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Researchers Characterize Microbiomes of Fecal Microbiota Transplant Patients Over Time

NEW YORK (GenomeWeb Daily News) – The microbiomes of recipients of fecal microbiota transplants undergo changes immediately following the procedure, and they continue to change, albeit at a much slower pace, for at least 16 weeks after treatment, researchers from the University of Maryland School of Medicine reported in PLOS One yesterday. Eventually, they added, the recipients' microbiomes resembled those of their donors.

Fecal microbiota transplants have increasingly been used to treat people with recurrent Clostridium difficile infections that do not respond to treatment with antibiotics. While FMT appears to be effective in treating such infections, the researchers noted that the long-term effects of the treatment are unknown. In this study, they examined the fecal microbiota of 14 RCDI patients and their paired donors before treatment and for up to a year afterward.

“New genomic tools and bioinformatic analysis methods are allowing us to better study the subtle changes of the microbiota in patients after FMT," said Florian Fricke, an assistant professor at the at the University of Maryland School of Medicine's Institute for Genome Sciences. "This is especially important as we are only beginning to get an idea of whether FMT will permanently change the patient microbiota.”

C. difficile infection largely occurs after a patient has been treated with an antibiotic for another condition, and that antibiotic use throws off the balance of microbes in the gut, allowing C. difficile to thrive.

According to the University of Maryland, the rate of recurrent infection after standard antibiotic therapy is about 20 percent, and RCDI has been associated with some 14,000 deaths per year.

People with RCDI have been found to have a lower diversity of their gut bacteria. Restoring a healthy flora, such as through a fecal transplant, may fight the infection.

To track how FMT affects recipients' microbiomes, Fricke and his colleagues collected fecal samples from 14 patients and their respective donors before the treatment and in the weeks following it, for a total of 56 samples. The donors included spouses, children, and friends of the patients.

The researchers performed 16SrRNA gene sequencing on the samples using the Roche/454 GS FLX Titanium platform and generated an average 3,315 reads per sample with an average sequence length of 527 basepairs.

Following FMT, all patients reported the alleviation of their symptoms — usually diarrhea — within two to three days. One patient, though, experienced a recurrence about a month later after being treated with antibiotics for a urinary tract infection; she subsequently underwent a second FMT three months later that was also included in the researchers' analysis.

Using QIIME coupled with UCHIME and Microbiome Utilities, the researchers clustered the reads into operational taxonomic units, or OTUs.

Comparing the patients' bacterial diversity to the healthy donors, the researchers noted that the RCDI patients had decreased microbial diversity, even following treatment. After treatment, though, the diversity of patients' microbiome did increase, though not quite to the level of the healthy donors. The diversity, they noted, increased directly after treatment then remained stable.

"These results suggest that FMT restores the reduced microbiota diversity associated with RCDI," Fricke and his colleagues wrote.

In addition, the microbiomes of the recipients began to resemble those of the donors. The researchers identified a total 1,321 OTUs, and some 65 percent of them were only seen in the healthy donors or in the patients after FMT treatment. Further a UniFrac-based analysis, donor and post-FMT patient samples clustered more closely together than pre- and post-treatment samples.

The researchers also pointed out that a handful of patients had their microbiomes return to a state that was more similar to the pre-FMT microbiome state, though they remained symptom-free. Further, the patient who experienced a relapse following treatment of a UTI had a microbiome similar to other post-FMT patients and healthy donors.

Treatment seemed to primarily affect the levels of bacteria belonging to the phyla Firmicutes and Proteobacteria. For example, bacteria in the order Lactobacillales decreased in post-FMT patients as compared to before treatment, while levels of Lachnospiraceae, Peptostreptococcaceae, and Ruminococcaceae, all from the order Clostidiales, increased in patients after treatment.

The patient microbiomes appeared to continue to change over time following the same trends, though at a lower rate than they did initially.

While the researchers did not identify a so-called keystone species that plays a major role in RCDI or in FMT treatment, they noted that a specific function rather than a specific bug could be important. For instance, lower levels of Lachnospiraceae and Ruminococcaceae in RCDI patients could be interpreted as a decrease in butyrate-producing bacteria.

The researchers noted, though, that disentangling events leading to disease is complex as the infection is brought on by antibiotic treatment, which affects the microbiome, and the disease leads to diarrhea, which also affects microbiome composition. To solve that, the researchers said that prospective studies of people being treated with antibiotics that then develop RCDI are needed.

"Better insight into the microbiota events associated with the disease and FMT-induced recovery could lead to better treatments with a controlled, manufactured microbiota instead of fecal material, which might also prove to be relevant as a treatment option for other microbiota-associated diseases in the future," Fricke added.

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