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Which Microbes Mediate the Effects of Fecal Microbiota Transplantation and How?

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Researchers have identified transferable, donor-derived bacteria that correlate with response to fecal microbiota transplantation (FMT) in patients with ulcerative colitis (UC). They report in the January issue of Gastroenterology that Odoribacter splanchnicus provides metabolic and immune cell protection from colitis. These findings might be used to increase the efficacy of microbial therapies for UC.

Alterations in the intestinal microbiome have been associated with inflammatory bowel diseases (IBD) such as UC, and microbial-based therapies have been proposed for treatment. Trials have investigated the effects of FMT and its ability to induce remission in patients with UC. One limitation of FMT is that the fecal material transferred varies among donors in efficacy and safety. Researchers have therefore sought to indentify specific microbes or molecules in the fecal material that mediate the most beneficial effects.

et al performed metagenomic and immunoglobulin A–sequencing (IgA-seq) to identify transferable, immune-reactive (IgA-coated) microbes using fecal samples from 20 donors and recipients with active UC treated with FMT. Clinical response was based on endoscopic subscore and total Mayo score was assessed at week 4 after the FMT. Using a strain inference algorithm, Lima et al identified a core group of transferable bacterial species that correlate with clinical response.

The primary endpoint of clinical response was achieved by 35% of participants (change in Mayo score ≥3 with a rectal bleeding score ≤1) at week 4 after the FMT. Lima et al identified 12 bacterial species that were derived from the donors and found in responders at week 4, providing a core set of bacterial strains that correlate with clinical efficacy of FMT for UC. This population of fecal bacteria correlated with clinical response in an independent cohort of patients with UC, with an area under the curve of 0.80 (accuracy, 80%; sensitivity, 60%; specificity, 80%).

The authors investigated the contribution of these microbes to mucosal immunity by sorting and sequencing IgA-coated bacteria. Bacteroides, Coprococcus, Eubacterium, Lachnospiraceae, Odoribacter, and Ruminococcus were the only taxa found in the donors that were specific to the responders. Of the donor-derived genera, only the relative abundance of Odoribacter at week 4 and its increase following FMT correlated with a decrease in Mayo score.

In rectal biopsies from patients, numbers of T-regulatory (Foxp3+ CD4+) cells correlated with the relative abundance of Odoribacter-IgA+, but not Alistipes or Blautia, following FMT.

In mice with dextran sodium sulfate-induced colitis, administration of Odoribacter (O splanchnicus), but not Blautia producta or Alistipes finegoldii species (transferred microbes detected in responders and non-responders), reduced the severity of colitis. The O splanchnicus was found to activate T-regulatory cells (RORγt+ FOX3+) in the colonic lamina propria 21 days after colonization. Lymphocyte production of IL10, induced by O splanchnicus, was required for activation of T-regulatory cells, inhibition of inflammatory T-cells, and the reduced severity of colitis in mice.

O splanchnicus also produced short-chain fatty acids (SCFAs), which signal via GPR43 and GPR109A to promote healing in the colonic mucosa of the mice. SCFAs can have pleiotropic effects in promoting colon healing, by acting directly on epithelial cells and by modulating responses of T-regulatory cells.

The authors explain that production and consumption of SCFAs by the bacteria are likely regulated by factors that include the binding of IgA. These characteristics of O splanchnicus, along with its outer membrane vesicles, bile acid metabolism, and antigen-specific immunity, might mediate its protective effects in the colon, along with other commensals that induce IL10 and SCFAs. Studies are needed to determine how IgA binding might regulate the metabolic function of the gut microbiota.

This study shows that O splanchnicus is a key component of FMT that protects the colonic mucosa via immune cell and metabolic processes. These features will increase the efficacy of microbial therapy for UC.

 

 

 

 

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Kristine Novak

Kristine Novak

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About The Author:

Dr. Kristine Novak

Dr. Kristine Novak

Dr. Kristine Novak is a science writer and editor based in San Francisco. She has extensive experience covering gastroenterology, hepatology, immunology, oncology, clinical, and biotechnology research discoveries.

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