PREDICTION OF VITAMINS AND SHORT-CHAIN FATTY ACIDS SYNTHESIS PATHWAYS IN OBESE ADULTS

Мұқаба

Дәйексөз келтіру

Толық мәтін

Ашық рұқсат Ашық рұқсат
Рұқсат жабық Рұқсат берілді
Рұқсат жабық Тек жазылушылар үшін

Аннотация

Gut microbiota and its metabolites such as short-chain fatty acids (SCFAs) and vitamins are involved in maintaining energy homeostasis, which is relevant in the context of obesity. The aim was to screen the predicted representation of vitamin and SCFAs biosynthesis pathways based in patients with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO). The study included two groups: a control group (n = 130) and obese patients (n = 133), which was divided into subgroups with MHO (n = 38) and MUHO (n = 55). The predicted representation of metabolic pathways for the biosynthesis of vitamins and SCFAs in feces was studied using PICRUSt2. Obese patients had an increase in the representation of the synthesis of vitamins B1, B2, B5, B6, B7, B9 and vitamin K pathways, as well as a decrease in the pathways for the vitamin B12 synthesis. At the same time, the identified changes were determined by the metabolic phenotype of obesity. MHO was accompanied by an imbalance in the B1 synthesis pathways and an increased representation of vitamin K formation pathways. Whereas MUHO led to an increase in the ability of the gut microbiota to synthesize vitamins B1, B2, B5, B6, B7, B9 and K, as well as to inhibition of the B12-synthesizing pathways. In addition, patients with MUHO had an increase in the representation of the pathways for the SCFAs synthesis such as acetate, propanoate, and butanoate, which was not observed in MHO patients. In general, the change in the metabolic pathways representation of gut microbiota in obese patients is the result of the microorganism’s “selection” under the influence of specific factors, which are more pronounced in MUHO. Thus, the imbalance in the pathways for the vitamins and short-chain fatty acids biosynthesis of the gut microbiome reflects a violation of the metabolic symbiosis within the superorganism (“microbiota-macroorganism”).

Авторлар туралы

A. Shestopalov

Pirogov Russian National Research Medical University; National Medical Research Center for Endocrinology; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology; Center for Molecular Health

Email: ganenko.lilia@yandex.ru
Russia, Moscow; Russia, Moscow; Russia, Moscow; Russia, Moscow

L. Ganenko

Rostov State Medical University

Email: ganenko.lilia@yandex.ru
Russia, Rostov-on-Don

I. Kolesnikova

Pirogov Russian National Research Medical University; National Medical Research Center for Endocrinology

Email: ganenko.lilia@yandex.ru
Russia, Moscow; Russia, Moscow

T. Grigoryeva

Kazan (Volga Region) Federal University

Email: ganenko.lilia@yandex.ru
Russia, Kazan

I. Vasilyev

Kazan (Volga Region) Federal University

Email: ganenko.lilia@yandex.ru
Russia, Kazan

Yu. Naboka

Rostov State Medical University

Email: ganenko.lilia@yandex.ru
Russia, Rostov-on-Don

N. Volkova

Rostov State Medical University

Email: ganenko.lilia@yandex.ru
Russia, Rostov-on-Don

O. Borisenko

Pirogov Russian National Research Medical University

Email: ganenko.lilia@yandex.ru
Russia, Moscow

S. Roumiantsev

Pirogov Russian National Research Medical University; National Medical Research Center for Endocrinology; Center for Molecular Health

Email: ganenko.lilia@yandex.ru
Russia, Moscow; Russia, Moscow; Russia, Moscow

Әдебиет тізімі

  1. Piché ME, Tchernof A, Després JP (2020) Obesity Phenotypes, Diabetes, and Cardiovascular Diseases. Circ Res 126: 1477–1500. https://doi.org/10.1161/CIRCRESAHA.120.316101
  2. Lin X, Li H (2021) Obesity: Epidemiology, Pathophysiology, and Therapeutics. Front Endocrinol (Lausanne) 12. https://doi.org/10.3389/FENDO.2021.706978
  3. Boachie J, Adaikalakoteswari A, Samavat J, Saravanan P (2020) Low Vitamin B12 and Lipid Metabolism: Evidence from Pre-Clinical and Clinical Studies. Nutrients 12: 1–20. https://doi.org/10.3390/NU12071925
  4. Khan MJ, Gerasimidis K, Edwards CA, Shaikh MG (2016) Role of Gut Microbiota in the Aetiology of Obesity: Proposed Mechanisms and Review of the Literature. J Obes 2016. https://doi.org/10.1155/2016/7353642
  5. Stefan N (2020) Metabolically Healthy and Unhealthy Normal Weight and Obesity. Endocrinol Metab (Seoul) 35: 487–493. https://doi.org/10.3803/ENM.2020.301
  6. Duan M, Wang Y, Zhang Q, Zou R, Guo M, Zheng H (2021) Characteristics of gut microbiota in people with obesity. PLoS One 16. https://doi.org/10.1371/JOURNAL.PONE.0255446
  7. Гапонов АМ, Волкова НИ, Ганенко ЛА, Набока ЮЛ, Маркелова МИ, Синягина МН, Харченко АМ, Хуснутдинова ДР, Румянцев СА, Тутельян АВ, Макаров ВВ, Юдин СМ, Шестопалов АВ (2021) Особенности микробиома толстой кишки у пациентов с ожирением при его различных фенотипах (оригинальная статья). Журн микробиол эпидемиол иммунобиол 98: 144–155. [Gaponov AM, Volkova NI, Ganenko LA, Naboka YuL, Markelova MI, Siniagina MN, KharchenkoAM, Khusnutdinova DR, Rumyantsev SA, Tutelyan AV, Makarov VV, Yudin SM, Shestopalov AV (2021) Characteristics of the colonic microbiome in patients with different obesity phenotypes (the original article). J Microbiol Epidemiol Immunobiol 98 (2): 144–155. (In Russ)]. https://doi.org/10.36233/0372-9311-66
  8. Voland L, Le Roy T, Debédat J, Clément K (2022) Gut microbiota and vitamin status in persons with obesity: A key interplay. Obes Rev 23. https://doi.org/10.1111/OBR.13377
  9. Ciobârcă D, Cătoi AF, Copăescu C, Miere D, Crișan G (2020) Bariatric Surgery in Obesity: Effects on Gut Microbiota and Micronutrient Status. Nutrients 12. https://doi.org/10.3390/NU12010235
  10. Hooper LV, Midwedt T, Gordon JI (2002) How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr 22: 283–307. https://doi.org/10.1146/ANNUREV.NUTR.22.011602.092259
  11. Chambers ES, Preston T, Frost G, Morrison DJ (2018) Role of Gut Microbiota-Generated Short-Chain Fatty Acids in Metabolic and Cardiovascular Health. Curr Nutr Rep 7: 198–206. https://doi.org/10.1007/S13668-018-0248-8
  12. Zhou SS, Li D, Zhou YM, Sun WP, Liu QG (2010) B-vitamin consumption and the prevalence of diabetes and obesity among the US adults: population based ecological study. BMC Public Health 10. https://doi.org/10.1186/1471-2458-10-746
  13. O’Riordan KJ, Collins MK, Moloney GM, Knox EG, Aburto MR, Fülling C, Morley SJ, Clarke G, Schellekens H, Cryan JF (2022) Short chain fatty acids: Microbial metabolites for gut-brain axis signalling. Mol Cell Endocrinol 546. https://doi.org/10.1016/J.MCE.2022.111572
  14. Martínez-Cuesta MC, del Campo R, Garriga-García M, Peláez C, Requena T (2021) Taxonomic Characterization and Short-Chain Fatty Acids Production of the Obese Microbiota. Front Cell Infect Microbiol 11. https://doi.org/10.3389/FCIMB.2021.598093
  15. Douglas GM, Maffei VJ, Zaneveld JR, Yurgel SN, Brown JR, Taylor CM, Huttenhower C, Langille MGI (2020) PICRUSt2 for prediction of metagenome functions. Nat Biotechnol 38: 685–688. https://doi.org/10.1038/S41587-020-0548-6
  16. Osadnik K, Osadnik T, Gierlotka M, Windak A, Tomasik T, Mastej M, Kuras A, Jóźwiak K, Penson PE, Lip GYH, Mikhailidis DP, Toth PP, Catapano AL, Ray KK, Howard G, Tomaszewski M, Charchar FJ, Sattar N, Williams B, MacDonald TM, Banach M, Jóź-wiak J, LIPIDOGRAM Investigators (2023) Metabolic syndrome is associated with similar long-term prognosis in non-obese and obese patients. An analysis of 45 615 patients from the nationwide LIPIDOGRAM 2004-2015 cohort studies. Eur J Prev Cardiol. https://doi.org/10.1093/EURJPC/ZWAD101
  17. Меньшиков ВВ (ред) (2009) Методики клинических лабораторных исследований: справочное пособие: в 3 т. Т. 3: Клиническая микробиология. Бактериологические исследования. Микологические исследования. Паразитологические исследования. Инфекционная иммунодиагностика. Молекулярные исследования в диагностике инфекционных заболеваний. М. Лабора. [Menshikov VV (ed) (2009) Methods of clinical laboratory research: a reference guide: in 3 volumes. V. 3: Clinical microbiology. bacteriological research. Mycological research. parasitological research. Infectious immunodiagnostics. Molecular studies in the diagnosis of infectious diseases. M. Labora. (In Russ)].
  18. Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, Alexander H, Alm EJ, Arumugam M, Asnicar F, Bai Y, Bisanz JE, Bittinger K, Brejnrod A, Brislawn CJ, Brown CT, Callahan BJ, Caraballo-Rodríguez AM, Chase J, Cope EK, Da Silva R, Diener C, Dorrestein PC, Douglas GM, Durall DM, Duvallet C, Edwardson CF, Ernst M, Estaki M, Fouquier J, Gauglitz JM, Gibbons SM, Gibson DL, Gonzalez A, Gorlick K, Guo J, Hillmann B, Holmes S, Holste H, Huttenhower C, Huttley GA, Janssen S, Jarmusch AK, Jiang L, Kaehler BD, Kang K Bin, Keefe CR, Keim P, Kelley ST, Knights D, Koester I, Kosciolek T, Kreps J, Langille MGI, Lee J, Ley R, Liu YX, Loftfield E, Lozupone C, Maher M, Marotz C, Martin BD, McDonald D, McIver LJ, Melnik A V., Metcalf JL, Morgan SC, Morton JT, Naimey AT, Navas-Molina JA, Nothias LF, Orchanian SB, Pearson T, Peoples SL, Petras D, Preuss ML, Pruesse E, Rasmussen LB, Rivers A, Robeson MS, Rosenthal P, Segata N, Shaffer M, Shiffer A, Sinha R, Song SJ, Spear JR, Swafford AD, Thompson LR, Torres PJ, Trinh P, Tripathi A, Turnbaugh PJ, Ul-Hasan S, van der Hooft JJJ, Vargas F, Vázquez-Baeza Y, Vogtmann E, von Hippel M, Walters W, Wan Y, Wang M, Warren J, Weber KC, Williamson CHD, Willis AD, Xu ZZ, Zaneveld JR, Zhang Y, Zhu Q, Knight R, Caporaso JG (2019) Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol 37: 852–857. https://doi.org/10.1038/S41587-019-0209-9
  19. Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, Peplies J, Glöckner FO (2013) The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 41. https://doi.org/10.1093/NAR/GKS1219
  20. Geiker NRW, Veller M, Kjoelbaek L, Jakobsen J, Ritz C, Raben A, Astrup A, Lorenzen JK, Larsen LH, Bügel S (2018) Effect of low energy diet for eight weeks to adults with overweight or obesity on folate, retinol, vitamin B12, D and E status and the degree of inflammation: a post hoc analysis of a randomized intervention trial. Nutr Metab (Lond) 15. https://doi.org/10.1186/S12986-018-0263-1
  21. Baltaci D, Kutlucan A, Turker Y, Yilmaz A, Karacam S, Deler H, Ucgun T, Kara IH (2013) Association of vitamin B12 with obesity, overweight, insulin resistance and metabolic syndrome, and body fat composition; primary care-based study. Med Glas (Zenica) 10: 203–210.
  22. Thomas-Valdés S, Tostes M das GV, Anunciação PC, da Silva BP, Sant’Ana HMP (2017) Association between vitamin deficiency and metabolic disorders related to obesity. Crit Rev Food Sci Nutr 57: 3332–3343. https://doi.org/10.1080/10408398.2015.1117413
  23. Kim MH, Yun KE, Kim J, Park E, Chang Y, Ryu S, Kim HL, Kim HN (2020) Gut microbiota and metabolic health among overweight and obese individuals. Sci Rep 10. https://doi.org/10.1038/S41598-020-76474-8
  24. Fangmann D, Theismann EM, Turk K, Schulte DM, Relling I, Hartmann K, Keppler JK, Knipp JR, Rehman A, Heinsen FA, Franke A, Lenk L, Freitag-Wolf S, Appel E, Gorb S, Brenner C, Seegert D, Waetzig GH, Rosenstiel P, Schreiber S, Schwarz K, Laudes M (2018) Targeted Microbiome Intervention by Microencapsulated Delayed-Release Niacin Beneficially Affects Insulin Sensitivity in Humans. Diabetes Care 41: 398–405. https://doi.org/10.2337/DC17-1967
  25. Polegato BF, Pereira AG, Azevedo PS, Costa NA, Zornoff LAM, Paiva SAR, Minicucci MF (2019) Role of Thiamin in Health and Disease. Nutr Clin Pract 34: 558–564. https://doi.org/10.1002/NCP.10234
  26. Kerns JC, Arundel C, Chawla LS (2015) Thiamin deficiency in people with obesity. Adv Nutr 6: 147–153. https://doi.org/10.3945/AN.114.007526
  27. Thornalley PJ, Babaei-Jadidi R, Al Ali H, Rabbani N, Antonysunil A, Larkin J, Ahmed A, Rayman G, Bodmer CW (2007) High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia 50: 2164–2170. https://doi.org/10.1007/S00125-007-0771-4
  28. Mazur-Bialy AI, Pocheć E (2016) Riboflavin Reduces Pro-Inflammatory Activation of Adipocyte-Macrophage Co-culture. Potential Application of Vitamin B2 Enrichment for Attenuation of Insulin Resistance and Metabolic Syndrome Development. Molecules 21. https://doi.org/10.3390/MOLECULES21121724
  29. Iacobini C, Pugliese G, Blasetti Fantauzzi C, Federici M, Menini S (2019) Metabolically healthy versus metabolically unhealthy obesity. Metabolism 92: 51–60. https://doi.org/10.1016/j.metabol.2018.11.009
  30. Chawla J, Kvarnberg D (2014) Hydrosoluble vitamins. Handb Clin Neurol 120: 891–914. https://doi.org/10.1016/B978-0-7020-4087-0.00059-0
  31. Naruta E, Buko V (2001) Hypolipidemic effect of pantothenic acid derivatives in mice with hypothalamic obesity induced by aurothioglucose. Exp Toxicol Pathol 53: 393–398. https://doi.org/10.1078/0940-2993-00205
  32. Zhou H, Zhang H, Ye R, Yan C, Lin J, Huang Y, Jiang X, Yuan S, Chen L, Jiang R, Zheng K, Cheng Z, Zhang Z, Dong M, Jin W (2022) Pantothenate protects against obesity via brown adipose tissue activation. Am J Physiol Endocrinol Metab 323: E69–E79. https://doi.org/10.1152/AJPENDO.00293.2021
  33. Haidari F, Mohammadshahi M, Zarei M, Haghighizadeh MH, Mirzaee F (2021) The Effect of Pyridoxine Hydrochloride Supplementation on Leptin, Adiponectin, Glycemic Indices, and Anthropometric Indices in Obese and Overweight Women. Clin Nutr Res 10: 230. https://doi.org/10.7762/CNR.2021.10.3.230
  34. Tong L (2013) Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci 70: 863–891. https://doi.org/10.1007/S00018-012-1096-0
  35. Filenko NA, Kolar C, West JT, Abbie Smith S, Hassan YI, Borgstahl GEO, Zempleni J, Lyubchenko YL (2011) The role of histone H4 biotinylation in the structure of nucleosomes. PLoS One 6. https://doi.org/10.1371/JOURNAL.PONE.0016299
  36. Belda E, Voland L, Tremaroli V, Falony G, Adriouch S, Assmann KE, Prifiti E, Aron-Wisnewsky J, Debédat J, Le Roy T, Nielsen T, Amouyal C, André S, Andreelli F, Blüher M, Chakaroun R, Chilloux J, Coelho LP, Dao MC, Das P, Fellahi S, Forslund S, Galleron N, Hansen TH, Holmes B, Ji B, Krogh Pedersen H, Le P, Le Chatelier E, Lewinter C, Mannerås-Holm L, Marquet F, Myridakis A, Pelloux V, Pons N, Quinquis B, Rouault C, Roume H, Salem JE, Sokolovska N, Søndertoft NB, Touch S, Vieira-Silva S, Galan P, Holst J, Gøtze JP, Køber L, Vestergaard H, Hansen T, Hercberg S, Oppert JM, Nielsen J, Letunic I, Dumas ME, Stumvoll M, Pedersen OB, Bork P, Ehrlich SD, Zucker JD, Bäckhed F, Raes J, Clément K (2022) Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism. Gut 71. https://doi.org/10.1136/GUTJNL-2021-325753
  37. Shulpekova Y, Nechaev V, Kardasheva S, Sedova A, Kurbatova A, Bueverova E, Kopylov A, Malsagova K, Dlamini JC, Ivashkin V (2021) The Concept of Folic Acid in Health and Disease. Molecules 26. https://doi.org/10.3390/MOLECULES26123731
  38. Köse S, Sözlü S, Bölükbaşi H, Ünsal N, Gezmen-Karadaǧ M (2020) Obesity is associated with folate metabolism. Int J Vitam Nutr Res 90: 353–364. https://doi.org/10.1024/0300-9831/A000602
  39. Guetterman HM, Huey SL, Knight R, Fox AM, Mehta S, Finkelstein JL (2022) Vitamin B-12 and the Gastrointestinal Microbiome: A Systematic Review. Advances in Nutrition 13: 530. https://doi.org/10.1093/ADVANCES/NMAB123
  40. Al-Musharaf S, Aljuraiban GS, Hussain SD, Alnaami AM, Saravanan P, Al-Daghri N (2020) Low Serum Vitamin B12 Levels Are Associated with Adverse Lipid Profiles in Apparently Healthy Young Saudi Women. Nutrients 12: 1–11. https://doi.org/10.3390/NU12082395
  41. Roland BC, Lee D, Miller LS, Vegesna A, Yolken R, Severance E, Prandovszky E, Zheng XE, Mullin GE (2018) Obesity increases the risk of small intestinal bacterial overgrowth (SIBO). Neurogastroenterol Motil 30. https://doi.org/10.1111/NMO.13199
  42. Lai Y, Masatoshi H, Ma Y, Guo Y, Zhang B (2022) Role of Vitamin K in Intestinal Health. Front Immunol 12. https://doi.org/10.3389/FIMMU.2021.791565
  43. Ellis JL, Karl JP, Oliverio AM, Fu X, Soares JW, Wolfe BE, Hernandez CJ, Mason JB, Booth SL (2021) Dietary vitamin K is remodeled by gut microbiota and influences community composition. Gut Microbes 13: 1–16. https://doi.org/10.1080/19490976.2021.1887721
  44. Liu M, Matuszek G, Azcarate-Peril MA, Loeser RF, Shea MK (2023) An Exploratory Case-Control Study on the Associations of Bacterially-Derived Vitamin K Forms with the Intestinal Microbiome and Obesity-Related Osteoarthritis. Curr Dev Nutr 7: 100049. https://doi.org/10.1016/J.CDNUT.2023.100049
  45. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L (2014) The role of short-chain fatty acids in health and disease. Adv Immunol 121: 91–119. https://doi.org/10.1016/B978-0-12-800100-4.00003-9
  46. Brahe LK, Astrup A, Larsen LH (2013) Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases? Obes Rev 14: 950–959. https://doi.org/10.1111/OBR.12068
  47. Amabebe E, Robert FO, Agbalalah T, Orubu ESF (2020) Microbial dysbiosis-induced obesity: role of gut microbiota in homoeostasis of energy metabolism. Br J Nutr 123: 1127–1137. https://doi.org/10.1017/S0007114520000380
  48. Beisner J, Filipe Rosa L, Kaden-Volynets V, Stolzer I, Günther C, Bischoff SC (2021) Prebiotic Inulin and Sodium Butyrate Attenuate Obesity-Induced Intestinal Barrier Dysfunction by Induction of Antimicrobial Peptides. Front Immunol 12. https://doi.org/10.3389/FIMMU.2021.678360
  49. Yang J, Keshavarzian A, Rose DJ (2013) Impact of dietary fiber fermentation from cereal grains on metabolite production by the fecal microbiota from normal weight and obese individuals. J Med Food 16: 862–867. https://doi.org/10.1089/JMF.2012.0292
  50. de la Cuesta-Zuluaga J, Mueller NT, Álvarez-Quintero R, Velásquez-Mejía EP, Sierra JA, Corrales-Agudelo V, Carmona JA, Abad JM, Escobar JS (2018) Higher Fecal Short-Chain Fatty Acid Levels Are Associated with Gut Microbiome Dysbiosis, Obesity, Hypertension and Cardiometabolic Disease Risk Factors. Nutrients 11. https://doi.org/10.3390/NU11010051
  51. Sanna S, van Zuydam NR, Mahajan A, Kurilshikov A, Vich Vila A, Võsa U, Mujagic Z, Masclee AAM, Jonkers DMAE, Oosting M, Joosten LAB, Netea MG, Franke L, Zhernakova A, Fu J, Wijmenga C, McCarthy MI (2019) Causal relationships between gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet 51: 600. https://doi.org/10.1038/S41588-019-0350-X
  52. Kaiko GE, Ryu SH, Koues OI, Collins PL, Solnica-Krezel L, Pearce EJ, Pearce EL, Oltz EM, Stappenbeck TS (2016) The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites. Cell 165: 1708–1720. https://doi.org/10.1016/J.CELL.2016.05.018
  53. Salvi PS, Cowles RA (2021) Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease. Cells 10. https://doi.org/10.3390/CELLS10071775
  54. Hou J, Xu J, Liu Y, Zhang H, Wang S, Jiao Y, Guo L, Li S (2022) Sodium butyrate inhibits osteogenesis in human periodontal ligament stem cells by suppressing smad1 expression. BMC Oral Health 22. https://doi.org/10.1186/S12903-022-02255-6
  55. Шестопалов АВ, Ганенко ЛА, Григорьева ТВ, Лайков АВ, Васильев ИЮ, Колесникова ИМ, Набока ЮЛ, Волкова НИ, Румянцев СА (2023) Адипокины и миокины как индикаторы фенотипов ожирения и их связь с показателями разнообразия микробиома кишечника. Вестн Российск гос мед унив 2023 (1): 49–58. [Shestopalov AV, Ganenko LA, Grigoryeva TV, Laikov AV, Vasilyev IYu, Kolesnikova IM, Naboka Yu, Volkova NI, Roumiantsev SA (2023) Adipokines and myokines as indicators of obese phenotypes and their association with the gut microbiome diversity indices. Bull Russ State Med Univ 2023 (1): 49–58. (In Russ)]. https://doi.org/10.24075/vrgmu.2023.004
  56. Shi N, Li N, Duan X, Niu H (2017) Interaction between the gut microbiome and mucosal immune system. Mil Med Res 4. https://doi.org/10.1186/S40779-017-0122-9

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