Obese mice fed a diet supplemented with enzyme-treated wheat bran display marked shifts in the liver metabolome concurrent with altered gut bacteria

Journal of Nutrition

Volumn 146, Issue 12, 2016, Pages 2445-2460

  Kieffer, Dorothy A ^a,b   Piccolo, Brian D ^c,d   Marco, Maria L ^a   Kim, Eun Bae ^a,e   Goodson, Michael L ^a   Keenan, Michael J ^f   Dunn, Tamara N ^a,b   Knudsen, Knud Erik Bach ^g   Adams, Sean H ^a,c,d   Martin, Roy J ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b AGRICULTURAL RESEARCH SERVICE   (United States)

^c UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

^d UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

^e Kangwon National University   (South Korea)

^f LOUISIANA STATE UNIVERSITY AGRICULTURAL CENTER   (United States)

^g AARHUS UNIVERSITY   (Denmark)

Author keywords

Dietary fiber; Gut microbiota; Metabolomics; Transcriptomics; Xenobiotic

Indexed keywords

1,5 ANHYDROSORBITOL; 2 HYDROXYGLUTARIC ACID; 3 HYDROXYBUTYRIC ACID; ALPHA TOCOPHEROL; ARACHIDONIC ACID; ASPARTIC ACID; CARBOHYDRATE; CREATININE; CYSTEINE; DECANOIC ACID; FATTY ACID; FRUCTOSE; FUCOSE; GLUCOSE; GLUCURONIC ACID; GLUTATHIONE; GLYCEROL STEARATE; INSULIN; LINOLEIC ACID; METHIONINE SULFOXIDE; NONANOIC ACID; OCTANOIC ACID; REACTIVE OXYGEN METABOLITE; RHAMNOSE; RIBITOL; SITOSTEROL; STARCH; TAGATOSE; TRIACYLGLYCEROL; XYLITOL;

ACTINOBACTERIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BACTEROIDETES; BODY WEIGHT; CALORIC INTAKE; CECUM; CONTROLLED STUDY; DIET INDUCED OBESITY; DIET SUPPLEMENTATION; ENZYME TREATED WHEAT BRAN; FATTY ACID BLOOD LEVEL; FATTY LIVER; FIRMICUTES; GENE EXPRESSION; GLUCOSE BLOOD LEVEL; INSULIN BLOOD LEVEL; INTESTINE FLORA; LIPID DIET; LIPID METABOLISM; LIVER METABOLISM; LIVER WEIGHT; MALE; METABOLOME; MOLLICUTES; MOUSE; NONHUMAN; OBESITY; ORAL GLUCOSE TOLERANCE TEST; PROTEOBACTERIA; TRIACYLGLYCEROL BLOOD LEVEL; VERRUCOMICROBIA; WHEAT BRAN; ANALYSIS; ANIMAL; ANIMAL FOOD; BACTERIUM; C57BL MOUSE; CLASSIFICATION; DIET; DIETARY FIBER; DIETARY SUPPLEMENT; GASTROINTESTINAL TRACT; GENE EXPRESSION REGULATION; LIVER; METABOLISM; MICROBIOLOGY;

ADIPOSITY; ANIMAL FEED; ANIMALS; BACTERIA; DIET; DIETARY FIBER; DIETARY SUPPLEMENTS; GASTROINTESTINAL TRACT; GENE EXPRESSION REGULATION; LIVER; MALE; MICE; MICE, INBRED C57BL; OBESITY;

EID: 84997312148     PISSN: 00223166     EISSN: 15416100     Source Type: Journal    
DOI: 10.3945/jn.116.238923     Document Type: Article

References (91)

1. Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obesity 2008;32:1431-7.
2. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:274-85.
3. Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr 2013;162:496-500, e1.
4. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-53.
5. Pal S, Khossousi A, Binns C, Dhaliwal S, Ellis V. The effect of a fibre supplement compared to a healthy diet on body composition, lipids, glucose, insulin and other metabolic syndrome risk factors in overweight and obese individuals. Br J Nutr 2011;105:90-100.
6. Babiker R, Merghani TH, Elmusharaf K, Badi RM, Lang F, Saeed AM. Effects of gum arabic ingestion on body mass index and body fat percentage in healthy adult females: two-arm randomized, placebo controlled, double-blind trial. Nutr J 2012;11:111.
7. Robertson MD, Wright JW, Loizon E, Debard C, Vidal H, Shojaee-Moradie F, Russell-Jones D, Umpleby AM. Insulin-sensitizing effects on muscle and adipose tissue after dietary fiber intake in men and women with metabolic syndrome. J Clin Endocrinol Metab 2012;97:3326-32.
8. Wang J, Cao Y, Wang C, Sun B. Wheat bran xylooligosaccharides improve blood lipid metabolism and antioxidant status in rats fed a high-fat diet. Carbohydr Polym 2011;86:1192-7.
9. King DE, Mainous AG III, Lambourne CA. Trends in dietary fiber intake in the United States, 1999-2008. J Acad Nutr Diet 2012;112:642-8.
10. USDA. Dietary guidelines for Americans 2010. 7th ed. Washington (DC): USDA; 2010.
11. Delzenne NM, Neyrinck AM, Cani PD. Gut microbiota and metabolic disorders: how prebiotic can work? Br J Nutr 2013;109(Suppl 2):S81-5.
12. Graf D, Di Cagno R, Fak F, Flint HJ, Nyman M, Saarela M, Watzl B. Contribution of diet to the composition of the human gut microbiota. Microb Ecol Health Dis 2015;26.
13. Gill SR, Pop M, DeBoy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE. Metagenomic analysis of the human distal gut microbiome. Science 2006;312:1355-9.
14. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464 (7285):59-65. [cited 2014 Aug 24]. Available from: http://www.nature. com/nature/journal/v464/n7285/suppinfo/nature08821_S1.html.
15. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014;505:559-63.
16. Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004;101:15718-23.
17. Keenan MJ, Zhou J, McCutcheon KL, Raggio AM, Bateman HG, Todd E, Jones CK, Tulley RT, Melton S, Martin RJ, et al. Effects of resistant starch, a non-digestible fermentable fiber, on reducing body fat. Obesity (Silver Spring) 2006;14:1523-34
18. Jensen MT, Cox RP, Jensen BB. Microbial production of skatole in the hind gut of pigs given different diets and its relation to skatole deposition in backfat. Anim Sci 1995;61:293-304.
19. Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013;62:1787-94.
20. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 2009;106:3698-703.
21. Ingerslev AK, Theil PK, Hedemann MS, Laerke HN, Bach Knudsen KE. Resistant starch and arabinoxylan augment SCFA absorption, but affect postprandial glucose and insulin responses differently. Br J Nutr 2014;111:1564-76.
22. Thomas AP, Dunn TN, Oort PJ, Grino M, Adams SH. Inflammatory phenotyping identifies CD11d as a gene markedly induced in white adipose tissue in obese rodents and women. J Nutr 2011;141:1172-80.
23. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957;226:497-509.
24. Ali SF, LeBel CP, Bondy SC. Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity. Neurotoxicology 1992;13:637-48.
25. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-75.
26. Barry KA, Wojcicki BJ, Bauer LL, Middelbos IS, Vester Boler BM, Swanson KS, Fahey GC. Adaptation of healthy adult cats to select dietary fibers in vivo affects gas and short-chain fatty acid production from fiber fermentation in vitro. J Anim Sci 2011;89:3163-9.
27. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Lozupone CA, Turnbaugh PJ, Fierer N, Knight R. Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci USA 2011;108(Suppl 1):4516-22.
28. Yin X, Yan Y, Kim EB, Lee B, Marco ML. Short communication: effect of milk and milk containing Lactobacillus casei on the intestinal microbiota of mice. J Dairy Sci 2014;97:2049-55.
29. Bokulich NA, Subramanian S, Faith JJ, Gevers D, Gordon JI, Knight R, Mills DA, Caporaso JG. Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing. Nat Methods 2013;10:57-9.
30. Magoc T, Salzberg SL. FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics 2011;27:2957-63.
31. DeSantis TZ, Hugenholtz P, Larsen N, Rojas M, Brodie EL, Keller K, Huber T, Dalevi D, Hu P, Andersen GL. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol 2006;72:5069-72.
32. Fiehn O, Kind T. Metabolite profiling in blood plasma. Methods Mol Biol 2007;358:3-17.
33. Fiehn O, Wohlgemuth G, Scholz M. Setup and annotation of metabolomic experiments by integrating biological and mass spectrometric metadata. In: Ludäscher B, Raschid L, editors. Data integration in the life sciences. Berlin, Heidelberg (Germany): Springer; 2005. p. 224-39.
34. Scholz M, Fiehn O. SetupX-a public study design database for metabolomic projects. Stanford (CA): Shriram Center for BioE & ChemE. Pac Symp Biocomput 2007:169-80.
35. Zhang B, Kirov S, Snoddy J. WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res 2005;33(Web Server issue):W741-8.
36. Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res 2013;41(Web Server issue):W77-83.
37. Oort PJ, Warden CH, Baumann TK, Knotts TA, Adams SH. Characterization of Tusc5, an adipocyte gene co-expressed in peripheral neurons. Mol Cell Endocrinol 2007;276:24-35.
38. R Core Team. R: a language and environment for statistical computing. Vienna (Austria): R Foundation for Statistical Computing; 2014.
39. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol 1995;57:289-300.
40. Mevik B, Wehrens, R., Liland, KH. Pls: partial least squares and principal component regression. J Stat Software; 2013.
41. Komsta L. Outliers: tests for outliers. R package version 0.14. [Internet]; 2011 [cited 2014 Aug 8]. Available from: http://CRAN.Rproject. org/package=outliers.
42. Wong J. Imputation: imputation. R package version 2.0.1 [Internet]. [cited 2014 Aug 8]. Available from: http://CRAN.R-project.org/package=imputation.
43. Mehmood T, Liland KH, Snipen L, Sæbø S. A review of variable selection methods in partial least squares regression. Chemom Intell Lab Syst 2012;118:62-9.
44. Wold S, Sjöström M, Eriksson L. PLS-regression: a basic tool of chemometrics. Chemom Intell Lab Syst 2001;58:109-30.
45. Canty A, Ripley B. Boot: Bootstrap R (S-Plus) functions. R package version 2.0.1. [Internet]; 2015 [cited 2015 Sep 15]. Available from: https://cran.r-project.org/package=boot.
46. Neyrinck AM, Van Hee VF, Piront N, De Backer F, Toussaint O, Cani PD, Delzenne NM. Wheat-derived arabinoxylan oligosaccharides with prebiotic effect increase satietogenic gut peptides and reduce metabolic endotoxemia in diet-induced obese mice. Nutr Diabetes 2012;2:e28.
47. Neyrinck AM, Possemiers S, Druart C, Van de Wiele T, De Backer F, Cani PD, Larondelle Y, Delzenne NM. Prebiotic effects of wheat arabinoxylan related to the increase in bifidobacteria, Roseburia and Bacteroides/Prevotella in diet-induced obese mice. PLoS One 2011;6: e20944.
48. Lu ZX, Walker KZ, Muir JG, O'Dea K. Arabinoxylan fibre improves metabolic control in people with Type II diabetes. Eur J Clin Nutr 2004;58:621-8.
49. Broekaert WF, Courtin CM, Verbeke K, Van de Wiele T, Verstraete W, Delcour JA. Prebiotic and other health-related effects of cereal-derived arabinoxylans, arabinoxylan-oligosaccharides, and xylooligosaccharides. Crit Rev Food Sci Nutr 2011;51:178-94.
50. Zhang S, Li W, Smith CJ, Musa H. Cereal-derived arabinoxylans as biological response modifiers: extraction, molecular features, and immunestimulating properties. Crit Rev Food Sci Nutr 2015;55:1035-52.
51. Kristensen M, Jensen MG, Aarestrup J, Petersen K, Søndergaard L, Mikkelsen MS, Astrup A. Flaxseed dietary fibers lower cholesterol and increase fecal fat excretion, but magnitude of effect depend on food type. Nutr Metab (Lond) 2012;9.
52. Reddy JK, Mannaerts GP. Peroxisomal lipid metabolism. Annu Rev Nutr 1994;14:343-70.
53. Lian J, Wei E, Wang SP, Quiroga AD, Li L, Di Pardo A, van der Veen J, Sipione S, Mitchell GA, Lehner R. Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis in mice. Hepatology 2012;56:2154-62.
54. Xu S, Jay A, Brunaldi K, Huang N, Hamilton JA. CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry 2013;52:7254-61.
55. Hunt MC, Alexson SEH. The role acyl-CoA thioesterases play in mediating intracellular lipid metabolism. Prog Lipid Res 2002;41:99-130.
56. Ellis JM, Bowman CE, Wolfgang MJ. Metabolic and tissue-specific regulation of acyl-CoA metabolism. PLoS One 2015;10.
57. Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 2000;105:1067-75.
58. Jang H-H, Park M-Y, Kim H-W, Lee Y-M, Hwang K-A, Park J-H, Park D-S, Kwon O. Black rice (Oryza sativa L.) extract attenuates hepatic steatosis in C57BL/6 J mice fed a high-fat diet via fatty acid oxidation. Nutr Metab (Lond) 2012;9:27.
59. Hoek-van den Hil EF, Keijer J, Bunschoten A, Vervoort JJ, Stankova B, Bekkenkamp M, Herreman L, Venema D, Hollman PC, Tvrzicka E, et al. Quercetin induces hepatic lipid omega-oxidation and lowers serum lipid levels in mice. PLoS One 2013;8:e51588.
60. Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1-22.
61. van den Bosch HM, Bunger M, de Groot P, van der Meijde J, Hooiveld G, Muller M. Gene expression of transporters and phase I/II metabolic enzymes in murine small intestine during fasting. BMC Genomics 2007;8:267.
62. Nordlie RC, Foster JD, Lange AJ. Regulation of glucose production by the liver. Annu Rev Nutr 1999;19:379-406.
63. She P, Shiota M, Shelton KD, Chalkley R, Postic C, Magnuson MA. Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism. Mol Cell Biol 2000;20:6508-17.
64. Luo X, Zhang Y, Ruan X, Jiang X, Zhu L, Wang X, Ding Q, Liu W, Pan Y, Wang Z, et al. Fasting-induced protein phosphatase 1 regulatory subunit contributes to postprandial blood glucose homeostasis via regulation of hepatic glycogenesis. Diabetes 2011;60: 1435-45.
65. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010; 107:14691-6.
66. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006;444(7122):1022-3. [cited 2014 Sep 18]. Available from: http://www.nature.com/nature/journal/v444/n7122/suppinfo/4441022a_S1.html.
67. Kaoutari AE, Armougom F, Gordon JI, Raoult D, Henrissat B. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nat Rev Micro 2013;11(7):497-504. [cited 2014 Sep 18]. Available from: http://www.nature.com/nrmicro/journal/v11/n7/abs/nrmicro3050.html#supplementary-information.
68. Koropatkin NM, Cameron EA, Martens EC. How glycan metabolism shapes the human gut microbiota. Nat Rev Microbiol 2012;10:323-35.
69. Lee SM, Han HW, Yim SY. Beneficial effects of soy milk and fiber on high cholesterol diet-induced alteration of gut microbiota and inflammatory gene expression in rats. Food Funct 2015;6: 492-500.
70. Zhong Y, Nyman M, Fak F. Modulation of gut microbiota in rats fed high-fat diets by processing whole-grain barley to barley malt. Mol Nutr Food Res 2015;59:2066-76.
71. Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol 2004;54:1469-76.
72. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 2013;110: 9066-71.
73. Tachon S, Zhou J, Keenan M, Martin R, Marco ML. The intestinal microbiota in aged mice is modulated by dietary resistant starch and correlated with improvements in host responses. FEMS Microbiol Ecol 2013;83:299-309.
74. Jakobsdottir G, Xu J, Molin G, Ahrné S, Nyman M. High-fat diet reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects. PLoS One 2013;8:e80476.
75. Earle KA, Billings G, Sigal M, Lichtman JS, Hansson GC, Elias JE, Amieva MR, Huang KC, Sonnenburg JL. Quantitative imaging of gut microbiota spatial organization. Cell Host Microbe 2015;18: 478-88.
76. Sakata T. Stimulatory effect of short-chain fatty acids on epithelial cell proliferation in the rat intestine: a possible explanation for trophic effects of fermentable fibre, gut microbes and luminal trophic factors. Br J Nutr 1987;58:95-103.
77. Zhou J, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Shen L, Danna SC, Tripathy S, Hegsted M, Keenan MJ. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am J Physiol Endocrinol Metab 2008;295: E1160-6.
78. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013;504:451-5.
79. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. In: Frederick WA, editor. Adv Immunol 2014;121:91-119.
80. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015;11:577-91.
81. Campbell C, Grapov D, Fiehn O, Chandler CJ, Burnett DJ, Souza EC, Casazza GA, Gustafson MB, Keim NL, Newman JW. Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin. PLoS One 2014;9:e84260.
82. Charrier JA, Martin RJ, McCutcheon KL, Raggio AM, Goldsmith F, Goita M, Senevirathne RN, Brown IL, Pelkman C, Zhou J, et al. High fat diet partially attenuates fermentation responses in rats fed resistant starch from high-amylose maize. Obesity (Silver Spring) 2013;21:2350-5.
83. Selma MV, Espín JC, Tomás-Barberán FA. Interaction between phenolics and gut microbiota: role in human health. J Agric Food Chem 2009;57:6485-501.
84. Ou K, Sarnoski P, Schneider KR, Song K, Khoo C, Gu L. Microbial catabolism of procyanidins by human gut microbiota. Mol Nutr Food Res 2014;58:2196-205.
85. Anson NM, Selinheimo E, Havenaar R, Aura AM, Mattila I, Lehtinen P, Bast A, Poutanen K, Haenen GR. Bioprocessing of wheat bran improves in vitro bioaccessibility and colonic metabolism of phenolic compounds. J Agric Food Chem 2009;57:6148-55.
86. Zhao Z, Egashira Y, Sanada H. Digestion and absorption of ferulic acid sugar esters in rat gastrointestinal tract. J Agric Food Chem 2003;51:5534-9.
87. Duda-Chodak A, Tarko T, Satora P, Sroka P. Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota: a review. Eur J Nutr 2015;54:325-41.
88. Bradbury KE, Appleby PN, Key TJ. Fruit, vegetable, and fiber intake in relation to cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Clin Nutr 2014;100(Suppl 1):394S-8S.
89. Aune D, Chan DSM, Lau R, Vieira R, Greenwood DC, Kampman E, Norat T. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 2011;343.
90. Zhang Z, Xu G, Ma M, Yang J, Liu X. Dietary fiber intake reduces risk for gastric cancer: a meta-analysis. Gastroenterology 2013;145:113-20, e3.
91. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388-93.