The Influence of the Indigenous Microflora on Mammalian Metabolism and Nutrition

1. Ravdin IS , Rhoads JE : Certain problems illustrating the importance of a knowledge of biochemistry by the surgeon. Surg Clin North Am 15:85–100, 1935.

2. Dudrick SJ , Vars IIM , Rawnsley HM et al: Total intravenous feeding and growth in puppies. Fed Proc 25:481, 1966.

3. Dudrick SJ , Vars HM , Rhoads JE : Growth of puppies receiving all nutritional requirements by vein. (Sympos der Int Soc Parenteral Nutr) Fortsch Parenteral Ernahrung 2:16–18, 1967.

4. Wilmore DW , Dudrick, SJ , Vars HM et al: Long-term intravenous hyperalimentation. Fed Proc 27:486, 1968.

5. Dudrick SJ , Wilmore DW , Vars HM et al: Long-term total parenteral nutrition with growth, development, and positive nitrogen balance. Surgery 64:134–142, 1968.

6. Dudrick SJ , Wilmore DW , Steiger E et al: Reversal of uremia and body wasting with intravenous essential amino acids. Fed Proc 28:808, 1968.

7. Rhoads JE : Approaches to an artificial gastrointestinal tract, (Presidential address, Society for Surgery of the Alimentary Tract). Am J Surg 117:3–10, 1969.

8. Dudrick SJ , Wilmore DW , Vars HM et al: Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Ann Surg 169:974–984, 1969.

9. Pasteur L : Observations relatives a la note precedente de M Duclaux. CR Acad Sci, (Paris) 100:68, 1885.

10. Ducleaux , cited by Wostmann BS: Nutrition and metabolism of the germfree mammal. World Rev Nutr Diet 22:40–92, 1975.

11. Nuttall GHF , Thierfelder H : Thierisches leben ohne bakterienim verdanungkanol. Z Physiol Chem 21:109–121, 1895.

12. Schottelius M : Die bedeutung der darmbakterien fur die ernahiung. II. Arch Hyg 42:48–70, 1902.

13. Cohendy M : Experiences sur la vie sans microbes. Ann Inst Pasteur 26:106–137, 1912.

14. Kuster E : Zentr backteriol. Parasitenk 54:55–58, 1912.

15. Metchnikoff E : The nature of man. In Mitchell Chalmers P (ed): Studies in Optimistic Philosophy (English trans). New York, Putnam, 1905.

16. Glimstedt G : Das leben ohne bakterien. Verhandl Anat Ges Ergaenzungsheft Anal Anz 41:79–89, 1932.

17. Reyniers JA , Trexler PC : Micrurgical and germfree techniques. Springfield, Illinois, Thomas, 1943, p 114.

18. Miyakawa M , Iijima S , Kishimoto H et al: Rearing germfree guinea pigs. Acta Pathol Jpn 8:55–78, 1958.

19. Gustafsson BE : Lightweight stainless steel systems for rearing germfree animals. Ann NY Acad Sci 78:17–28, 1959.

20. Trexler PC , Reynolds LI : Flexible film apparatus for the rearing and use of germfree animals. Appl Microbiol 5:406–412, 1957.

21. Levenson SM , and Tennant B : Some metabolic and nutritional studies with germfree animals. Fed Proc 22, (1, pt I): 109–119, 1963.

22. Mickelsen O : Nutrition-germfree animal research. Ann Rev Biochem 31:515–548, 1962.

23. Miyakawa M , Luckey TD (eds): Advances in germfree research and gnotobiology. Proc Int Sympos on Germfree Life Research, Nagoya and Inuyama, Japan. Cleveland, CRC Press, April 1967.

24. Mirand EA (ed): Germfree biology. Advances in Experimental Medicine and Biology, vol III. New York, Plenum Press, 1969.

25. Heneghan JB (ed): Proceedings of the Fourth International Symposium on Germfree Research, April 16-20, 1972, Louisiana State Univ, New Orleans. New York, Academic Press Inc.

26. Dubos R , Schaedler RW : The effect of the intestinal flora on the growth of mice, and on their susceptibility to experimental infections. J Exp Med 111:407–417, 1960.

27. Lee C-J , Dubos R : Lasting biological effects on early environmental influences. III. Metabolic responses of mice to neonatal infection with a filterable weight-depressing agent. J Exp Med 128:753–762, 1968.

28. Lee C-J , Dubos R : Lasting biological effects of early environmental influences. IV. Notes on the physiochemical and immunologic characteristics of an entero virus that depresses the growth of mice. J Exp Med 130:955–962, 1969.

29. Eijkman C : Eine beri beri-ahnliche krankheit der huhner. Arch Pathol Anat Physiol 148:523–532, 1897.

30. Cooper EA : On the protective and curative properties of certain foodstuffs against polyneuritis induced in birds by a diet of polished rice. J Hyg 14:12–22, 1914.

31. Fridericia LS : Refection, a transmissible change in theintestinal content, enabling rats to grow and thrive without B-vitamin in the food. Scand Arch Physiol 49:129–130, 1926.

32. Coates ME , Fuller R , Harrison GF et al: A comparison of the growth of chicks in the Gustafsson germfree apparatus and in a conventional environment, with and without dietary supplements of penicillin. Br J Nutr 17:141–150, 1963.

33. Osborne TB , Mendel LB , Ferry E : Feeding experiments with isolated food substances. Washington DC, Carnegie Institute, pub 156, pt 1 & 2, 1911.

34. Steenbock H , Sell MT , Nelson EM : Vitamin B. I. A modified technique in the use of the rat for determinations of vitamin B. J Biol Chem 55:399–410, 1923.

35. Barnes RH , Fiala G , Kwong E : Decreased growth rate resulting from prevention of coprophagy. Fed Proc 22:125–128, 1963.

36. Briggs GM , Luckey TD , Elvehjem CA et al: Effect of ascorbic acid on chick growth when added to purified rations. Proc Soc Exp Biol Med 55:130–134, 1944.

37. Moore PR , Evenson A , Luckey TD et al: Use of sulfasuxidine streptothricin and streptomycin in nutritional studies with the chick. J Biol Chem 165:437–441, 1946.

38. Mameesh MS , Johnson BC : Dietary vitamin K requirement of the rat. Proc Soc Exp Biol Med 103:378–380, 1960.

39. Doft FS , Ashburn LL , Sebrell WH : Biotin deficiency and other changes in rats given sulfanilyguanidine or succinylsulfathiazole in purified diets. Science 96:321–322, 1942.

40. Nielsen E , Elvehjen CA : The growth-promoting effect of folic acid and biotin in rats fed succinylsulfathiazole. J Biol Chem 145:713–714, 1942.

41. Mickelsen O : Intestinal synthesis of vitamins in the non-ruminant. Vitam Horm 14:1–95, 1956.

42. Stokstad ELR , Jukes TH : Effect of various levels of vitamin B12 upon growth response produced by aureomycin in chicks. Proc Soc Exp Biol Med 76:73–76, 1951.

43. Francois AC , Michel MC : Mode d'action des antibiotiques sur la croissance. In Bibl Nutritio et dieta. vol X. New York, Basel, Karger, 1968, pp 35–59.

44. Levenson SM , Doft F , Lev M et al: Influence of microorganisms on oxygen consumption, carbon dioxide production and colonic temperature of rats. J Nutr 97(4):542–552, 1969.

45. Young V : Energy metabolism. Houston, Texas, American Society for Parenteral and Enteral Nutrition, Feb 1-4, 1978.

46. Desplaces A , Zagury D , Sacquet E : Etude de la fonction thyroidienne du rat prive de bacteries. C R Acad Sci (Paris) 257:756–758, 1963.

47. Windmueller HG , Mc Daniel EG , Spaeth A : Orotic acid-induced fatty liver. Metabolic studies in conventional and germfree rats. Arch Biochem Biophys 109:13–19, 1965.

48. Wostmann BS , Bruckner-Kardoss E , Knight PL Jr : Cecal enlargement, cardiac output, and O2 consumption in germfree rats. Proc Soc Exp Biol Med 128:137–141, 1968.

49. Sewell DL , Bruckner-Kardoss E , Lorenz LM et al: Glucose tolerance, insulin, and catecolamine levels in germfree rats. Proc Soc Exp Biol Med 152:16–19, 1976.

50. Abrams GA , Bauer H , Sprinz H : Influence of the normal flora on mucosal morphology and cellular renewals in the ileum. A comparison of germfree and conventional mice. Lab Invest 12:355–364, 1963.

51. Wostmann BS , Bruckner-Kardoss E , Knight PL : Cecal enlargement, cardiac output and O2 consumption in germfree rats. Proc Soc Exp Biol 128:137–141, 1968.

52. Gordon HA : A substance acting on smooth muscle in intestinal contents of germfree animals. Ann NY Acad Sci 147:83–106, 1967.

53. Levenson SM , Kan D : Lack of effect of cecectomy on oxygen consumption and colonic temperature of germfree rats. J Nutr 105(10): 1237–1240, 1975.

54. Allen DJ , Marley E : Effect of sympathomimetic and allied amines on temperature and oxygen consumption in chickens. Br J Pharmacol Chemother 31:290–312, 1967.

55. Tennant B , Malm OJ , Horowitz RE et al: Response of germfree, conventional, conventionalized and E. coli monocontaminated mice to starvation. J Nutr 94(2): 151–160, 1968.

56. Gustafsson BE , Daft FS , Mc Daniel EG et al: Effects of vitamin K-active compounds and intestinal microorganisms in vitamin K-deficient germfree rats. J Nutr 78:461–468, 1962.

57. Rhoads JE , Fitz-Hugh T Jr : Idiopathic hypopro-thrombinemia–an apparently unrecorded condition. Am J Med Sci 202:662–670, 1941.

58. Levenson SM , Tennant B , Geever E et al: Influence of microorganisms on scurvy. Arch Intern Med 110:693–702, 1962.

59. Griffith WH , Wade NJ : Choline metabolism; interrelationship of choline, cystine, and methionine in occurrence and prevention of hemorrhagic degeneration in young rats. J Biol Chem 132:627, 1940.

60. Levenson SM , Nagler AL , Geever EF et al: Acute choline deficiency in germfree, conventionalized and open-animal-room rats: Effects of neomycin, chlortetracycline. vitamin B12 and coprophagy prevention. J Nutr 95(2):247–270. 1968.

61. Levenson SM, Brown N, Horowitz RE: Dietary cirrhosis of the liver in the germfree rat, abstracted Fifth International Congress on Nutrition. Washington DC, 1960, p 14.

62. Gyorgy P : Antibiotics and liver injury. Ann NY Acad Sci 57:925–931, 1954.

63. Rutenburg AM , Sonnenblick E , Koven I et al: Role of intestinal bacteria in the development of dietary cirrhosis in rats. J Exp Med 106:1–13, 1957.

64. Prentiss PG , Rosen H , Brown N et al: The metabolism of choline by the germfree rats. Arch Biochem Biophys 94:424–429, 1961.

65. Baxter JH : Protective effect of thiouracil, dibenamine against renal injury due to choline deficiency: Influence of endocrine and autonomic systems. J Pharmacol Exp Ther 107:394–401, 1953.

66. Mulford DJ , Griffith WH : Choline metabolism. VIII. Relation of cystine and of methionine to requirement of choline in young rats. J Nutr 23:91–100. 1942.

67. Doft F, Mc Daniel EG: Personal communication.

68. Baez S , Gordon HA : Tone and reactivity of vascular smooth muscle in germfree rat mesentery. J Exp Med 134:846–856. 1971.

69. Nagler AL , Baez S , Levenson SM : Status of the microcirculation during acute choline deficiency. J Nutr 97(2):232–236, 1969.

70. Rhodes RA , Sarles WB , Monson WJ et al: Stimulation and inhibition by antibiotics of intestinal bacteria in chicks. J Nutr 53:289–302, 1954.

71. Arnstein HRV , Newberger A : The effect of cobalamin on the quantitative utilization of serine, glycine and formate for the synthesis of choline and methyl groups of methionine. Biochem J 55:259–271, 1953.

72. Patek AP Jr , de Fritsch NM , Hirsch RL : Strain differences in susceptibility of the rat to dietary cirrhosis. Proc Soc Exp Biol Med 121:569–573. 1966.

73. Smith JC , Mc Daniel EG , Mc Bean LD et al: Effect of microorganisms upon zinc metabolism using germfree and conventional rats. J Nutr 102:711–719, 1972.

74. Gustafsson B , Norman A : Urinary calculi in germfree rats. J Exp Med 116:273–283, 1962.

75. Levenson SM, Kan D, Gruber C et al: Unpublished data.

76. Reddy BS , Pleasants JR , Wostmann BS : Effect of intestinal microflora on calcium, phosphorus and magnesium metabolism in rats. J Nutr 99:353–362, 1969.

77. Reddy BS , Pleasants JR , Wostmann BS : Studies on calcium, phosphorus and magnesium metabolism in rats: Effect of intestinal microflora. In Masek J , Osancova K , Cuthbertson D (eds): Eighth International Congress on Nutrition, Prague, 1969. Amsterdam, Excerpta Medica, 1970, pp 418–421.

78. Wostmann BS : Nutrition and metabolism of the germfree mammal. World Rev Nutr Diet 22:40–92, 1975.

79. Demarne Y , Flanzy J , Sacquet E : The influence of gastrointestinal flora on digestion and utilization of fatty acids in rats. In Heneghan Germfree Research: Biological Effects of Gnoto-biotic Environments. New York, Academic Press, 1973, p 553.

80. Michel MC : Metabolisme de la flore intestinale de pore degradation des formes Let Ddesacidesamines. Ann Biol Anim Biochem Biophys 6:33–46, 1966.

81. Levenson SM , Crowley LV , Horowitz RE et al: The metabolisms of carbon-labeled urea in the germfree rat. J Biol Chem 234:2061–2062, 1959.

82. Seifter E, Rettura G, Levenson SM: Unpublished data.

83. Seifter E , Rettura G , Reissman D et al: Nutritional response to feeding L-phenyllactic, shikimic and D-quinic acids in weanling rats. J Nutr 101:747–754, 1971.

84. Greenstein JP , Birnbaum SM , Winitz M et al: Quantitative nutritional studies with water-soluble, chemically defined diets. I. Growth, reproduction and lactation in rats. Arch Biochem Biophys 72:396–416, 1957.

85. Harper AE , Benevenga NJ , Wholhueter RM : Effects ofingestion of disproportionate amounts of amino acids. Physiol Rev 50:428–558, 1970.

86. Greenstein JP , Birnbaum SM , Winitz M : Quantitative nutritional studies with water-soluble, chemically defined diets. I. Growth, reproduction, and lactation in rats. Arch Biochem Biophys 72:396–416, 1957.

87. Birnbaum SM , Greenstein JP , Winitz M : Quantitative nutritional studies with water-soluble, chemically defined diets. II. Nitrogen balance and metabolism. Arch Biochem Biophys 72:417–427, 1957.

88. Birnbaum SM , Winitz M , Greenstein JP : Quantitative nutritional studies with water-soluble, chemically defined diets. III. Individual amino acids as sources of “non-essential” nitrogen. Arch Biochem Biophys 72:428–436, 1957.

89. Winitz M , Birnbaum SM , Greenstein JP : Quantitative nutritional studies with water-soluble, chemically defined diets. IV. Influence of various carbohydrates on growth, with special reference to D-glucosamine. Arch Biochem Biophys 72:437–447, 1957.

90. Winitz M , Greenstein JP , Birnbaum SM : Quantitative nutritional studies with water-soluble, chemically defined diets. V. Role of isomeric arginines in growth. Arch Biochem Biophys 72:448–456, 1957.

91. Birnbaum SM , Greenstein ME , Winitz M et al: Quantitative nutritional studies with water-soluble, chemically defined diets. VI. Growth studies on mice. Arch Biochem Biophys 78:245–247, 1958.

92. Sugimura T , Birnbaum SM , Winitz M et al: Quantitative nutritional studies with water-soluble, chemically defined diets. VII. Nitrogen balance in normal and tumor-bearing rats following forced feeding. Arch Biochem Biophys 81:439–447, 1959.

93. Sugimura T , Birnbaum SM , Winitz M et al: Quantitative nutritional studies with water-soluble, chemically defined diets. VIII. The forced feeding of diets each lacking in one essential amino acid. Arch Biochem Biophys 81:448–455, 1959.

94. Greenstein JP , Otey MC , Birbaum SM et al: Quantitative nutritional studies with water-soluble, chemically defined diets. X. Formulation of a nutritionally complete liquid diet. J Natl Cancer Inst 24:211–219, 1960.

95. Winitz M , Birnbaum SM , Sugimura T et al: Quantitative nutritional and in vivo metabolic studies with water-soluble chemically defined diets. In Edsall JT (ed): Amino Acids, Proteins and Cancer Biochemistry. Jesse P Greenstein Memorial Symposium. New York, Academic Press, 1960, pp 9–29.

96. Geever EF , Seifter E , Levenson SM : Pancreatic pathology, chemically defined liquid diets and bacterial flora in the rat. Br J Exp Pathol 51:341–347, 1970.

97. Levenson SM , Kan D , Gruber C et al: Hemolytic anemia and pancreatic acinar atrophy and fibrosis conditioned by “elemental” liquid diets and the ordinary intestinal microflora. Ann Surg 174:469–510, 1971.

98. Levenson SM , Kan D , Gruber C et al: Strange hemolytic anemia and pancreatic acinar atrophy and fibrosis. Fed Proc 30:1785–1802, 1971.

99. Hsiehl HS , Seifter E , Jaffe E et al: Intracorpuscular hemolytic anemia in rats fed a chemically defined liquid diet. Fed Proc 32:927, 1973.

100. Harper AE , Benevenga NJ , Wohlhueter RM : Effects ofingestion of disproportionate amounts of amino acids. Physiol Rev 50:428–558, 1970.

101. Mengel CE , Klavins JV : Development of hemolytic anemia in rats fed methionine. J Nutr 92(1):104–110. 1967.

102. Seifter E , Shapiro R , Geever E et al: In Miyakowa M , Luckey TD (eds): Advances in Germfree Research and Gnotobiology. Cleveland. The Chemical Rubber Co, 1968, pp 96–101.

103. Shapiro R , Rosenthal NA , Gold BK : Studies on the cause of a hemorrhagic syndrome in rats fed a water-soluble chemically defined diet. J Nutr 97:389–398. 1969.

104. Levenson SM , Kan D , Gruber C et al: Role of cysteine ethyl ester and indigenous microflora in the pathogenesis of an experimental hemolytic anemia, azotemia, and pancreatic acinar atrophy. In Heneghan JB (ed): Proceedings of the Fourth International Symposium on Germfree Research, April 16-20, 1972, Louisiana State Univ, New Orleans. Louisiana. New York, Academic Press Inc. 1973, pp 297–304.

105. Levenson SM, Seifter E, Kan D et al: Unpublished data.

106. Pollard M : Viral status of “germfree” mice. US Natl Cancer Inst Monogr 20:167–177, 1965.

107. Pollard M : Carcinogenesis in germfree animals. Prog Immunobiol Stand 5:226–230, 1972.

108. Spatz M , Smith DWE , Mc Daniel EG et al: Role of intestinal microorganisms in determining cycasin toxicity. Proc Soc Exp Biol Med 124:691–697, 1965.

109. Laquer GL : Gnotobiotes as a useful tool in. studies in carcinogenesis with cycasin, a natural glucoside. In Mirand EA , Bak N (eds): Germfree Biology: Experimental and Clinical Aspects. N.Y. Plenum Press, pp 163–167. 1969.

110. Reddy BS , Wynder EL : Large-bowel carcinogenesis: Fecal constituents of populations with diverse incidence rates of colon cancer. J Natl Cancer Inst 50:1437–1442. 1973.

111. Weisburger JH , Grantham PH , Horton RE et al: Metabolism of the carcinogen N-hydroxy-N-2 fluorenyl-acetamide in germfree rats. Biochem Pharmacol 19:151–162, 1970.

112. Drasar BS , Hill MJ : Intestinal bacteria and capcer. Am J Clin Nutr 25:1399–1404. 1972.

113. Ranken R , Wilson R , Bealmear PM : Increased turnover of intestinal mucosal cells of germfree mice induced by cholicacid. Proc Soc Exp Biol Med 138:270–272. 1971.

114. Mastromarino AJ , Wilson R : Increased intestinal mucosal turnover and radiosensitivity to supralethal whole body irradiation resulting from cholic acid-induced alterations of the intestinal microbiology of germfree CFW mice. Radiat Res 66:393–400, 1976.

115. Reddy BS , Watanabe K , Weisburger JH et al: Promoting effect of bile acids in colon carcinogenesis in germfree and conventional F 344 rats. Cancer Res 47:3238–3242, 1977.

116. Asano T , Pollard M , Madsen D : Effects of cholestyramine on 1,2 dimethylhydrazine-induced enteric carcinoma in germfree rats. Proc Soc Exp Biol Med 150:780–785, 1975.

117. Hill MJ , Drasar BS , Aries V et al: Bacteria and aetiology of cancer of large bowel. Lancet 1:95, 1971.

118. Gorbach S : Metabolism of carcinogens by intestinal bacteria. Preview 1:1–8, Dec 1976.

119. Pollard M : Spontaneous and induced neoplasms in germfree rats. In Environment and Cancer. Baltimore, Williams & Wilkins, 1972, p 394.

120. Munro H : Protein metabolism. Houston, Texas, American Society for Parenteral and Enteral Nutrition, Feb 2-4, 1978.

121. Pollard M : Senescence in germfree rats. Gerontologia 17:333–338, 1971.

122. Rosebury T : Microorganisms Indigenous to Man. New York, Mc Graw Hill, 1962.