humans and animal models and the direction of the relationships between gut microbiome and behavioral and cognitive performance measures or other health-related measures necessarily go in the same direction across all studies. Our mouse data indicate that the directions of these relationships are genotype-dependent. In addition, as discussed by the authors, there might be differences in aging gut dynamics in distinct human populations (for example, healthy community-dwelling elderly versus fragile long-term-care residents) and in the resilience of individuals to detrimental effects of the gut microbiome on plasma metabolites.

    Epigenetic changes in the hippocampus might be involved in mediating the effects of the gut microbiome on the brain. In a subset of female mice, we investigated whether alterations in hippocampal DNA methylation were associated with the gut microbiome. An integrated gut microbiome/hippocampal DNA methylation analysis revealed a positive relationship between amplicon sequence variants within the Lachnospiraceae family and methylation at the Apoe gene (Kundu et al., 2021). These microbes may elicit an effect on AD-relevant behavioral and cognitive performance via epigenetic changes in AD-susceptibility genes in neural tissue. Alternatively, epigenetic changes might elicit alterations in intestinal physiology that affect the growth of these taxa in the gut.

    As sex-dependent effects are seen in gut microbiome studies in animal models and the MrOS cohort only includes men, it was important that the correlation between uniqueness and age remained independent of sex. A potential limitation of this study is that alcohol use might be an important contributor to the results, because alcohol use majorly affects the gut microbiome and therefore masks other effects (Leviatan and Segal, 2020). 

    The age window at which the gut microbiome becomes more unique in people with a healthy trajectory and distinct from those with a less-healthy trajectory suggests that alterations in the gut microbiome might be important predictive biomarkers of healthy and less-healthy aging. The gut microbiome might be important to consider for predicting treatment responses in patients with neurodegenerative conditions as well. For example, the gut microbiome profile is critical in the response of patients with metastatic melanoma to checkpoint inhibitor immunotherapy (Limeta et al., 2020) and some refractory patients respond following fecal microbiota transplantation (No authors listed, Cancer Discov., 2021). Clearly, increased efforts are warranted to study the role of the gut microbiome in brain function under physiological and pathological conditions in humans and animal models.

    References:

    Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013 May;36(5):305-12. Epub 2013 Feb 4 PubMed.

    Allen AP, Dinan TG, Clarke G, Cryan JF. A psychology of the human brain-gut-microbiome axis. Soc Personal Psychol Compass. 2017 Apr;11(4):e12309. Epub 2017 Apr 18 PubMed.

    Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci. 2015;9:392. Epub 2015 Oct 14 PubMed.

    Lynch JB, Hsiao EY. Microbiomes as sources of emergent host phenotypes. Science. 2019 Sep 27;365(6460):1405-1409. PubMed.

    Vuong HE, Yano JM, Fung TC, Hsiao EY. The Microbiome and Host Behavior. Annu Rev Neurosci. 2017 Jul 25;40:21-49. Epub 2017 Mar 8 PubMed.

    Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004 Jul 1;558(Pt 1):263-75. Epub 2004 May 7 PubMed.

    Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016 Dec 1;167(6):1469-1480.e12. PubMed.

    Dodiya HB, Kuntz T, Shaik SM, Baufeld C, Leibowitz J, Zhang X, Gottel N, Zhang X, Butovsky O, Gilbert JA, Sisodia SS. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J Exp Med. 2019 Jul 1;216(7):1542-1560. Epub 2019 May 16 PubMed.

    Kundu P, Torres ER, Stagaman K, Kasschau K, Okhovat M, Holden S, Ward S, Nevonen KA, Davis BA, Saito T, Saido TC, Carbone L, Sharpton TJ, Raber J. Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice. Sci Rep. 2021 Feb 25;11(1):4678. PubMed.

    Magnusson KR, Hauck L, Jeffrey BM, Elias V, Humphrey A, Nath R, Perrone A, Bermudez LE. Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience. 2015 May 14;300:128-140. PubMed.

    Raber J, Fuentes Anaya A, Torres ER, Lee J, Boutros S, Grygoryev D, Hammer A, Kasschau KD, Sharpton TJ, Turker MS, Kronenberg A. Effects of Six Sequential Charged Particle Beams on Behavioral and Cognitive Performance in B6D2F1 Female and Male Mice. Front Physiol. 2020;11:959. Epub 2020 Aug 28 PubMed.

    Torres ER, Akinyeke T, Stagaman K, Duvoisin RM, Meshul CK, Sharpton TJ, Raber J. Effects of Sub-Chronic MPTP Exposure on Behavioral and Cognitive Performance and the Microbiome of Wild-Type and mGlu8 Knockout Female and Male Mice. Front Behav Neurosci. 2018;12:140. Epub 2018 Jul 18 PubMed.

    Leviatan S, Segal E. Identifying gut microbes that affect human health. Nature. 2020 Nov;587(7834):373-374. PubMed.

    Limeta A, Ji B, Levin M, Gatto F, Nielsen J. Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma. JCI Insight. 2020 Dec 3;5(23) PubMed.

    Gut Microbiome Manipulation May Facilitate Immunotherapy Response. Cancer Discov. 2021 Feb;11(2):221. Epub 2020 Dec 18 PubMed.

    View all comments by Jacob Raber

Make a Comment

To make a comment you must login or register.