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The gut microbiome–derived metabolite trimethylamine N-oxide modulates neuroinflammation and cognitive function with aging

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Abstract

Aging is associated with declines in cognitive performance, which are mediated in part by neuroinflammation, characterized by astrocyte activation and higher levels of pro-inflammatory cytokines; however, the upstream drivers are unknown. We investigated the potential role of the gut microbiome–derived metabolite trimethylamine N-oxide (TMAO) in modulating neuroinflammation and cognitive function with aging. Study 1: In middle-aged and older humans (65 ± 7 years), plasma TMAO levels were inversely related to performance on NIH Toolbox Cognition Battery tests of memory and fluid cognition (both r2 = 0.07, p < 0.05). Study 2: In mice, TMAO concentrations in plasma and the brain increased in parallel with aging (r2 = 0.60), suggesting TMAO crosses the blood-brain barrier. The greater TMAO concentrations in old mice (27 months) were associated with higher brain pro-inflammatory cytokines and markers of astrocyte activation vs. young adult mice (6 months). Study 3: To determine if TMAO independently induces an “aging-like” decline in cognitive function, young mice (6 months) were supplemented with TMAO in chow for 6 months. Compared with controls, TMAO-supplemented mice performed worse on the novel object recognition test, indicating impaired memory and learning, and had increased neuroinflammation and markers of astrocyte activation. Study 4: Human astrocytes cultured with TMAO vs. control media exhibited changes in cellular morphology and protein markers consistent with astrocyte activation, indicating TMAO directly acts on these cells. Our results provide translational insight into a novel pathway that modulates neuroinflammation and cognitive function with aging, and suggest that TMAO might be a promising target for prevention of neuroinflammation and cognitive decline with aging.

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Acknowledgments

The authors would like to sincerely thank Brian Ziemba, James Richey, Danijel Djukovic, Lauren Cuevas, Christopher J. Angiletta, Laura E. Griffin, and Patrick K. Gonzales for their assistance with the data collection and analysis.

Funding

This work was supported by the National Institutes of Health awards R01 HL143887 (D.R.S.), F32 HL140875 (V.E.B.), and R01 NS063964 (C.D.L.); Administrative Supplement to NS063964 (T.J.L.) and Colorado CTSA UL1 TR002535; and the Hatch Program of the National Institute of Food and Agriculture, US Department of Agriculture (A.P.N.).

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  1. Andrew P. Neilson

    Present address: Plants for Human Health Institute, Department of Food, Bioprocessing and Nutrition Sciences, North Carolina State University, Kannapolis, NC, USA

Authors and Affiliations

  1. Department of Integrative Physiology, University of Colorado Boulder, 1725 Pleasant St, 354 UCB, Boulder, CO, 80309, USA

    Vienna E. Brunt, Thomas J. LaRocca, Amy E. Bazzoni, Zachary J. Sapinsley, Jill Miyamoto-Ditmon, Rachel A. Gioscia-Ryan, Christopher D. Link & Douglas R. Seals

  2. Department of Health and Exercise Science and the Center for Healthy Aging, Colorado State University, Fort Collins, CO, USA

    Thomas J. LaRocca

  3. Department of Food Science and Technology, Virginia Tech, Blacksburg, VA, USA

    Andrew P. Neilson

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Contributions

V.E.B., T.J.L., C.D.L., and D.R.S. conceived and designed the experiments. V.E.B., T.J.L., A.E.B., Z.J.S., J.M-D., R.A.G.-R., and A.P.N. collected and analyzed the data. V.E.B., T.J.L., C.D.L., and D.R.S. interpreted the data. V.E.B. wrote the initial draft of the manuscript. All authors revised the manuscript critically for intellectual content, approved the final version, and agree to be accountable for all aspects of the work.

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Correspondence to Douglas R. Seals.

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All procedures involving human subjects were approved by the Institutional Review Board at the University of Colorado Boulder and were conducted in accordance with the Declaration of Helsinki. All animal procedures were approved by the University of Colorado Boulder Institutional Animal Care and Use Committee and complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Brunt, V.E., LaRocca, T.J., Bazzoni, A.E. et al. The gut microbiome–derived metabolite trimethylamine N-oxide modulates neuroinflammation and cognitive function with aging. GeroScience 43, 377–394 (2021). https://doi.org/10.1007/s11357-020-00257-2

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