Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Gut microbiota: a potential new territory for drug targeting

Nature Reviews Drug Discovery volume 7, pages 123–129 (2008)Cite this article

Abstract

The significant involvement of the gut microbiota in human health and disease suggests that manipulation of commensal microbial composition through combinations of antibiotics, probiotics and prebiotics could be a novel therapeutic approach. A systems perspective is needed to help understand the complex host–bacteria interactions and their association with pathophysiological phenotypes so that alterations in the composition of the gut microbiota in disease states can be reversed. In this article, we describe the therapeutic rationale and potential for targeting the gut microbiota, and discuss strategies and systems-oriented technologies for achieving this goal.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic view of how the gut microbiota affects host fat storage.
Figure 2: Schematic view of gut microbiota-targeted therapeutic strategy.
Figure 3: Metabolic profiling and urinary mammal–microbial metabolites in rats.

Similar content being viewed by others

References

  1. Nicholson, J. K., Holmes, E., Lindon, J. C. & Wilson, I. D. The challenges of modeling mammalian biocomplexity. Nature Biotech. 22, 1268–1274 (2004).

    Article  CAS  Google Scholar 

  2. Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006).

    Article  CAS  Google Scholar 

  3. Riesenfeld, C. S., Schloss, P. D. & Handelsman, J. Metagenomics: genomic analysis of microbial communities. Annu. Rev. Genet. 38, 525–552 (2004).

    Article  CAS  Google Scholar 

  4. Dumas, M. E. et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl Acad. Sci. USA 103, 12511–12516 (2006).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  6. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    Article  CAS  Google Scholar 

  7. Brugman, S. et al. Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? Diabetologia 49, 2105–2108 (2006).

    Article  CAS  Google Scholar 

  8. Strober, W., Fuss, I. & Mannon, P. The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 117, 514–521 (2007).

    Article  CAS  Google Scholar 

  9. Chu, F. F. et al. Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes. Cancer Res. 64, 962–968 (2004).

    Article  CAS  Google Scholar 

  10. Guarner, F. & Malagelada, J. R. Gut flora in health and disease. Lancet 361, 512–519 (2003).

    Article  Google Scholar 

  11. Xu, J. & Gordon, J. I. Honor thy symbionts. Proc. Natl Acad. Sci. USA 100, 10452–10459 (2003).

    Article  CAS  Google Scholar 

  12. O'Hara, A. M. & Shanahan, F. The gut flora as a forgotten organ. EMBO Rep. 7, 688–693 (2006).

    Article  CAS  Google Scholar 

  13. Nicholson, J. K. & Wilson, I. D. Understanding 'global' systems biology: metabonomics and the continuum of metabolism. Nature Rev. Drug Discov. 2, 668–676 (2003).

    Article  CAS  Google Scholar 

  14. Grangette, C. et al. Enhanced antiinflammatory capacity of a Lactobacillus plantarum mutant synthesizing modified teichoic acids. Proc. Natl Acad. Sci. USA 102, 10321–10326 (2005).

    Article  CAS  Google Scholar 

  15. Wakabayashi, C., Hasegawa, H., Murata, J. & Saiki, I. In vivo antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration. Oncol. Res. 9, 411–417 (1997).

    CAS  PubMed  Google Scholar 

  16. Ebbels, T. et al. Toxicity classification from metabonomic data using a density superposition approach: 'CLOUDS'. Anal. Chim. Acta 490, 109–122 (2003).

    Article  CAS  Google Scholar 

  17. Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).

    Article  Google Scholar 

  18. Yamanaka, K., Ohba, H., Hasegawa, A., Sawamura, R. & Okada, S. Mutagenicity of dimethylated metabolites of inorganic arsenics. Chem. Pharm. Bull. (Tokyo) 37, 2753–2756 (1989).

    Article  CAS  Google Scholar 

  19. Rizzo, R., Gulisano, M., Pavone, P., Fogliani, F. & Robertson, M. M. Increased antistreptococcal antibody titers and anti-basal ganglia antibodies in patients with Tourette syndrome: controlled cross-sectional study. J. Child. Neurol. 21, 747–753 (2006).

    Article  Google Scholar 

  20. Mell, L. K., Davis, R. L. & Owens, D. Association between streptococcal infection and obsessive-compulsive disorder, Tourette's syndrome, and tic disorder. Pediatrics 116, 56–60 (2005).

    Article  Google Scholar 

  21. Nicholson, J. K., Holmes, E. & Wilson, I. D. Gut microorganisms, mammalian metabolism and personalized health care. Nature Rev. Microbiol. 3, 431–438 (2005).

    Article  CAS  Google Scholar 

  22. Arvola, T. et al. Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections: a randomized study. Pediatrics 104, e64 (1999).

    Article  CAS  Google Scholar 

  23. Mendall, M. A. & Kumar, D. Antibiotic use, childhood affluence and irritable bowel syndrome (IBS). Eur. J. Gastroenterol. Hepatol. 10, 59–62 (1998).

    Article  CAS  Google Scholar 

  24. Wilcox, M. H. Gastrointestinal disorders and the critically ill. Clostridium difficile infection and pseudomembranous colitis. Best Pract. Res. Clin. Gastroenterol. 17, 475–493 (2003).

    Article  Google Scholar 

  25. Jernberg, C., Lofmark, S., Edlund, C. & Jansson, J.K. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J. 1, 56–66 (2007).

    Article  CAS  Google Scholar 

  26. Hadley, C. The infection connection. Helicobacter pylori is more than just the cause of gastric ulcers — it offers an unprecedented opportunity to study changes in human microecology and the nature of chronic disease. EMBO Rep. 7, 470–473 (2006).

    Article  CAS  Google Scholar 

  27. Xu, J. et al. A genomic view of the human–Bacteroides thetaiotaomicron symbiosis. Science 299, 2074–2076 (2003).

    Article  CAS  Google Scholar 

  28. Kelly, D. et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nature Immunol. 5, 104–112 (2004).

    Article  CAS  Google Scholar 

  29. Samuel, B. S. et al. Genomic and metabolic adaptations of Methanobrevibacter smithii to the human gut. Proc. Natl Acad. Sci. USA 104, 10643–10648 (2007).

    Article  CAS  Google Scholar 

  30. Tampakaki, A. P., Fadouloglou, V. E., Gazi, A. D., Panopoulos, N. J. & Kokkinidis, M. Conserved features of type III secretion. Cell. Microbiol. 6, 805–816 (2004).

    Article  CAS  Google Scholar 

  31. Chan, F. K. et al. Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet 359, 9–13 (2002).

    Article  CAS  Google Scholar 

  32. Rachmilewitz, D. et al. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126, 520–528 (2004).

    Article  CAS  Google Scholar 

  33. Rastall, R. A. et al. Modulation of the microbial ecology of the human colon by probiotics, prebiotics and synbiotics to enhance human health: an overview of enabling science and potential applications. FEMS Microbiol. Ecol. 52, 145–152 (2005).

    Article  CAS  Google Scholar 

  34. Matsuzaki, T., Yamazaki, R., Hashimoto, S. & Yokokura, T. Antidiabetic effects of an oral administration of Lactobacillus casei in a non-insulin-dependent diabetes mellitus (NIDDM) model using KK-Ay mice. Endocr. J. 44, 357–365 (1997).

    Article  CAS  Google Scholar 

  35. Matsuzaki, T. et al. Prevention of onset in an insulin-dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei. APMIS 105, 643–649 (1997).

    Article  CAS  Google Scholar 

  36. Matsuzaki, T. et al. Effect of oral administration of Lactobacillus casei on alloxan-induced diabetes in mice. APMIS 105, 637–642 (1997).

    Article  CAS  Google Scholar 

  37. Tabuchi, M. et al. Antidiabetic effect of Lactobacillus GG in streptozotocin-induced diabetic rats. Biosci. Biotechnol. Biochem. 67, 1421–1424 (2003).

    Article  CAS  Google Scholar 

  38. Yadav, H., Jain, S. & Sinha, P. R. Antidiabetic effect of probiotic dahi containing Lactobacillus acidophilus and Lactobacillus casei in high fructose fed rats. Nutrition 23, 62–68 (2007).

    Article  Google Scholar 

  39. Schlee, M. et al. Induction of human β-defensin 2 by the probiotic Escherichia coli Nissle 1917 is mediated through flagellin. Infect. Immun. 75, 2399–2407 (2007).

    Article  CAS  Google Scholar 

  40. Gibson, G. R. & Roberfroid, M. B. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J. Nutr. 125, 1401–1412 (1995).

    Article  CAS  Google Scholar 

  41. Chen, C. C. & Walker, W. A. Probiotics and prebiotics: role in clinical disease states. Adv. Pediatr. 52, 77–113 (2005).

    Article  Google Scholar 

  42. Furrie, E. et al. Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut 54, 242–249 (2005).

    Article  CAS  Google Scholar 

  43. Gunatilaka, A. A. Natural products from plant-associated microorganisms: distribution, structural diversity, bioactivity, and implications of their occurrence. J. Nat. Prod. 69, 509–526 (2006).

    Article  CAS  Google Scholar 

  44. Dunlap, W. C. et al. Biomedicinals from the phytosymbionts of marine invertebrates: a molecular approach. Methods 42, 358–376 (2007).

    Article  CAS  Google Scholar 

  45. Brindle, J. T. et al. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nature Med. 8, 1439–1444 (2002).

    Article  CAS  Google Scholar 

  46. Qiu, Y. et al. Application of ethyl chloroformate derivatization for gas chromatography-mass spectrometry based metabonomic profiling. Anal. Chim. Acta 583, 277–283 (2007).

    Article  CAS  Google Scholar 

  47. Wang, X. et al. Simultaneous determination of 17 ginsenosides in rat urine by ultra performance liquid chromatography-mass spectrometry with solid-phase extraction. Anal. Chim. Acta 594, 265–273 (2007).

    Article  CAS  Google Scholar 

  48. Phipps, A. N., Stewart, J., Wright, B. & Wilson, I. D. Effect of diet on the urinary excretion of hippuric acid and other dietary-derived aromatics in rat. A complex interaction between diet, gut microflora and substrate specificity. Xenobiotica 28, 527–537 (1998).

    Article  CAS  Google Scholar 

  49. Wang, Y. et al. Metabonomic investigations in mice infected with Schistosoma mansoni: an approach for biomarker identification. Proc. Natl Acad. Sci. USA 101, 12676–12681 (2004).

    Article  CAS  Google Scholar 

  50. Clayton, T. A. et al. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature 440, 1073–1077 (2006).

    Article  CAS  Google Scholar 

  51. Li, H. et al. Pharmacometabonomic phenotyping reveals different responses to xenobiotic intervention in rats. J. Proteome Res. 6, 1364–1370 (2007).

    Article  CAS  Google Scholar 

  52. Williams, R. E., Eyton-Jones, H. W., Farnworth, M. J., Gallagher, R. & Provan, W. M. Effect of intestinal microflora on the urinary metabolic profile of rats: a 1H-nuclear magnetic resonance spectroscopy study. Xenobiotica 32, 783–794 (2002).

    Article  CAS  Google Scholar 

  53. Handelsman, J. Metagenomics: application of genomics to uncultured microorganisms. Microbiol. Mol. Biol. Rev. 68, 669–685 (2004).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  55. Wilcks, A., van Hoek, A. H., Joosten, R. G., Jacobsen, B. B. & Aarts, H. J. Persistence of DNA studied in different ex vivo and in vivo rat models simulating the human gut situation. Food Chem. Toxicol. 42, 493–502 (2004).

    Article  CAS  Google Scholar 

  56. Pang, X. et al. Inter-species transplantation of gut microbiota from human to pigs ISME J. 1, 156–162 (2007).

    Article  CAS  Google Scholar 

  57. Malfertheiner, P. et al. Helicobacter pylori eradication and gastric ulcer healing — comparison of three pantoprazole-based triple therapies. Aliment. Pharmacol. Ther. 17, 1125–1135 (2003).

    Article  CAS  Google Scholar 

  58. Surawicz, C. M. et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology 96, 981–988 (1989).

    Article  CAS  Google Scholar 

  59. Surawicz, C. M. et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin. Infect. Dis. 31, 1012–1017 (2000).

    Article  CAS  Google Scholar 

  60. Cummings, J. H., Macfarlane, G. T. & Macfarlane, S. Intestinal bacteria and ulcerative colitis. Curr. Issues Intest. Microbiol. 4, 9–20 (2003).

    CAS  PubMed  Google Scholar 

  61. Subramanian, S., Campbell, B. J. & Rhodes, J. M. Bacteria in the pathogenesis of inflammatory bowel disease. Curr. Opin. Infect. Dis. 19, 475–484 (2006).

    Article  Google Scholar 

  62. Andoh, A. & Fujiyama, Y. Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease. World J. Gastroenterol. 12, 4452–4460 (2006).

    Article  Google Scholar 

  63. O'Mahony, L. et al. Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice. Aliment. Pharmacol. Ther. 15, 1219–1225 (2001).

    Article  CAS  Google Scholar 

  64. Singh, J. et al. Bifidobacterium longum, a lactic acid-producing intestinal bacterium inhibits colon cancer and modulates the intermediate biomarkers of colon carcinogenesis. Carcinogenesis 18, 833–841 (1997).

    Article  CAS  Google Scholar 

  65. Dobbs, R. J. et al. Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 1: eradication of Helicobacter in the cachexia of idiopathic parkinsonism. Helicobacter 10, 267–275 (2005).

    Article  CAS  Google Scholar 

  66. Bjarnason, I. T. et al. Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 2: response of facets of clinical idiopathic parkinsonism to Helicobacter pylori eradication. A randomized, double-blind, placebo-controlled efficacy study. Helicobacter 10, 276–287 (2005).

    Article  CAS  Google Scholar 

  67. Weller, C. et al. Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 3: predicted probability and gradients of severity of idiopathic parkinsonism based on H. pylori antibody profile. Helicobacter 10, 288–297 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Basic Research Program of China (2007CB914700) and the International Collaborative Project, Chinese Ministry of Science and Technology (2006DFA02700).

Author information

Authors and Affiliations

  1. Wei Jia, Haukai Li and Liping Zhao are at the School of Pharmacy and at the Institute for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.,

    Wei Jia, Houkai Li & Liping Zhao

  2. Jeremy K. Nicholson is at the Department of Biomolecular Medicine, Division of Surgery Oncology Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK,

    Jeremy K. Nicholson

Authors
  1. Wei Jia
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Houkai Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Liping Zhao
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Jeremy K. Nicholson
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Wei Jia.

Related links

Related links

DATABASES

Entrez Genome Project

Bacteroides thetaiotaomicron

Clostridium difficile

Escherichia coli

Helicobacter pylori

Lactobacillus acidophilus

Lactobacillus casei

Methanobrevibacter smithii

OMIM

ADHD

inflammatory bowel disease

obesity

Tourette syndrome

FURTHER INFORMATION

The Consortium on Metabonomic Toxicology

Glossary

Metabonomics

The quantitative measurement of the multivariate metabolic responses of multicellular systems to pathophysiological stimuli or genetic modification. It is an approach to understanding the global metabolic regulation of an organism and its commensal and symbiotic partners.

Metagenomics

A culture-independent and sequence-based analysis of the collective microbial genomes contained in an environmental sample including soil, the oral cavity, faeces and aquatic habitats. The term is derived from the statistical concept of meta-analysis (the process of statistically combining separate analyses) and genomics (the comprehensive analysis of an organism's genetic material).

Microbiome

The entire set of microbial species living in the human body.

Pachinko model

A model for the illustration of xenobiotic metabolism in the host, in which the outcome of a xenobiotic is the result of a series of probabilistic interactions with endogenous and sym-endogenous elements.

Pharmaco-metabonomics

The prediction of the outcome of a drug or xenobiotic intervention in an individual based on a mathematical model of pre-intervention metabolite signatures.

Prebiotics

A non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria that can improve host health.

Probiotics

Live microorganisms that, when administered in adequate amounts, confer a health benefit to the host.

Type III secretion system

A complex protein secretion and delivery system used by many animal- and plant-interacting bacteria, especially Gram-negative pathogenic bacteria, for delivering effector proteins into eukaryotic cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jia, W., Li, H., Zhao, L. et al. Gut microbiota: a potential new territory for drug targeting. Nat Rev Drug Discov 7, 123–129 (2008). https://doi.org/10.1038/nrd2505

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2505

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing
pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy