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Fecal microbiota transplantation results in bacterial strain displacement in patients with inflammatory bowel diseases.

ABSTRACT: Fecal microbiota transplantation (FMT), which is thought to have the potential to correct dysbiosis of gut microbiota, has been used to treat inflammatory bowel disease (IBD) for almost a decade. Here, we report an interventional prospective cohort study performed to elucidate the extent of and processes underlying microbiota engraftment in IBD patients after FMT treatment. The cohort included two categories of patients: (a) patients with moderate to severe Crohn's disease (CD) (Harvey-Bradshaw Index ≥ 7, n = 11) and (b) patients with ulcerative colitis (UC) (Montreal classification S2 and S3, n = 4). All patients were treated with a single FMT (via mid-gut, from healthy donors), and follow-up visits were performed at baseline, 3 days, 1 week, and 1 month after FMT (missing time points included). At each follow-up time point, fecal samples and clinical metadata were collected. For comparative analysis, 10 fecal samples from 10 healthy donors were included to represent the diversity level of normal gut microbiota. Additionally, the metagenomic data of 25 fecal samples from five individuals with metabolic syndrome who underwent autologous FMT treatment were downloaded from a previous published paper to represent fluctuations in microbiota induced during FMT. All fecal samples underwent shotgun metagenomic sequencing. We found that 3 days after FMT, 11 out of 15 recipients were in remission (three out of four UC recipients; 8 out of 11 CD recipients). Generally, bacterial colonization was observed to be lower in CD recipients than in UC recipients at both species and strain levels. Furthermore, across species, different strains displayed disease-specific displacement advantages under two-disease status. Finally, most post-FMT species (> 80%) could be properly predicted (area under the curve > 85%) using a random forest classification model, with the gut microbiota composition and clinical parameters of pre-FMT recipients acting as factors that contribute to prediction accuracy.

SUBMITTER: Zou M

PROVIDER: S-EPMC6943227 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFecal microbiota transplantation (FMT) is an effective treatment of recurrent Clostridioides difficile infections (rCDI), but has more limited efficacy in treating either ulcerative colitis (UC) or Crohn's disease (CD), two major forms of inflammatory bowel diseases (IBD). We hypothesize that FMT recipients with rCDI and/or IBD have baseline fecal bile acid (BA) compositions that differ significantly from that of their healthy donors and that FMT will normalize the BA compositions.AimTo study the effect of single colonoscopic FMT on microbial composition and function in four recipient groups: 1.) rCDI patients without IBD (rCDI-IBD); 2.) rCDI with IBD (rCDI+IBD); 3.) UC patients without rCDI (UC-rCDI); 4.) CD patients without rCDI (CD-rCDI).MethodsWe performed 16S rRNA gene sequence, shotgun DNA sequence and quantitative bile acid metabolomic analyses on stools collected from 55 pairs of subjects and donors enrolled in two prospective single arm FMT clinical trials (Clinical Trials.gov ID NCT03268213, 479696, UC no rCDI ≥ 2x IND 1564 and NCT03267238, IND 16795). Fitted linear mixed models were used to examine the effects of four recipient groups, FMT status (Donor, pre-FMT, 1-week post-FMT, 3-months post-FMT) and first order Group*FMT interactions on microbial diversity and composition, bile acid metabolites and bile acid metabolizing enzyme gene abundance.ResultsThe pre-FMT stools collected from rCDI ± IBD recipients had reduced α-diversity compared to the healthy donor stools and was restored post-FMT. The α-diversity in the pre-FMT stools collected from UC-rCDI or CD-rCDI recipients did not differ significantly from donor stools. FMT normalized some recipient/donor ratios of genus level taxa abundance in the four groups. Fecal secondary BA levels, including some of the secondary BA epimers that exhibit in vitro immunomodulatory activities, were lower in rCDI±IBD and CD-rCDI but not UC-rCDI recipients compared to donors. FMT restored secondary BA levels. Metagenomic baiE gene and some of the eight bile salt hydrolase (BSH) phylotype abundances were significantly correlated with fecal BA levels.ConclusionRestoration of multiple secondary BA levels, including BA epimers implicated in immunoregulation, are associated with restoration of fecal baiE gene counts, suggesting that the 7-α-dehydroxylation step is rate-limiting.

Project description:For fecal microbiota transplantation (FMT) to be successful in immune diseases like inflammatory bowel disease, it is assumed that therapeutic microbes and their beneficial functions and immune interactions must colonize a recipient patient and persist in sufficient quantity and for a sufficient period of time to produce a clinical benefit. Few studies, however, have comprehensively profiled the colonization and persistence of transferred microbes along with the transfer of their microbial functions and interactions with the host immune system. Using 16S, metagenomic, and immunoglobulin A (IgA) sequencing, we analyzed hundreds of longitudinal microbiome samples from a randomized controlled trial of 12 patients with ulcerative colitis who received fecal transplant or placebo for 12 weeks. We uncovered diverse competitive dynamics among donor and patient strains, showing that persistence of transferred microbes is far from static. Indeed, one patient experienced a dramatic loss of donor bacteria 10 weeks into the trial, coinciding with a bloom of pathogenic bacteria and worsening symptoms. We evaluated the transfer of microbial functions, including desired ones, such as butyrate production, and unintended ones, such as antibiotic resistance. By profiling bacteria coated with IgA, we identified bacteria associated with inflammation and found that microbial interactions with the host immune system can be transferred across people, which could play a role in gut microbiome therapeutics for immune-related diseases. Our findings shed light on the colonization dynamics of gut microbes and their functions in the context of FMT to treat a complex disease-information that may provide a foundation for developing more-targeted therapeutics. IMPORTANCE Fecal microbiota transplantation (FMT)-transferring fecal microbes from a healthy donor to a sick patient-has shown promise for gut diseases such as inflammatory bowel disease. Unlike pharmaceuticals, however, fecal transplants are complex mixtures of living organisms, which must then interact with the microbes and immune system of the recipient. We sought to understand these interactions by tracking the microbes of 12 inflammatory bowel disease patients who received fecal transplants for 12 weeks. We uncovered a range of dynamics. For example, one patient experienced successful transfer of donor bacteria, only to lose them after 10 weeks. We similarly evaluated transfer of microbial functions, including how they interacted with the recipient's immune system. Our findings shed light on the colonization dynamics of gut microbes, as well as their functions in the context of FMT-information that may provide a critical foundation for the development of more-targeted therapeutics.

Project description:Background & aimsA significant fraction of patients with recurrent Clostridium difficile infections (CDI) have inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) can break the cycle of CDI recurrence and can be performed without evaluation of the colon. We evaluated the efficacy of colonoscopic FMT in patients with and without IBD, and whether we could identify IBD in patients during this procedure.MethodsWe collected clinical meta-data and colonoscopy results from 272 consecutive patients that underwent FMT for recurrent CDI at the University of Minnesota from 2008 through 2015. Patients had at least 2 spontaneous relapses of CDI following their initial episode and did not clear the infection after 1 extended antibiotic regimen. We collected random mucosal biopsies from patients' right colons to identify lymphocytic or collagenous colitis during the FMT procedure. Failure or success in clearing CDI was determined within or at 2 months after the FMT.ResultsOf patients undergoing FMT, 15% had established IBD and 2.6% were found to have IBD during the FMT procedure. A single colonoscopic FMT cleared CDI from 74.4% of patients with IBD and 92.1% of patients without IBD (P = .0018). Patients had similar responses to FMT regardless of immunosuppressive therapy. More than one-quarter of patients with IBD (25.6%) had a clinically significant flare of IBD after FMT. Lymphocytic colitis was documented in 7.4% of patients with endoscopically normal colon mucosa; only 3 of these patients (20%) required additional treatment for colitis after clearance of CDI.ConclusionsBased on an analysis of 272 patients, FMT is somewhat less effective in clearing recurrent CDI from patients with IBD, compared with patients without IBD, regardless of immunosuppressive therapy. More than 25% of patients with IBD have a disease flare following FMT. Lymphocytic colitis did not affect the outcome of FMT, but a small fraction of these patients required pharmacologic treatment after the procedure.

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Fecal microbiota transplantation results in bacterial strain displacement in patients with inflammatory bowel diseases.

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