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  • Review Article
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Contributions of the microbial hydrogen economy to colonic homeostasis

Nature Reviews Gastroenterology & Hepatology volume 9, pages 504–518 (2012)Cite this article

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Abstract

Colonic gases are among the most tangible features of digestion, yet physicians are typically unable to offer long-term relief from clinical complaints of excessive gas. Studies characterizing colonic gases have linked changes in volume or composition with bowel disorders and shown hydrogen gas (H2), methane, hydrogen sulphide, and carbon dioxide to be by-products of the interplay between H2-producing fermentative bacteria and H2 consumers (reductive acetogens, methanogenic archaea and sulphate-reducing bacteria [SRB]). Clinically, H2 and methane measured in breath can indicate lactose and glucose intolerance, small intestinal bacterial overgrowth and IBS. Methane levels are increased in patients with constipation or IBS. Hydrogen sulphide is a by-product of H2 metabolism by SRB, which are ubiquitous in the colonic mucosa. Although higher hydrogen sulphide and SRB levels have been detected in patients with IBD, and to a lesser extent in colorectal cancer, this colonic gas might have beneficial effects. Moreover, H2 has been shown to have antioxidant properties and, in the healthy colon, physiological H2 concentrations might protect the mucosa from oxidative insults, whereas an impaired H2 economy might facilitate inflammation or carcinogenesis. Therefore, standardized breath gas measurements combined with ever-improving molecular methodologies could provide novel strategies to prevent, diagnose or manage numerous colonic disorders.

Key Points

  • The colonic gases hydrogen (H2), carbon dioxide and methane (CH4) are end products of microbial fermentation; their concentrations depend on the interplay between host physiology and H2-producing (hydrogenogenic) and H2-using (hydrogenotrophic) microbes

  • Colonic H2 production is most readily measured via excretion in breath; clinically, breath H2 and CH4 are commonly measured to assess lactose and glucose intolerance and small intestinal bacterial overgrowth, and increasingly IBS

  • Improved understanding of microbial H2 metabolism and its relation to expired gas concentrations will reinforce the breath gas test as a widely applicable, easy and cost-effective diagnostic or prognostic tool

  • Use of breath gas tests in diagnosis could enable novel therapeutic or preventative measures for a wide array of colonic diseases

  • Although emphasis has been given to the potential inflammatory or carcinogenic properties of colonic gases, emerging evidence suggests these gases might have a beneficial effect in colonic health

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Figure 1: Milestones in the measurement of colonic gases in breath and flatus.
Figure 2: Biochemical pathways of H2 production from bacterial fermentation.
Figure 3: H2 gas is inherently produced during microbial fermentation in the human colon.

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References

  1. Suarez, F., Furne, J., Springfield, J. & Levitt, M. Insights into human colonic physiology obtained from the study of flatus composition. Am. J. Physiol. 272, G1028–G1033 (1997).

    CAS  PubMed  Google Scholar 

  2. Suarez, F., Furne, J., Springfield, J. & Levitt, M. Production and elimination of sulfur-containing gases in the rat colon. Am. J. Physiol. 274, G727–G733 (1998).

    CAS  PubMed  Google Scholar 

  3. Levitt, M. D. & Bond, J. H. Jr. Volume, composition, and source of intestinal gas. Gastroenterology 59, 921–929 (1970).

    Article  CAS  PubMed  Google Scholar 

  4. Christl, S. U., Murgatroyd, P. R., Gibson, G. R. & Cummings, J. H. Production, metabolism, and excretion of hydrogen in the large intestine. Gastroenterology 102, 1269–1277 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Kirk, E. The quantity and composition of human colonic flatus. Gastroenterology 12, 782–794 (1949).

    CAS  PubMed  Google Scholar 

  6. Steggerda, F. R. Gastrointestinal gas following food consumption. Ann. NY Acad. Sci. 150, 57–66 (1968).

    Article  CAS  PubMed  Google Scholar 

  7. Tomlin, J., Lowis, C. & Read, N. W. Investigation of normal flatus production in healthy volunteers. Gut 32, 665–669 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Beazell, J. M. & Ivey, A. C. The quantity of colonic flatus excreted by the “normal” individual. Am. J. Dig. Dis. 8, 128–129 (1941).

    Article  Google Scholar 

  9. Askevold, F. Investigations on the influence of diet on the quantity and composition of intestinal gas in humans. Scand. J. Clin. Lab. Invest. 8, 87–94 (1956).

    Article  CAS  PubMed  Google Scholar 

  10. Ruge, E. Beitrag sur kennuness der darmgase [German]. Sitsber. Kaiserlicken Akad. 44, 739 (1861).

    Google Scholar 

  11. Levitt, M. D., Gibson, G. R. & Christl, S. U. in Human Colonic Bacteria: Role in Nutrition, Physiology, and Pathology (eds Gibson, G. R. & Macfarlane, G. T.) 131–154 (CRC Press, Boca Raton, 1975).

    Google Scholar 

  12. Steggerda, F. R. & Dimmick, J. F. Effects of bean diets on concentration of carbon dioxide in flatus. Am. J. Clin. Nutr. 19, 120–124 (1966).

    Article  CAS  PubMed  Google Scholar 

  13. Levitt, M. D. & Ingelfinger, F. J. Hydrogen and methane production in man. Ann. NY Acad. Sci. 150, 75–81 (1968).

    Article  CAS  PubMed  Google Scholar 

  14. Levitt, M. D., Hirsh, P., Fetzer, C. A., Sheahan, M. & Levine, A. S. H2 excretion after ingestion of complex carbohydrates. Gastroenterology 92, 383–389 (1987).

    Article  CAS  PubMed  Google Scholar 

  15. Wolin, M. J. & Miller, T. L. in Human Intestinal Microflora in Health and Disease (ed. Hentges, D. J.) 147–165 (Academic Press, New York, 1983).

    Book  Google Scholar 

  16. Strocchi, A. & Levitt, M. D. Factors affecting hydrogen production and consumption by human fecal flora. The critical roles of hydrogen tension and methanogenesis. J. Clin. Invest. 89, 1304–1311 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hammer, H. F. Colonic hydrogen absorption: quantification of its effect on hydrogen accumulation caused by bacterial fermentation of carbohydrates. Gut 34, 818–822 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Le Marchand, L., Wilkens, L. R., Harwood, P. & Cooney, R. V. Use of breath hydrogen and methane as markers of colonic fermentation in epidemiologic studies: circadian patterns of excretion. Environ. Health Perspect. 98, 199–202 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Strocchi, A., Ellis, C. & Levitt, M. D. Reproducibility of measurements of trace gas concentrations in expired air. Gastroenterology 101, 175–179 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Calloway, D. H. Respiratory hydrogen and methane as affected by consumption of gas-forming foods. Gastroenterology 51, 383–389 (1966).

    Article  CAS  PubMed  Google Scholar 

  21. Calloway, D. H. & Murphy, E. L. The use of expired air to measure intestinal gas formation. Ann. NY Acad. Sci. 150, 82–95 (1968).

    Article  CAS  PubMed  Google Scholar 

  22. Bjorneklett, A. & Jenssen, E. Relationships between hydrogen (H2) and methane (CH4) production in man. Scand. J. Gastroenterol. 17, 985–992 (1982).

    CAS  PubMed  Google Scholar 

  23. Cloarec, D. et al. Breath hydrogen response to lactulose in healthy subjects: relationship to methane producing status. Gut 31, 300–304 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vernia, P., Camillo, M. D., Marinaro, V. & Caprilli, R. Effect of predominant methanogenic flora on the outcome of lactose breath test in irritable bowel syndrome patients. Eur. J. Clin. Nutr. 57, 1116–1119 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Calloway, D. H., Murphy, E. L. & Bauer, D. Determination of lactose intolerance by breath analysis. Am. J. Dig. Dis. 14, 811–815 (1969).

    Article  CAS  PubMed  Google Scholar 

  26. Levitt, M. D. & Donaldson, R. M. Use of respiratory hydrogen (H2) excretion to detect carbohydrate malabsorption. J. Lab. Clin. Med. 75, 937–945 (1970).

    CAS  PubMed  Google Scholar 

  27. Metz, G., Jenkins, D. J., Peters, T. J., Newman, A. & Blendis, L. M. Breath hydrogen as a diagnostic method for hypolactasia. Lancet 1, 1155–1157 (1975).

    Article  CAS  PubMed  Google Scholar 

  28. Rhodes, J. M., Middleton, P. & Jewell, D. P. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scand. J. Gastroenterol. 14, 333–336 (1979).

    Article  CAS  PubMed  Google Scholar 

  29. Khoshini, R., Dai, S. C., Lezcano, S. & Pimentel, M. A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Dig. Dis. Sci. 53, 1443–1454 (2008).

    Article  PubMed  Google Scholar 

  30. Bures, J. et al. Small intestinal bacterial overgrowth syndrome. World J. Gastroenterol. 16, 2978–2990 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Caride, V. J. et al. Scintigraphic determination of small intestinal transit time: comparison with the hydrogen breath technique. Gastroenterology 86, 714–720 (1984).

    CAS  PubMed  Google Scholar 

  32. Bond, J. H., Engel, R. R. & Levitt, M. D. Factors influencing pulmonary methane excretion in man—indirect method of studying in situ metabolism of methane-producing colonic bacteria. J. Exp. Med. 133, 572–588 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Levitt, M. D., Furne, J. K., Kuskowski, M. & Ruddy, J. Stability of human methanogenic flora over 35 years and a review of insights obtained from breath methane measurements. Clin. Gastroenterol. Hepatol. 4, 123–129 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Gibson, G. R., Macfarlane, G. T. & Cummings, J. H. Occurrence of sulphate-reducing bacteria in human faeces and the relationship of dissimilatory sulphate reduction to methanogenesis in the large gut. J. Appl. Bacteriol. 65, 103–111 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Segal, I., Walker, A. R., Lord, S. & Cummings, J. H. Breath methane and large bowel cancer risk in contrasting African populations. Gut 29, 608–613 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wilkens, L. R., Le Marchand, L., Harwood, P. & Cooney, R. V. Use of breath hydrogen and methane as markers of colonic fermentation in epidemiological studies: variability in excretion. Cancer Epidemiol. Biomarkers Prev. 3, 149–153 (1994).

    CAS  PubMed  Google Scholar 

  37. O'Keefe, S. J. et al. Why do African Americans get more colon cancer than Native Africans? J. Nutr. 137, 175S–182S (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Thauer, R. K., Jungermann, K. & Decker, K. Energy conservation in chemotrophic anaerobic bacteria. Bacteriol. Rev. 41, 100–180 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Nava, G. M., Carbonero, F., Croix, J. A., Greenberg, E. & Gaskins, H. R. Abundance and diversity of mucosa-associated hydrogenotrophic microbes in the healthy human colon. ISME J. 6, 57–70 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fite, A. et al. Identification and quantitation of mucosal and faecal desulfovibrios using real time polymerase chain reaction. Gut 53, 523–529 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zinkevich, V. V. & Beech, I. B. Screening of sulfate-reducing bacteria in colonoscopy samples from healthy and colitic human gut mucosa. FEMS Microbiol. Ecol. 34, 147–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Chassard, C. et al. Assessment of metabolic diversity within the intestinal microbiota from healthy humans using combined molecular and cultural approaches. FEMS Microbiol. Ecol. 66, 496–504 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Harding, G. K., Sutter, V. L., Finegold, S. M. & Bricknell, K. S. Characterization of Bacteroides melaninogenicus. J. Clin. Microbiol. 4, 354–359 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Simmering, R. et al. Ruminococcus luti sp. nov., isolated from a human faecal sample. Syst. Appl. Microbiol. 25, 189–193 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Miller, T. L. & Wolin, M. J. Formation of hydrogen and formate by Ruminococcus albus. J. Bacteriol. 116, 836–846 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Schwiertz, A. et al. Anaerostipes caccae gen. nov., sp. nov., a new saccharolytic, acetate-utilising, butyrate-producing bacterium from human faeces. Syst. Appl. Microbiol. 25, 46–51 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Steer, T., Collins, M. D., Gibson, G. R., Hippe, H. & Lawson, P. A. Clostridium hathewayi sp. nov., from human faeces. Syst. Appl. Microbiol. 24, 353–357 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Kamlage, B., Gruhl, B. & Blaut, M. Isolation and characterization of two new homoacetogenic hydrogen-utilizing bacteria from the human intestinal tract that are closely related to Clostridium coccoides. Appl. Environ. Microbiol. 63, 1732–1738 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Pochart, P., Dore, J., Lemann, F., Goderel, I. & Rambaud, J. C. Interrelations between populations of methanogenic archaea and sulfate-reducing bacteria in the human colon. FEMS Microbiol. Lett. 77, 225–228 (1992).

    Article  CAS  PubMed  Google Scholar 

  50. Macfarlane, G. T., Gibson, G. R. & Cummings, J. H. Comparison of fermentation reactions in different regions of the human colon. J. Appl. Bacteriol. 72, 57–64 (1992).

    CAS  PubMed  Google Scholar 

  51. Pochart, P. et al. Pyxigraphic sampling to enumerate methanogens and anaerobes in the right colon of healthy humans. Gastroenterology 105, 1281–1285 (1993).

    Article  CAS  PubMed  Google Scholar 

  52. Flourie, B. et al. Site and substrates for methane production in human colon. Am. J. Physiol. 260, G752–G757 (1991).

    CAS  PubMed  Google Scholar 

  53. Gibson, G. R. et al. Alternative pathways for hydrogen disposal during fermentation in the human colon. Gut 31, 679–683 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Marteau, P. et al. Comparative study of bacterial groups within the human cecal and fecal microbiota. Appl. Environ. Microbiol. 67, 4939–4942 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Macfarlane, G. T. & Gibson, G. R. in Gastrointestinal Microbiology (eds Mackie, R. I. & White, B. A.) 269–318 (Chapman and Hall, New York, 1997).

    Book  Google Scholar 

  56. Duncan, S. H., Hold, G. L., Barcenilla, A., Stewart, C. S. & Flint, H. J. Roseburia intestinalis sp nov., a novel saccharolytic, butyrate-producing bacterium from human faeces. Int. J. Sys. Evol. Microbiol. 52, 1615–1620 (2002).

    CAS  Google Scholar 

  57. Duncan, S. H. et al. Proposal of Roseburia faecis sp. nov., Roseburia hominis sp. nov. and Roseburia inulinivorans sp. nov., based on isolates from human faeces. Int. J. Syst. Evol. Microbiol. 56, 2437–2441 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Duncan, S. H. & Flint, H. J. Proposal of a neotype strain (A1–86) for Eubacterium rectale. Request for an opinion. Int. J. Syst. Evol. Microbiol. 58, 1735–1736 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Chassard, C., Delmas, E., Lawson, P. A. & Bernalier-Donadille, A. Bacteroides xylanisolvens sp. nov., a xylan-degrading bacterium isolated from human faeces. Int. J. Syst. Evol. Microbiol. 58, 1008–1013 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Zoetendal, E. G., Plugge, C. M., Akkermans, A. D. & de Vos, W. M. Victivallis vadensis gen. nov., sp. nov., a sugar-fermenting anaerobe from human faeces. Int. J. Syst. Evol. Microbiol. 53, 211–215 (2003).

    Article  PubMed  Google Scholar 

  61. Derrien, M., Vaughan, E. E., Plugge, C. M. & de Vos, W. M. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int. J. Syst. Evol. Microbiol. 54, 1469–1476 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Duncan, S. H., Hold, G. L., Harmsen, H. J., Stewart, C. S. & Flint, H. J. Growth requirements and fermentation products of Fusobacterium prausnitzii, and a proposal to reclassify it as Faecalibacterium prausnitzii gen. nov., comb. nov. Int. J. Syst. Evol. Microbiol. 52, 2141–2146 (2002).

    CAS  PubMed  Google Scholar 

  63. Tolvanen, K. E., Mangayil, R. K., Karp, M. T. & Santala, V. P. Simple enrichment system for hydrogen producers. Appl. Environ. Microbiol. 77, 4246–4248 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cammack, R. Hydrogenase sophistication. Nature 397, 214–215 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Schmidt, O., Drake, H. L. & Horn, M. A. Hitherto unknown [Fe-Fe]-hydrogenase gene diversity in anaerobes and anoxic enrichments from a moderately acidic fen. Appl. Environ. Microbiol. 76, 2027–2031 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Schmidt, O. et al. Novel [NiFe]- and [FeFe]-hydrogenase gene transcripts indicative of active facultative aerobes and obligate anaerobes in earthworm gut contents. Appl. Environ. Microbiol. 77, 5842–5850 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Drake, H. L., Gossner, A. S. & Daniel, S. L. Old acetogens, new light. Ann. NY Acad. Sci. 1125, 100–128 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Lajoie, S. F., Bank, S., Miller, T. L. & Wolin, M. J. Acetate production from hydrogen and [13C]carbon dioxide by the microflora of human feces. Appl. Environ. Microbiol. 54, 2723–2727 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Bernalier, A. et al. Acetogenesis from H2 and CO2 by methane- and non-methane-producing human colonic bacterial communities. FEMS Microbiol. Ecol. 19, 193–202 (1996).

    Article  CAS  Google Scholar 

  70. Dore, J. et al. Enumeration of H2-utilizing methanogenic archaea, acetogenic and sulfate-reducing bacteria from human feces. FEMS Microbiol. Ecol. 17, 279–284 (1995).

    Article  CAS  Google Scholar 

  71. Bernalier, A., Rochet, V., Leclerc, M., Dore, J. & Pochart, P. Diversity of H2/CO2-utilizing acetogenic bacteria from feces of non-methane-producing humans. Curr. Microbiol. 33, 94–99 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Bernalier, A., Willems, A., Leclerc, M., Rochet, V. & Collins, M. D. Ruminococcus hydrogenotrophicus sp. nov., a new H2/CO2-utilizing acetogenic bacterium isolated from human feces. Arch. Microbiol. 166, 176–183 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Lovell, C. R. & Leaphart, A. B. Community-level analysis: key genes of CO2-reductive acetogenesis. Methods Enzymol. 397, 454–469 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Wolin, M. J. & Miller, T. L. Bacterial strains from human feces that reduce CO2 to acetic acid. Appl. Environ. Microbiol. 59, 3551–3556 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ohashi, Y., Igarashi, T., Kumazawa, F. & Fujisawa, T. Analysis of acetogenic bacteria in human feces with formyltetrahydrofolate synthetase sequences. Biosci. Microflora 26, 37–40 (2007).

    Article  CAS  Google Scholar 

  76. Cord-Ruwisch, R., Seitz, H. & Conrad, R. The capacity of hydrogenotrophic anaerobic bacteria to compete for traces of hydrogen depends on the redox potential of the terminal electron acceptor. Arch. Microbiol. 149, 350–357 (1988).

    Article  CAS  Google Scholar 

  77. Rey, F. E. et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285, 22082–22090 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Miller, T. L. & Wolin, M. J. Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Appl. Environ. Microbiol. 62, 1589–1592 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Hedderich, R. & Whitman, W. B. in The Prokaryotes (ed. Dworkin, M.) 1050–1079 (Springer, New York, 2006).

    Book  Google Scholar 

  80. Miller, T. L. & Wolin, M. J. Methanogens in human and animal intestinal tracts. Syst. Appl. Microbiol. 7, 223–229 (1986).

    Article  CAS  Google Scholar 

  81. Chassard, C., Delmas, E., Robert, C. & Bernalier-Donadille, A. The cellulose-degrading microbial community of the human gut varies according to the presence or absence of methanogens. FEMS Microbiol. Ecol. 74, 205–213 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Hansen, E. E. et al. Pan-genome of the dominant human gut-associated archaeon, Methanobrevibacter smithii, studied in twins. Proc. Natl Acad. Sci. USA 108, 4599–4606 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Miller, T. L. & Wolin, M. J. Methanosphaera stadtmaniae gen. nov., sp. nov.: a species that forms methane by reducing methanol with hydrogen. Arch. Microbiol. 141, 116–122 (1985).

    Article  CAS  PubMed  Google Scholar 

  84. Fricke, W. F. et al. The genome sequence of Methanosphaera stadtmanae reveals why this human intestinal archaeon is restricted to methanol and H2 for methane formation and ATP synthesis. J. Bacteriol. 188, 642–658 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Zhang, H. et al. Human gut microbiota in obesity and after gastric bypass. Proc. Natl Acad. Sci USA 106, 2365–2370 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Weaver, G. A., Krause, J. A., Miller, T. L. & Wolin, M. J. Incidence of methanogenic bacteria in a sigmoidoscopy population: an association of methanogenic bacteria and diverticulosis. Gut 27, 698–704 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Miller, T. L. & Wolin, M. J. Enumeration of Methanobrevibacter smithii from human feces. Arch. Microbiol. 45, 317 (1982).

    Google Scholar 

  89. Abell, G. C. J., Conlon, M. A. & McOrist, A. L. Methanogenic archaea in adult human faecal samples are inversely related to butyrate concentration. Microb. Ecol. Health Dis. 18, 154–160 (2006).

    Article  CAS  Google Scholar 

  90. Scanlan, P. D., Shanahan, F. & Marchesi, J. R. Human methanogen diversity and incidence in healthy and diseased colonic groups using mcrA gene analysis. BMC Microbiol. 8, 79 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mihajlovski, A., Alric, M. & Brugere, J. F. A putative new order of methanogenic Archaea inhabiting the human gut, as revealed by molecular analyses of the mcrA gene. Res. Microbiol. 159, 516–521 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Marquet, P., Duncan, S. H., Chassard, C., Bernalier-Donadille, A. & Flint, H. J. Lactate has the potential to promote hydrogen sulphide formation in the human colon. FEMS Microbiol. Lett. 299, 128–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Kleessen, B., Kroesen, A. J., Buhr, H. J. & Blaut, M. Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls. Scand. J. Gastroenterol. 37, 1034–1041 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Gibson, G. R., Macfarlane, S. & Macfarlane, G. T. Metabolic interactions involving sulphate-reducing and methanogenic bacteria in the human large intestine. FEMS Microbiol. Ecol. 12, 117–125 (1993).

    Article  CAS  Google Scholar 

  95. Newton, D. F., Cummings, J. H., Macfarlane, S. & Macfarlane, G. T. Growth of a human intestinal Desulfovibrio desulfuricans in continuous cultures containing defined populations of saccharolytic and amino acid fermenting bacteria. J. Appl. Microbiol. 85, 372–380 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Hopkins, M. J., Macfarlane, G. T., Furrie, E., Fite, A. & Macfarlane, S. Characterisation of intestinal bacteria in infant stools using real-time PCR and northern hybridisation analyses. FEMS Microbiol. Ecol. 54, 77–85 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Gibson, G. R., Cummings, J. H. & Macfarlane, G. T. Growth and activities of sulphate-reducing bacteria in gut contents of healthy subjects and patients with ulcerative colitis. FEMS Microbiol. Lett. 86, 103–111 (1991).

    Article  CAS  Google Scholar 

  98. Willis, C. L., Cummings, J. H., Neale, G. & Gibson, G. R. Nutritional aspects of dissimilatory sulfate reduction in the human large intestine. Curr. Microbiol. 35, 294–298 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Zverlov, V. et al. Lateral gene transfer of dissimilatory (bi)sulfite reductase revisited. J. Bacteriol. 187, 2203–2208 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Klein, M. et al. Multiple lateral transfers of dissimilatory sulfite reductase genes between major lineages of sulfate-reducing prokaryotes. J. Bacteriol. 183, 6028–6035 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wagner, M., Roger, A. J., Flax, J. L., Brusseau, G. A. & Stahl, D. A. Phylogeny of dissimilatory sulfite reductases supports an early origin of sulfate respiration. J. Bacteriol. 180, 2975–2982 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Meyer, B. & Kuever, J. Phylogeny of the alpha and beta subunits of the dissimilatory adenosine-5′-phosphosulfate (APS) reductase from sulfate-reducing prokaryotes—origin and evolution of the dissimilatory sulfate-reduction pathway. Microbiology 153, 2026–2044 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Hungin, A. P., Chang, L., Locke, G. R., Dennis, E. H. & Barghout, V. Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact. Aliment. Pharmacol. Ther. 21, 1365–1375 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Everhart, J. E. in The Burden of Digestive Diseases in the United States (ed. Everhart, J. E.) 77–87 (US Government Printing Office. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Washington, DC, 2008).

    Google Scholar 

  105. Drossman, D. A. et al. A prospective assessment of bowel habit in irritable bowel syndrome in women: defining an alternator. Gastroenterology 128, 580–589 (2005).

    Article  PubMed  Google Scholar 

  106. Drossman, D. A. et al. International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J. Clin. Gastroenterol. 43, 541–550 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Hasler, W. L. Irritable bowel syndrome and bloating. Best Pract. Res. Clin. Gastroenterol. 21, 689–707 (2007).

    Article  PubMed  Google Scholar 

  108. Serra, J., Azpiroz, F. & Malagelada, J. R. Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. Gut 48, 14–19 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Salonen, A., de Vos, W. M. & Palva, A. Gastrointestinal microbiota in irritable bowel syndrome: present state and perspectives. Microbiology 156, 3205–3215 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Kunkel, D. et al. Methane on breath testing is associated with constipation: a systematic review and meta-analysis. Dig. Dis. Sci. 56, 1612–1618 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Spiegel, B. M. R. Questioning the bacterial overgrowth hypothesis of irritable bowel syndrome: An epidemiologic and evolutionary perspective. Clin. Gastroenterol. Hepatol. 9, 461–469 (2011).

    Article  PubMed  Google Scholar 

  112. Chatterjee, S., Park, S., Low, K., Kong, Y. & Pimentel, M. The degree of breath methane production in IBS correlates with the severity of constipation. Am. J. Gastroenterol. 102, 837–841 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. King, T. S., Elia, M. & Hunter, J. O. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 352, 1187–1189 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Simren, M. & Stotzer, P. O. Use and abuse of hydrogen breath tests. Gut 55, 297–303 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pimentel, M., Chow, E. J. & Lin, H. C. Comparison of peak breath hydrogen production in patients with irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia. Gastroenterology 118, A413–A413 (2000).

    Google Scholar 

  116. Pimentel, M., Chow, E. J. & Lin, H. C. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am. J. Gastroenterol. 95, 3503–3506 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Yu, D., Cheeseman, F. & Vanner, S. Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS. Gut 60, 334–340 (2011).

    Article  PubMed  Google Scholar 

  118. Quigley, E. M. Germs, gas and the gut; the evolving role of the enteric flora in IBS. Am. J. Gastroenterol. 101, 334–335 (2006).

    Article  PubMed  Google Scholar 

  119. Quigley, E. M. M. The enteric microbiota in the pathogenesis and management of constipation. Best Pract. Res. Clin. Gastroenterol. 25, 119–126 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Pimentel, M., Park, S., Kong, Y., Low, K. & Chatterjee, S. Methane gas is associated with constipation predominant symptoms in IBS: Results from a double-blind controlled study. Gastroenterology 130, A514 (2006).

    Google Scholar 

  121. Pimentel, M. et al. Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1089–G1095 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Rajilic-Stojanovic, M. et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 141, 1792–1801 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Quigley, E. M. & Quera, R. Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics, and probiotics. Gastroenterology 130, S78–S90 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Evans, B. W., Clark, W. K., Moore, D. J. & Whorwell, P. J. Tegaserod for the treatment of irritable bowel syndrome and chronic constipation. Cochrane Database Syst. Rev. Issue 4. Art. No.: CD003960 (2007).

  125. Kim, D. Y. & Camilleri, M. Serotonin: a mediator of the brain-gut connection. Am. J. Gastroenterol. 95, 2698–2709 (2000).

    CAS  PubMed  Google Scholar 

  126. De Ponti, F. & Tonini, M. Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs 61, 317–332 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Ford, A. C. et al. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am. J. Gastroenterol. 104, 1831–1843 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Kawabata, A. et al. Hydrogen sulfide as a novel nociceptive messenger. Pain 132, 74–81 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Matsunami, M. et al. Luminal hydrogen sulfide plays a pronociceptive role in mouse colon. Gut 58, 751–761 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Schemann, M. & Grundy, D. Role of hydrogen sulfide in visceral nociception. Gut 58, 744–747 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Distrutti, E. et al. A nitro-arginine derivative of trimebutine (NO2-Arg-Trim) attenuates pain induced by colorectal distension in conscious rats. Pharmacol. Res. 59, 319–329 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Roediger, W. E., Duncan, A., Kapaniris, O. & Millard, S. Reducing sulfur compounds of the colon impair colonocyte nutrition: Implications for ulcerative colitis. Gastroenterology 104, 802–809 (1993).

    Article  CAS  PubMed  Google Scholar 

  133. Roediger, W. E., Duncan, A., Kapaniris, O. & Millard, S. Sulphide impairment of substrate oxidation in rat colonocytes: a biochemical basis for ulcerative colitis? Clin. Sci. (Lond.) 85, 623–627 (1993).

    Article  CAS  Google Scholar 

  134. O'Neil, M. J. The Merck Index. An Encyclopedia of Chemicals, Drugs, and Biologicals (Merck & Co, Whitehouse Station, NJ, 2001).

  135. Strocchi, A., Ellis, C. J. & Levitt, M. D. Use of metabolic inhibitors to study H2 consumption by human feces: evidence for a pathway other than methanogenesis and sulfate reduction. J. Lab. Clin. Med. 121, 320–327 (1993).

    CAS  PubMed  Google Scholar 

  136. Roediger, W. E., Moore, J. & Babidge, W. Colonic sulfide in pathogenesis and treatment of ulcerative colitis. Dig. Dis. Sci. 42, 1571–1579 (1997).

    Article  CAS  PubMed  Google Scholar 

  137. Tragnone, A. et al. Dietary habits as risk factors for inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 7, 47–51 (1995).

    CAS  PubMed  Google Scholar 

  138. Truelove, S. C. Ulcerative colitis provoked by milk. Br. Med. J. 1, 154–160 (1961).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pitcher, M. C., Beatty, E. R. & Cummings, J. H. The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis. Gut 46, 64–72 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Edmond, L. M., Hopkins, M. J., Magee, E. A. & Cummings, J. H. The effect of 5-aminosalicylic acid-containing drugs on sulfide production by sulfate-reducing and amino acid-fermenting bacteria. Inflamm. Bowel Dis. 9, 10–17 (2003).

    Article  PubMed  Google Scholar 

  141. Moore, J., Babidge, W., Millard, S. & Roediger, W. Colonic luminal hydrogen sulfide is not elevated in ulcerative colitis. Dig. Dis. Sci. 43, 162–165 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. Duffy, M. et al. Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis. Dis. Colon Rectum 45, 384–388 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Ohge, H. et al. Association between fecal hydrogen sulfide production and pouchitis. Dis. Colon Rectum 48, 469–475 (2005).

    Article  PubMed  Google Scholar 

  144. Gibson, G. R., Cummings, J. H. & Macfarlane, G. T. Growth and activities of sulphate-reducing bacteria in gut contents of healthy subjects and patients with ulcerative colitis. FEMS Microbiol. Lett. 86, 103–111 (1991).

    Article  CAS  Google Scholar 

  145. Pitcher, M. C. L., Beatty, E. R., Gibson, G. R. & Cummings, J. H. Incidence and activities of sulphate-reducing bacteria in patients with ulcerative colitis. Gut 36, A63 (1995).

    Google Scholar 

  146. Levine, J., Ellis, C. J., Furne, J. K., Springfield, J. & Levitt, M. D. Fecal hydrogen sulfide production in ulcerative colitis. Am. J. Gastroenterol. 93, 83–87 (1998).

    Article  CAS  PubMed  Google Scholar 

  147. Loubinoux, J., Bronowicki, J. P., Pereira, I. A., Mougenel, J. L. & Faou, A. E. Sulfate-reducing bacteria in human feces and their association with inflammatory bowel diseases. FEMS Microbiol. Ecol. 40, 107–112 (2002).

    Article  CAS  PubMed  Google Scholar 

  148. Tsai, H. H., Sunderland, D., Gibson, G. R., Hart, C. A. & Rhodes, J. M. A novel mucin sulphatase from human faeces: its identification, purification and characterization. Clin. Sci. (Lond.) 82, 447–454 (1992).

    Article  CAS  Google Scholar 

  149. Croix, J. A. et al. On the relationship between sialomucin and sulfomucin expression and hydrogenotrophic microbes in the human colonic mucosa. PLoS ONE 6, e24447 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Bjorneklett, A., Fausa, O. & Midtvedt, T. Bacterial overgrowth in jejunal and ileal disease. Scand. J. Gastroenterol. 18, 289–298 (1983).

    Article  CAS  PubMed  Google Scholar 

  151. McKay, L. F., Eastwood, M. A. & Brydon, W. G. Methane excretion in man—a study of breath, flatus, and faeces. Gut 26, 69–74 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Peled, Y., Weinberg, D., Hallak, A. & Gilat, T. Factors affecting methane production in humans. Gastrointestinal diseases and alterations of colonic flora. Dig. Dis. Sci. 32, 267–271 (1987).

    Article  CAS  PubMed  Google Scholar 

  153. Pimentel, M. et al. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig. Dis. Sci. 48, 86–92 (2003).

    Article  PubMed  Google Scholar 

  154. Perman, J. A. Methane and colorectal cancer. Gastroenterology 87, 728–730 (1984).

    Article  CAS  PubMed  Google Scholar 

  155. Karlin, D. A., Jones, R. D., Stroehlein, J. R., Mastromarino, A. J. & Potter, G. D. Breath methane excretion in patients with unresected colorectal cancer. J. Natl Cancer Inst. 69, 573–576 (1982).

    CAS  PubMed  Google Scholar 

  156. Haines, A., Metz, G., Dilawari, J., Blendis, L. & Wiggins, H. Breath-methane in patients with cancer of the large bowel. Lancet 2, 481–483 (1977).

    Article  CAS  PubMed  Google Scholar 

  157. Pique, J. M., Pallares, M., Cuso, E., Vilar-Bonet, J. & Gassull, M. A. Methane production and colon cancer. Gastroenterology 87, 601–605 (1984).

    Article  CAS  PubMed  Google Scholar 

  158. Karlin, D. A., Mastromarino, A. J., Jones, R. D., Stroehlein, J. R. & Lorentz, O. Fecal skatole and indole and breath methane and hydrogen in patients with large bowel polyps or cancer. J. Cancer Res. Clin. Oncol. 109, 135–141 (1985).

    Article  CAS  PubMed  Google Scholar 

  159. Peled, Y. Methane production and colon cancer. Gastroenterology 88, 1294 (1985).

    Article  CAS  PubMed  Google Scholar 

  160. Kashtan, H., Rabau, M., Peled, Y., Milstein, A. & Wiznitzer, T. Methane production in patients with colorectal carcinoma. Isr. J. Med. Sci. 25, 614–616 (1989).

    CAS  PubMed  Google Scholar 

  161. Sivertsen, S. M., Bjorneklett, A., Gullestad, H. P. & Nygaard, K. Breath methane and colorectal-cancer. Scand. J. Gastroenterol. 27, 25–28 (1992).

    Article  CAS  PubMed  Google Scholar 

  162. Holma, R. et al. Colonic methanogenesis in vivo and in vitro and fecal pH after resection of colorectal cancer and in healthy intact colon. Int. J. Colorectal Dis. 27, 171–178 (2011).

    Article  PubMed  Google Scholar 

  163. Babidge, W., Millard, S. & Roediger, W. Sulfides impair short chain fatty acid beta-oxidation at acyl-CoA dehydrogenase level in colonocytes: implications for ulcerative colitis. Mol. Cell. Biochem. 181, 117–124 (1998).

    Article  CAS  PubMed  Google Scholar 

  164. Cai, W. J., Wang, M. J., Ju, L. H., Wang, C. & Zhu, Y. C. Hydrogen sulfide induces human colon cancer cell proliferation: role of Akt, ERK and p21. Cell. Biol. Int. 34, 565–572 (2010).

    Article  CAS  PubMed  Google Scholar 

  165. Deplancke, B. & Gaskins, H. R. Hydrogen sulfide induces serum-independent cell cycle entry in nontransformed rat intestinal epithelial cells. FASEB J. 17, 1310–1312 (2003).

    Article  CAS  PubMed  Google Scholar 

  166. Leschelle, X. et al. Adaptative metabolic response of human colonic epithelial cells to the adverse effects of the luminal compound sulfide. Biochim. Biophys. Acta 1725, 201–212 (2005).

    Article  CAS  PubMed  Google Scholar 

  167. Christl, S. U., Eisner, H. D., Dusel, G., Kasper, H. & Scheppach, W. Antagonistic effects of sulfide and butyrate on proliferation of colonic mucosa: a potential role for these agents in the pathogenesis of ulcerative colitis. Dig. Dis. Sci. 41, 2477–2481 (1996).

    Article  CAS  PubMed  Google Scholar 

  168. Attene-Ramos, M. S., Wagner, E. D., Plewa, M. J. & Gaskins, H. R. Evidence that hydrogen sulfide is a genotoxic agent. Mol. Cancer Res. 4, 9–14 (2006).

    Article  CAS  PubMed  Google Scholar 

  169. Attene-Ramos, M. S., Wagner, E. D., Gaskins, H. R. & Plewa, M. J. Hydrogen sulfide induces direct radical-associated DNA damage. Mol. Cancer Res. 5, 455–459 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Attene-Ramos, M. S. et al. DNA damage and toxicogenomic analyses of hydrogen sulfide in human intestinal epithelial FHs 74 Int cells. Environ. Mol. Mutagen. 51, 304–314 (2010).

    CAS  PubMed  Google Scholar 

  171. Kanazawa, K. et al. Factors influencing the development of sigmoid colon cancer—bacteriologic and biochemical studies. Cancer 77, 1701–1706 (1996).

    Article  CAS  PubMed  Google Scholar 

  172. Ramasamy, S., Singh, S., Taniere, P., Langman, M. J. & Eggo, M. C. Sulfide-detoxifying enzymes in the human colon are decreased in cancer and upregulated in differentiation. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G288–G296 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Balamurugan, R., Rajendiran, E., George, S., Samuel, G. V. & Ramakrishna, B. S. Real-time polymerase chain reaction quantification of specific butyrate-producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer. J. Gastroenterol. Hepatol. 23, 1298–1303 (2008).

    Article  CAS  PubMed  Google Scholar 

  174. Marchesi, J. R. et al. Towards the human colorectal cancer microbiome. PLoS ONE 6 e20447 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kostic, A. D. et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22, 292–298 (2011).

    Article  CAS  PubMed  Google Scholar 

  176. Castellarin, M. et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 22, 299–306 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Fiorucci, S., Distrutti, E., Cirino, G. & Wallace, J. L. The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology 131, 259–271 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Wang, R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 16, 1792–1798 (2002).

    Article  CAS  PubMed  Google Scholar 

  179. Wallace, J. L., Ferraz, J. & Muscara, M. Hydrogen sulfide: an endogenous mediator of resolution of inflammation and injury. Antioxid. Redox Signal http://dx.doi.org/10.1089/ars.2011.4351.

  180. Furne, J., Saeed, A. & Levitt, M. D. Whole tissue hydrogen sulfide concentrations are orders of magnitude lower than presently accepted values. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1479–R1485 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Brock, T. D. & Od'ea, K. Amorphous ferrous sulfide as a reducing agent for culture of anaerobes. Appl. Environ. Microbiol. 33, 254–256 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Hungate, R. E. in Methods in Microbiology (eds Norris, J. R. & Ribbons, D. W.) 117–132 (Academic Press, London, 1969).

    Google Scholar 

  183. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    Article  PubMed  Google Scholar 

  184. Haines, A. P., Imeson, J. D. & Wiggins, H. S. Relation of breath methane with obesity and other factors. Int. J. Obes. 8, 675–680 (1984).

    CAS  PubMed  Google Scholar 

  185. Million, M. et al. Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii. Int. J. Obes. (Lond.) http://dx.doi.org/10.1038/ijo.2011.153.

  186. Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 18, 190–195 (2010).

    Article  Google Scholar 

  187. Armougom, F., Henry, M., Vialettes, B., Raccah, D. & Raoult, D. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and methanogens in anorexic patients. PLoS ONE 4, e7125 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Zheng, X. F., Sun, X. J. & Xia, Z. F. Hydrogen resuscitation, a new cytoprotective approach. Clin. Exp. Pharmacol. Physiol. 38, 155–163 (2011).

    Article  CAS  PubMed  Google Scholar 

  189. Ohsawa, I. et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 13, 688–694 (2007).

    Article  CAS  PubMed  Google Scholar 

  190. Hong, Y., Chen, S. & Zhang, J. M. Hydrogen as a selective antioxidant: a review of clinical and experimental studies. J. Int. Med. Res. 38, 1893–1903 (2010).

    Article  CAS  PubMed  Google Scholar 

  191. Huang, C. S., Kawamura, T., Toyoda, Y. & Nakao, A. Recent advances in hydrogen research as a therapeutic medical gas. Free Rad. Res. 44, 971–982 (2010).

    Article  CAS  Google Scholar 

  192. Kajiya, M., Silva, M. J. B., Sato, K., Ouhara, K. & Kawai, T. Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochem. Biophys. Res. Commun. 386, 11–15 (2009).

    Article  CAS  PubMed  Google Scholar 

  193. Nakao, A., Toyoda, Y., Sharma, P., Evans, M. & Guthrie, N. Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome—an open label pilot study. J. Clin. Biochem. Nutr. 46, 140–149 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Metz, G. L., Blendis, L. M. & Jenkins, J. A. Proceedings: alveolar H2 in the diagnosis of carbohydrate malabsorption. Gut 16, 398 (1975).

    CAS  PubMed  Google Scholar 

  195. Metz, G., Gassull, M. A., Drasar, B. S., Jenkins, D. J. & Blendis, L. M. Breath-hydrogen test for small-intestinal bacterial colonisation. Lancet 1, 668–669 (1976).

    Article  CAS  PubMed  Google Scholar 

  196. El Oufir, L. et al. Relations between transit time, fermentation products, and hydrogen consuming flora in healthy humans. Gut 38, 870–877 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Pimentel, M., Kong, Y. & Park, S. IBS subjects with methane on lactulose breath test have lower postprandial serotonin levels than subjects with hydrogen. Dig. Dis. Sci. 49, 84–87 (2004).

    Article  CAS  PubMed  Google Scholar 

  198. Dear, K. L., Elia, M. & Hunter, J. O. Do interventions which reduce colonic bacterial fermentation improve symptoms of irritable bowel syndrome? Dig. Dis. Sci. 50, 758–766 (2005).

    Article  CAS  PubMed  Google Scholar 

  199. Levine, J., Furne, J. K. & Levitt, M. D. Ashkenazi Jews, sulfur gases, and ulcerative colitis. J. Clin. Gastroenterol. 22, 288–291 (1996).

    Article  CAS  PubMed  Google Scholar 

  200. Duffy, M. et al. Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis. Dis. Colon Rectum 45, 384–388 (2002).

    Article  CAS  PubMed  Google Scholar 

  201. Bullock, N. R., Booth, J. C. & Gibson, G. R. Comparative composition of bacteria in the human intestinal microflora during remission and active ulcerative colitis. Curr. Issues Intest. Microbiol. 5, 59–64 (2004).

    PubMed  Google Scholar 

  202. Smith, F. M. et al. A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased illeal pouch. Colorectal Dis. 7, 563–570 (2005).

    Article  CAS  PubMed  Google Scholar 

  203. Bambury, N., Coffey, J. C., Burke, J., Redmond, H. P. & Kirwan, W. O. Sulphomucin expression in ileal pouches: emerging differences between ulcerative colitis and familial adenomatous polyposis pouches. Dis. Colon Rectum 51, 561–567 (2008).

    Article  PubMed  Google Scholar 

  204. Coffey, J. C. et al. Pathogenesis of and unifying hypothesis for idiopathic pouchitis. Am. J. Gastroenterol. 104, 1013–1023 (2009).

    Article  PubMed  Google Scholar 

  205. Lim, M. et al. An assessment of bacterial dysbiosis in pouchitis using terminal restriction fragment length polymorphisms of 16S ribosomal DNA from pouch effluent microbiota. Dis. Colon Rectum 52, 1492–1500 (2009).

    Article  PubMed  Google Scholar 

  206. Rowan, F. et al. Desulfovibrio bacterial species are increased in ulcerative colitis. Dis. Colon Rectum 53, 1530–1536 (2010).

    Article  PubMed  Google Scholar 

  207. Verma, R., Verma, A. K., Ahuja, V. & Paul, J. Real-time analysis of mucosal flora in patients with inflammatory bowel disease in India. J. Clin. Microbiol. 48, 4279–4282 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Strauss, J. et al. Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm. Bowel Dis. 17, 1971–1978 (2011).

    Article  PubMed  Google Scholar 

  209. Scanlan, P. D., Shanahan, F. & Marchesi, J. R. Culture-independent analysis of desulfovibrios in the human distal colon of healthy, colorectal cancer and polypectomized individuals. FEMS Microbiol. Ecol. 69, 213–221 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Related research was supported by grants from the NIH (RO1 CA135379) and Carle Foundation-University of Illinois Translational Research Program. The authors thank Matthew T. Leslie for help in the bibliographical search. This Review is dedicated to the scientific legacies of Dr Michael D. Levitt and Dr. Meyer J. Wolin, both of whom consistently contributed key studies over many years relating to the importance of the microbial hydrogen economy on colonic homeostasis.

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    Franck Carbonero, Ann C. Benefiel & H. Rex Gaskins

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Carbonero, F., Benefiel, A. & Gaskins, H. Contributions of the microbial hydrogen economy to colonic homeostasis. Nat Rev Gastroenterol Hepatol 9, 504–518 (2012). https://doi.org/10.1038/nrgastro.2012.85

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