Gut microbiota: a potential new territory for drug targeting

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.

[1]  S. Pettersson,et al.  Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA , 2004, Nature Immunology.

[2]  L. Maunula,et al.  Prophylactic Lactobacillus GGReduces Antibiotic-Associated Diarrhea in Children With Respiratory Infections: A Randomized Study , 1999, Pediatrics.

[3]  P. Turnbaugh,et al.  Microbial ecology: Human gut microbes associated with obesity , 2006, Nature.

[4]  M. Pop,et al.  Metagenomic Analysis of the Human Distal Gut Microbiome , 2006, Science.

[5]  J. Nicholson,et al.  Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics , 2002, Nature Medicine.

[6]  S. Akira,et al.  Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. , 2004, Gastroenterology.

[7]  P. Mannon,et al.  The fundamental basis of inflammatory bowel disease. , 2007, The Journal of clinical investigation.

[8]  R. Williams,et al.  Effect of intestinal microflora on the urinary metabolic profile of rats: a 1 H-nuclear magnetic resonance spectroscopy study , 2002, Xenobiotica; the fate of foreign compounds in biological systems.

[9]  I. Wilson,et al.  Understanding 'Global' Systems Biology: Metabonomics and the Continuum of Metabolism , 2003, Nature Reviews Drug Discovery.

[10]  F. Guarner,et al.  Gut flora in health and disease , 2003, The Lancet.

[11]  J. Hotz [Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study]. , 1990, Zeitschrift fur Gastroenterologie.

[12]  W. Walker,et al.  Probiotics and prebiotics: role in clinical disease states. , 2005, Advances in pediatrics.

[13]  Tie Zhao,et al.  Simultaneous determination of 17 ginsenosides in rat urine by ultra performance liquid chromatography-mass spectrometry with solid-phase extraction. , 2007, Analytica chimica acta.

[14]  Mark M Huycke,et al.  Bacteria-Induced Intestinal Cancer in Mice with Disrupted Gpx1 and Gpx2 Genes , 2004, Cancer Research.

[15]  Liping Zhao,et al.  Pharmacometabonomic phenotyping reveals different responses to xenobiotic intervention in rats. , 2007, Journal of proteome research.

[16]  J. Gordon,et al.  Honor thy symbionts , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[18]  R. Davis,et al.  Association Between Streptococcal Infection and Obsessive-Compulsive Disorder, Tourette's Syndrome, and Tic Disorder , 2005, Pediatrics.

[19]  I. Wilson,et al.  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. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[20]  I. Saiki,et al.  In vivo antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration. , 1997, Oncology research.

[21]  M. Robertson,et al.  Increased Antistreptococcal Antibody Titers and Anti—Basal Ganglia Antibodies in Patients With Tourette Syndrome: Controlled Cross-Sectional Study , 2006, Journal of child neurology.

[22]  P. Long,et al.  Biomedicinals from the phytosymbionts of marine invertebrates: a molecular approach. , 2007, Methods.

[23]  R. G. Joosten,et al.  Persistence of DNA studied in different ex vivo and in vivo rat models simulating the human gut situation. , 2004, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[24]  J. Handelsman Metagenomics: Application of Genomics to Uncultured Microorganisms , 2004, Microbiology and Molecular Biology Reviews.

[25]  Ting Wang,et al.  The gut microbiota as an environmental factor that regulates fat storage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Tomita,et al.  Bifidobacterium longum, a lactic acid-producing intestinal bacterium inhibits colon cancer and modulates the intermediate biomarkers of colon carcinogenesis. , 1997, Carcinogenesis.

[27]  E. Mardis,et al.  An obesity-associated gut microbiome with increased capacity for energy harvest , 2006, Nature.

[28]  R. Kerwin,et al.  Role of Chronic Infection and Inflammation in the Gastrointestinal Tract in the Etiology and Pathogenesis of Idiopathic Parkinsonism , 2005, Helicobacter.

[29]  P. Malfertheiner,et al.  Helicobacter pylori eradication and gastric ulcer healing — comparison of three pantoprazole‐based triple therapies , 2003, Alimentary pharmacology & therapeutics.

[30]  M. McCarthy,et al.  Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice , 2006, Proceedings of the National Academy of Sciences.

[31]  A. Gunatilaka Natural products from plant-associated microorganisms: distribution, structural diversity, bioactivity, and implications of their occurrence. , 2006, Journal of natural products.

[32]  Justin C.Y. Wu,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 , 2002, The Lancet.

[33]  S. Okada,et al.  Mutagenicity of dimethylated metabolites of inorganic arsenics. , 1989, Chemical & pharmaceutical bulletin.

[34]  A. Andoh,et al.  Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease. , 2006, World journal of gastroenterology.

[35]  T. Matsuzaki,et al.  Prevention of onset in an insulin‐dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei , 1997, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[36]  M. Mendall,et al.  Antibiotic use, childhood affluence and irritable bowel syndrome (IBS) , 1998, European journal of gastroenterology & hepatology.

[37]  R. Wilson,et al.  Genomic and metabolic adaptations of Methanobrevibacter smithii to the human gut , 2007, Proceedings of the National Academy of Sciences.

[38]  J. Rhodes,et al.  Bacteria in the pathogenesis of inflammatory bowel disease , 2006, Current opinion in infectious diseases.

[39]  X. Hua,et al.  Inter-species transplantation of gut microbiota from human to pigs , 2007, The ISME Journal.

[40]  G. Reid,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. , 2005, FEMS microbiology ecology.

[41]  G. Macfarlane,et al.  Intestinal bacteria and ulcerative colitis. , 2003, Current issues in intestinal microbiology.

[42]  T. Hartung,et al.  Enhanced antiinflammatory capacity of a Lactobacillus plantarum mutant synthesizing modified teichoic acids. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Wilcox Clostridium difficile infection and pseudomembranous colitis , 2003 .

[44]  M. Kokkinidis,et al.  Conserved features of type III secretion , 2004, Cellular microbiology.

[45]  T. Matsuzaki,et al.  Effect of oral administration of Lactobacillus casei on alloxan‐induced diabetes in mice , 1997, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[46]  S. Walsh,et al.  Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial , 2005, Gut.

[47]  R. Yamazaki,et al.  Antidiabetic effects of an oral administration of Lactobacillus casei in a non-insulin-dependent diabetes mellitus (NIDDM) model using KK-Ay mice. , 1997, Endocrine journal.

[48]  M. Wilcox Gastrointestinal disorders and the critically ill. Clostridium difficile infection and pseudomembranous colitis. , 2003, Best practice & research. Clinical gastroenterology.

[49]  C. Surawicz,et al.  The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[50]  F. Shanahan,et al.  Probiotic impact on microbial flora, inflammation and tumour development in IL‐10 knockout mice , 2001, Alimentary pharmacology & therapeutics.

[51]  F. Shanahan,et al.  The gut flora as a forgotten organ , 2006, EMBO reports.

[52]  A. Hosono,et al.  Antidiabetic Effect of Lactobacillus GG in Streptozotocin-induced Diabetic Rats , 2003, Bioscience, biotechnology, and biochemistry.

[53]  Lynn K. Carmichael,et al.  A Genomic View of the Human-Bacteroides thetaiotaomicron Symbiosis , 2003, Science.

[54]  G R Gibson,et al.  Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. , 1995, The Journal of nutrition.

[55]  H. Yadav,et al.  Antidiabetic effect of probiotic dahi containing Lactobacillus acidophilus and Lactobacillus casei in high fructose fed rats. , 2007, Nutrition.

[56]  Elaine Holmes,et al.  The challenges of modeling mammalian biocomplexity , 2004, Nature Biotechnology.

[57]  J. Handelsman,et al.  Metagenomics: genomic analysis of microbial communities. , 2004, Annual review of genetics.

[58]  Minjun Chen,et al.  Application of ethyl chloroformate derivatization for gas chromatography-mass spectrometry based metabonomic profiling. , 2007, Analytica chimica acta.

[59]  C. Hadley The infection connection , 2006, EMBO reports.

[60]  J. Lindon,et al.  Pharmaco-metabonomic phenotyping and personalized drug treatment , 2006, Nature.

[61]  M. Tanner,et al.  Metabonomic investigations in mice infected with Schistosoma mansoni: an approach for biomarker identification. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[62]  Timothy M. D. Ebbels,et al.  Toxicity classification from metabonomic data using a density superposition approach: ‘CLOUDS’ , 2003 .

[63]  H. Harmsen,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? , 2006, Diabetologia.

[64]  K. Fellermann,et al.  Induction of Human β-Defensin 2 by the Probiotic Escherichia coli Nissle 1917 Is Mediated through Flagellin , 2007, Infection and Immunity.

[65]  I. Wilson,et al.  Gut microorganisms, mammalian metabolism and personalized health care , 2005, Nature Reviews Microbiology.