Table 2 Preclinical studies establishing the cause-and-effect role of gut microbiota in radiation injury
References | Animal model | Key techniques | Major endpoints | Conclusions and highlights |
|---|---|---|---|---|
Onoue, Japan, [16] | ICR mice, M, n = 10–42/group | TBI: 20 Gy Oral administration of single strain | Survival; histopathology of multiple organs | The first study distinguishing beneficial microorganisms from harmful ones based on the observation of radio-resistance in germ-free mice |
Crawford And Gordon, US, [4] | FVB/N, B6 mice, M/F, n = 3–27/group | TBI: 10–22 Gy Bacteria culture | Survival; histopathology of intestine | The radio-protective fasting-induced adipose factor is suppressed by the gut microbiota although the specific microbe(s) responsible were not identified |
Lam, US, [19] | Wistar rats, M, n = 5/group | TBI: 10, 18 Gy/6Fx Feaces for 16S rRNA sequencing | NA | The first study establishing microbiota-based acute and chronic ratios as effective biomarkers of prior radiation exposure |
Fan, China, [7] | B6 mice, M, n = 3–10/group | TAI: 5 Gy Feaces for 16S rRNA sequencing | Survival | Circadian rhythm disorder interacts with gut microbiota to augment radiation injury |
Fan, China, [5] | B6 mice, M/F, n = 4–18/group | TBI: 6.5 Gy Feaces for 16S rRNA sequencing + intestine for RNA sequencing | Survival; histopathology of intestine + circulating blood cell counting + spleen weight | Faecal microbiota transplantation is radio-protective without accelerating tumor growth |
Fan, China, [13] | B6 mice, M, n = 4–20/group | TAI: 15 Gy Feaces for 16S rRNA sequencing + intestine for microRNA assay | Survival; histopathology of intestine + circulating blood cell counting | Radio-protective hydrogen-water restores radiation-induced gut dysbiosis |
Gerassy, Israel, [17] | B6 mice, F, n = 8–33/group Germ-free Swiss Webster mice†for faecal MT assay | Rectum brachytherapy: 22 Gy/4Fx Feaces and colonic tissues for 16S rRNA sequencing + cytokine analysis | Survival; histopathology of intestine | The pro-inflammatory dysbiosis induced by radiation is transmissible via faecal microbiota transplantation and renders radio-sensitivity to intestine |
Tian, China, [22] | SD ratsa, n = 30/group | TBI: 0,4,8,12 Gy Feaces for 16S rRNA sequencing | Survival; histopathology of intestine | The first study showing the dose-dependent microbiota features in association with radiation injury in rodent models |
Carbonero, US, [21] | Gottingen minipig, M, n = 7–13/group Chinese rhesus macaques, M, n = 12–16/group | TBI: 1.65–2.25 Gy for minipig; 5.9–7.7 Gy for macaque Feaces for 16S rRNA sequencing | Survival | The first study showing the dose-dependent microbiota features in association with post-radiation survival in large primate models |
Kweon, Korea, [55] | B6, ICR mice, M/F, n = 3–5/group | TBI: 10 Gy or 12 Gy Gavage with lactate-producing microbes or conditioned medium or lactate + intestine for lactate measurement | Survival; histopathology of intestine + organoid measurement | Probiotics-derived lactate imposes intestinal radio-protection by activating Wnt/β-catenin in intestinal stem cells to accelerate epithelial repairment |
B6b, BALB/ca, n = 4–10/group | TBI: 12 Gy, TAI: 28-32 Gy/7-8Fx Gavage with live or heat-killed Lactobacillus or Lactobacillus-conditioned medium Luminal microbial analysis using qPCR | Survival; histopathology of intestine + circulating lymphocyte & hematopoietic stem cell counting | Lactobacillus-derived lipoteichoic acid imposes intestinal radio-protection without compromising anticancer efficacy by activating EGF pathway in intestinal stem cells | |
Fan, China, [11] | B6 mice, M, n = 3–10/group | TAI: 15 Gy Feaces for 16S rRNA sequencing | Survival; histopathology of intestine + circulating blood cell & bone marrow cell counting | Radio-protective 3,3’-diindolylmethane restores radiation-induced gut dysbiosis |
Li, China, [12] | B6 mice, M, n = 3–15/group | TBI: 9 Gy Feaces for 16S rRNA sequencing + intestine for RNA sequencing | Survival; histopathology of intestine + organoid culture | Radio-protective VND3207 restores radiation-induced gut dysbiosis |
Fan, China, [9] | B6 mice M/F, n = 5–24/group | TBI: 7 Gy for survival; 4 Gy for hematopoietic toxicity; TAI: 12 Gy for gastrointestinal toxicity; Feaces for 16S rRNA sequencing + intestine for RNA sequencing | Survival; histopathology of intestine + spleen & thymus weight and blood inflammatory markers | Simvastatin and high-fat diet is radio-protective in male and female mice respectively, which relies on the existence of the sex-specific gut microbiota |
Fan, China, [8] | B6 mice M, n = 12/group | TAI: 12-15 Gy Feaces for 16S rRNA sequencing & SCFA quantification (LC) | Survival; histopathology of intestine | Polysorbate-80 aggravates acute RE by altering the gut microbiota and decreasing butyrate level; post-radiation administration of butyrate reverses the effects of polysorbate-80 |
Fan, China, [42] | B6 mice, M/F, n = 3–12/group | TBI: 4-7 Gy; TAI: 12-15 Gy Feaces for 16S rRNA sequencing & SCFA quantification (LC) + intestine for peptide quantification (MS) | Survival; histopathology of intestine + spleen & thymus weight and blood inflammatory markers | Microbiota-derived valerate alleviates radiation injury by up-regulating AML1/KRT1 which is down-regulated after radiation and is radio-protective |
Fan, China, [43] | B6 mice & Balb/c nude mice, M/F, n = 6–30/group | TBI: 7.2 Gy for survival; 4 Gy for hematopoietic toxicity; TAI: 12 Gy for gastrointestinal toxicity; Feaces for 16S rRNA sequencing & untargeted metabolomics (LC/MS) + intestine for peptide quantification (MS) | Survival; histopathology of intestine + spleen & thymus weight and blood inflammatory markers | Microbiota-derived IPA alleviates radiation injury by re-activating the PXR-ACBP pathway without compromising anticancer efficacy |
Guo, US, [47] | B6 mice, M/F, n = 4–33/group | TBI: 8.0–9.2 Gy Feaces for 16S rRNA sequencing & SCFA quantification (GC) & untargeted metabolomics (LC) | Survival; histopathology of intestines, spleen & bone marrow | Microbiota-derived SCFAs and tryptophan metabolites confer hematopoietic and gastrointestinal radio-protection without compromising anticancer efficacy |
Tian, China, [20] | B6 mice, M, n = 5–10/group | TBI: 0,4,8,12 Gy for dose-dependent assay and 9 Gy for probiotic assay; Feaces for 16S rRNA sequencing | Survival; histopathology of intestine | A longitudinal study demonstrating that microbial quantifications at day3.5 after radiotherapy provide biomarkers for radio-dosimetry and radiation injury |
Fan, China, [14] | B6 mice, M, n = 5–8/group | Total chest irradiation: 15 Gy Feaces for 16S rRNA sequencing + LC/MS | Body weight, histopathology of lung and heart | Radio-protection of L-Histidine relies on the existence of the gut microbiota |
Fan, China, [10] | B6 mice M/F, n = /group | TBI: 5 Gy; TAI: 12 Gy Feaces for 16S rRNA sequencing | Survival; histopathology of intestine + circulating blood cell counting | Radio-protection of caloric-restriction diet relies on the existence of the gut microbiota |
Kweon, Korea, [63] | B6, F, n = 3–5/group | TBI: 10 Gy Gavage with Akkermansia or conditioned medium + Cecal contents for SCFA quantification (LC/MS) | Survival; histopathology of intestine + organoid measurement | Akkermansia-derived SCFAs impose intestinal radio-protection by activating Wnt/β-catenin in intestinal stem cells to promote proliferation and differentiation |
Epperly, US, [23] | B6, BALB/c, sv129 mice, M, n = 10–20/group | TBI: 9.25 Gy Feaces for 16S rRNA sequencing and qPCR validation | Survival | Akkermansia muciniphila improves post-radiation survival in TBI mice |
Epperly, US, [24] | B6 mice, F, n = 12/group | TBI: 9.25 Gy; TAI: 19.75 Gy; Feaces for 16S rRNA sequencing | Survival; inflammatory protein expression + bone marrow cells counting | Engineered IL-22- producing microbe ameliorates radiation injury |
Epperly, US, [25] | B6 mice, M, n = 10–15/group | TBI: 9.25 Gy Feaces for 16S rRNA sequencing | Survival | Inclusion of microbiota information improves the predictability of survival when controlling for administration of radiation mitigators |
Dar, US, [52] | B6 mice, F, n = 3–5/group | TBI: 9.25 Gy Feaces for bacterium counting + intestine for lipidomics (LC/MS) | Survival; histopathology of intestine | Pseudomonas aeruginosa-derived 15-lipoxygenase increases lipid peroxidation and ferroptosis, thereby exacerbating local inflammation and radiation injury |