Abstract
Fecal microbiota transplantation (FMT) is an effective procedure against Clostridioides difficile infection (CDI), with promising but still suboptimal performance in other diseases, such as ulcerative colitis (UC). The recipient’s mucosal immune response against the donor’s microbiota could be relevant factor in the effectiveness of FMT. Our aim was to design and validate an individualized immune-based test to optimize the fecal donor selection for FMT. First, we performed an in vitro validation of the test by co-culturing lymphocytes obtained from the small intestine mucosa of organ donor cadavers (n=7) and microbe-associated molecular patterns (MAMPs) obtained from the feces of 19 healthy donors. The inflammatory response was determined by interleukin supernatant quantification using the Cytometric Bead Array kit (B&D). We then conducted a clinical pilot study with 4 patients with UC using immunocompetent cells extracted from rectal biopsies and MAMPs from 3 donor candidates. We employed the test results to guide donor selection for FMT, which was performed by colonoscopy followed by 4 booster instillations by enema in the following month. The microbiome engraftment was assessed by 16S rDNA massive sequencing in feces, and the patients were clinically followed-up for 16 weeks. The results demonstrated that IL-6, IL-8, and IL-1ß were the most variable markers, although we observed a general tolerance to the microbial insults. Clinical and colonoscopy remission of the patients with UC was not achieved after 16 weeks, although FMT provoked enrichment of the Bacteroidota phylum and Prevotella genus, with a decrease in the Actinobacteriota phylum and Agathobacter genus. The most relevant result was the lack of Akkermansia engraftment in UC. In summary, the clinical success of FMT in patients with UC appears not to be influenced by donor selection based on the explored recipient’s local immunological response to FMT, suggesting that this approach would not be valid for FMT fecal donor optimization in such patients.
Highlights
The interaction between the gut microbiota and immune system plays a relevant role in the etiopathogenesis of inflammatory bowel diseases, such as ulcerative colitis (UC) [1, 2]
As co-cultures with alive bacteria provoked apoptosis of the immunocompetent cells, the most suitable conditions for ensuring their viability corresponded to the use of the nondiluted microbe-associated molecular patterns (MAMPs) supernatant and incubations of 18 h (Figure 1)
Fecal microbiota transplantation (FMT) has a clinical efficacy in Clostridioides difficile infection (CDI) of approximately 90%, it rarely achieves rates above 40-50% in UC [11, 23]
Summary
The interaction between the gut microbiota and immune system plays a relevant role in the etiopathogenesis of inflammatory bowel diseases, such as ulcerative colitis (UC) [1, 2]. Relevant differences in microbiota composition between inflamed and noninflamed intestinal mucosa have been reported in UC, according with the activity status of the disease [2, 4]. Fecal microbiota transplantation (FMT) has emerged as a therapeutic option for UC, aiming to modulate the gut microbiota composition and the chronic inflammatory status [8, 9], its clinical effectiveness is not as high as reported for Clostridioides difficile infection (CDI) [10, 11]. A recent randomized controlled trial identified specific taxa from donor feces associated with higher clinical response rates in patients with UC who underwent FMT [16]. Donor selection for FMT in UC is not specific, resulting in random matching in most cases, and the molecular mechanisms by which the autoimmune response is modulated have not yet been elucidated
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