Science：有辐射防护作用的肠道细菌和代谢物 | 热心肠日报
Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites
对辐射幸存者的多组学分析鉴定出具有辐射防护作用的微生物和代谢物
10.1126/science.aay9097
10-30, Article
Abstract & Authors:展开
Abstract:收起
INTRODUCTION: The toxicity of high-dose ionizing radiation is associated with the induction of both chronic and acute radiation syndromes that occur after partial or total body radiation and can be further characterized into hematopoietic, gastrointestinal, and cerebrovascular syndromes. The intestine is the major target of radiation and the biggest niche for gut microbiota. Although there are sporadic descriptive studies showing a potential correlation between the gut microbiota and radiation-induced damage, the detailed underpinnings of this relationship remain obscure. In addition, medical intervention to counteract radiation injury is still a global challenge despite decades of rigorous research.
RATIONALE: Over the last decade, numerous investigations have demonstrated highly diverse gut microbiota between individuals and significant correlations of gut microbiota with multiple diseases. Gut microbes, as well as microbe-derived metabolites represented by short-chain fatty acids (SCFAs) and tryptophan metabolites, have essential roles in regulating host metabolism and immunity. The imbalance or dysbiosis of a microbial community is associated with potential diseases, risks, or even to the clear onset of clinical symptoms. We have previously corroborated the biological importance of gut microbiota and certain bacteria (e.g., Lachnospiraceae) together with SCFAs in attenuating colitis and obesity. It has also been reported that SCFAs and tryptophan metabolites can reduce proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interferon-γ and promote the anti-inflammatory cytokines, all of which are vital mediators of radiation-induced damage. These findings raise the possibility that the gut microbiota and metabolites play a key role in the regulation of disease susceptibility after radiation challenge.
RESULTS: We found that a small percentage of mice could survive a high dose of radiation and live a normal life span. These “elite-survivors” harbored a distinct gut microbiome that developed after radiation. Taking advantage of this finding, we used a combination of fecal engraftment and dirty cage sharing to demonstrate that the microbiota from elite-survivors provided substantial radioprotection in both germ-free and conventionally housed recipients, characterized by enhanced survival and ameliorated clinical scores. An unbiased microbiome analysis identified Lachnospiraceae and Enterococcaceae as the most enriched bacteria in elite-survivors. Monoassociation analysis provided direct evidence for the protective role of Lachnospiraceae and Enterococcaceae in promoting hematopoiesis and attenuating gastrointestinal damage. Clinical relevance in humans was supported by an analysis of leukemia patients who were exposed to whole-body radiation. The elevated abundance of Lachnospiraceae and Enterococcaceae was associated with fewer adverse effects in a highly statistically significant fashion. Treatment with SCFAs, especially propionate, rendered mice resistant to radiation, mediated by attenuation of DNA damage and reactive oxygen species release both in hematopoietic and gastrointestinal tissues. Further, an untargeted metabolomics study revealed a realm of metabolites that were affected by radiation and selectively increased in elite-survivors. Among these, two tryptophan pathway metabolites, 1H-indole-3-carboxaldehyde (I3A) and kynurenic acid (KYNA), provided long-term radioprotection in vivo.
CONCLUSION: Our findings emphasize a crucial role for the gut microbiota as a master regulator of host defense against radiation, capable of protecting both the hematopoietic and gastrointestinal systems. Lachnospiraceae and Enterococcaceae, together with downstream metabolites represented by propionate and tryptophan pathway members, contribute substantially to radioprotection. This study sheds light on the pivotal role that the microbiota-metabolite axis plays in generating broad protection against radiation and provides promising therapeutic targets to treat the adverse side effects of radiation exposure.
First Authors:
Hao Guo
Correspondence Authors:
Jenny P Y Ting
All Authors:
Hao Guo,Wei-Chun Chou,Yunjia Lai,Kaixin Liang,Jason W Tam,W June Brickey,Liang Chen,Nathan D Montgomery,Xin Li,Lauren M 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 Lu,Jenny P Y Ting