Gut Microbiota Dysbiosis Induced by Decreasing Endogenous Melatonin Mediates the Pathogenesis of Alzheimer’s Disease and Obesity
Open accessAbstract
Lifestyle choices, external environment, aging, and other factors influence the synthesis of melatonin. Although the physiological functions of melatonin have been widely studied in relation to specific organs, the systemic effects of endogenous melatonin reduction has not been reported. This study evaluates the systemic changes and possible pathogenic risks in an endogenous melatonin reduction (EMR) mouse model deficient in the rate limiting enzyme in melatonin production, arylalkylamine N-acetyltransferase (Aanat) gene. Using this model, we identified a new relationship between melatonin, Alzheimer’s disease (AD), and gut microbiota. Systematic changes were evaluated using multi-omics analysis. Fecal microbiota transplantation (FMT) was performed to examine the role of gut microbiota in the pathogenic risks of EMR. EMR mice exhibited a pan-metabolic disorder, with significant transcriptome changes in 11 organs, serum metabolome alterations as well as microbiota dysbiosis. Microbiota dysbiosis was accompanied by increased gut permeability along with gut and systemic inflammation. Correlation analysis revealed that systemic inflammation may be related to the increase of Ruminiclostridium_5 relative abundance. 8-month-old EMR mice had AD-like phenotypes, including Iba-1 activation, A β protein deposition and decreased spatial memory ability. Moreover, EMR mice showed decreased anti stress ability, under high-fat diet, EMR mice had greater body weight and more obvious hepatic steatosis compared with WT group. FMT improved gut permeability, systemic inflammation, and AD-related phenotypes, while reducing obesity in EMR mice. Our findings suggest EMR causes systemic changes mediated by gut microbiota dysbiosis, which may be a pathogenic factor for AD and obesity, we further proved the gut microbiota is a potential target for the prevention and treatment of AD and obesity.
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?
Levels of gut melatonin can be anywhere from 10 to 100 times greater than melatonin in blood serum levels.
“Levels of gut melatonin can be anywhere from 10 to 100 times greater than melatonin in blood serum levels [37,38].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [37]
Preliminary animal research indicates a relationship between gut dysbiosis, endogenous melatonin production, and pathological changes associated with Alzheimer's disease.
“Preliminary animal research indicates a relationship between gut dysbiosis, endogenous melatonin production, and pathological changes associated with Alzheimer’s disease [37].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [37]
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
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease
Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., Gradinaru, V., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.018 · Cited by 3,622 · see citing works
Hematoxylin and Eosin Staining of Tissue and Cell SectionsPreprint
Fischer, A. H., Jacobson, K. A., Rose, J., & Zeller, R. (2008) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot4986 · Cited by 2,146 · see citing works
ISOLATION OF MELATONIN, THE PINEAL GLAND FACTOR THAT LIGHTENS MELANOCYTES 1
Lerner, A. B., Case, J. D., TAKAHASHI, Y., Lee, T. H., & Mori, W. (1958) · Journal of the American Chemical Society · doi:10.1021/ja01543a060 · Cited by 1,759 · see citing works
Wang, X., Sun, G., Feng, T., Zhang, J., Huang, X., Wang, T., Xie, Z., Chu, X., Yang, J., Wang, H., et al. (2019) · Cell Research · doi:10.1038/s41422-019-0216-x · Cited by 1,144 · see citing works
Self-citationMicrobial Regulation of Host Physiology by Short-chain Fatty Acids
van der Hee, B., & Wells, J. M. (2021) · Trends in Microbiology · doi:10.1016/j.tim.2021.02.001 · Cited by 988 · see citing works
A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease
Baik, S. H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J.-I., & Mook-Jung, I. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.005 · Cited by 843 · see citing works
Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways
Pandi-Perumal, S. R., Trakht, I. N., SRINIVASAN, V., SPENCE, D., Maestroni, G. J. M., Zisapel, N., & Cardinali, D. P. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2008.04.001 · Cited by 799 · see citing works
Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella Pneumoniae
Yuan, J., Chen, C., Cui, J., Lu, J., Yan, C., Wei, X., Zhao, X., Li, N., Li, S., Xue, G., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.018 · Cited by 548 · see citing works
Gut microbiota and metabolic syndrome
Festi, D., Schiumerini, R., Eusebi, L. H., Marasco, G., Taddia, M., & Colecchia, A. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i43.16079 · Cited by 534 · see citing works
Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532 · see citing works
McNabney, S. M., & Henagan, T. M. (2017) · Nutrients · doi:10.3390/nu9121348 · Cited by 513 · see citing works
Melatonin reprogramming of gut microbiota improves lipid dysmetabolism in high‐fat diet‐fed mice
Yin, J., Li, Y., Han, H. L., Chen, S., Gao, J., Liu, G., Wu, X., Deng, J., Yu, Q., Huang, X., et al. (2018) · Journal of Pineal Research · doi:10.1111/jpi.12524 · Cited by 384 · see citing works
Self-citationReview: Systemic inflammation and<scp>A</scp>lzheimer's disease
Holmes, C. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2012.01307.x · Cited by 356 · see citing works
Connecting the immune system, systemic chronic inflammation and the gut microbiome: the role of sex
Rizzetto, L., Fava, F., Tuohy, K. M., & Selmi, C. (2018) · Journal of Autoimmunity · doi:10.1016/j.jaut.2018.05.008 · Cited by 331 · see citing works
Gut microbiota dysbiosis worsens the severity of acute pancreatitis in patients and mice
Zhu, Y., He, C., Li, X., Cai, Y., Hu, J., Liao, Y., Zhao, J., Xia, L., He, W., Liu, L., et al. (2019) · Journal of Gastroenterology · doi:10.1007/s00535-018-1529-0 · Cited by 250 · see citing works
The gut microbiota contributes to the development of Staphylococcus aureus -induced mastitis in mice
Hu, X., Guo, J., Zhao, C., Jiang, P., Maimai, T., Li, Y., Cao, Y., Fu, Y., & Zhang, N. (2020) · The ISME Journal · doi:10.1038/s41396-020-0651-1 · Cited by 221 · see citing works
Chidambaram, S. B., Essa, M. M., Rathipriya, A. G., Bishir, M., Ray, B., Mahalakshmi, A. M., Tousif, A. H., Sakharkar, M. K., Kashyap, R. S., Friedland, R. P., et al. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107988 · Cited by 204 · see citing works
Ogata, H., Kobayashi, T., Chinen, T., Takaki, H., Sanada, T., Minoda, Y., Koga, K., Takaesu, G., Maehara, Y., Iida, M., et al. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.04.025 · Cited by 183 · see citing works
Melatonin alleviates weanling stress in mice: Involvement of intestinal microbiota
Ren, W., Wang, P., Yan, J., Liu, G., Zeng, B., Hussain, T., Peng, C., Yin, J., Li, T., Wei, H., et al. (2017) · Journal of Pineal Research · doi:10.1111/jpi.12448 · Cited by 175 · see citing works
Self-citationWang, H., Lü, M., Deng, Y., Liu, Y., Wei, X., Liu, M., Zhou, J., Ma, H., Zheng, P., Yuan, J., et al. (2018) · Nutrition · doi:10.1016/j.nut.2018.11.018 · Cited by 166 · see citing works
Dudek, M., Yang, N., Ruckshanthi, J. P. D., Williams, J. L., Borysiewicz, E., Wang, P., Adamson, A. D., Li, J., Bateman, J. F., White, M., et al. (2016) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2016-209428 · Cited by 165 · see citing works
Bubenik, G. A. (2001) · Neurosignals · doi:10.1159/000046903 · Cited by 161 · see citing works
Inflammatory pathways in Alzheimer’s disease mediated by gut microbiota
Qian, X.-H., Song, X.-X., Liu, X.-L., Chen, S.-D., & Tang, H.-D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101317 · Cited by 153 · see citing works
Uric Acid and Cognitive Function in Older Individuals
Tana, C., Ticinesi, A., Prati, B., Nouvenne, A., & Meschi, T. (2018) · Nutrients · doi:10.3390/nu10080975 · Cited by 149 · see citing works
Connexin 43 and plakophilin-2 as a protein complex that regulates blood–testis barrier dynamics
Li, M., Mruk, D. D., Lee, W. M., & Cheng, C. Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901700106 · Cited by 145 · see citing works
Loman, B. R., Jordan, K. R., Haynes, B., Bailey, M. T., & Pyter, L. M. (2019) · Scientific Reports · doi:10.1038/s41598-019-52893-0 · Cited by 143 · see citing works
WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad
Chassot, A., Bradford, S. T., Auguste, A., Gregoire, E. P., Pailhoux, É., de Rooij, D. G., Schedl, A., & Chaboissier, M. (2012) · Development · doi:10.1242/dev.078972 · Cited by 124 · see citing works
Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis
Zhang, X., Li, S., Zhou, Y., Su, W., Ruan, X. Z., Wang, B., Zheng, F., Warner, M. N., Gustafsson, J.-Α., & Guan, Y. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700172114 · Cited by 123 · see citing works
Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease
Александровна, П. Е., Pchitskaya, E. I., & Борисович, Б. И. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7506 · Cited by 102 · see citing works
Lin, S., Hoffmann, K., Gao, C., Petrulionis, M., Herr, I., & Schemmer, P. (2017) · Journal of Pineal Research · doi:10.1111/jpi.12398 · Cited by 96 · see citing works
Melanogenesis: a realistic target for antimelanoma therapy?
Riley, P. A. (1991) · European Journal of Cancer and Clinical Oncology · doi:10.1016/0277-5379(91)90319-9 · Cited by 93 · see citing works
Stefanova, N. A., Maksimova, K. Y., Владимировна, К. Е., Rudnitskaya, E. A., Muraleva, N. A., & Kolosova, N. G. (2015) · Journal of Pineal Research · doi:10.1111/jpi.12248 · Cited by 85 · see citing works
Kong, Y., Si, L., Li, Y., Wu, X., Xu, X., Dai, J., Tang, H., Ma, M., Chi, Z., Sheng, X., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1110 · Cited by 79 · see citing works
Hypothalamic volume loss is associated with reduced melatonin output in Parkinson's disease
Breen, D. P., Nombela, C., Vuono, R., Jones, P. S., Fisher, K., Burn, D. J., Brooks, D. J., Reddy, A. B., Rowe, J. B., & Barker, R. A. (2016) · Movement Disorders · doi:10.1002/mds.26592 · Cited by 79 · see citing works
Melatonin and metabolic regulation: a review
Navarro‐Alarcón, M., Ruiz‐Ojeda, F. J., Blanca-Herrera, R. M., A‐Serrano, M. M., Acuña-Castroviejo, D., Fernández‐Vázquez, G., & Agil, A. (2014) · Food & Function · doi:10.1039/c4fo00317a · Cited by 76 · see citing works
Han, W., Hu, C., Fan, Z.-J., et al. (2021) · Scientific Reports · doi:10.1038/s41598-020-80336-8 · Cited by 73 · see citing works
Infection-Induced Systemic Inflammation Is a Potential Driver of Alzheimer's Disease Progression
Giridharan, V. V., Masud, F. N., Petronilho, F. C., Dal‐Pizzol, F., & Barichello, T. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00122 · Cited by 67 · see citing works
Stefani, O., Freyburger, M., Veitz, S., Basishvili, T., Meyer, M., Weibel, J., Kobayashi, K., Shirakawa, Y., & Cajochen, C. (2020) · Journal of Pineal Research · doi:10.1111/jpi.12714 · Cited by 66 · see citing works
Meierjohann, S., Hufnagel, A., Wende, E., et al. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-201 · Cited by 63 · see citing works
Hossain, M. F., Wang, N., Chen, R., Li, S., Roy, J., Uddin, M. G., Li, Z., Lim, L. W., & Song, Y. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101304 · Cited by 62 · see citing works
Roles and Mechanisms of Axon-Guidance Molecules in Alzheimer’s Disease
Zhang, L., Qi, Z., Li, J., Li, M., Du, X., Wang, S., Zhou, G., Xu, B., Liu, W., Xi, S., et al. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02311-2 · Cited by 57 · see citing works
Yuan, Y., Chen, Y., Zhou, Z., et al. (2017) · European Spine Journal · doi:10.1007/s00586-017-5363-5 · Cited by 53 · see citing works
Sadeghi, R. S., Kulej, K., Kathayat, R. S., Garcia, B. A., Dickinson, B. C., Brady, D. C., & Witze, E. S. (2018) · eLife · doi:10.7554/elife.34362 · Cited by 44 · see citing works
Melatonin exerts oncostatic capacity and decreases melanogenesis in human MNT‐1 melanoma cells
Kleszczyński, K., Kim, T., Bilska, B., Sarna, M., Mokrzynski, K. T., Stegemann, A., Pyza, E., Reiter, R. J., Steinbrink, K., Böhm, M., et al. (2019) · Journal of Pineal Research · doi:10.1111/jpi.12610 · Cited by 44 · see citing works
Self-citationIncreased HOX C13 expression in metastatic melanoma progression
Cantile, M., Scognamiglio, G., Anniciello, A., Farina, M., Gentilcore, G., Santonastaso, C., Fulciniti, F., Cillo, C., Franco, R., Ascierto, P. A., et al. (2012) · Journal of Translational Medicine · doi:10.1186/1479-5876-10-91 · Cited by 43 · see citing works
Wilczyńska, K., & Waszkiewicz, N. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9113452 · Cited by 42 · see citing works
Melanocortin 1 Receptor Regulates Melanoma Cell Migration by Controlling Syndecan-2 Expression
Chung, H., Lee, J., Jeong, D., Han, I., & Oh, E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.334730 · Cited by 39 · see citing works
Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma
Iida, Y., Ciechanover, A. J., Marzese, D. M., Hata, K., Bustos, M. A., Ono, S., Wang, J., Salomon, M. P., Tran, K. D., Lam, S., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0146 · Cited by 37 · see citing works
Hajj, P. E., Gilot, D., Migault, M., Theunis, A., van Kempen, L. C. L. T., Salès, F., Fayyad‐Kazan, H., Badran, B., Larsimont, D., Awada, A. H., et al. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.194 · Cited by 36 · see citing works
Paronetto, M. P., Dimauro, I., Grazioli, E., Palombo, R., Guidotti, F., Fantini, C., Sgrò, P., Francesco, D. D., Luigi, L. D., Capranica, L., et al. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.06.037 · Cited by 34 · see citing works
Melatonin as adjunctive therapy in the treatment of periodontitis associated with obesity
Virto, L., Cano, P., Jiménez‐Ortega, V., et al. (2018) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.13013 · Cited by 32 · see citing works
Wu, M., Liu, J., Li, F., Huang, S., He, J., Xue, Y., Fu, T., Feng, S., & Li, Z. (2019) · Mucosal Immunology · doi:10.1038/s41385-019-0193-x · Cited by 32 · see citing works
Ehd4 is required to attain normal prepubertal testis size but dispensable for fertility in male mice
George, M., Rainey, M. A., Naramura, M., Ying, G., Harms, D. W., Vitaterna, M. H., Doglio, L. T., Crawford, S. E., Hess, R. A., Band, V., et al. (2010) · genesis · doi:10.1002/dvg.20620 · Cited by 25 · see citing works
Zhong, P., Cao, Q., & Yan, Z. (2022) · Cerebral Cortex · doi:10.1093/cercor/bhac036 · Cited by 22 · see citing works
Zhang, W., Kong, H., Gao, X., et al. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i35.5287 · Cited by 17 · see citing works
Baekelandt, S., Mandiki, S. N. M., & Kestemont, P. (2019) · Journal of Pineal Research · doi:10.1111/jpi.12573 · Cited by 16 · see citing works
NAFLD Aggravates Septic Shock Due to Inadequate Adrenal Response and 11β-HSDs Dysregulation in Rats
Huang, H., Tsai, M.-H., Lee, F., Lin, T., Chang, C.-C., Chuang, C., Hsu, S., Hou, M., & Huang, Y. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12050403 · Cited by 12 · see citing works
Bai, W., Liu, Q. F., Chang, H., Liu, Q., Gao, C., Bai, Y., Zhou, H., & Shi, S. (2021) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2021.1952212 · Cited by 11 · see citing works
Yu, D., Li, J., Han, Y., Shuku, L., Ning, X., Yunsong, L., Xiaojun, S., & Zhidong, L. (2014) · Chinese Medical Journal · doi:10.3760/cma.j.issn.0366-6999.20132949 · Cited by 7 · see citing works
High SYT7 expression is associated with poor prognosis in human non-small cell lung carcinoma
Han, Q., Zou, D., Lv, F., et al. (2020) · Pathology - Research and Practice · doi:10.1016/j.prp.2020.153101 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Wang, X., Wang, Z., Cao, J., Dong, Y., & Chen, Y. (2023) · Microbiome · doi:10.1186/s40168-022-01452-3 · Cited by 273 · see citing works
Self-citationMinich, D. M., Henning, M., Darley, C., Fahoum, M., Schuler, C. B., & Frame, J. (2022) · Nutrients · doi:10.3390/nu14193934 · Cited by 176 · see citing works
“Levels of gut melatonin can be anywhere from 10 to 100 times greater than melatonin in blood serum levels [37,38].”
BackgroundGut microbiome and Alzheimer’s disease: What we know and what remains to be explored
Kapoor, B., Biswas, P., Gulati, M., Rani, P., & Gupta, R. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102570 · Cited by 46 · see citing works
- Authors
- Zhang, B., Chen, T., Cao, M., Yuan, C., Reiter, R. J., Zhao, Z., Zhao, Y., Chen, L., Fan, W., Wang, X., Zhou, X., & Li, C.
- Affiliations
- Jilin University (CN)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Zhou, Xu
- Li, Chunjin
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2022-05-10
- Volume
- 13
- Pages
- 900132-900132
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC9127079
- OpenAlex
- W4229446879
- Cited by
- 80
- References
- 62
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 32 · 2023: 24 · 2022: 6
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (32172726 , 31301969)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- melatonin, arylalkylamine N-acetyltransferase, gut dysbiosis, Alzheimer's disease, obesity, intestinal permeability, systemic inflammation, amyloid-beta deposition, hepatic steatosis, high-fat diet, fecal microbiota transplantation, stress response, multi-omics
- MeSH terms
- Gastrointestinal Microbiome, Alzheimer Disease, Animals, Inflammation, Melatonin, Obesity, Mice, Dysbiosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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
