Probióticos. Introducción y definiciones

26.02.2018
Probiotyki – aktualny stan wiedzy i zalecenia dla praktyki klinicznej
Hanna Szajewska

Szajewska H., “Probiotyki – aktualny stan wiedzy i zalecenia dla praktyki klinicznej”, Med. Prakt., 2017, 7-8: 19-37.

Nota del editor: El artículo se basa en una ponencia presentada durante la 16.a Conferencia Nacional Formativa de la Sociedad Polaca de Medicina Internista “Avances en la medicina interna” (Interna 2017).

Siglas y abreviaturas: ACG — American Gastroenterological Society (Sociedad Estadounidense de Gastroenterología), ESPGHAN — European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (Sociedad Europea de Gastroenterología, Hepatología y Nutrición Pediátrica), IC — intervalo de confianza, RCT (randomized controlled trial) — prueba controlada aleatorizada, RR — riesgo relativo

Introducción

El mercado ofrece decenas de probióticos, si bien la decisión sobre su uso y la elección de un preparado adecuado a veces constituyen un problema. No todos los probióticos han sido examinados en pruebas fidedignas, lo cual conlleva dudas sobre su eficacia. Aquí y en la segunda parte del presente artículo presentamos la información básica sobre la microbiota y los datos acerca de la eficacia clínica y seguridad del uso de los probióticos. Con este fin se ha revisado la base de datos médicos MEDLINE y Cochrane Library (hasta el junio de 2017). El análisis aborda pruebas controladas aleatorizadas (RCT) o sus metaanálisis, publicados durante los últimos 5 años (2012-2017). Dentro de lo posible presentamos también las opiniones de las sociedades científicas.

Definiciones

Microbiota y microbioma

En Europa el término “microbiota” designa todos los microorganismos (bacterias, eucariotas y virus) presentes en el organismo humano (sobre todo en el tracto digestivo), además de sus genes.1 El término “microbioma” hace referencia solamente a los genes pertenecientes a la microbiota. En otras partes del mundo (p. ej. en EE. UU) microbioma es un sinónimo de microbiota. En la literatura científica los términos “microbiota“/”microbioma” han sustituido completamente el término “microflora”, que se refiere al mundo de la flora. Se estima que en la composición de la microbiota se distinguen aprox. 1000 especies de bacterias, pero tan solo 150-170 son dominantes en cada persona. El número de genes de los microorganismos asciende a 3 millones, es decir, supera 150 veces el número de genes del ser humano.2

Disbiosis

El término “disbiosis” se refiere al desequilibrio en la composición y función de los microorganismos. La etiopatogenia de varias enfermedades, entre otras, de la diarrea asociada al uso de los antibióticos, síndrome del intestino irritable, enteritis inespecífica, alergias, diabetes mellitus y obesidad, se relaciona con los trastornos en la microbiota.3-6 La disbiosis parece jugar un papel importante también en los trastornos del espectro de autismo, así como en la depresión, esquizofrenia y enfermedades neurodegenerativas. En todos los casos hablamos solamente de las asociaciones y no de las relaciones causa-efecto documentadas. No se dispone de un “patrón” claro de los trastornos de la microbiota característicos para cada una de las enfermedades. La característica más consistente es la disminución en la diversidad de la microbiota. Es raro o incluso imposible que el desequilibrio de la microbiota sea el único factor etiológico de una enfermedad.

Bibliografía:

1. Lozupone C.A., Stombaugh J.I., Gordon J.I. y cols., Diversity, stability and resilience of the human gut microbiota, Nature, 2012, 489: 220–230.
2. Arumugam M., Raes J., Pelletier E. y cols., MetaHIT Consortium. Enterotypes of the human gut microbiome, Nature, 2011, 473: 174–180.
3. deVos W.M., de Vos E.A.: Role of the intestinal microbiome in health and disease: from correlation to causation, Nutr. Rev., 2012, 70 (suppl. 1): S45–S56.
4. Everard A., Belzer C., Geurts L. y cols., Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity, Proc. Natl. Acad. Sci. USA, 2013, 110: 9066–9071.
5. Gilbert J.A., Krajmalnik-Brown R., Porazinska D.L. y cols., Toward effective probiotics for autism and other neurodevelopmental disorders, Cell, 2013, 155: 1446–1448.
6. Lynch S.V., Pedersen O.: The Human Intestinal Microbiome in Health and Disease, N. Engl. J. Med., 2016, 375: 2369–2379.
7. Foxx-Orenstein A.E., Chey W.D.: Manipulation of the gut microbiota as a novel treatment strategy for gastrointestinal disorders, Am. J. Gastroenterol. Suppl., 2012, 1: 41–46.
8. Hill C., Guarner F., Reid G. y cols., Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic,. Nat. Rev. Gastroenterol. Hepatol., 2014, 11: 506–514.
9. FAO/WHO Expert Consultation: Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria, 2001.
10. Floch MH, Walker WA, Guandalini S. y cols., Recommendations for probiotic use – 2008, J. Clin. Gastroenterol., 2008, 42 (suppl. 2): S104–S108.
11. Ouwehand A.C.: A review of dose-responses of probiotics in human studies, Benef. Microbes, 2017, 8: 143–151.
12. Kolodziej M., Lukasik J.M., Szajewska H.: Mikroenkapsulacja probiotyków, Pediatria Pol., 2017 (avance de la edición impresa).
13. Szajewska H., Fordymacka A., Bardowski J. y cols., Microbiological and genetic analysis of probiotic products licensed for medicinal purposes, Med. Sci. Monit., 2004, 10: 346–350.
14. Hamilton-Miller J.M., Shah S., Smith C.T.: „Probiotic” remedies are not what they seem, BMJ, 1996, 312: 55–56.
15. Gilliland S.E., Speck M.L.: Enumeration and identity of lactobacilli in dietary products, J. Food Prot., 1977, 40: 760–762.
16. Hoa N.T., Baccigalupi L., Huxham A. y cols., Characterization of Bacillus species used for oral bacteriotherapy and bacterioprophylaxis of gastrointestinal disorders, Appl. Envir. Microbiol., 2000, 66: 5241–5247.
17. Kolacek S., Hojsak I., Canani R.B. i wsp., ESPGHAN Working Group for Probiotics and Prebiotics: Commercial probiotic products: a call for improved quality control. A Position Paper by the ESPGHAN Working Group for Probiotics and Prebiotics, J. Pediatr. Gastroenterol. Nutr., 2017, doi: 10.1097/MPG.0 000 000 000 001 603.
18. Szajewska H.: Advances and limitations of evidence-based medicine – impact for probiotics, Ann. Nutr. Metab., 2010, 57 (suppl.): 6–9.
19. Szajewska H., Guarino A, Hojsak I. y cols., Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics, J. Pediatr. Gastroenterol. Nutr., 2014, 58: 531–539.
20. Guarino A., Ashkenazi S., Gendrel D. y cols., European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases Evidence-based Guidelines for the Management of Acute Gastroenteritis in Children in Europe: update 2014, J. Pediatr. Gastroenterol. Nutr., 2014, 59: 132–152.
21. http://www.worldgastroenterology.org/UserFiles/file/guidelines/Probiotics-and-prebiotics-English2017. pdf
22. Riddle M.S., DuPont H.L., Connor B.A., ACG Clinical Guideline: Diagnosis, Treatment, and Prevention of Acute Diarrheal Infections in Adults, Am. J. Gastroenterol., 2016, 111: 602–622.
23. Hempel S., Newberry S.J., Maher A.R. y cols., Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis, JAMA, 2012, 307: 1959–1969.
24. Szajewska H., Kolodziej M.: Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea, Aliment. Pharmacol. Ther., 2015, 42: 793–801.
25. Szajewska H., Kolodziej M.: Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults, Aliment. Pharmacol. Ther., 2015, 42: 1149–1157.
26. Szajewska H., Canani R.B., Guarino A. y cols., ESPGHAN Working Group for Probiotics & Prebiotics: Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Children, J. Pediatr. Gastroenterol. Nutr., 2016, 62: 495–506
27. Surawicz C.M., Brandt L.J., Binion D.G. y cols., Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections, Am. J. Gastroenterol., 2013, 108: 478–498.
28. Johnston B.C., Ma S.S., Goldenberg J.Z. y cols., Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis, Ann. Intern. Med., 2012, 157: 878–888.
29. Goldenberg Joshua Z., Ma Stephanie S.Y., Saxton Jane D. y cols., Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children, Cochrane Database Syst. Rev., 2013, 5: CD006 095.
30. Lau C.S., Chamberlain R.S.: Probiotics are effective at preventing Clostridium difficile-associated diarrhea: a systematic review and meta-analysis, Int. J. Gen. Med., 2016, 9: 27–37.
31. Shen N.T., Maw A., Tmanova L.L. y cols., Timely Use of Probiotics in Hospitalized Adults Prevents Clostridium difficile Infection: A Systematic Review With Meta-Regression Analysis, Gastroenterology, 2017 Feb 10. pii: S0016-5085(17)30 136–1.
32. McFarland L.V., Deciphering meta-analytic results: a mini-review of probiotics for the prevention of paediatric antibiotic-associated diarrhoea and Clostridium difficile infections, Benef. Microbes, 2015, 6: 189–194.
33. Debast S.B., Bauer M.P., Kuijper E.J., European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection, Clin. Microbiol. Infect., 2014, 20 (suppl. 2): 1–26.
34. https://wwwnc.cdc.gov/travel/yellowbook/2016/the-pre-travel-consultation/travelers-diarrhea
35. Kollaritsch H., Holst H., Grobara P. y cols., [Prevention of traveler’s diarrhea with SaccharomyceS. boulardii. Results of a placebo controlled double-blind study], Fortschr. Med., 1993, 111: 152–156.
36. Kollaritsch H.H., Kremsner P., Wiedermann G. y cols., Prevention of traveller’s diarrhea: comparison of different non-antibiotic preparations, Travel Med. Int., 1989, 9–17.
37. Malfertheiner P., Megraud F., O’Morain C.A. y cols., European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report, Gut, 2017, 66: 6–30.
38. Zhang M.M., Qian W., Qin Y.Y. y cols., Probiotics in Helicobacter pylori eradication therapy: a systematic review and meta-analysis, World J. Gastroenterol., 2015, 21: 4345–4357.
39. Dang Y., Reinhardt J.D., Zhou X., Zhang G.: The effect of probiotics supplementation on Helicobacter pylori eradication rates and side effects during eradication therapy: a meta-analysis, PloS One, 2014, 9 (11): e111 030
40. Szajewska H., Horvath A., Kolodziej M., Systematic review with meta-analysis: Saccharomyces boulardii supplementation and eradication of Helicobacter pylori infection, Aliment. Pharmacol. Ther., 2015, 41: 1237–1245.
41. Jones N.L., Koletzko S., Goodman K. y cols., Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016), J. Pediatr. Gastroenterol. Nutr., 2017, 64: 991–1003.
42. Ford A.C., Quigley E.M., Lacy B.E. y cols., Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis, Am. J. Gastroenterol., 2014, 109: 1547–1561.
43. Ford A.C., Moayyedi P., Lacy B.E. y cols., Task Force on the Management of Functional Bowel Disorders. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation, Am. J. Gastroenterol., 2014, 109 (suppl 1): S2–S26.
44. National Institute for Health and Clinical Excellence (NICE). Irritable bowel syndrome in adults: Diagnosis and management of irritable bowel syndrome in primary care. http:// publications.nice.org.uk/irritable-bowel-syndrome-in-adults-cg61
45. Layer P., Andresen V., Pehl C. y cols., Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten, Deutschen Gesellschaft für Neurogastroenterologie und Motilität. [Irritable bowel syndrome: German consensus guidelines on definition, pathophysiology and management], Z. Gastroenterol., 2011, 49: 237–293.
46. Whorwell P.J, Altringer L., Morel J. y cols., Efficacy of an encapsulated probiotic Bifidobacterium infantis 35 624 in women with irritable bowel syndrome, Am. J. Gastroenterol., 2006, 101: 1581–1590.
47. Ducrotté P., Sawant P., Jayanthi V., Clinical trial: Lactobacillus plantarum 299v (DSM 9843) improves symptoms of irritable bowel syndrome, World J. Gastroenterol., 2012, 18: 4012–4018.
48. Horvath A., Dziechciarz P., Szajewska H.: Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood, Aliment. Pharmacol. Ther., 2011, 33: 1302–1310.
49. Kruis W., Schütz E., Fric P. y cols., Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis, Aliment. Pharmacol. Ther., 1997, 11: 853–858.
50. Rembacken B.J., Snelling A.M., Hawkey P.M. y cols., Non-pathogenic Escherichia coli vs mesalazine for the treatment of ulcerative colitis: a randomised trial, Lancet, 1999, 354: 635–639.
51. Kruis W., Fric P., Pokrotnieks J. y cols., Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine, Gut, 2004, 53: 1617–1623.
52. Henker J., Müller S., Laass M.W. y cols., Probiotic Escherichia coli Nissle 1917 [EcN] for successful remission maintenance of ulcerative colitis in children and adolescents: an open-label pilot study, Z. Gastroenterol., 2008, 46: 874–875.
53. Harbord M., Eliakim R., Bettenworth D. y cols., European Crohn’s and Colitis Organisation [ECCO]. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management, J. Crohns Colitis, 2017, doi: 10.1093/ ecco-jcc/jjx009
54. Turner D., Levine A., Escher J.C. y cols., European Crohn’s and Colitis Organization, European Society for Paediatric Gastroenterology, Hepatology, and Nutrition. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines, J. Pediatr. Gastroenterol. Nutr., 2012, 55: 340–361.
55. Forbes A., Escher J., Hébuterne X. y cols., ESPEN guideline: Clinical nutrition in inflammatory bowel disease, Clin. Nutr., 2017, 36: 321–347.
56. Dignass A., Van Assche G. y cols., European Crohn’s and Colitis Organisation (ECCO). The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: current management, J. Crohns Colitis, 2010, 4: 28–62. Erratum in: J. Crohns Colitis, 2010, 4: 353. Dosage error in article text.
57. Ruemmele F.M., Veres G., Kolho K.L. y cols., ECCO/ESPGHAN. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease, J. Crohns Colitis, 2014, 8: 1179–1207.
58. Gomollón F., Dignass A., Annese V. y cols., ECCO. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management, J. Crohns Colitis, 2017, 11: 3–25.
59. Tabbers M.M., DiLorenzo C., Berger M.Y. y cols., European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, North American Society for Pediatric Gastroenterology. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN, J. Pediatr. Gastroenterol. Nutr., 2014, 58: 258–274.
60. Besselink M.G., van Santvoort H.C., Buskens E. y cols., Dutch Acute Pancreatitis Study Group. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial, Lancet, 2008, 371: 651–659.
61. Poropat G., Giljaca V., Hauser G., Štimac D.: Enteral nutrition formulations for acute pancreatitis, Cochrane Database Syst. Rev., 2015, 3: CD010 605.
62. Tenner S., Baillie J., DeWitt J., Vege S.S., American College of Gastroenterology. American College of Gastroenterology guideline: management of acute pancreatitis, Am. J. Gastroenterol., 2013, 108: 1400–1415, 1416.
63. Kim S.O., Ah Y.M., Yu Y.M. y cols., Effects of probiotics for the treatment of atopic dermatitis: a meta-analysis of randomized controlled trials, Ann. Allergy Asthma Immunol., 2014, 113: 217–226.
64. Betsi G.I., Papadavid E., Falagas M.E., Probiotics for the treatment or prevention of atopic dermatitis: a review of the evidence from randomized controlled trials, Am. J. Clin. Dermatol., 2008, 9: 93–103.
65. Michail S.K., Stolfi A., Johnson T., Onady G.M., Efficacy of probiotics in the treatment of pediatric atopic dermatitis: a meta-analysis of randomized controlled trials, Ann. Allergy Asthma Immunol., 2008, 101: 508–516.
66. Lee J., Seto D., Bielory L., Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis, J. Allergy Clin. Immunol., 2008, 121: 116–121.e11
67. Boyle R.J., Bath-Hextall F.J., Leonardi-Bee J. y cols., Probiotics for treating eczema, Cochrane Database Syst. Rev., 2008, 4: CD006 135
68. Zajac A.E., Adams A.S., Turner J.H., A systematic review and meta-analysis of probiotics for the treatment of allergic rhinitis, Int. Forum Allergy Rhinol., 2015, 5: 524–532.
69. Peng Y., Li A., Yu L., Qin G., The role of probiotics in prevention and treatment for patients with allergic rhinitis: a systematic review, Am. J. Rhinol. Allergy, 2015, 29: 292–298.
70. Das R.R., Singh M., Shafiq N.: Probiotics in treatment of allergic rhinitis, World Allergy Organ J., 2010, 3: 239–244.
71. Vliagoftis H., Kouranos V.D., Betsi G.I., Falagas M.E., Probiotics for the treatment of allergic rhinitis and asthma: systematic review of randomized controlled trials, Ann. Allergy Asthma Immunol., 2008, 101: 570–579.
72. He M., Wang T., Zhang H.P. y cols., Probiotics for prevention and treatment of bronchial asthma: a systematic review, Chin. J. Evid. Based Med., 2012, 12: 460–469.
73. Bäckhed F., Ding H., Wang T. y cols., The gut microbiota as an environmental factor that regulates fat storage, Proc. Natl. Acad. Sci. USA, 2004, 101: 15 718–15 723.
74. Bäckhed F., Manchester J.K., Semenkovich C.F., Gordon J.I., Mechanisms underlying the resistance to diet-induced obesity in germ-free mice, Proc. Natl. Acad. Sci. USA, 2007, 104: 979–984.
75. Zhang Q., Wu Y., Fei X., Effect of probiotics on body weight and body-mass index: a systematic review and meta-analysis of randomized, controlled trials, Int. J. Food Sci. Nutr., 2015, 67: 571–580.
76. Weiss B., Bujanover Y., Yahav Y. y cols., Probiotic supplementation affects pulmonary exacerbations in patients with cystic fibrosis: a pilot study, Pediatr. Pulmonol., 2010, 45: 536–540.
77. Bruzzese E., Raia V., Spagnuolo M.I. y cols., Effect of Lactobacillus GG supplementation on pulmonary exacerbations in patients with cystic fibrosis: a pilot study, Clin. Nutr., 2007, 26: 322–328.
78. Parracho H.M.R.T., Gibson G.R., Knott F. y cols., A double blind, placebo-controlled, crossover-designed probiotic feeding study in children diagnosed with autistic spectrum disorders, Int. J. Probiotics Prebiotics, 2010, 5: 69–74.
79. Akbari E., Asemi Z., Daneshvar Kakhaki R. y cols., Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: a randomized, double-blind and controlled trial, Front Aging Neurosci., 2016, 8: 256.
80. Näse L., Hatakka K., Savilahti E. y cols., Effect of Long-Term Consumption of a Probiotic Bacterium, Lactobacillus rhamnosus GG, in Milk on Dental Caries and Caries Risk in Children, Caries Res., 2001, 35: 412–420.
81. Bo L., Li J., Tao T. y cols., Probiotics for preventing ventilator-associated pneumonia, Cochrane Database Syst. Rev., 2014, 10: CD009 066.
82. Kontiokari T., Sundqvist K., Nuutinen M. y cols., Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women, BMJ, 2001, 322: 1571.
83. Smecuol E., Hwang H.J., Sugai E. y cols., Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis natren life start strain super strain in active celiac disease, J. Clin. Gastroenterol., 2013, 47: 139–147.
84. Olivares M., Castillejo G., Varea V., Sanz Y., Double-blind, randomised, placebo-controlled intervention trial to evaluate the effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed coeliac disease, Br. J. Nutr., 2014, 112: 30–40.
85. Quagliariello A., Aloisio I., Bozzi Cionci N. y cols., Effect of Bifidobacterium breve on the Intestinal Microbiota of Coeliac Children on a Gluten Free Diet: A Pilot Study, Nutrients, 2016, pii: E660.
86. Klemenak M., Dolinšek J., Langerholc T. y cols., Administration of Bifidobacterium breve Decreases the Production of TNF-α in Children with Celiac Disease, Dig. Dis. Sci., 2015, 60: 3386–3392.
87. Fuccio L., Guido A.: Probiotics supplementation for the prevention of gastrointestinal radiation-induced side effects: the time is now, Am. J. Gastroenterol., 2013, 108: 277.
88. Fuccio L., Guido A., Eusebi L.H. y cols., Effects of probiotics for the prevention and treatment of radiation-induced diarrhea, J. Clin. Gastroenterol., 2009, 43: 506–513.
89. Wang Y.H., Yao N., Wei K.K. y cols., The efficacy and safety of probiotics for prevention of chemoradiotherapy-induced diarrhea in people with abdominal and pelvic cancer: a systematic review and meta-analysis, Eur. J. Clin. Nutr., 2016, 70: 1246–1253.
90. Aller R., De Luis D.A., Izaola O. y cols., Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial, Eur. Rev. Med. Pharmacol. Sci., 2011, 15: 1090–1095.
91. Malaguarnera M., Vacante M., Antic T. y cols., Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis, Dig. Dis. Sci., 2012, 57: 545–553.
92. http://www.efsa.europa.eu/en/topics/topic/qps.htm
93. http://www.accessdata.fda.gov/scripts/fdcc/?set=GRASNotices
94. Boyle R.J., Robins-Browne R.M., Tang M.L.K., Probiotic use in clinical practice: what are the risks?, Am. J. Clin. Nutr., 2006, 83: 1256–1264.

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