From Stool Transplants to Next-Generation Microbiota Therapeutics
2014; Elsevier BV; Volume: 146; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2014.01.004
ISSN1528-0012
AutoresElaine O. Petrof, Alexander Khoruts,
Tópico(s)Gastrointestinal motility and disorders
ResumoThe epidemic of Clostridium difficile infection fueled by new virulent strains of the organism has led to increased use of fecal microbiota transplantation (FMT). The procedure is effective for even the most desperate cases after failure of multiple courses of antibiotics. The approach recognizes microbiota to be integral to normal human physiology, and microbiota being used in FMT represents a new class of therapeutics. Imbalance in the composition and altered activity of the microbiota are associated with many diseases. Consequently, there is growing interest in applying FMT to non–C difficile indications. However, this may succeed only if microbiota therapeutics are developed systematically, based on mechanistic understanding, and applying up-to-date principles of microbial ecology. We discuss 2 pathways in the development of this new therapeutic class: whole microbial communities separated from donor stool and an assembly of specific fecal microorganisms grown in vitro. The epidemic of Clostridium difficile infection fueled by new virulent strains of the organism has led to increased use of fecal microbiota transplantation (FMT). The procedure is effective for even the most desperate cases after failure of multiple courses of antibiotics. The approach recognizes microbiota to be integral to normal human physiology, and microbiota being used in FMT represents a new class of therapeutics. Imbalance in the composition and altered activity of the microbiota are associated with many diseases. Consequently, there is growing interest in applying FMT to non–C difficile indications. However, this may succeed only if microbiota therapeutics are developed systematically, based on mechanistic understanding, and applying up-to-date principles of microbial ecology. We discuss 2 pathways in the development of this new therapeutic class: whole microbial communities separated from donor stool and an assembly of specific fecal microorganisms grown in vitro. Alexander KhorutsView Large Image Figure ViewerDownload Hi-res image Download (PPT) The gastrointestinal tract contains a dense population of organized and highly specialized microbial communities that regulate host immunity and metabolism. The pathogenesis of many diseases is thought to involve compositional and functional changes in commensal microbiota, caused by use of antibiotics and other environmental factors such as dietary changes.1Blaser M.J. Falkow S. What are the consequences of the disappearing human microbiota?.Nat Rev Microbiol. 2009; 7: 887-894Crossref PubMed Scopus (628) Google Scholar Consequently, there is intense interest in manipulation of the composition of commensal microbiota as a therapeutic strategy. Although the public and many physicians may not distinguish this approach from use of probiotics or dietary supplements, large-scale alteration of the intestinal microbiota requires a different set of definitions and requirements, as well as research and the development of live biotherapeutics. Regulatory agencies such as the US Food and Drug Administration (FDA) consider any agents given to patients to cure, treat, mitigate, or prevent disease to be drugs. Therefore, their approval for testing and use in patients requires demonstrations of safety and efficacy. In contrast, probiotics are defined as live microorganisms that might provide health benefits.2Schrezenmeir J. de Vrese M. Probiotics, prebiotics, and synbiotics–approaching a definition.Am J Clin Nutr. 2001; 73: 361S-364SPubMed Scopus (1072) Google Scholar, 3de Vrese M. Schrezenmeir J. 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Given the serious public health challenge posed by the C difficile epidemic and lack of therapeutic alternatives, the FDA, for the time being, permits FMT for CDI that does not respond to standard antibiotic therapies, even though fecal microbiota are not formally approved for this or any other indication. However, it is difficult to imagine that this situation will continue indefinitely, and it is reasonable to expect that microbiota-based therapies will be developed for other conditions. Advances in high-throughput technologies that have enabled characterization of complex microbial communities in terms of taxonomy, gene expression, and production of metabolites within the human host will move this field of research forward. We review the promises and challenges of developing microbiota-based therapeutics. Coprophagy (consumption of the feces) is common in the animal kingdom, and has been observed in many species.11Ley R.E. Lozupone C.A. 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Chinese medicine provided the earliest known documentation of FMT in human beings, referring to various forms of fecal preparations, including fresh, fermented, dried, and infant-derived products that were used to treat multiple gastrointestinal maladies.18Zhang F. Luo W. Shi Y. et al.Should we standardize the 1,700-year-old fecal microbiota transplantation?.Am J Gastroenterol. 2012; 107 (author reply 6): 1755Crossref PubMed Scopus (437) Google Scholar In Europe, for centuries there was widespread belief in medical applications for fecal material. Franz Christian Paullini, a German physician, observed that fecal consumption was common in animals as well as human beings (since manure was used as a fertilizer). In 1696 he published a book “Hailsame Dreck-Apotheke” (Salutary Filth-Pharmacy) on medical uses of human and animal feces.19Lehrer S. 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Bacterial diversity is decreased markedly in fecal samples of patients with recurrent CDI; these often contain increased proportions of members of the Enterobacteraceae family of γ-Proteobacteria and reduced proportions of the Bacteroidetes and Firmicutes phyla.40Hamilton M.J. Weingarden A.R. Unno T. et al.High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria.Gut Microbes. 2013; 4: 125-135Crossref PubMed Scopus (240) Google Scholar, 41van Nood E. Vrieze A. Nieuwdorp M. et al.Duodenal infusion of donor feces for recurrent Clostridium difficile.N Engl J Med. 2013; 368: 407-415Crossref PubMed Scopus (2712) Google Scholar, 47Chang J.Y. Antonopoulos D.A. Kalra A. et al.Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea.J Infect Dis. 2008; 197: 435-438Crossref PubMed Scopus (815) Google Scholar FMT promptly restores normal, donor-like composition of intestinal microbiota dominated by Bacteroidetes and Firmicutes, and containing diminished proportions of γ-Proteobacteria.40Hamilton M.J. Weingarden A.R. Unno T. et al.High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria.Gut Microbes. 2013; 4: 125-135Crossref PubMed Scopus (240) Google Scholar, 41van Nood E. Vrieze A. Nieuwdorp M. et al.Duodenal infusion of donor feces for recurrent Clostridium difficile.N Engl J Med. 2013; 368: 407-415Crossref PubMed Scopus (2712) Google Scholar, 48Khoruts A. Dicksved J. 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For example, Lactobacillus delbrueckii species Bulgaricus B-30892 was shown to block C difficile adhesion and toxicity to epithelial cells via release of unknown factors, but have no effects on vegetative growth of C difficile bacteria.52Banerjee P. Merkel G.J. Bhunia A.K. Lactobacillus delbrueckii ssp. bulgaricus B-30892 can inhibit cytotoxic effects and adhesion of pathogenic Clostridium difficile to Caco-2 cells.Gut Pathog. 2009; 1: 8Crossref PubMed Google Scholar Furthermore, bacteriocin secreted by Bacillus thuringensis, named thuricin CD, was found to have narrow-spectrum activity against C difficile in an in vitro model of fecal microbiota in the distal colon.53Rea M.C. Dobson A. 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Fecal samples from patients with recurrent CDI have increased concentrations of primary bile salts and undetectable amounts of secondary bile acids, whereas FMT quickly restores a donor-like composition of fecal bile acid.59Weingarden A.R. Chen C. Bobr A. et al.Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.Am J Physiol Gastrointest Liver Physiol. 2014; 306: G310-G319Crossref PubMed Scopus (315) Google Scholar Interestingly, cholestyramine has been successful in anecdotal reports of treatment for recurrent CDI,60Kunimoto D. Thomson A.B. Recurrent Clostridium difficile-associated colitis responding to cholestyramine.Digestion. 1986; 33: 225-228Crossref PubMed Scopus (27) Google Scholar, 61Pruksananonda P. Powell K.R. Multiple relapses of Clostridium difficile-associated diarrhea responding to an extended course of chol
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