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

ABSTRACT

The gastrointestinal microbiome plays a significant role in modulating numerous host processes, including metabolism. Prior studies show that when mice receive fecal transplants from obese donors on high-fat diets (HFD) (even when recipient mice are fed normal diets after transplantation), they develop obese phenotypes, demonstrating the prominent role that gut microbiota play in determining lean and obese phenotypes. While much of the credit has been given to gut bacteria, the impact of gut viruses on these phenotypes is understudied. To address this shortcoming, we gavaged mice with viromes isolated from donors fed HFD or normal chow over a 4-week study. By characterizing the gut bacterial biota via 16S rRNA amplicon sequencing and measuring mouse weights over time, we demonstrate that transplanted viruses affect the gut bacterial community, as well as weight gain/loss. Notably, mice fed chow but gavaged with HFD-derived viromes gained more weight than their counterparts receiving chow-derived viromes. The converse was also true: mice fed HFD but gavaged with chow-derived viromes gained less weight than their counterparts receiving HFD-derived viromes. Results were replicated in two independent experiments and phenotypic changes were accompanied by significant and identifiable differences in the fecal bacterial biota. Due to methodological limitations, we were unable to identify the specific bacterial strains responsible for respective phenotypic changes. This study confirms that virome-mediated perturbations can alter the fecal microbiome in vivo and indicates that such perturbations are sufficient to drive lean and obese phenotypes in mice.

KEYWORDS:

• High fat diet
• virome
• fecal microbiota
• bacteriophages
• obesity
• gut microbiome

Acknowledgments

We thank Martin J. Blaser and Emma Allen Vercoe for feedback on the conception and design of this project, Jonathan B. Shurin for contributing valuable input on analyses, and Michael Overton for assistance with the Triton Shared Computing Cluster. We also thank the San Diego Digestive Diseases Research Center (SDDRC) for their support of this study.

Disclosure statement

B.S. has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals and Takeda. B.S.’s institution UC San Diego has received grant support from Artizan Biosciences, Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. B.S. is founder of Nterica Bio. C.G. is founder and CEO of Bioharmony Therapeutics and CSO of Emily’s Entourage.

Authors’ contributions

Conceived and designed project: JMB, DTP, BS, and CG.

Performed experiments: JMB, RL, YW, JC, PK, and LH.

Analyzed the data: JMB, RL, YW, DTP, BS, and XT.

Statistical analysis: JMB, TW, and XMT.

Wrote and edited the manuscript: JMB, RL, DTP, BS, JRM, CG, TW, and XMT.

Provided materials for the study: YW and BS.

All authors reviewed the manuscript.

Data availability statement

All sequences included in this study have been deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA930016.

Animal welfare approval

All animal studies and research presented here were reviewed and approved by the Institutional Animal Care and Use Committee of the University of California, San Diego.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2236750

Additional information

Funding

This work was supported by NIH center [P30 DK120515] and [NSF DEB-2018058].