nogutsnoglory
Moderator
"CHICAGO -- A randomized trial of fecal microbiota transplant (FMT) in ulcerative colitis ended early because of lack of efficacy, but investigators remain intrigued by the procedure's therapeutic potential.
After 6 weeks of follow-up, seven of 31 patients randomized to FMT met response criteria as compared with two of 30 in the placebo group. The difference did not achieve statistical significance, nor did any of the secondary endpoints, leading to termination of the trial for futility before patient accrual reached the midpoint, according to Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ontario, and colleagues.
Describing a placebo-treated patient who improved dramatically after open-label FMT despite a 20-year history of severe, refractory ulcerative colitis, Moayyedi told an audience here at Digestive Disease Week that FMT works in some patients. Improving the success rate likely depends on learning more about the microbiome dysfunction associated with ulcerative colitis and factors that seem to normalize the colonic environment.
"Cases like this make you think that something is going on in some patients," Moayyedi said.
Noting that the patient had returned to near normal after 20 weeks, he said, "What we're finding is that 6 weeks usually is not enough. If we continue longer, we can get remission in some patients. At 20 weeks, his mucosa looked healed, his Mayo score was 0. He was doing fine on no other medications, having been 2 years before with severe disease."
Another presentation from the same study showed that patient's microbiome had become more like the normal microbiome of the transplant donor. A third study involving patients with Crohn's disease provided additional insights into the dysfunction associated with inflammatory bowel disease (IBD) and how the microbiome changes over time and in response to interventions.
IBD Study Details
Historically, therapeutic development for IBD has focused on the immune system and effecting changes that can correct the dysfunction. Little attention has been given to the environment, Moayyedi said.
"The immune system is acting on the environment and surely there is something there that is driving the immune dysregulation," he said. "The inflammation is limited to the colon, so it is likely that the antigen that is causing ulcerative colitis is either in the food ingested or the gut microbiome. Given the involvement of the colon, the most likely candidate is the gut microbiome, and we feel this should be the focus."
Several strategies to alter the gut microbiome have been evaluated, including prebiotics, probiotics, and antibiotics. In small randomized trials, the efficacy strategies has been disappointing, Moayyedi said. FMT has had success in treating Clostridium difficile, and some people have assumed the success would translate to IBD, given that both conditions involve colitis.
A few case series have evaluated FMT in IBD, primarily patients with ulcerative colitis, and the results have been mixed. In an effort to make some headway in determining whether FMT has a therapeutic future in IBD, Moayyedi and colleagues performed a randomized, placebo-controlled trial of FMT in patients with ulcerative colitis.
Investigators enrolled patients with any degree of ulcerative colitis activity or severity. Eligibility criteria included a Mayo score >3, persistent disease activity despite a stable medication regimen for 12 weeks (4 weeks in the case of steroids), no evidence of infection (including no antibiotics within the past 2 weeks), and no requirement for hospitalization.
Patients were randomized to weekly FMT in the form of a rectal enema or to a water enema. Patients provided stool samples prior to each FMT administration. The primary outcome was remission at 6 weeks, defined as a Mayo score <3 and a Mayo endoscopy score of 0.
The trial had an accrual goal of 130 patients, and a planned interim analysis occurred after 61 patients had been enrolled. The investigators found no significant differences in the primary outcome or any of the secondary outcomes, which included the Inflammatory Bowel Disease Questionnaire and the EQ5D health status assessment.
In general, adverse events were consistent with expectations and tolerated by patients. The exception was a change in diagnosis that was much greater than expected in three patients in the FMT group.
"We are not sure why this occurred, and of course, the worry is that FMT may have changed the [disease] phenotype," Moayyedi said.
Despite encouraging continued investigation of FMT in IBD, Moayyedi emphasized that treatment should remain limited to clinical studies at this point.
Another report from the trial described changes in the patient microbiome over time after FMT. Investigators compared the microbiome of patients who responded to FMT with those who did not. The results showed that response to FMT was associated with an increase in butyrate-producing bacteria, particularly Ruminococcus, according to Josie Libertucci, MS, also of McMaster University.
Patients who responded to FMT also tended to have decreases in Streptococcus and Escherichia, as well as proinflammatory organisms such as Fusobacterium. The shifts did not substantially alter the diversity of the microbiome in patients who responded and those who did not.
Research in Crohn's Disease
Another study reported at DDW focused on changes in the microbiome of patients with Crohn's disease. The study included a well-characterized inception cohort for Crohn's disease in children involving 28 centers in North America, reported by Dirk Gevers, MD, of the Broad Institute in Boston.
The analysis included 447 patients, ages 3 to 17, and a control group of 221 patients with noninflammatory conditions. Investigators examined mucosal and luminal microbiota and compared findings in the Crohn's patients and control group.
The data showed that increased levels of Enterobacteriaceae, Pasteurellaceae, Veillonellaceae, and Fusobacteriaceae, and decreased Erysipelotrichales, Bacteroidales, and Clostridiales correlated with disease activity. The data also showed that antibiotic therapy increased the "microbial dysbiosis" associated with Crohn's disease.
Examination of microbial signatures at the ileum, rectum, and in fecal samples showed that even in an early stage of the disease process, assessment of the rectal mucosa-associated microbiome was a better predictor than was the fecal microbiome.
Patients Interested in FMT
Interest in and enthusiasm for the therapeutic potential of FMT has increased dramatically in recent years, which gastroenterologist Colleen Kelly, MD, attributes to three key factors.
"First, fecal transplant is most widely used in the treatment of C. difficile infection, and in the last decade we've seen the rate of C. difficile infection quadruple," said Kelly, of the Lifespan Women's Medicine Collaborative in Providence, R.I. "At the same time, our understanding of the bacteria has grown with the efforts of the Human Microbiome Project and other scientific research. We're really understanding how these alterations in gut flora result in IBD.
"Lastly, we have social media. Patients can go online and find these treatments. I've been doing fecal transplants for about 6 years, and I think that more than half the patients who come to me aren't referred by their doctor."
http://www.medpagetoday.com/MeetingCoverage/DDW/45685
After 6 weeks of follow-up, seven of 31 patients randomized to FMT met response criteria as compared with two of 30 in the placebo group. The difference did not achieve statistical significance, nor did any of the secondary endpoints, leading to termination of the trial for futility before patient accrual reached the midpoint, according to Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ontario, and colleagues.
Describing a placebo-treated patient who improved dramatically after open-label FMT despite a 20-year history of severe, refractory ulcerative colitis, Moayyedi told an audience here at Digestive Disease Week that FMT works in some patients. Improving the success rate likely depends on learning more about the microbiome dysfunction associated with ulcerative colitis and factors that seem to normalize the colonic environment.
"Cases like this make you think that something is going on in some patients," Moayyedi said.
Noting that the patient had returned to near normal after 20 weeks, he said, "What we're finding is that 6 weeks usually is not enough. If we continue longer, we can get remission in some patients. At 20 weeks, his mucosa looked healed, his Mayo score was 0. He was doing fine on no other medications, having been 2 years before with severe disease."
Another presentation from the same study showed that patient's microbiome had become more like the normal microbiome of the transplant donor. A third study involving patients with Crohn's disease provided additional insights into the dysfunction associated with inflammatory bowel disease (IBD) and how the microbiome changes over time and in response to interventions.
IBD Study Details
Historically, therapeutic development for IBD has focused on the immune system and effecting changes that can correct the dysfunction. Little attention has been given to the environment, Moayyedi said.
"The immune system is acting on the environment and surely there is something there that is driving the immune dysregulation," he said. "The inflammation is limited to the colon, so it is likely that the antigen that is causing ulcerative colitis is either in the food ingested or the gut microbiome. Given the involvement of the colon, the most likely candidate is the gut microbiome, and we feel this should be the focus."
Several strategies to alter the gut microbiome have been evaluated, including prebiotics, probiotics, and antibiotics. In small randomized trials, the efficacy strategies has been disappointing, Moayyedi said. FMT has had success in treating Clostridium difficile, and some people have assumed the success would translate to IBD, given that both conditions involve colitis.
A few case series have evaluated FMT in IBD, primarily patients with ulcerative colitis, and the results have been mixed. In an effort to make some headway in determining whether FMT has a therapeutic future in IBD, Moayyedi and colleagues performed a randomized, placebo-controlled trial of FMT in patients with ulcerative colitis.
Investigators enrolled patients with any degree of ulcerative colitis activity or severity. Eligibility criteria included a Mayo score >3, persistent disease activity despite a stable medication regimen for 12 weeks (4 weeks in the case of steroids), no evidence of infection (including no antibiotics within the past 2 weeks), and no requirement for hospitalization.
Patients were randomized to weekly FMT in the form of a rectal enema or to a water enema. Patients provided stool samples prior to each FMT administration. The primary outcome was remission at 6 weeks, defined as a Mayo score <3 and a Mayo endoscopy score of 0.
The trial had an accrual goal of 130 patients, and a planned interim analysis occurred after 61 patients had been enrolled. The investigators found no significant differences in the primary outcome or any of the secondary outcomes, which included the Inflammatory Bowel Disease Questionnaire and the EQ5D health status assessment.
In general, adverse events were consistent with expectations and tolerated by patients. The exception was a change in diagnosis that was much greater than expected in three patients in the FMT group.
"We are not sure why this occurred, and of course, the worry is that FMT may have changed the [disease] phenotype," Moayyedi said.
Despite encouraging continued investigation of FMT in IBD, Moayyedi emphasized that treatment should remain limited to clinical studies at this point.
Another report from the trial described changes in the patient microbiome over time after FMT. Investigators compared the microbiome of patients who responded to FMT with those who did not. The results showed that response to FMT was associated with an increase in butyrate-producing bacteria, particularly Ruminococcus, according to Josie Libertucci, MS, also of McMaster University.
Patients who responded to FMT also tended to have decreases in Streptococcus and Escherichia, as well as proinflammatory organisms such as Fusobacterium. The shifts did not substantially alter the diversity of the microbiome in patients who responded and those who did not.
Research in Crohn's Disease
Another study reported at DDW focused on changes in the microbiome of patients with Crohn's disease. The study included a well-characterized inception cohort for Crohn's disease in children involving 28 centers in North America, reported by Dirk Gevers, MD, of the Broad Institute in Boston.
The analysis included 447 patients, ages 3 to 17, and a control group of 221 patients with noninflammatory conditions. Investigators examined mucosal and luminal microbiota and compared findings in the Crohn's patients and control group.
The data showed that increased levels of Enterobacteriaceae, Pasteurellaceae, Veillonellaceae, and Fusobacteriaceae, and decreased Erysipelotrichales, Bacteroidales, and Clostridiales correlated with disease activity. The data also showed that antibiotic therapy increased the "microbial dysbiosis" associated with Crohn's disease.
Examination of microbial signatures at the ileum, rectum, and in fecal samples showed that even in an early stage of the disease process, assessment of the rectal mucosa-associated microbiome was a better predictor than was the fecal microbiome.
Patients Interested in FMT
Interest in and enthusiasm for the therapeutic potential of FMT has increased dramatically in recent years, which gastroenterologist Colleen Kelly, MD, attributes to three key factors.
"First, fecal transplant is most widely used in the treatment of C. difficile infection, and in the last decade we've seen the rate of C. difficile infection quadruple," said Kelly, of the Lifespan Women's Medicine Collaborative in Providence, R.I. "At the same time, our understanding of the bacteria has grown with the efforts of the Human Microbiome Project and other scientific research. We're really understanding how these alterations in gut flora result in IBD.
"Lastly, we have social media. Patients can go online and find these treatments. I've been doing fecal transplants for about 6 years, and I think that more than half the patients who come to me aren't referred by their doctor."
http://www.medpagetoday.com/MeetingCoverage/DDW/45685
