Intraspecies strain exclusion, antibiotic pretreatment, and donor selection control microbiota engraftment after fecal transplantation

Abstract

Fecal microbiota transplantation (FMT) is both a promising therapeutic approach to treat microbiota-associated pathologies and an experimental tool to establish a causal role of microbiome dysbiosis in human pathologies. Although clearly efficacious in resolving recurrent Clostridioides difficile infection (rCDI), the therapeutic value of FMT in other pathologies is not yet established, and our mechanistic and ecological understanding of how FMT alters the microbiome in patients is incomplete. Here, we assembled the most comprehensive FMT trial microbiota dataset to date, including new and previously generated fecal metagenomes from FMT trials in rCDI, inflammatory bowel disease (IBD), metabolic syndrome (MetS), drug-resistant pathogen colonization (MDR), and resistance to immune checkpoint inhibitor anti-tumor therapy (ICI). We characterized post-FMT microbiota assembly in the recipients by establishing the origin of the detected strains, and we identified the clinical and ecological factors that determine the engraftment of donor strains. Our findings showed little coexistence of donor and recipient strains and linked the magnitude of donor strain engraftment to dysbiosis of the recipient microbiome. Dysbiosis and strain engraftment were low in pathologies other than rCDI but could be enhanced through pretreatment with antibiotics and lavage. Using generalized linear mixed-effects models, we demonstrate that both ecological (low recipient and high donor ɑ-diversity and relative species abundance) and clinical (antibiotic pretreatment, bowel lavage, multiple rounds of FMT) variables are associated with increased donor microbiota engraftment, and that donor strain engraftment events are predictable for individual patients and strains. Overall donor strain engraftment was not linked to FMT outcome in IBD patients but was higher in ICI patients that responded to immunotherapy after FMT. Our findings provide an ecological framework for post-FMT microbiota assembly that can predict donor strain engraftment and determine its importance for clinical outcomes, informing more targeted and personalized approaches to increase the therapeutic benefits of FMTs.

Recent insights into the role of microbiome in the pathogenesis of obesity

“…They furthermore showed that increasing the α-diversity by pooling donor samples was predicted not to increase donor strain engraftment, indicating that pooling donor samples is not functionally equivalent to a single high α-diversity donor sample. 156 Subsequent analyses on the cohort by Kootte et al revealed that the P. copri had a beneficial effect in subjects receiving an allogenic FMT. P. copri was further negatively correlated to BMI, C-reactive protein and fasting insulin levels.…”