NEW YORK (Reuters Health) – Successful fecal microbiota transplantation (FMT) reverses the suppression of microRNAs (miRNAs) implicated in recurrent Clostridioides difficile infection (rCDI), pinpointing new potential therapeutic targets, researchers suggest.
To investigate the molecular mechanisms underlying successful FMT for rCDI, Dr. Tanya Monaghan of the University of Nottingham, in the U.K., and colleagues analyzed sera from two independent rCDI patient cohorts. In addition, they studied rCDI-FMT and toxin-treated animals and human colonoids to compare intestinal tissue and circulating miRNAs.
Their research was published in Gastroenterology.
“Our findings reveal that C. difficile, through its toxins, suppresses expression of a specific set of miRNAs in the circulation of infected patients,” Dr. Monaghan told Reuters Health by email. “These toxins, which are major virulence factors, highjack the molecular mechanism important for miRNA maturation, a process important for miRNA activity.”
“We went on to show that successful FMT for rCDI can reverse these effects,” she said.
Specifically, the team identified upregulation of 64 circulating miRNAs in rCDI patients four and 12 weeks following FMT, and validated the top six. RT-qPCR analyses of sera and cecal RNA extracts in a mouse model of relapsing CDI showed that these miRNAs were suppressed, and that FMT reversed that effect.
In addition, using mouse colon and human colonoids, the team found that C. difficile toxin B (TcdB) mediated CDI’s suppressive effects on miRNAs. CDI also dysregulated the Drosha enzyme, another effect reversed by FMT.
“We further demonstrated that FMT-regulated miRNAs target IL-12B, IL-18, and FGF21 and TNFRSF9, (and) showed that a combination of specific miRNAs (miR-23a and miR-150) can protect the intestinal barrier against the effects of C. difficile bacterial toxins,” Dr. Monaghan said.
“Our next steps,” she added, “are to test the effects of these cytoprotective miRNAs alone and in combination with standard antimicrobial therapies in animal models of CDI.”
“Although we still need to test the efficacy of these miRNAs in vivo, we think that this new approach could be an effective adjunctive therapy for most patients with CDI,” she noted. “However, for those with severe or fulminant infection, miRNA-based drugs may not be as effective due to the overwhelming inflammatory response and tissue damage.”
Dr. Olga Aroniadis, director of Clinical Research at the Renaissance School of Medicine at Stony Brook University in New York, told Reuters Health by email, “The findings from this study are extremely exciting and promising for the creation of novel therapeutics for patients with C. difficile. This is the first study that has implicated miRNAs in the mechanism of action of FMT.”
“In addition to studying human sera before and after FMT, the authors used different animal models, human colonoids and colonic epithelial cells to substantiate that C. difficile alters miRNAs and that miRNA restoration via FMT can result in therapeutic benefit,” she said. “These translational aspects of the work further support the role of miRNA in the pathogenesis of C. difficile and the mechanisms of action of FMT.”
“Mapping of the epitranscriptomic changes following FMT will be important for future research,” she noted. “MiRNAs exert immunoregulatory actions in patients with C. difficile; however, through epitranscriptomic research we will gain insight into these mechanisms and determine whether FMT directly modulates immunoregulation via miRNAs.”
“Ultimately,” she added, “the goal will be to develop miRNA-based drugs and other novel therapeutics, including microbial products, for treatment of C. difficile.”
SOURCE: https://bit.ly/3sTYK2K Gastroenterology, online April 9, 2021.
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