Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites
Hao Guo, Wei-Chun Chou, Yunjia Lai, Kaixin Liang, Jason W. Tam, W. June Brickey, Liang Chen, Nathan D. Montgomery, Xin Li, Lauren Bohannon, Anthony D. Sung, Nelson J. Chao, Jonathan U. Peled, Antonio L. C. Gomes, Marcel R.M. van den Brink, Matthew J. French, Andrew N. Macintyre, Gregory D Sempowski, Xianming Tan, R. Balfour Sartor, Kun Lü, Jenny P.‐Y. Ting
Abstract
Abstract Ionizing-radiation causes acute radiation syndrome leading to hematopoietic, gastrointestinal and cerebrovascular injuries. Substantial federal efforts have been made to develop therapeutic radioprotectants for routine clinical use, however it remains a long-standing and unresolved problem. We investigated a population of mice that recovered from high-dose radiation to live normal lifespans. These elite-survivors harbored distinct gut microbiota that developed post-radiation and protected against radiation-induced damage and death in germ-free and conventionally housed recipients. Elevated abundances of members of the bacterial taxa Lachnospiraceae and Enterococcaceae were associated with post-radiation restoration of hematopoiesis and gastrointestinal repair. These bacteria were also found to be more abundant in leukemia patients undergoing radiotherapy who also displayed milder gastrointestinal dysfunction. Metabolomics revealed increased fecal concentrations of microbially derived propionate and tryptophan metabolites in elite-survivors. The concentrations of these metabolites correlated with long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in pro-inflammatory responses. The novelty of our work lies in the first identification of gut microbiota and downstream metabolites in providing protection against lethal radiation. Furthermore, our work provides a comprehensive omics dataset at the bacteria and metabolite levels that is of broad interest and serves as a powerful resource and example for the identification of actionable therapeutic targets derived from microbiome studies.