Role of gut bacteria in human toxicology and pharmacology

Cover Page......Page 1 Title Page......Page 3 ISBN 0748401105......Page 4 1. The normal gut bacterial flora......Page 5 3. The use of gnotobiotic animals in studies of toxicology......Page 6 5 Nitrate pharmacology and toxicology......Page 7 7 Metabolism of nitrogen compounds: miscellaneous compounds......Page 8 9 Toxicology of butyrate and short-chain fatty acids......Page 9 11 Interactions between fat substitutes and gut bacteria......Page 10 13. Sulphate-reducing bacteria (SRB)......Page 11 15. Vitamin K and selected water-soluble vitamins: roles of the gut bacteria in nutrition and pharmacology......Page 12 16. Factors governing biliary excretion......Page 13 18. Influence of the probiotics, lactobacilli and bifidobacteria on gastrointestinal disorders in adults......Page 14 Index......Page 15 Introduction......Page 16 References......Page 17 D.C.Ellwood......Page 18 B.J.Moran......Page 19 T.G.Schlagheck......Page 20 J.H.P.Watson......Page 21 Section 1 Gut bacteriology......Page 22 1.2.1 Sampling problems......Page 23 1.2.2 Cultivation problems......Page 24 1.3.2 Flora of the stomach......Page 25 1.3.4 Flora of the lower ileum......Page 29 1.3.6 The colonic mucosal flora......Page 30 1.4 Factors controlling the gut flora composition......Page 31 1.4.1 pH......Page 32 1.4.2 Nutrient supply......Page 33 1.4.5 Facultative anaerobes......Page 34 1.4.8 Relevance to the human gut......Page 35 1.5.1 Bacteriophage......Page 36 1.6.1 Lysozyme......Page 37 References......Page 38 2.2.1 Methods of assay—pure strains versus caecal contents......Page 40 2.2.2 Methods of expressing the data......Page 41 2.3 Effect of diet on faecal enzyme activity......Page 42 2.3.2 Specific substrate supply......Page 43 2.3.3 Induction of specific enzymes......Page 44 2.4 Relevance to toxicological studies......Page 45 References......Page 46 3.1 Introduction......Page 47 3.2.2 Characteristics of germ-free animals......Page 48 3.3.1 Metabolism of xenobiotics......Page 49 3.3.2 Secondary effects of the presence of the flora......Page 51 3.4 The human-flora-associated (HFA) rat......Page 52 3.5 Comments and conclusions......Page 53 References......Page 54 Section 2 Nitrogen metabolism......Page 58 4.1 Introduction......Page 59 4.1.1 Nitrogen as an element essential for life......Page 60 4.2 Nitrogen balance, amino acid flux and protein turnover......Page 61 4.3 Urea hydrolysis......Page 64 4.4 Role of microflora......Page 66 4.5 Colonic nitrogen metabolism......Page 67 4.5.1 Source of colonic urea......Page 69 4.6 Destiny of hydrolyzed urea nitrogen in the colon......Page 70 4.7 Adaptation to suboptimal protein intakes is dependent on an intact urea-nitrogen salvage mechanism......Page 71 4.8 Clinical implications of the salvage of urea nitrogen......Page 72 4.9 Conclusion......Page 74 References......Page 75 5.2 Pharmacology......Page 80 5.3.1 Short-term/acute effects......Page 81 5.3.2 Long-term/chronic effects......Page 82 5.4.1 Nitrate metabolism......Page 83 5.4.2 Nitrite metabolism......Page 84 References......Page 85 6.1 Introduction......Page 90 6.3 N-nitrosation involving gaseous nitrogen oxides......Page 92 6.4 N-nitrosation involving bacterial enzyme systems......Page 93 6.5 N-nitrosation involving mammalian enzyme systems......Page 96 References......Page 97 7.2.1 Introduction......Page 101 7.2.2 Bacterial azoreductase......Page 103 7.2.3 Factors affecting in vivo activity......Page 104 7.2.4 Toxicological consequences......Page 105 7.3.2 Gut bacterial nitro reductase......Page 106 7.3.3 Reduction of environmental contaminants......Page 107 7.4.2 Amino acid decarboxylase......Page 108 7.4.3 Toxicological significance......Page 109 7.5.3 Pharmacological significance......Page 110 7.6.2 Tyrosine metabolism......Page 111 7.6.3 Tryptophan metabolism......Page 112 References......Page 113 Section 3 Carbohydrate metabolism......Page 116 8.2 Monosaccharide metabolism......Page 117 8.3 Glycosidases......Page 118 8.3.2 β-glucosidase......Page 119 8.4 Polysaccharide breakdown......Page 121 8.4.2 Dietary fibre......Page 122 8.5 Toxicological importance of polysaccharide degradation......Page 124 References......Page 125 9.2 Butyrate as both metabolic fuel and inducer of differentiation......Page 127 9.4 Acetylation neutralizes positive charges at the N-terminal domains of core histones......Page 130 9.5 The impact of the butyrate signal on chromatin structure......Page 131 9.6 Hyperacetylation and arrest of the cell cycle......Page 134 9.7 Butyrate and activation of gene expression......Page 136 9.8 Butyrate and inhibition of gene expression......Page 137 9.9 Butyrate and human colon cancer cell lines......Page 139 9.10 Butyrate and various other transformed cell lines......Page 140 9.12 Butyrate and cancerogenesis in vivo......Page 142 9.13 Butyrate and intestinal cells in vivo......Page 143 9.14 Short-chain fatty acids and human diseases other than cancer......Page 144 References......Page 145 Section 4 Fat metabolism......Page 150 10.1 Introduction......Page 151 10.2 Fat digestion......Page 152 10.2.1 Metabolism of fats and phospholipids......Page 153 10.4 Bacterial metabolism of bile salts......Page 155 10.4.1 Cholylglycine hydrolase......Page 156 10.4.2 7-Dehydroxylase......Page 157 10.4.3 Hydroxysteroid dehydrogenases......Page 159 10.4.4 Toxicological consequences of bile acid metabolism......Page 160 References......Page 161 11.1 Fat substitutes......Page 163 11.2.2 Metabolism of fat substitutes......Page 164 11.2.3 Effects on normal microflora function and activity......Page 165 11.3.1 Approaches for assessing the microbial metabolism of fat substitutes......Page 166 11.3.2 Definitive studies on the metabolism of olestra......Page 167 11.4 Effect of fat substitutes on microbial metabolism......Page 168 11.5.1 Microbial fermentation......Page 169 11.5.2 Microbial bioconversions......Page 170 11.7 Metabolism of enterohepatically circulating steroid hormones......Page 173 11.7.2 Microbial metabolism of xenobiotics......Page 174 11.9 Faecal microflora composition......Page 175 References......Page 176 Section 5 Sulphur metabolism......Page 179 12.2 Delivery of the sulphur compound to the intestinal bacteria......Page 180 12.2.1 Oral delivery......Page 182 12.2.3 Secretion into the gut lumen......Page 183 12.3.1 Reduction reactions......Page 185 12.3.2 Hydrolysis reactions......Page 190 References......Page 198 13.1 Introduction......Page 206 13.3 Presence of SRB in human faeces......Page 207 13.4 SRB and heavy metal pharmacology......Page 210 References......Page 211 Section 6 Metabolism of miscellaneous compounds......Page 213 14.2 Effect of iron on the intestinal microflora......Page 214 14.3 Role of the gut flora in the metabolism of toxic metals......Page 215 14.4.2 In vitro metabolism of arsenicals by the gut flora......Page 216 14.4.4 Microbial metabolism of other arsenicals......Page 217 14.5.1 Chemical forms, exposure and toxic effects......Page 218 14.5.2 Metabolism of mercury compounds by gut bacteria......Page 219 14.5.4 Implications of bacterial demethylation of MeHg......Page 223 14.6 Conclusions......Page 225 References......Page 226 15.1 Introduction......Page 230 15.2 Vitamin K......Page 231 15.2.1 Gut bacteria as a source of vitamin K......Page 232 15.2.2 Vitamin K absorption......Page 233 15.2.3 Human infants......Page 235 15.2.4 Effects of drugs and vitamin K nutrition......Page 236 15.3 Biotin......Page 237 15.3.1 Gut bacteria and biotin supply......Page 238 15.4 Vitamin B12......Page 239 15.5 Folic acid......Page 240 15.6.1 Gut bacteria and riboflavin supply......Page 241 References......Page 242 Section 7 Biliary excretion and enterohepatic circulation......Page 246 16.1 General aspects of bile formation and enterohepatic cycling......Page 247 16.3 Composition of bile......Page 248 16.4 Generation of bile flow......Page 249 16.5 Experimental procedures for studying bile formation......Page 250 16.7 Sinusoidal uptake......Page 251 16.8 Intracellular movements and metabolism......Page 252 16.9 Canalicular secretory processes......Page 254 16.10 Retention of components in the biliary tree: biliary versus renal excretion......Page 255 16.12 Conjugation of native or biotransformed molecules as a determinant of biliary secretion: biliary versus renal excretion......Page 256 Acknowledgements......Page 257 References......Page 258 17.2 Role of microfloral metabolism in EHC and species differences......Page 260 17.3 The influence of EHC on pharmacokinetics and persistence......Page 264 17.5 Influence of EHC on toxicity......Page 267 17.6 Influence of EHC on carcinogenesis......Page 268 Acknowledgements......Page 270 References......Page 271 Section 8 Probiotics......Page 276 18.1 Introduction......Page 277 18.3 Bifidobacteria......Page 278 18.5 Survival of ingested probiotics in the gastrointestinal tract......Page 279 18.6.1 Disturbances in the protective flora......Page 280 18.7.2 Attempts to re-establish the microflora, after treatment with antimicrobial agents......Page 281 18.7.3 Clostridium difficile diarrhoea and pseudomembranous colitis......Page 283 18.7.5 Enteritis......Page 284 18.7.8 Radiation therapy......Page 285 18.7.11 Lactose intolerance......Page 286 18.7.12 Antimutagenic and anticarcinogenic effects......Page 287 18.7.13 Liver cirrhosis and hepatic encephalopathy......Page 290 References......Page 291 Index......Page 298 The digestive tract is the site in the human body most richly colonized by bacteria. Microorganisms mediate between host and environment by interacting with food components, drugs, food additives and environmental contaminants. The toxicological importance of microorganisms is still only slowly being recognised. Role of Gut Bacteria in Human Toxicology and Pharmacology examines the composition and metabolic activity of the microorganisms most commonly found in the human gut. Comparisons are made between microbiol and mammalian metabolism with comments on the person-to-person variations in enzyme activity. Individual chapters describe the effects gut flora have on ingested compounds, vitamin production and gastrointestinal disorders. As a means of updating the reader on the role of the metabolic activity of gut bacteria in pharmacology and toxicology, the book opens with a background section on gut bacterial composition and metabolic activity in general. Chapters then follow on the major groups of macronutrients (e.g., fats, nitrogen compounds, carbohydrates) and micronutrients (e.g., vitamins, metal compounds), concluding with a review of the importance of probiotics. In the final section, the possible future importance of probiotics in the treatment or prevention of gastrointestinal disease and the maintenance of gastrointestinal health is discussed