Etiology of inflammatory bowel disease: A unified hypothesis

World Journal of Gastroenterology

Volumn 18, Issue 15, 2012, Pages 1708-1722

  Qin, Xiaofa ^a  

^a RUTGERS NEW JERSEY MEDICAL SCHOOL   (United States)

Author keywords

Crohn's disease; Dietary chemicals; Etiology; Inflammatory bowel disease; Saccharin; Sucralose; Ulcerative colitis

Indexed keywords

PROTEINASE; SACCHARIN; SUCRALOSE;

CARCINOGENICITY; CROHN DISEASE; ENTERITIS; HUMAN; INTESTINE FLORA; MORBIDITY; NONHUMAN; REVIEW; RISK FACTOR; ULCERATIVE COLITIS; UNITED KINGDOM; UNITED STATES; WAR;

EID: 84866173368     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v18.i15.1708     Document Type: Review

References (171)

1. Kirsner JB. Historical review: the historical basis of the idiopathic inflammatory bowel disease. Inflamm Bowel Dis 1995; 1: 2-26
2. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011; 140: 1785-1794
3. Russel MG. Changes in the incidence of inflammatory bowel disease: what does it mean? Eur J Intern Med 2000; 11: 191-196
4. Hwang JM, Varma MG. Surgery for inflammatory bowel disease. World J Gastroenterol 2008; 14: 2678-2690
5. Ekbom A. The changing faces of Crohn's disease and ulcerative colitis. In: Targan SR, Shanahan F, Karp LC. Inflammatory bowel disease: from bench to bedside. New York: Springer, 2005: 5-20
6. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW, Kaplan GG. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46-54.e42; quiz e30
7. Kirsner JB. Historical origins of current IBD concepts. World J Gastroenterol 2001; 7: 175-184
8. Korzenik JR. Past and current theories of etiology of IBD: toothpaste, worms, and refrigerators. J Clin Gastroenterol 2005; 39: S59-S65
9. Elliman DA, Bedford HE. Measles, mumps and rubella vaccine, autism and inflammatory bowel disease: advising concerned parents. Paediatr Drugs 2002; 4: 631-635
10. Carbonnel F, Jantchou P, Monnet E, Cosnes J. Environmental risk factors in Crohn's disease and ulcerative colitis: an update. Gastroenterol Clin Biol 2009; 33 Suppl 3: S145-S157
11. Powell JJ, Harvey RS, Thompson RP. Microparticles in Crohn's disease--has the dust settled? Gut 1996; 39: 340-341
12. Lomer MC, Thompson RP, Powell JJ. Fine and ultrafine particles of the diet: influence on the mucosal immune response and association with Crohn's disease. Proc Nutr Soc 2002; 61: 123-130
13. Kefalakes H, Stylianides TJ, Amanakis G, Kolios G. Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality? Eur J Clin Pharmacol 2009; 65: 963-970
14. Patel B, Schutte R, Sporns P, Doyle J, Jewel L, Fedorak RN. Potato glycoalkaloids adversely affect intestinal permeability and aggravate inflammatory bowel disease. Inflamm Bowel Dis 2002; 8: 340-346
15. Tobacman JK. Review of harmful gastrointestinal effects of carrageenan in animal experiments. Environ Health Perspect 2001; 109: 983-994
16. Hugot JP, Alberti C, Berrebi D, Bingen E, Cézard JP. Cro hn's disease: the cold chain hypothesis. Lancet 2003; 362: 2012-2015
17. Dalziel TK. Chronic interstitial enteritis. Br Med J (Clin Res Ed) 1913; 2: 1068-1070
18. Rosenfeld G, Bressler B. Mycobacterium avium paratuberculosis and the etiology of Crohn's disease: a review of the controversy from the clinician's perspective. Can J Gastroen terol 2010; 24: 619-624
19. Van Kruiningen HJ. Where are the weapons of mass destruction - the Mycobacterium paratuberculosis in Crohn's disease? J Crohns Colitis 2011; 5: 638-644
20. Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses 2002; 59: 159-163
21. Qin X. What caused the recent worldwide increase of inflammatory bowel disease: should sucralose be added as a suspect? Inflamm Bowel Dis 2011; 17: E139
22. Ruegg SG. Some data concerning saccharin. The Louisiana Planter and Sugar Manufacturer 1911; 47: 39-41
23. Constantin Fahlberg. The Louisiana Planter and Sugar Manu facturer 1910; 45: 243-244
24. Kleber C. 25 years in the service of the saccharin industry. Pharmaceutical Review 1903; 21: 467-471
25. Coal-tar saccharine. Nature 1886; 34: 134-135
26. Hicks J. The pursuit of sweet: a history of saccharin. Chem Herit Mag 2010; 28: 1-3
27. Saccharin. In: Myers RL. The 100 most important chemical compounds. Westport, CT/London: Greenwood Publishing Group, 2007: 241-243
28. Saccharine. The Chemical Trade Journal 1887; 1: 77
29. Wotiz JH. The discovery of saccharin. J Chem Educ 1978; 55: 161
30. Saccharin. Chemist and Druggist 1889; 34: 194
31. Molinari E. Treatise on general and industrial organic chemistry. Foreign letters-Berlin. The Louisiana Planter and Sugar Manufacturer 1901; 26: 7
32. Special-Correspondence. Foreign letters - Berlin. The Louisiana Planter and Sugar Manufacturer 1901; 26: 7
33. Germans guard wild fruit. In: The New York Times. New York city, NY: The New York Times Company, 1916. Available from: URL: http://query.nytimes.com/mem/archivefree/pdf?res=9E07E0DD1F31E733A05753C1A96F9C946796D6CF
34. The rival saccharins. Chemist and druggist 1895; 46: 381-382
35. Saccharin Corporaton (Limited) v. Anglo-Continental Che mical Works (Limited) and Reitmeyer. (a). The Weekly Re porter 1900; 48: 444
36. Pearson RL. Saccharin. In: Nabors LOB. Alternative sweeteners. 3rd ed. New York: Marcel Dekker, 2001: 147-166
37. Saccharin. Chemist and Druggist 1889; 35: 541
38. Ruprecht W. The historical development of the consumption of sweetenersa learning approach. J Evol Econ 2005; 15: 247-272
39. Is saccharin Injurious? The Analyst 1892; 17: 134-136
40. Different views of saccharin. Chemist and Druggist 1890; 37: 468
41. Saccharin smugglers in Europe. The Pharmaceutical Era 1914; 47: 388
42. Crespi A. A chapter on benzoylsulphonicionide, or saccharine. Hardwicke's Science-Gossip 1888; 24: 51-52
43. Saccharine. Bulletin of Miscellaneous Information (Royal Gardens, Kew) 1888; 13: 23-24
44. Keane CA. Obituary: Henry Enfield Roscoe. The Analyst 1916; 41: 63-70
45. Harmlessness of saccharin. Medical and Surgical Reporter 1889; 60: 746
46. The place of saccharin in pharmacy. Chemist and Druggist 1889; 34: 124-125
47. The place of saccharin in pharmacy. Medical and Surgical Re porter 1889; 60: 209
48. Saccharin. The Louisiana Planter and Sugar Manufacturer 1909; 43: 210
49. Saccharin. Chemist and Druggist 1889; 34: 151
50. Washburn. Saccharin. Bulletin of Pharmacy 1893; 7: 85-86
51. Phillips S. A Discussion on Ulcerative Colitis. Proc R Soc Med 1909; 2: 88-90
52. Saccharin. The Canadian Horticulturist 1893; 16: 144
53. The role of saccharin during the war. The Chemical Engineer 1917; 26: 23
54. Merki CM. From prohibition to promotion: the sugar substitute saccharin before and during World War I in Europe. In: Munting R, Szmressanyi T. Competing for the sugar bowl. Katharinen, Germany: Scripta Mercaturae Verlag, 2000: 127-140
55. Economising sugar. Nature 1918; 100: 347-348
56. Morrison AB. Sugar substitutes. Can Med Assoc J 1979; 120: 633-637
57. Saccharin. In: United States Tariff Commission. Statistics of imports and duties, 1908 to 1918, inclusive: Printed for the use of Committee on ways and means, House of Representatives. Indexed. Washington, D.C.: Washington Govenment Print Office, 1920: 101
58. Evans TC. The surgical treatment of chronic ulcerative colitis. Br Med J 1925; 1: 204-205
59. Lups S. Vaccine therapy in ulcerative colitis. Am J Dig Dis Nutr 1935; 2: 65-90
60. Thorlakson PH. Ulcerative Colitis. Can Med Assoc J 1928; 19: 656-659
61. Logan AH. Chronic ulcerative colitis: a review of 117 cases. In: Mellish MH. Collected papers of the Mayo Clinic, Rochester, Minnesota. Philadelphia and London: W.B. Saunders Company, 1918: 180-202
62. Bargen J. Complications and sequelae of chronic ulcerative colitis. Ann Intern Med 1929; 3: 335-352
63. Discussion on ulcerative colitis. Proc R Soc Med 1931; 24: 785-803
64. Yeomans FC. Chronic ulcerative colitis. Transactions of the Sections on Gastro-Enterology and Proctology 1922; 72: 160-172
65. Woolf MS. Chronic ulcerative colitis. Cal West Med 1926; 24: 191-193
66. McKittrick LS, Miller RH. Idiopathic ulcerative colitis: a review of 149 cases with particular reference to the value of, and indications for surgical treatment. Ann Surg 1935; 102: 656-673
67. Santee HE. Ulcerative colitis. Ann Surg 1928; 87: 704-710
68. Berger L. Sigma diagnostics: pioneer of kits for clinical chemistry. Clin Chem 1993; 39: 902-903
69. Acheson ED, Nefzger MD. Ulcerative colitis in the United States Army in 1944. Epidemiology: comparisons between patients and controls. Gastroenterology 1963; 44: 7-19
70. United States War Dept. Annual report of the secretary of war. Washington, D.C.: Washington Government Printing Office, 1896: 384
71. Smith AF. Julia Nidetchs Diet. In: Smith AF. Eating history: 30 turning points in the making of American cuisine. New York: Columbia University Press, 2009: 245-256
72. Committee for a Study on Saccharin and Food Safety Policy (U.S.). History of the use and safety of saccharin. In: Food safety policy: Scientific and societal considerations. Part 2 of a two-part study of the Committee for a Study on Saccharin and Food Safety PolicyA report prepared in response to Public Law 95-203 (Saccharin Study and Labeling Act). Washington, D.C.: National Academy of Sciences, 1979: A6
73. Stowe SP, Redmond SR, Stormont JM, Shah AN, Chessin LN, Segal HL, Chey WY. An epidemiologic study of inflammatory bowel disease in Rochester, New York. Hospital incidence. Gastroenterology 1990; 98: 104-110
74. Consumption of saccharin. In: Saccharin: technical assessment of risks and benefitsPart 1 of a 2 part study of the Committee for a Study on Saccharin and Food Safety Policy. Washington, D.C.: National Academy of Sciences, 1978: 2-3
75. Schucker RE, Stokes RC, Stewart ML, Henderson DP. The impact of the saccharin warning label on sales of diet soft drinks in supermarkets. J Public Policy Mark 1983; 2: 46-56
76. Loftus CG, Loftus EV, Harmsen WS, Zinsmeister AR, Tremaine WJ, Melton LJ, Sandborn WJ. Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000. Inflamm Bowel Dis 2007; 13: 254-261
77. Pinchbeck BR, Kirdeikis J, Thomson AB. Inflammatory bowel disease in northern Alberta. An epidemiologic study. J Clin Gastroenterol 1988; 10: 505-515
78. Langholz E, Munkholm P, Nielsen OH, Kreiner S, Binder V. Incidence and prevalence of ulcerative colitis in Copenhagen county from 1962 to 1987. Scand J Gastroenterol 1991; 26: 1247-1256
79. Munkholm P, Langholz E, Nielsen OH, Kreiner S, Binder V. Incidence and prevalence of Crohn's disease in the county of Copenhagen, 1962-87: a sixfold increase in incidence. Scand J Gastroenterol 1992; 27: 609-614
80. Daiss W, Scheurlen M, Malchow H. Epidemiology of inflammatory bowel disease in the county of Tübingen (West Germany). Scand J Gastroenterol Suppl 1989; 170: 39-43; discussion 50-55
81. Yoshida Y, Murata Y. Inflammatory bowel disease in Japan: studies of epidemiology and etiopathogenesis. Med Clin North Am 1990; 74: 67-90
82. Calkins BM. Inflammatory Bowel Disease. In: Everhart JE. Digestive Disease in the United States: Epidemiology and Impact. Darby, PA: Diane Publishing Co., 1994: 509-550
83. Tysk C, Järnerot G. Ulcerative proctocolitis in Orebro, Sweden. A retrospective epidemiologic study, 1963-1987. Scand J Gastroenterol 1992; 27: 945-950
84. Lindberg E, Jörnerot G. The incidence of Crohn's disease is not decreasing in Sweden. Scand J Gastroenterol 1991; 26: 495-500
85. Logan RF. Inflammatory bowel disease incidence: up, down or unchanged? Gut 1998; 42: 309-311
86. Lapidus A, Bernell O, Hellers G, Persson PG, Löfberg R. Incidence of Crohn's disease in Stockholm County 1955-1989. Gut 1997; 41: 480-486
87. Lee FI, Nguyen-Van-Tam JS. Prospective study of incidence of Crohn's disease in northwest England: no increase since the late 1970's. Eur J Gastroenterol Hepatol 1994; 6: 27-31
88. Fellows IW, Freeman JG, Holmes GK. Crohn's disease in the city of Derby, 1951-85. Gut 1990; 31: 1262-1265
89. Gunesh S, Thomas GA, Williams GT, Roberts A, Hawthorne AB. The incidence of Crohn's disease in Cardiff over the last 75 years: an update for 1996-2005. Aliment Pharmacol Ther 2008; 27: 211-219
90. Srivastava ED, Mayberry JF, Morris TJ, Smith PM, Williams GT, Roberts GM, Newcombe RG, Rhodes J. Incidence of ulcerative colitis in Cardiff over 20 years: 1968-87. Gut 1992; 33: 256-258
91. Taylor SE. Artificial sweeteners. Washington, D.C.: Congressional Research Service, Library of Congress, 1985: 9-11
92. Vind I, Riis L, Jess T, Knudsen E, Pedersen N, Elkjaer M, Bak Andersen I, Wewer V, Nørregaard P, Moesgaard F, Bendtsen F, Munkholm P. Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005: a population-based study from the Danish Crohn colitis database. Am J Gastro enterol 2006; 101: 1274-1282
93. Lapidus A. Crohn's disease in Stockholm County during 1990-2001: an epidemiological update. World J Gastroenterol 2006; 12: 75-81
94. Rönnblom A, Samuelsson SM, Ekbom A. Ulcerative colitis in the county of Uppsala 1945-2007: incidence and clinical characteristics. J Crohns Colitis 2010; 4: 532-536
95. Chappel CI. A review and biological risk assessment of sodium saccharin. Regul Toxicol Pharmacol 1992; 15: 253-270
96. Weihrauch MR, Diehl V. Artificial sweeteners--do they bear a carcinogenic risk? Ann Oncol 2004; 15: 1460-1465
97. Gougeon R, Spidel M, Lee K, Field CJ. Canadian diabetes association national nutrition committee technical review: non-nutritive intense sweeteners in diabetes management. Can J Diabetes 2004; 28: 385-399
98. Position of the American Dietetic Association: use of nutritive and nonnutritive sweeteners. J Am Diet Assoc 2004; 104: 255-275
99. Tian DX. The abnormal development of commercial competition as the result of lacking uniform taxation. Caihui Yuekan (Chinese) 1985; 4
100. Increased saccharin production may be deleterious to public health. Jiating Yishengbao (Chinese) 2000; 17
101. Saccharin from China: Investigation No. 731-TA-1013 (Review). Washington, DC: United States International Trade Commission, 2009
102. Qin X. Is the incidence of inflammatory bowel disease in the developed countries increasing again? Is that surprising? Inflamm Bowel Dis 2007; 13: 804-805
103. Hviid A, Svanström H, Frisch M. Antibiotic use and inflammatory bowel diseases in childhood. Gut 2011; 60: 49-54
104. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn's disease and ulcerative colitis. Am J Gastroenterol 2011; 106: 2133-2142
105. Saccharin. The lancet 1888; 2: 140-141
106. Saccharin as an antiseptic. Albany Mecial Annals 1889; 10: 227
107. Saccharin as an antiseptic. The Medical News 1888; 53: 700
108. Qin X. The effect of dietary chemicals on gut bacteria and IBD demands further study. J Crohns Colitis 2011; 5: 175
109. Knight I. The development and applications of sucralose, a new high-intensity sweetener. Can J Physiol Pharmacol 1994; 72: 435-439
110. Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, McLen-don RE, Schiffman SS. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A 2008; 71: 1415-1429
111. Wrobel I, Butzner J, Nguyen N, Withers G, Nelson K. Epidemiology of pediatric IBD in a population-based cohort in southern Alberta, Canada (1983-2005). J Pediatr Gastroenterol Nutr 2006; 43: S54-S55
112. Lowe AM, Roy PO, B-Poulin M, Michel P, Bitton A, St-Onge L, Brassard P. Epidemiology of Crohn's disease in Québec, Canada. Inflamm Bowel Dis 2009; 15: 429-435
113. Bernstein CN, Wajda A, Svenson LW, MacKenzie A, Koe-hoorn M, Jackson M, Fedorak R, Israel D, Blanchard JF. The epidemiology of inflammatory bowel disease in Canada: a population-based study. Am J Gastroenterol 2006; 101: 1559-1568
114. Qin X. What made Canada become a country with the highest incidence of inflammatory bowel disease: could sucralose be the culprit? Can J Gastroenterol 2011; 25: 511
115. Hanigan K, Radford-Smith G. The incidence of IBD in north Brisbane-a population study. J Gastroenterol Hepatol 2008; 23 Suppl 4: A215
116. Gearry RB, Richardson A, Frampton CM, Collett JA, Burt MJ, Chapman BA, Barclay ML. High incidence of Crohn' s disease in Canterbury, New Zealand: results of an epidemiologic study. Inflamm Bowel Dis 2006; 12: 936-943
117. Abramson O, Durant M, Mow W, Finley A, Kodali P, Wong A, Tavares V, McCroskey E, Liu L, Lewis JD, Allison JE, Flowers N, Hutfless S, Velayos FS, Perry GS, Cannon R, Herrinton LJ. Incidence, prevalence, and time trends of pediatric inflammatory bowel disease in Northern California, 1996 to 2006. J Pediatr 2010; 157: 233-239.e1
118. Perminow G, Brackmann S, Lyckander LG, Franke A, Borthne A, Rydning A, Aamodt G, Schreiber S, Vatn MH. A characterization in childhood inflammatory bowel disease, a new population-based inception cohort from South-Eastern Norway, 2005-07, showing increased incidence in Crohn's disease. Scand J Gastroenterol 2009; 44: 446-456
119. Brusick D, Grotz VL, Slesinski R, Kruger CL, Hayes AW. The absence of genotoxicity of sucralose. Food Chem Toxicol 2010; 48: 3067-3072
120. Loos R, Gawlik BM, Boettcher K, Locoro G, Contini S, Bidoglio G. Sucralose screening in European surface waters using a solid-phase extraction-liquid chromatography-triple quadrupole mass spectrometry method. J Chromatogr A 2009; 1216: 1126-1131
121. Lerner I. Sweet nothings. ICIS Chemical Business 2009; 275: 28-29
122. Qin X. Food additives: possible cause for recent remarkable increase of inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 2012; 54: 564
123. Bassler A. The etiology and treatment of chronic ulcerative colitis (non-specific). Am J Dig Dis 1949; 16: 275-285
124. De Dombal FT. Ulcerative colitis: definition, historical background, aetiology, diagnosis, naturel history and local complications. Postgrad Med J 1968; 44: 684-692
125. Korzenik JR, Dieckgraefe BK. Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease. Dig Dis Sci 2000; 45: 1121-1129
126. Weinstock JV, Elliott DE. Helminths and the IBD hygiene hypothesis. Inflamm Bowel Dis 2009; 15: 128-133
127. Sartor RB. Mechanisms of disease: pathogenesis of Crohn' s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol 2006; 3: 390-407
128. Fiocchi C. Future of IBD pathogenesis: how much work is left to do? Inflamm Bowel Dis 2008; 14 Suppl 2: S145-S147
129. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol 2010; 28: 573-621
130. Söderholm JD, Olaison G, Lindberg E, Hannestad U, Vindels A, Tysk C, Järnerot G, Sjödahl R. Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence? Gut 1999; 44: 96-100
131. Katz KD, Hollander D, Vadheim CM, McElree C, Delahunty T, Dadufalza VD, Krugliak P, Rotter JI. Intestinal permeability in patients with Crohn's disease and their healthy relatives. Gastroenterology 1989; 97: 927-931
132. Breslin NP, Nash C, Hilsden RJ, Hershfield NB, Price LM, Meddings JB, Sutherland LR. Intestinal permeability is increased in a proportion of spouses of patients with Crohn's disease. Am J Gastroenterol 2001; 96: 2934-2938
133. Qin X. What caused the increase of autoimmune and allergic diseases: a decreased or an increased exposure to luminal microbial components? World J Gastroenterol 2007; 13: 1306-1307
134. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448: 427-434
135. Veloso FT. Extraintestinal manifestations of inflammatory bowel disease: do they influence treatment and outcome? World J Gastroenterol 2011; 17: 2702-2707
136. Qin X. Has Crohn's disease really occurred anywhere in the digestive tract? Inflamm Bowel Dis 2008; 14: 1461-1462
137. Qin X. Inhibition of gut bacteria by dietary chemicals and the hygiene hypothesis. Ann Allergy Asthma Immunol 2007; 98: 602
138. Qin X. What caused the extra high incidence of inflammatory bowel disease in the industrialized countries in the West: lack of some nutrients or increased intake of some harmful agents? Inflamm Bowel Dis 2009; 15: 319
139. Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. Am J Gastroenterol 2008; 103: 2955-2956
140. Qin X. High incidence of inflammatory bowel disease with improved hygiene and failure to get human-like IBD in laboratory animals. World J Gastroenterol 2007; 13: 3271
141. Qin X. Inactivation of digestive proteases by deconjugated bilirubin: the possible evolutionary driving force for bilirubin or biliverdin predominance in animals. Gut 2007; 56: 1641-1642
142. Qin X. Inactivation of digestive proteases: another mechanism that probiotics may have conferred a protection. Am J Gastroenterol 2007; 102: 2109
143. Qin X. Primary sclerosing cholangitis and inflammatory bowel disease: where is the link? Am J Gastroenterol 2007; 102: 1332-1333
144. Qin X. Synergic effect of bacterial glycosidases and digestive proteases on mucus degradation and the reduced risk of inflammatory bowel disease-like gut damage in both germ-free and poor hygiene conditions. Inflamm Bowel Dis 2008; 14: 145-146
145. Qin X. Can meat and protein really increase, while vegetables and fruits decrease the risk of inflammatory bowel disease? How? J Crohns Colitis 2009; 3: 136
146. Qin X. What is human inflammatory bowel disease (IBD) more like: Johne's disease in cattle or IBD in dogs and cats? Inflamm Bowel Dis 2008; 14: 138
147. Qin X. Reduced production of digestive proteases and the efficacy of enteral and parenteral nutrition on inflammatory bowel disease. Inflamm Bowel Dis 2008; 14: 871
148. Qin X. Inactivation of digestive proteases: another aspect of gut bacteria that should be taken into more consideration. World J Gastroenterol 2007; 13: 2390-2391
149. Qin X. With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflamm Bowel Dis 2008; 14: 1607-1608
150. Qin X. Gut microbiota: a new aspect that should be taken into more consideration when assessing the toxicity of chemicals or the adverse effects and efficacy of drugs. Regul Toxicol Pharmacol 2008; 51: 251
151. Qin X. Inactivation of digestive proteases by deconjugated bilirubin and the physiological significance of fasting hyperbilirubinemia. Gastroen Res 2009; 2: 62
152. Schirbel A, Fiocchi C. Inflammatory bowel disease: Established and evolving considerations on its etiopathogenesis and therapy. J Dig Dis 2010; 11: 266-276
153. Levine A. Pediatric inflammatory bowel disease: is it different? Dig Dis 2009; 27: 212-214
154. Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 2011; 140: 1704-1712
155. Zhu B, Wang X, Li L. Human gut microbiome: the second genome of human body. Protein Cell 2010; 1: 718-725
156. Latella G, Fiocchi C, Caprili R. News from the "5th International Meeting on Inflammatory Bowel Diseases" CAPRI 2010. J Crohns Colitis 2010; 4: 690-702
157. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011; 474: 307-317
158. Blumberg R, Cho J, Lewis J, Wu G. Inflammatory bowel disease: an update on the fundamental biology and clinical management. Gastroenterology 2011; 140: 1701-1703
159. Nunes T, Fiorino G, Danese S, Sans M. Familial aggregation in inflammatory bowel disease: is it genes or environment? World J Gastroenterol 2011; 17: 2715-2722
160. Probert CS, Jayanthi V, Rampton DS, Mayberry JF. Epidemiology of inflammatory bowel disease in different ethnic and religious groups: limitations and aetiological clues. Int J Colorectal Dis 1996; 11: 25-28
161. Saccharin as a substitute. The Bulletin of Pharmacy 1918; 32: 398
162. Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev 2004; 3: 394-400
163. Tandon BN, Mathur AK, Mohapatra LN, Tandon HD, Wig KL. A study of the prevalence and clinical pattern of nonspecific ulcerative colitis in northern India. Gut 1965; 6: 448-453
164. Tripathi M, Khanna SK, Das M. Usage of saccharin in food products and its intake by the population of Lucknow, India. Food Addit Contam 2006; 23: 1265-1275
165. Green C, Elliott L, Beaudoin C, Bernstein CN. A populationbased ecologic study of inflammatory bowel disease: searching for etiologic clues. Am J Epidemiol 2006; 164: 615-623; discussion 624-628
166. Lok KH, Hung HG, Ng CH, Li KK, Li KF, Szeto ML. The epidemiology and clinical characteristics of Crohn's disease in the Hong Kong Chinese population: experiences from a regional hospital. Hong Kong Med J 2007; 13: 436-441
167. Björnsson S, Jóhannsson JH. Inflammatory bowel disease in Iceland, 1990-1994: a prospective, nationwide, epidemiological study. Eur J Gastroenterol Hepatol 2000; 12: 31-38
168. Hou JK, El-Serag H, Thirumurthi S. Distribution and manifestations of inflammatory bowel disease in Asians, Hispanics, and African Americans: a systematic review. Am J Gastroenterol 2009; 104: 2100-2109
169. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. JAMA 1932; 99: 1323-1329
170. Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, Higuchi LM, Hyams JS, Kirschner BS, Kugathasan S, Baldassano RN, Russo PA. Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America. J Pediatr Gastroenterol Nutr 2007; 44: 653-674
171. Qin X. How can we really reduce the morbidity of inflammatory bowel diseaseesearch on genes and cytokines, or find out the causative factors in the environment? J Crohns Colitis 2009; 3: 315