Faecal virome transplantation decrease symptoms of type-2-diabetes and obesity in a murine model

Abstract

ObjectiveDevelopment of obesity and type-2-diabetes (T2D) are associated with gut microbiota (GM) changes. The gut viral community is predominated by bacteriophages (phages), which are viruses that attack bacteria in a host-specific manner. As a proof-of-concept we demonstrate the efficacy of faecal virome transplantation (FVT) from lean donors for shifting the phenotype of obese mice into closer resemblance of lean mice.\n\nDesignThe FVT consisted of viromes extracted from the caecal content of mice fed a low-fat (LF) diet for fourteen weeks. Male C57BL/6NTac mice were divided into five groups: LF (as control), high-fat diet (HF), HF+Ampicillin (Amp), HF+Amp+FVT and HF+FVT. At week six and seven of the study the HF+FVT and HF+Amp+FVT mice were treated with FVT by oral gavage. The Amp groups were treated with ampicillin 24 h prior to first FVT treatment.\n\nResultsSix weeks after first FVT the HF+FVT mice showed a significant decrease in weight gain compared to the HF group. Further, glucose tolerance was comparable between the lean LF and HF+FVT mice, while the other HF groups all had impaired glucose tolerance. These observations were supported by significant shifts in GM composition, blood plasma metabolome, and expression levels of genes involved in obesity and T2D development.\n\nConclusionsTransfer of gut viral communities from mice with a lean phenotype into those with an obese phenotype reduce weight gain and normalise blood glucose parameters relative to lean mice. We hypothesise that this effect is mediated via FVT-induced GM changes.\n\nSignificance of this studyWhat is already known about this subject?\n\nO_LIObesity and type-2-diabetes (T2D) are associated with gut microbiota (GM) dysbiosis.\nC_LIO_LIFaecal microbiota transplant from lean donors has previously shown potential in treating obesity and T2D.\nC_LIO_LIPatients suffering from recurrent Clostridium difficile infections (rCDI) have been cured with sterile filtered donor faeces (containing enteric viruses and no bacteria), here defined as faecal virome transplantation (FVT).\nC_LI\n\nWhat are the new findings?\n\nO_LIFVT from lean donors lead to decreased weight gain and normalised blood sugar tolerance in a diet-induced obesity (DIO) mouse model.\nC_LIO_LIFVT significantly changed the bacterial and viral GM component, as well as the plasma metabolome and the expression profiles of obesity and T2D associated genes.\nC_LIO_LIInitial treatment with ampicillin prior FVT seems to counteract the beneficial effects associated with FVT.\nC_LI\n\nHow might it impact on clinical practice in the foreseeable future?\n\nO_LIWe here show a proof-of-concept, providing a solid base for designing a clinical study of FVT targeting obesity and T2D in humans. This is further augmented by the increased safety related to FVT, since bacteria and other microorganisms are removed from the donor faeces, and therefore minimises the risk of disease transmission.\nC_LIO_LIThese findings highlight the potential application of FVT treatment of various diseases related to GM dysbiosis and further support the vital role of the viral community in maintaining and shaping the GM.\nC_LI