Altered Gut Microbial Metabolites in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Signals in Host–Microbe Interplay
Open accessAbstract
Intimate metabolic host–microbiome crosstalk regulates immune, metabolic, and neuronal response in health and disease, yet remains untapped for biomarkers or intervention for disease. Our recent study identified an altered microbiome in patients with pre-onset amnestic mild cognitive impairment (aMCI) and dementia Alzheimer’s disease (AD). Thus, we aimed to characterize the gut microbial metabolites among AD, aMCI, and healthy controls (HC). Here, a cohort of 77 individuals (22 aMCI, 27 AD, and 28 HC) was recruited. With the use of liquid-chromatography/gas chromatography mass spectrometry metabolomics profiling, we identified significant differences between AD and HC for tryptophan metabolites, short-chain fatty acids (SCFAs), and lithocholic acid, the majority of which correlated with altered microbiota and cognitive impairment. Notably, tryptophan disorders presented in aMCI and SCFAs decreased progressively from aMCI to AD. Importantly, indole-3-pyruvic acid, a metabolite from tryptophan, was identified as a signature for discrimination and prediction of AD, and five SCFAs for pre-onset and progression of AD. This study showed fecal-based gut microbial signatures were associated with the presence and progression of AD, providing a potential target for microbiota or dietary intervention in AD prevention and support for the host–microbe crosstalk signals in AD pathophysiology.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Reduced SCFA-producing species and SCFA levels are reported in individuals with mild cognitive impairment and AD patients.
“Several studies have reported reduced SCFAs-producing species and SCFA levels in individuals with mild cognitive impairment (MCI) and AD patients.292–295”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [295]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Mild cognitive impairment as a diagnostic entity
Petersen, R. C. (2004) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2004.01388.x · Cited by 7,864 · see citing works
Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., Iwatsubo, T., Jack, C. R., Kaye, J., Montine, T. J., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.003 · Cited by 7,155 · see citing works
From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites
Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bäckhed, F. (2016) · Cell · doi:10.1016/j.cell.2016.05.041 · Cited by 7,070 · see citing works
Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria
Dubois, B., Feldman, H. H., Jacova, C., DeKosky, S. T., Barberger-Gateau, P., Cummings, J., Delacourte, A., Galasko, D., Gauthier, S., Jicha, G., et al. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70178-3 · Cited by 4,411 · see citing works
Host microbiota constantly control maturation and function of microglia in the CNS
Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569 · see citing works
Gut microbiota, metabolites and host immunity
Rooks, M. G., & Garrett, W. S. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.42 · Cited by 3,409 · see citing works
The role of short-chain fatty acids in microbiota–gut–brain communication
Dalile, B., Van Oudenhove, L., Vervliet, B., & Verbeke, K. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0157-3 · Cited by 3,357 · see citing works
Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease
Agus, A., Planchais, J., & Sokol, H. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2018.05.003 · Cited by 3,180 · cited 4× · see citing works
“The dialogue between the microbiota and host are mediated by metabolites that are either produced by the microbiota or derived from the transformation of environmental or host molecules [7,8].”
InfluentialOpen source clustering software
de Hoon, M., Imoto, S., Nolan, J., & Miyano, S. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bth078 · Cited by 3,043 · see citing works
The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication
Silva, Y. P., Bernardi, A., & Frozza, R. L. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00025 · Cited by 3,043 · see citing works
The gut microbiota influences blood-brain barrier permeability in mice
Braniste, V., Al-Asmakh, M., Kowal, C., Anuar, F., Abbaspour, A., Tóth, M., Korecka, A., Bakocevic, N., Ng, L. G., Kundu, P., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009759 · Cited by 2,530 · see citing works
2019 Alzheimer’s disease facts and figures.
Alzheimer's Association (2019) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.01.010 · Cited by 2,461 · see citing works
Gut microbiome alterations in Alzheimer’s disease
Vogt, N. M., Kerby, R. L., Dill-McFarland, K. A., Harding, S. J., Merluzzi, A. P., Johnson, S. C., Carlsson, C. M., Asthana, S., Zetterberg, H., Blennow, K., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-13601-y · Cited by 2,137 · see citing works
Rothhammer, V., Mascanfroni, I. D., Bunse, L., Takenaka, M. C., Kenison, J. E., Mayo, L., Chao, C.-C., Patel, B., Yan, R., Blain, M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4106 · Cited by 1,559 · see citing works
Synergy between amyloid-β and tau in Alzheimer’s disease
Busche, M. A., & Hyman, B. T. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0687-6 · Cited by 1,242 · see citing works
Symbiotic gut microbes modulate human metabolic phenotypes
Li, M., Wang, B., Zhang, M., Rantalainen, M., Wang, S., Zhou, H., Zhang, Y., Shen, J., Pang, X., Zhang, M., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712038105 · Cited by 1,144 · see citing works
Self-citation2011 Alzheimer's disease facts and figures
Alzheimer's Association (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2011.02.004 · Cited by 914 · see citing works
Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota
Harach, T., Marungruang, N., Duthilleul, N., Cheatham, V., Mc Coy, K. D., Frisoni, G., Neher, J. J., Fåk, F., Jucker, M., Lasser, T., et al. (2017) · Scientific Reports · doi:10.1038/srep41802 · Cited by 901 · see citing works
The fecal metabolome as a functional readout of the gut microbiome
Zierer, J., Jackson, M. A., Kastenmüller, G., Mangino, M., Long, T., Telenti, A., Mohney, R. P., Small, K. S., Bell, J. T., Steves, C. J., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0135-7 · Cited by 736 · see citing works
MahmoudianDehkordi, S., Arnold, M., Nho, K., Ahmad, S., Jia, W., Xie, G., Louie, G., Kueider‐Paisley, A., Moseley, M. A., Thompson, J. W., et al. (2019) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.07.217 · Cited by 706 · see citing works
Liu, P., Wu, L., Peng, G., Han, Y., Tang, R., Ge, J., Zhang, L., Jia, L., Yue, S., Zhou, K., et al. (2019) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2019.05.008 · Cited by 669 · see citing works
Self-citationNagpal, R., Neth, B. J., Wang, S., Craft, S., & Yadav, H. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.08.032 · Cited by 653 · see citing works
Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier
Hoyles, L., Snelling, T., Umlai, U.-K., Nicholson, J. K., Carding, S. R., Glen, R. C., & McArthur, S. (2018) · Microbiome · doi:10.1186/s40168-018-0439-y · Cited by 591 · see citing works
Varma, V. R., Oommen, A. M., Varma, S., Casanova, R., An, Y., Andrews, R. M., O’Brien, R., Pletniková, O., Troncoso, J. C., Toledo, J. B., et al. (2018) · PLoS Medicine · doi:10.1371/journal.pmed.1002482 · Cited by 464 · see citing works
Govindarajan, N., Agis-Balboa, R. C., Walter, J., Sananbenesi, F., & Fischer, A. (2011) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-110080 · Cited by 405 · see citing works
Alzheimer’s Disease and Vascular Aging
Cortes-Canteli, M., & Iadecola, C. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.10.062 · Cited by 400 · see citing works
Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair
Tang, T. W. H., Chen, H.-C., Chen, C.-Y., Yen, C. Y. T., Lin, C.-J., Prajnamitra, R. P., Chen, L.-L., Ruan, S.-C., Lin, J.-H., Lin, P.-J., et al. (2019) · Circulation · doi:10.1161/circulationaha.118.035235 · Cited by 348 · see citing works
Sparkman, N. L., Buchanan, J. B., Heyen, J. R. R., Chen, J., Beverly, J. L., & Johnson, R. W. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3376-06.2006 · Cited by 307 · see citing works
Self-citationNeurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease
Xu, Y., Yan, J., Zhou, P., Li, J., Gao, H., Xia, Y., & Wang, Q. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.02.002 · Cited by 303 · see citing works
Human gut microbiota: the links with dementia development
Alkasir, R., Li, J., Li, X., Jin, M., & Zhu, B. (2016) · Protein & Cell · doi:10.1007/s13238-016-0338-6 · Cited by 283 · see citing works
Metabolic control of regulatory T cell development and function
Zeng, H., & Chi, H. (2014) · Trends in Immunology · doi:10.1016/j.it.2014.08.003 · Cited by 275 · see citing works
Regulation of microglial inflammatory response by sodium butyrate and short‐chain fatty acids
Huuskonen, J., Suuronen, T., Nuutinen, T., Kyrylenko, S., & Salminen, A. (2004) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705682 · Cited by 274 · see citing works
A targeted metabolomic protocol for short-chain fatty acids and branched-chain amino acids
Zheng, X., Qiu, Y., Zhong, W., Baxter, S. A., Su, M., Li, Q., Xie, G., Ore, B. M., Qiao, S., Spencer, M., et al. (2013) · Metabolomics · doi:10.1007/s11306-013-0500-6 · Cited by 241 · see citing works
Alterations of Bile Acids and Gut Microbiota in Obesity Induced by High Fat Diet in Rat Model
Lin, H., An, Y., Tang, H., & Wang, Y. (2019) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.9b00249 · Cited by 235 · see citing works
Self-citationToxicity of bile acids on the electron transport chain of isolated rat liver mitochondria
Krähenbühl, S., Talos, C., Fischer, S., & Reichen, J. (1994) · Hepatology · doi:10.1002/hep.1840190228 · Cited by 228 · see citing works
Chen, J., Wang, W., Lv, S., et al. (2009) · Analytica Chimica Acta · doi:10.1016/j.aca.2009.03.039 · Cited by 218 · see citing works
Self-citationZhou, S.-Y., Gillilland, M. G., Wu, X., Leelasinjaroen, P., Zhang, G., Zhou, H. R., Ye, B., Lu, Y., & Owyang, C. (2017) · Journal of Clinical Investigation · doi:10.1172/jci92390 · Cited by 204 · see citing works
Levey, A. I., Lah, J. J., Goldstein, F. C., Steenland, K., & Bliwise, D. L. (2006) · Clinical Therapeutics · doi:10.1016/j.clinthera.2006.07.006 · Cited by 180 · see citing works
Marksteiner, J., Blasko, I., Kemmler, G., Koal, T., & Humpel, C. (2017) · Metabolomics · doi:10.1007/s11306-017-1297-5 · Cited by 158 · see citing works
Ma, N., He, T., Johnston, L. J., & Ma, X. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1758008 · Cited by 158 · see citing works
Metabolomic Profiling of Bile Acids in Clinical and Experimental Samples of Alzheimer’s Disease
Pan, X., Elliott, C. T., McGuinness, B., Passmore, P., Kehoe, P. G., Hölscher, C., McClean, P. L., Graham, S. F., & Green, B. D. (2017) · Metabolites · doi:10.3390/metabo7020028 · Cited by 153 · see citing works
Metabolomic changes in autopsy‐confirmed Alzheimer's disease
Kaddurah-Daouk, R. F., Rozen, S., Matson, W. R., Han, X., Hulette, C. M., Burke, J. R., Doraiswamy, P. M., & Welsh-Bohmer, K. A. (2010) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.06.001 · Cited by 145 · see citing works
Relevance of gutmicrobiota in cognition, behaviour and Alzheimer’s disease
de J.R. De-Paula, V., Forlenza, A. S., & Forlenza, O. V. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.07.007 · Cited by 145 · see citing works
Wang, B., Chen, D., Chen, Y., Hu, Z., Cao, M., Xie, Q., Chen, Y., Xu, J., Zheng, S., & Li, L. (2011) · Journal of Proteome Research · doi:10.1021/pr2009252 · Cited by 135 · see citing works
Self-citationA Blood-Based, 7-Metabolite Signature for the Early Diagnosis of Alzheimer's Disease
Olazarán, J., Gil‐de‐Gómez, L., Rodríguez‐Martín, A., Valentí, M., Payo, B. F., Marín-Muñoz, J., Antúnez, C., Frank, A., Acedo, C., Gracia, L. M., et al. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-142925 · Cited by 116 · see citing works
Cao, H., Huang, H., Xu, W., Chen, D., Yu, J., Li, ., & Li, L. (2011) · Analytica Chimica Acta · doi:10.1016/j.aca.2011.02.038 · Cited by 105 · see citing works
Self-citationBile acid transport in cultured rat hepatocytes
Dyke, R. W. V., Stephens, J. E., & Scharschmidt, B. F. (1982) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1982.243.6.g484 · Cited by 102 · see citing works
Rapid profiling method for mammalian feces short chain fatty acids by GC-MS
Furuhashi, T., Sugitate, K., Nakai, T., Jikumaru, Y., & Ishihara, G. (2017) · Analytical Biochemistry · doi:10.1016/j.ab.2017.12.001 · Cited by 86 · see citing works
Cui, Y., Liu, X., Wang, M., Liu, L., Sun, X., Ma, L., Xie, W., Wang, C., Tang, S., Wang, D., et al. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000116 · Cited by 81 · see citing works
Metabolomics and incident dementia in older Chinese adults: The Shanghai Aging Study
Cui, M., Jiang, Y., Zhao, Q., Zhu, Z., Liang, X., Zhang, K., Wu, W., Dong, Q., An, Y., Tang, H., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12074 · Cited by 69 · see citing works
Bile acids content in brain of common duct ligated rats
Tripodi, V. P., Contin, M. D., Fernández, M. A., & Lemberg, A. (2012) · Annals of Hepatology · doi:10.1016/s1665-2681(19)31420-6 · Cited by 40 · see citing works
Ma, Y., Li, F., Wang, L., et al. (2018) · Human Reproduction · doi:10.1093/humrep/dey366 · Cited by 32 · see citing works
Simonato, M., Fochi, I., Vedovelli, L., Giambelluca, S., Carollo, C., Padalino, M. A., Carnielli, V. P., & Cogo, P. E. (2019) · Metabolomics · doi:10.1007/s11306-019-1605-3 · Cited by 26 · see citing works
Penno, C. A., Arsenijevic, D., Cunha, T. D., Kullak-Ublick, G. A., Montani, J., & Odermatt, A. (2013) · Analytical Methods · doi:10.1039/c3ay26520j · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
Chen, Y., Xu, J., & Chen, Y. (2021) · Nutrients · doi:10.3390/nu13062099 · Cited by 917 · see citing works
Sun, J., Zhang, Y., Kong, Y., Ye, T., Yu, Q., Kumaran Satyanarayanan, S., Su, K.-P., & Liu, J. (2022) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2022.08.003 · Cited by 255 · see citing works
The Potential Role of Gut Microbiota in Alzheimer’s Disease: From Diagnosis to Treatment
Varesi, A., Pierella, E., Romeo, M., Piccini, G. B., Alfano, C., Bjørklund, G., Oppong, A., Ricevuti, G., Esposito, C., Chirumbolo, S., et al. (2022) · Nutrients · doi:10.3390/nu14030668 · Cited by 225 · see citing works
Short-chain fatty acids: Important components of the gut-brain axis against AD
Huang, Y., Wang, Y. F., Miao, J., Zheng, R. F., & Li, J. Y. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116601 · Cited by 70 · see citing works
Self-citationNutrition, gut microbiota, and alzheimer’s disease
Romanenko, M., Kholin, V., Koliada, A., & Vaiserman, A. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.712673 · Cited by 56 · see citing works
- Authors
- Wu, L., Han, Y., Zheng, Z., Peng, G., Liu, P., Yue, S., Zhu, S., Chen, J., Lv, H., Shao, L., Sheng, Y., Wang, Y., Li, L., Li, L., & Wang, B.
- Affiliations
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University of Technology (CN)
- Nanyang Technological University (SG)
- University of Alberta (CA)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Wang, Baohong
- ORCID
- Venue
- Nutrients
- Publisher
- MDPI AG
- Published
- 2021-01-14
- Volume
- 13
- Issue
- 1
- Pages
- 228
- ISSN
- 2072-6643 (ISSN-L)
- PMC
- PMC7829997
- OpenAlex
- W3120104891
- Cited by
- 227
- References
- 54
- Citations by year
- 2026: 23 · 2025: 48 · 2024: 53 · 2023: 53 · 2022: 36 · 2021: 14
- FWCI
- 12.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nutrients (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
- Funders
- Major Program of National Natural Science Foundation of China (81790633, 81790630)
- CAMS Innovation Fund for Medical Sciences (2019-I2M-5-045)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, amnestic mild cognitive impairment, gut microbiota, gut microbiota metabolites, tryptophan metabolites, indole-3-pyruvic acid, short-chain fatty acids, lithocholic acid, host-microbe crosstalk, fecal metabolomics, biomarkers, disease progression, dementia
- MeSH terms
- Gastrointestinal Microbiome, Aged, Aged, 80 and over, Alzheimer Disease, Bacteria, Fatty Acids, Volatile, Feces, Female, Humans, Male, Middle Aged, Tryptophan, Metabolome, Cognitive Dysfunction
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.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
