Overcoming donor variability and risks associated with fecal microbiota transplants through bacteriophage-mediated treatments

• DOI: 10.1186/s40168-024-01820-1
• Publication Date: 2024-07-01T20:31:54Z
• Authors: Torben Sølbeck Ra...; Xiaotian Mao; Sarah Forster; Sabina Birgitte L...; Alexandra Von Mün...; Kaare Dyekær Tranæs; Anders Brunse; Frej Larsen; Josue Leonardo Ca...; Signe Adamberg; Axel Kornerup Hansen; Kaarel Adamberg; Camilla Hartmann ...; Dennis Sandris Ni...
• Keywords: Fecal bacteriotherapy; Medical microbiology; Phage therapy

Abstract Background Fecal microbiota transplantation (FMT) and fecal virome (FVT, sterile filtrated donor feces) have been effective in treating recurrent Clostridioides difficile infections, possibly through bacteriophage-mediated modulation of the gut microbiome. However, challenges like variability, costly screening, coupled with concerns over pathogen transfer (incl. eukaryotic viruses) FMT or FVT hinder their wider clinical application less acute diseases. Methods To overcome these challenges, we developed methods to broaden FVT’s while maintaining efficacy increasing safety. Specifically, employed following approaches: (1) chemostat-fermentation reproduce bacteriophage component remove viruses (FVT-ChP), (2) solvent-detergent treatment inactivate enveloped (FVT-SDT), (3) pyronin-Y inhibit RNA virus replication (FVT-PyT). We assessed processed FVTs a C. infection mouse model compared them untreated (FVT-UnT), FMT, saline. Results FVT-SDT, FVT-UnT, FVT-ChP reduced incidence mice reaching humane endpoint (0/8, 2/7, 3/8, respectively) FVT-PyT, saline (5/8, 7/8, 5/7, significantly load colonizing cells associated toxin A/B levels. There was potential elimination colonization, seven out eight treated FVT-SDT testing negative qPCR. In contrast, all other treatments exhibited continued presence . Moreover, results were supported by changes microbiome profiles, cecal cytokine levels, histopathological findings. Assessment viral engraftment FMT/FVT host-phage correlations analysis suggested that phages likely an important contributing factor efficacy. Conclusions This proof-of-concept study shows specific modifications hold promise addressing related variability risks. Two strategies lead limiting colonization mice, solvent/detergent chemostat propagation emerging as promising approaches.