Fecal Transplant in Patients With Active Ulcerative Colitis
Fecal Transplant in Patients With Active Ulcerative Colitis
Objectives: Fecal microbiota transplantation (FMT) from healthy donors, which is an effective alternative for treatment of Clostridium difficile–associated disease, is being considered for several disorders such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome. Disease remission upon FMT is thought to be facilitated by an efficient colonization of healthy donor microbiota, but knowledge of the composition and temporal stability of patient microbiota after FMT is lacking.
Methods: Five patients with moderately to severely active ulcerative colitis (Mayo score ≥6) and refractory to standard therapy received FMT via nasojejunal tube and enema. In addition to clinical activity and adverse events, the patients' fecal bacterial communities were monitored at multiple time points for up to 12 weeks using 16S rRNA gene-targeted pyrosequencing.
Results: FMT elicited fever and a temporary increase of C-reactive protein. Abundant bacteria from donors established in recipients, but the efficiency and stability of donor microbiota colonization varied greatly. A positive clinical response was observed after 12 weeks in one patient whose microbiota had been effectively augmented by FMT. This augmentation was marked by successive colonization of donor-derived phylotypes including the anti-inflammatory and/or short-chain fatty acid–producing Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus. Disease severity (as measured by the Mayo score) was associated with an overrepresentation of Enterobacteriaceae and an underrepresentation of Lachnospiraceae.
Conclusions: This study highlights the value of characterizing temporally resolved microbiota dynamics for a better understanding of FMT efficacy and provides potentially useful diagnostic indicators for monitoring FMT success in the treatment of ulcerative colitis.
Humans and their trillions of intestinal microorganisms have coevolved to form a largely beneficial symbiosis. The human host provides a stable, nutrient-rich ecosystem, and commensal microorganisms contribute energy and cellular precursors in the form of short-chain fatty acids, prevent infections, and modulate and train the host immune system. This dynamic multipartner symbiosis can, however, become unbalanced through genetic and external factors, leading to severe diseases of the intestinal tract. Approximately 4 million people worldwide, mostly in the United States and Europe, are affected by chronic intestinal bowel disease (IBD), primarily Crohn's disease (CD) and ulcerative colitis (UC). IBD has no single etiology but is rather the consequence of a detrimental interaction of intestinal microbiota, epithelium, and immune system in genetically susceptible individuals. Application of modern molecular methods that allow comprehensive analysis of the gut microbiota has shown that IBD patients have a distorted, low-diversity intestinal microbiota (reviewed in Packey and Sartor and Reiff and Kelly. A specific IBD microbiota has however not yet been revealed, which might in part be because of interindividual and interintestinal (ileum vs. colon, mucosa vs. lumen) variability, different disease characteristics or subtypes, and differences in data acquisition and analysis.
Standard IBD management employs anti-inflammatory and/or immunosuppressive medication or surgical intervention, but no cure is available. Alternative IBD treatment approaches aimed at modifying the composition of the intestinal microbiota in order to overcome gut dysbiosis have become of major interest in recent years. Recently, a meta-analysis of randomized controlled trials has revealed a significant benefit of antibiotic therapy in IBD patients. There is also some evidence that probiotics may facilitate and stabilize clinical remission, especially in patients with UC. However, it is not known whether a commercial probiotic preparation, which only consists of a low number and diversity of bacterial species, or a short-term antibiotic therapy is able to durably modify the intestinal microbial ecosystem. Additional treatment approaches aimed at modifying the composition of the intestinal microbiota in order to overcome dysbiosis have thus become of major interest in recent years, and transplantation of the fecal microbiota from healthy donors is being discussed as an alternative therapy option for IBD.
Fecal microbiota transplantation (FMT), also called fecal bacteriotherapy, has been occasionally used for >50 years for treatment of Clostridium difficile–associated diarrhea and pseudomembranous colitis with great success. Two recent systematic reviews of 317 patients across 27 case series and 124 patients across 7 case series highlighted a disease improvement or resolution rate of 92% and 83%, respectively, with very few adverse effects. In contrast, FMT has rarely been used for IBD management.
Given the high success rate of FMT and the underlying assumption that it correlates with efficient colonization of the recipient's intestine by the donor microbiota, it is surprising that hardly any information exists regarding the fate of the transplanted microbiota. Very few studies have compared the fecal microbiota composition of donor and recipient, and these have analyzed only a single or very few selected time points after FMT. Furthermore, with only one exception, 16S rRNA gene-targeted fingerprinting methods were used that lack the phylogenetic resolution for comprehensive comparative analysis of the diverse gut microbiota. Thus, it remains to be demonstrated whether and to what extent resolution of clinical symptoms correlates with colonization of the recipient's intestinal tract by the donor microbiota.
In the present pilot study, we addressed this and the following specific research questions regarding the fate of the intestinal microbiota after FMT. How does the composition of the new intestinal microbiota (the composite donor–patient microbiota) change in the short and long term after transplantation? Is colonization of the receiving intestinal environment an instant "all-or-none" event or a continuous process characterized by successive establishment of individual microorganisms? How stable is donor-derived microbiota over time, and what is the identity of microorganisms that become temporally stable residents in the new intestinal environment? Here, we report the first study of temporal microbiota dynamics in five UC patients followed up to 3 months after receiving FMT. Comparative fecal microbiota analysis was performed using highly parallel pyrosequencing of bacterial 16S rRNA gene amplicons retrieved at 5–9 time points after FMT. Microbiota data and clinical measures of disease severity were compared to identify indicator taxa for disease at various levels of phylogenetic resolution.
Abstract and Introduction
Abstract
Objectives: Fecal microbiota transplantation (FMT) from healthy donors, which is an effective alternative for treatment of Clostridium difficile–associated disease, is being considered for several disorders such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome. Disease remission upon FMT is thought to be facilitated by an efficient colonization of healthy donor microbiota, but knowledge of the composition and temporal stability of patient microbiota after FMT is lacking.
Methods: Five patients with moderately to severely active ulcerative colitis (Mayo score ≥6) and refractory to standard therapy received FMT via nasojejunal tube and enema. In addition to clinical activity and adverse events, the patients' fecal bacterial communities were monitored at multiple time points for up to 12 weeks using 16S rRNA gene-targeted pyrosequencing.
Results: FMT elicited fever and a temporary increase of C-reactive protein. Abundant bacteria from donors established in recipients, but the efficiency and stability of donor microbiota colonization varied greatly. A positive clinical response was observed after 12 weeks in one patient whose microbiota had been effectively augmented by FMT. This augmentation was marked by successive colonization of donor-derived phylotypes including the anti-inflammatory and/or short-chain fatty acid–producing Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus. Disease severity (as measured by the Mayo score) was associated with an overrepresentation of Enterobacteriaceae and an underrepresentation of Lachnospiraceae.
Conclusions: This study highlights the value of characterizing temporally resolved microbiota dynamics for a better understanding of FMT efficacy and provides potentially useful diagnostic indicators for monitoring FMT success in the treatment of ulcerative colitis.
Introduction
Humans and their trillions of intestinal microorganisms have coevolved to form a largely beneficial symbiosis. The human host provides a stable, nutrient-rich ecosystem, and commensal microorganisms contribute energy and cellular precursors in the form of short-chain fatty acids, prevent infections, and modulate and train the host immune system. This dynamic multipartner symbiosis can, however, become unbalanced through genetic and external factors, leading to severe diseases of the intestinal tract. Approximately 4 million people worldwide, mostly in the United States and Europe, are affected by chronic intestinal bowel disease (IBD), primarily Crohn's disease (CD) and ulcerative colitis (UC). IBD has no single etiology but is rather the consequence of a detrimental interaction of intestinal microbiota, epithelium, and immune system in genetically susceptible individuals. Application of modern molecular methods that allow comprehensive analysis of the gut microbiota has shown that IBD patients have a distorted, low-diversity intestinal microbiota (reviewed in Packey and Sartor and Reiff and Kelly. A specific IBD microbiota has however not yet been revealed, which might in part be because of interindividual and interintestinal (ileum vs. colon, mucosa vs. lumen) variability, different disease characteristics or subtypes, and differences in data acquisition and analysis.
Standard IBD management employs anti-inflammatory and/or immunosuppressive medication or surgical intervention, but no cure is available. Alternative IBD treatment approaches aimed at modifying the composition of the intestinal microbiota in order to overcome gut dysbiosis have become of major interest in recent years. Recently, a meta-analysis of randomized controlled trials has revealed a significant benefit of antibiotic therapy in IBD patients. There is also some evidence that probiotics may facilitate and stabilize clinical remission, especially in patients with UC. However, it is not known whether a commercial probiotic preparation, which only consists of a low number and diversity of bacterial species, or a short-term antibiotic therapy is able to durably modify the intestinal microbial ecosystem. Additional treatment approaches aimed at modifying the composition of the intestinal microbiota in order to overcome dysbiosis have thus become of major interest in recent years, and transplantation of the fecal microbiota from healthy donors is being discussed as an alternative therapy option for IBD.
Fecal microbiota transplantation (FMT), also called fecal bacteriotherapy, has been occasionally used for >50 years for treatment of Clostridium difficile–associated diarrhea and pseudomembranous colitis with great success. Two recent systematic reviews of 317 patients across 27 case series and 124 patients across 7 case series highlighted a disease improvement or resolution rate of 92% and 83%, respectively, with very few adverse effects. In contrast, FMT has rarely been used for IBD management.
Given the high success rate of FMT and the underlying assumption that it correlates with efficient colonization of the recipient's intestine by the donor microbiota, it is surprising that hardly any information exists regarding the fate of the transplanted microbiota. Very few studies have compared the fecal microbiota composition of donor and recipient, and these have analyzed only a single or very few selected time points after FMT. Furthermore, with only one exception, 16S rRNA gene-targeted fingerprinting methods were used that lack the phylogenetic resolution for comprehensive comparative analysis of the diverse gut microbiota. Thus, it remains to be demonstrated whether and to what extent resolution of clinical symptoms correlates with colonization of the recipient's intestinal tract by the donor microbiota.
In the present pilot study, we addressed this and the following specific research questions regarding the fate of the intestinal microbiota after FMT. How does the composition of the new intestinal microbiota (the composite donor–patient microbiota) change in the short and long term after transplantation? Is colonization of the receiving intestinal environment an instant "all-or-none" event or a continuous process characterized by successive establishment of individual microorganisms? How stable is donor-derived microbiota over time, and what is the identity of microorganisms that become temporally stable residents in the new intestinal environment? Here, we report the first study of temporal microbiota dynamics in five UC patients followed up to 3 months after receiving FMT. Comparative fecal microbiota analysis was performed using highly parallel pyrosequencing of bacterial 16S rRNA gene amplicons retrieved at 5–9 time points after FMT. Microbiota data and clinical measures of disease severity were compared to identify indicator taxa for disease at various levels of phylogenetic resolution.
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