Fecal virome transplantation is sufficient to alter fecal microbiota and drive lean and obese body phenotypes in mice

Abstract

Background: The gastrointestinal microbiome plays a significant role in numerous host processes and has an especially large impact on modulating the host metabolism. Prior studies have shown that when mice receive fecal transplants from obese donors that were fed high-fat diets (HFD) (even when recipient mice are fed normal diets after transplantation), they develop obese phenotypes. These studies demonstrate the prominent role that the gut microbiota play in determining lean and obese phenotypes. While much of the credit has been given to gut bacteria, studies have not measured the impact of gut viruses on these phenotypes. To address this shortcoming, we gavaged mice with viromes isolated from donors fed HFD or normal chow. By characterizing the mice gut bacterial biota and weight-gain phenotypes over time, we demonstrate that viruses can shape the gut bacterial community and affect weight gain or loss. Results: We gavaged mice longitudinally over 4 weeks while measuring their body weights and collecting fecal samples for 16S rRNA amplicon sequencing. We evaluated mice that were fed normal chow or high-fat diets, and gavaged each group with either chow-derived fecal viromes, HFD-derived fecal viromes, or phosphate buffered saline controls. We found a significant effect of gavage type, where mice fed chow but gavaged with HFD-derived viromes gained significantly more weight than their counterparts receiving chow-derived viromes. The converse was also true: mice fed HFD but gavaged with chow-derived viromes gained significantly less weight than their counterparts receiving HFD-derived viromes. These results were replicated in two separate experiments and the phenotypic changes were accompanied by significant and identifiable differences in the fecal bacterial biota. Notably, there were differences in Lachnospirales and Clostridia in mice fed chow but gavaged with HFD-derived fecal viromes, and in Peptostreptococcales, Oscillospirales, and Lachnospirales in mice fed HFD but gavaged with chow-derived fecal viromes. Due to methodological limitations, we were unable to identify specific bacterial species or strains that were responsible for respective phenotypic changes. Conclusions: This study confirms that virome-mediated perturbations can alter the fecal microbiome in an in vivo model and indicates that such perturbations are sufficient to drive lean and obese phenotypes in mice.

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

“…For instance, FVT influenced the composition of the murine gut microbiome following initial perturbation with antibiotics [15]. Additionally, FVT treatment from lean donors alleviated symptoms of metabolic syndrome in three different diet-induced obesity murine models [16–18], and FVT from term piglets prevented the development of necrotizing enterocolitis in a preterm piglet model [19]. FVT has the advantage over FMT in that it significantly diminishes the transfer of viable bacteria, and FVT has recently been demonstrated to be less intrusive for both the gut microbial structure and linked to a reduced likelihood of causing harm to the jejunum in broiler chickens compared to FMT [20].…”

“…FVT has the advantage over FMT in that it significantly diminishes the transfer of viable bacteria, and FVT has recently been demonstrated to be less intrusive for both the gut microbial structure and linked to a reduced likelihood of causing harm to the jejunum in broiler chickens compared to FMT [20]. In addition to the viruses, these FVT preparations would also be expected to contain a certain level of bacterial spores and cells with sizes that allow them to pass through the 0.45 µm filter membrane pores, fecal metabolites, and extracellular vesicles of which contributions to the observed effects following FVT [12,13,[15][16][17][18][19][20][21]] are yet to be elucidated. Furthermore, the sterile filtration process commonly used in FVT does not eliminate the risk of transferring eukaryotic viruses, which previously have been detected in specific pathogen-free mice [22].…”

Transfer of modified fecal viromes improve blood glucose regulation and alleviates symptoms of metabolic dysfunction-associated fatty liver disease in an obesity male mouse model

“…This approach is often referred to as fecal virome transplantation (FVT). In preclinical settings, FVT has also been shown to alleviate symptoms of type-2 diabetes and obesity in male mice 25,26 , prevent the onset of necrotizing enterocolitis in preterm piglets 7 , restore the GM after antibiotic intervention 27 , and improve the proliferation of commensal gut Akkermansia muciniphila 28 . These findings highlight the promising application of FVT as a GM restoring treatment targeting various diseases associated with GM dysbiosis.…”

Fecal Virome Transplantation (FVT) from healthy humans remodels the gut bacteriome and virome and reduces metabolic syndrome in mice

“…In mice, the FVT reduced intestinal bacterial overgrowth [17] and improved weight and glucose tolerance in type 2 diabetes [15]. The FVT can also change gut bacteria and drive lean and obese body phenotypes [20]. However, these experiments only involved FVT from mice to mice and human to human.…”

“…FVT has also shown promising results in treating metabolic diseases such as type 2 diabetes (T2D) and obesity, decreasing weight gain, and normalizing blood glucose tolerance in diet-induced obese mice [19]. It has also been demonstrated that FVT can change fecal microbiota and induce lean and obese body phenotypes in mice [20]. On the other hand, human studies have found that FVT from healthy and lean donors can improve glucose levels in individuals with MetS [21].…”