Sterile faecal filtrate transplantation alters phage-microbe dynamics in individuals with metabolic syndrome: a double blind, randomised, placebo-controlled clinical trial assessing efficacy and safety

Abstract

Objective Bacteriophages (phages) are viruses of bacteria and have been shown to shape microbial communities. Previous studies have shown that altering the microbiota through faecal microbiota transplantation (FMT) can improve insulin resistance in individuals with metabolic syndrome (MetSyn). Interestingly, similar effects were observed in diet-induced obese mice after a faecal virome transplantation (FVT), raising the question whether phages of a healthy donor can improve glucose metabolism in individuals with MetSyn as well. Design We performed a double-blind, randomised, placebo-controlled pilot study in which 24 individuals with MetSyn were randomised to receive a sterile faecal filtrate transplantation (FFT) from a lean healthy donor or a placebo. From baseline up to 28 days, we assessed safety, effects on glucose metabolism, and longitudinal changes within the bacteriome and phageome. Results The FFT was well-tolerated and safe and glucose variability (time between 3.9-10 mmol/L glucose) improved in the week following the FFT. Glucose excursions during oral glucose tolerance tests were comparable in both the FFT and placebo group after 28 days. The phage virion composition was significantly altered two days after FFT as compared to placebo. Moreover, we found that FFT induced more virulent phage-microbe interactions within the first two days after administration, while these interactions appeared more temperate in the placebo group. Conclusion We provide evidence that gut phages from a healthy donor can be safely administered to transiently alter the gut microbiota of recipients, thereby providing a critical basis for follow-up studies. Trial registration number Dutch Trial Registry: NL8289