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Title of Journal: Curr Gastroenterol Rep

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Abbravation: Current Gastroenterology Reports

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Springer US

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10.1007/s00190-001-0231-8

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1534-312X

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Fecal Microbiota Transplantation: Indications, Methods, Evidence, and Future Directions

Authors: Thomas J. Borody, Sudarshan Paramsothy, Gaurav Agrawal,

Publish Date: 2013/07/14
Volume: 15, Issue:8, Pages: 337-
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Abstract

Fecal microbiota transplantation (FMT) has attracted great interest in recent years, largely due to the global Clostridium difficile infection (CDI) epidemic and major advances in metagenomic sequencing of the gastrointestinal (GI) microbiota, with growing understanding of its structure and function. FMT is now recommended as the most effective therapy for relapsing CDI and, with further refinement, may even be used in “first-time” CDI. There is interest also in other conditions related to GI dysbiosis—for example, inflammatory bowel disease, irritable bowel syndrome, obesity, and diabetes mellitus—although quality evidence is at present lacking. A few trials are now underway in FMT for ulcerative colitis. Many unanswered questions remain, including FMT methodology—for example, optimal route of administration, what makes a “good donor,” safety issues, and long-term effects of FMT.Fecal microbiota transplantation (FMT) is the introduction of a fecal suspension derived from a healthy donor into the gastrointestinal (GI) tract of a diseased individual. While not a new therapeutic concept [1, 2], it has, over the last few years, experienced a significant growth in interest, with an evolving methodology and clinical indications largely due to two factors: (1) the global CDI epidemic and (2) a growing appreciation of the complexity of the GI microbiome and its active role in health and disease. FMT is no longer considered an “alternative,” last-resort medical practice but, rather, is now gaining mainstream acceptance as a valuable, although still poorly understood, therapy with biological plausibility. This is reflected in the increasing number of scientific publications related to FMT. In this review, we will summarize the latest evidence, indications, and methods of administering FMT, and provide some insight into future directions and therapeutic potentials.The human GI microbiota is considered a tissue, not an organ, and is used in FMT to implant in a recipient’s GI tract. To understand the utility of FMT, it is first necessary to appreciate the compositional complexity of the GI microbiota, along with its associated functional implications. There are about 1014 bacterial cells in our body—10 times more than the roughly 1013 human cells [3]—and most of these bacterial cells reside in the GI tract. Only about 30 % of the GI microbiota is detectable by culture-based techniques [4]. Detailed sequencing studies suggest that 15,000–36,000 different bacterial species are known to inhabit the human GI tract [5, 6], with each individual hosting roughly 500–1,500 species, although only a small subset of these are prevalent. Recent metagenomic sequencing analysis established a human gut microbial gene catalogue, identifying 3.3 million nonredundant microbial genes, approximately 150 times larger than the entire human gene complement [7]. The GI microbiota and their genetic products exist in a complex, but balanced, homeostasis and have important roles in nutrition, energy metabolism, host defense, and immune system development [8, 9, 10, 11••]. Dysbiosis, or abnormal compositional disturbance of this homeostasis, can be associated with various disease states. Such conditions are potentially amenable to therapy with FMT to correct these changes.FMT is most widely used, and now recommended, in the indication of Clostridium difficile infection (CDI) [12••]. CDI is an ideal condition for FMT, since it is primarily a GI dysbiosis with Clostridium difficile overgrowth. CDI has traditionally yet counterintuitively been treated with antibiotics such as metronidazole, vancomycin, and, more recently, fidaxomicin or rifaximin. However, antibiotic therapy results in further microbiota damage and in recurrence rates of at least 20 %, which rise with each subsequent CDI episode [13, 14, 15]. Furthermore, antibiotics do not correct the abnormal microbiome but, rather, potentiate the problem. Conversely, FMT corrects the imbalanced microbiota that underlies CDI pathogenesis by providing the patient with a healthy microbiota that has a structural and functional homeostasis derived from a suitable donor.Historically, FMT has been offered only in a few specialized centers globally, but in the last few years, there has been growing use of FMT, with numerous publications from many international sites demonstrating efficacy in CDI. Most of these have been uncontrolled, but they have all reported high success rates of around 90 % or more [16, 17, 18, 19, 20, 21]. The global experience of FMT in CDI is now in excess of 500 patients.The first randomized controlled trial involving FMT for relapsing CDI was published earlier this year and demonstrated vast superiority of FMT over traditional antibiotic therapy [22••]. FMT had a success rate of 81 % following a single naso-duodenal infusion and 94 % following a second infusion, while vancomycin 500 mg qid for 2 weeks with or without bowel lavage had only 23 %–31 % efficacy. After FMT, there was increased bacterial diversity, with increases in Bacteroidetes species, Clostridia class IV and XIVa, and decreased Proteobacteria. No significant adverse events were noted other than mild infusion-related diarrhea and discomfort. The trial was stopped early after interim analysis, given the difference between treatments and success of FMT. This study provided the highest-level evidence for superiority of FMT over current optimal care antibiotics. It also shifted FMT into the focus of mainstream medicine, soon followed by the American College of Gastroenterology formally recommending FMT in its Guidelines for Relapsing CDI (R-CDI) [12••]. Future research in FMT for CDI should now shift to refining the microbiota product, administration methodology, luminal effects of FMT on the resident flora, and assessing safety. An important area to study will be the use of FMT in severe and fulminant CDI and in certain high-risk patient groups, such as the profoundly immunosuppressed.Another area of FMT use is the treatment of CDI coinfection in inflammatory bowel disease (IBD). The original report of this approach included 6 patients, 4 with UC and 2 with Crohn’s disease (CD). All were treated successfully with improvement in colitis symptoms [23]. Other cases of successful treatment have recently been reviewed by Anderson et al. [24•], who identified eight case series/reports with a total of 15 patients treated with FMT for CDI coinfecting IBD (9 UC, 6 CD). All had resolution of CDI, with 86 % demonstrating improved response to IBD medications. Reddy et al. [25] adds further to our total experience in this area. The coexistence with IBD may require additional infusions to ensure successful CDI eradication [17].


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