Radioprotective bacteria A common symptom of radiation treatment for cancer is gastrointestinal disruption. The damage caused can become so severe and debilitating that it interrupts treatment. Guo et al. noticed that mice surviving experimental radiation exposure had distinctive taxonomic representation in their gut microbiota. A similar correlation was also observed in a small group of human subjects. Further experiments in mice revealed that some strains of bacteria produced high levels of short-chain fatty acids, which seemed to be dampening inflammatory responses and alleviating the damage caused by reactive oxygen species released by the radiation. A metabolomics analysis also implicated a role for tryptophan metabolic pathways in radiation survivorship. Science, this issue p. eaay9097 Certain families of gut microbes appear to enhance host mouse survival responses to radiation damage. 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. Gut microbiota and metabolites mediate radioprotection. Gut microbes, especially Lachnospiraceae and Enterococcaceae along with bacteria-derived metabolites represented by SCFA (propionate) and tryptophan pathway members (I3A and KYNA), tune host resistance against high doses of radiation by facilitating hematopoiesis and gastrointestinal recovery. Ionizing radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, and cerebrovascular injuries. We investigated a population of mice that recovered from high-dose radiation to live normal life spans. These “elite-survivors” harbored distinct gut microbiota that developed after radiation and protected against radiation-induced damage and death in both germ-free and conventionally housed recipients. Elevated abundances of members of the bacterial taxa Lachnospiraceae and Enterococcaceae were associated with postradiation 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. In our study in mice, metabolomics revealed increased fecal concentrations of microbially derived propionate and tryptophan metabolites in elite-survivors. The administration of these metabolites caused long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in proinflammatory responses.

中文翻译：

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对辐射幸存者的多组学分析确定了辐射防护微生物和代谢物


放射防护细菌 癌症放射治疗的一个常见症状是胃肠道紊乱。造成的损害可能变得非常严重和虚弱，以至于中断治疗。郭等人。注意到在实验辐射暴露中幸存的小鼠的肠道微生物群具有独特的分类学特征。在一小群人类受试者中也观察到类似的相关性。在小鼠身上进行的进一步实验表明，某些细菌菌株产生高水平的短链脂肪酸，这似乎可以抑制炎症反应并减轻辐射释放的活性氧造成的损害。代谢组学分析还表明色氨酸代谢途径在辐射生存中的作用。科学，本期第 14 页。 eaay9097 某些肠道微生物家族似乎可以增强宿主小鼠对辐射损伤的生存反应。引言 高剂量电离辐射的毒性与部分或全身辐射后发生的慢性和急性辐射综合征有关，可进一步分为造血、胃肠道和脑血管综合征。肠道是辐射的主要目标，也是肠道微生物群的最大生态位。尽管有零星的描述性研究表明肠道微生物群与辐射引起的损伤之间存在潜在的相关性，但这种关系的详细基础仍然不清楚。此外，尽管经过了数十年的严格研究，对抗辐射损伤的医疗干预仍然是一个全球性挑战。 基本原理在过去的十年中，大量研究表明个体之间的肠道微生物群高度多样化，并且肠道微生物群与多种疾病存在显着相关性。肠道微生物以及以短链脂肪酸（SCFA）和色氨酸代谢物为代表的微生物衍生代谢物在调节宿主代谢和免疫方面具有重要作用。微生物群落的不平衡或失调与潜在的疾病、风险，甚至与临床症状的明显发作有关。我们之前已经证实了肠道微生物群和某些细菌（例如毛螺菌科）与短链脂肪酸 SCFA 在减轻结肠炎和肥胖方面的生物学重要性。据报道，短链脂肪酸和色氨酸代谢物可以减少促炎细胞因子，如肿瘤坏死因子-α、白细胞介素-6和干扰素-γ，并促进抗炎细胞因子的产生，所有这些细胞因子都是辐射损伤的重要介质。这些发现提出了肠道微生物群和代谢物在辐射挑战后疾病易感性调节中发挥关键作用的可能性。结果我们发现一小部分小鼠能够在高剂量辐射下存活下来并过上正常的寿命。这些“精英幸存者”拥有在辐射后形成的独特肠道微生物群。利用这一发现，我们结合使用粪便植入和肮脏的笼子共享来证明来自精英幸存者的微生物群为无菌和传统饲养的受者提供了实质性的辐射防护，其特点是提高了存活率并改善了临床评分。 一项公正的微生物组分析确定，毛螺菌科和肠球菌科是精英幸存者中最丰富的细菌。单关联分析为毛螺菌科和肠球菌科在促进造血和减轻胃肠道损伤方面的保护作用提供了直接证据。对暴露于全身辐射的白血病患者的分析支持了人类的临床相关性。毛螺菌科和肠球菌科丰度的增加与较少的不良反应相关，且具有高度统计显着性。 SCFA（尤其是丙酸）治疗使小鼠对辐射产生抵抗力，这是通过减弱造血组织和胃肠组织中 DNA 损伤和活性氧释放来介导的。此外，一项非目标代谢组学研究揭示了受辐射影响并在精英幸存者中选择性增加的代谢物领域。其中，两种色氨酸途径代谢物，1H-吲哚-3-甲醛（I3A）和犬尿酸（KYNA），在体内提供长期辐射防护。结论我们的研究结果强调了肠道微生物群作为宿主防御辐射的主要调节因子的关键作用，能够保护造血系统和胃肠系统。毛螺菌科和肠球菌科，以及以丙酸和色氨酸途径成员为代表的下游代谢物，对辐射防护做出了重大贡献。这项研究揭示了微生物群-代谢物轴在产生广泛的辐射保护方面所发挥的关键作用，并为治疗辐射暴露的不良副作用提供了有希望的治疗靶点。肠道微生物群和代谢物介导辐射防护。 肠道微生物，特别是毛螺菌科和肠球菌科，以及以 SCFA（丙酸）和色氨酸途径成员（I3A 和 KYNA）为代表的细菌衍生代谢物，通过促进造血和胃肠道恢复来调节宿主对高剂量辐射的抵抗力。电离辐射会引起急性辐射综合征，从而导致造血、胃肠道和脑血管损伤。我们研究了一群从高剂量辐射中恢复并过着正常寿命的小鼠。这些“精英幸存者”拥有独特的肠道微生物群，这些微生物群是在辐射后形成的，可以保护无菌和传统饲养的受者免受辐射引起的损伤和死亡。细菌类群毛螺菌科和肠球菌科成员的丰度升高与辐射后造血和胃肠道修复的恢复有关。这些细菌还被发现在接受放射治疗的白血病患者中更为丰富，而且这些患者也表现出较轻微的胃肠功能障碍。在我们对小鼠的研究中，代谢组学显示，精英幸存者粪便中微生物来源的丙酸和色氨酸代谢物浓度增加。这些代谢物的施用导致了长期的放射防护、造血和胃肠道综合征的缓解以及促炎症反应的减少。