Fecal Microbiota Transplantation Indications Met

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 “firsttime” 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 longterm effects of FMTFecal 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” lastresort 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 potentialsThe 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 culturebased techniques 4 Detailed sequencing studies suggest that 15000–36000 different bacterial species are known to inhabit the human GI tract 5 6 with each individual hosting roughly 500–1500 species although only a small subset of these are prevalent Recent metagenomic sequencing analysis established a human gut microbial gene catalogue identifying 33 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 changesFMT 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 donorHistorically 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 patientsThe 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 nasoduodenal 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 infusionrelated diarrhea and discomfort The trial was stopped early after interim analysis given the difference between treatments and success of FMT This study provided the highestlevel 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 RCDI 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 highrisk patient groups such as the profoundly immunosuppressedAnother 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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