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

ABSTRACT Objective: Development 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. The antagonistic behaviour of phages have the potential to alter the GM. 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. Design: The FVT consisted of viromes with distinct profiles extracted from the caecal content of mice from different vendors that were fed a low-fat (LF) diet for 14 weeks. Male C57BL/6NTac mice were divided into five groups: LF (as diet 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. Results: Six 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 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 associated with obesity and T2D development. Conclusions: Transfer of caecal viral communities from mice with a lean phenotype into mice with an obese phenotype led to reduced weight gain and normalised blood glucose parameters relatively to lean mice. We hypothesise that this effect is mediated via FVT-induced GM changes.

摘要
研究目的：肥胖与2型糖尿病（type-2-diabetes, T2D）的发生发展与肠道菌群（gut microbiota, GM）改变密切相关。肠道病毒群落以噬菌体（bacteriophages, phages）为主，这类病毒以宿主特异性方式侵染细菌。噬菌体的拮抗作用具备调控肠道菌群的潜力。本研究作为概念验证，证实了来自瘦型供体的粪便病毒组移植（faecal virome transplantation, FVT）可将肥胖小鼠的表型向更接近瘦型小鼠的方向重塑。
实验设计：本研究的粪便病毒组提取自不同供应商来源、经低脂（low-fat, LF）饲料喂养14周的小鼠盲肠内容物，其病毒组具有独特的组成特征。将雄性C57BL/6NTac小鼠分为5组：低脂饲料对照组（LF）、高脂饲料组（HF）、高脂+氨苄青霉素组（HF+Amp）、高脂+氨苄青霉素+FVT组（HF+Amp+FVT）以及高脂+FVT组（HF+FVT）。在实验第6周和第7周，对HF+FVT组与HF+Amp+FVT组小鼠通过口服灌胃方式进行FVT处理；氨苄青霉素干预组在首次FVT治疗前24小时给予氨苄青霉素处理。
实验结果：首次FVT处理6周后，HF+FVT组小鼠的体重增长较HF组出现显著降低。此外，LF组与HF+FVT组小鼠的葡萄糖耐量水平相近，而其余高脂饲料组均出现葡萄糖耐量受损。上述观测结果得到了肠道菌群组成、血浆代谢组以及与肥胖和2型糖尿病发生相关基因表达水平发生显著改变的佐证。
结论：将瘦型表型小鼠的盲肠病毒群落转移至肥胖表型小鼠体内，可降低小鼠体重增长，并使其血糖参数恢复至与瘦型小鼠相近的水平。我们推测该效应通过粪便病毒组移植诱导的肠道菌群改变实现。