Gut Microbe Imbalance Drives Radiation Colitis From Iodine-125 Seed Therapy

A new study has revealed that the chronic intestinal inflammation suffered by some patients after iodine-125 seed brachytherapy may not be caused solely by radiation burning the bowel wall directly. Instead, researchers report that continuous low-dose-rate irradiation from implanted seeds profoundly restructures the gut microbiome, and that this microbial disruption is tightly coupled to shifts in the host’s own gene expression, offering a new integrated explanation for radiation colitis. The work, published in Immunity, Inflammation and Disease, combined microbiome sequencing, transcriptomics, histology and correlation network analysis in a mouse model of intraperitoneal iodine-125 seed implantation, and its findings could open the door to microbiome-targeted prevention strategies for a complication that has long been treated as an unavoidable side effect of an otherwise precise cancer therapy.

Iodine-125 seed implantation has become a mainstay of minimally invasive treatment for abdominal solid tumors, including cancers of the prostate, pancreas, liver, colorectum and gynecologic organs. The technique exploits the isotope’s low energy gamma emissions and 59.6-day half-life to deliver a continuous, low-dose-rate radiation field that concentrates lethal dose inside the tumor while sparing surrounding tissue. Yet because abdominal malignancies often sit adjacent to the bowel, unintended intestinal exposure remains a clinically significant problem. Radiation colitis, marked by persistent inflammation, breakdown of the mucosal barrier and impaired bowel function, is among the most common and serious consequences, producing chronic pain, diarrhea, bleeding and, in severe cases, obstruction. Until now, the prevailing explanation centered on direct radiobiological injury: ionizing radiation damages intestinal epithelial stem and crypt cells, inducing DNA double-strand breaks that trigger p53/p21-mediated cell cycle arrest and, when damage is irreparable, apoptosis or necrosis through pathways such as Caspase-3.

The research team, led by investigators at Army Medical University, set out to test whether a second, less visible mechanism operates alongside this classical one. They surgically implanted iodine-125 seeds near the descending colon of C57BL/6 mice, with each seed measuring 0.8 millimeters in diameter, 4.5 millimeters in length and emitting an initial dose rate of 5.13 centigray per hour at 0.7 millicuries of activity. Over the two-week observation window, treated mice developed soft stools or mild diarrhea but showed no bloody stool, significant weight loss or behavioral changes. Molecular analysis of colon tissue, however, told a sharper story: messenger RNA levels of the pro-inflammatory cytokines IL-1α, IL-1β, IL-6 and TNF-α were all significantly elevated compared with sham-operated controls, indicating a robust inflammatory response within the irradiated bowel wall.

Histological examination reinforced the picture of genuine tissue injury. Hematoxylin and eosin staining revealed widening of the submucosal space, detachment of the mucosal layer from the submucosa, pathological changes extending along both sides of the colonic mucosa and pronounced infiltration of inflammatory cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays detected apoptotic cells within the colonic mucosa, confirming epithelial cell death after exposure. Critically, Western blot analysis showed a marked reduction in the tight junction proteins ZO-1 and occludin, the molecular staples that seal the epithelial barrier. Their loss implies a leaky intestinal lining, a change that permits luminal contents and microbial products to cross into the tissue and further amplify inflammation, a self-reinforcing loop characteristic of colonic disease.

To determine what was happening to the trillions of microbes inhabiting the gut, the researchers performed 16S rRNA gene sequencing on fecal samples. Alpha diversity metrics such as chao1, ace, sobs, Shannon and Simpson indices varied between groups but did not reach statistical significance. Beta diversity, by contrast, told a different story. Principal co-ordinates analysis separated the two groups distinctly, with an analysis of similarities statistic of R = 0.352 and p = 0.038, and non-metric multidimensional scaling confirmed the result with a low stress value below 0.2. Exploratory indices added context: the gut microbiota health index suggested a healthier community in controls, while the microbial dysbiosis index indicated significant dysbiosis in the irradiated animals. In short, the overall species count was roughly preserved, but the identity and structure of the community had been fundamentally reorganized.

Compositional analysis pinpointed which taxa drove the shift. At the genus level, control mice harbored 125 genera, including 20 unique taxa, while irradiated mice carried 120 genera with 15 unique to that group. The relative abundances of unclassified Muribaculaceae and Ruminococcaceae increased after irradiation, whereas Lachnospiraceae NK4A136 group declined markedly. Linear discriminant analysis effect size identified the family Lachnospiraceae as enriched in controls, while Christensenellaceae and Bifidobacteriaceae rose significantly in irradiated mice. Wilcoxon rank-sum testing after abundance filtering singled out Lachnospiraceae NK4A136 group, Mucispirillum and Desulfovibrio as the most significantly altered genera. The loss of Lachnospiraceae is particularly notable because these organisms are major producers of short-chain fatty acids such as butyrate, metabolites that fuel intestinal epithelial cells and support barrier repair. Spearman correlation analysis found that Lachnospiraceae NK4A136 group, Lactobacillus and unclassified Oscillospiraceae trended negatively with pro-inflammatory cytokines, while Bifidobacterium trended positively, and Desulfovibrio correlated positively with barrier protein disruption. Redundancy analysis identified IL-1β and IL-6 as the cytokines most strongly associated with microbial community variation, and Procrustes analysis confirmed significant overall concordance between microbiota composition and host histopathological parameters.

The team then turned to the host side of the equation with RNA sequencing of colonic tissue. Of 28,102 genes shared between groups, 2,648 were unique to controls and 2,212 unique to irradiated mice, and cluster analysis cleanly separated the expression profiles. Among the top differentially expressed genes were angptl7, apoh, C7, ccl7, ciart, cish and cxcl14, all validated by quantitative PCR. Several of the most significant changes involved immunoglobulin variable region genes of the Igkv and Ighv families, integral components of B cell receptors, hinting at previously underappreciated local humoral immune activation within the irradiated mucosa. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed the strongest enrichment in cytokine-cytokine receptor interaction and IL-17 signaling, both central to immune cell recruitment and inflammatory mediation, while Reactome analysis pointed to SLC-mediated transmembrane transport and peptide ligand-binding receptors. Functionally, the chemokines Ccl7 and Cxcl14 recruit monocytes and macrophages that intensify tissue damage; complement component C7 can lyse epithelial cells when excessively activated; Apoh elevation is linked to microthrombosis and intestinal ischemia; Cish restrains JAK-STAT signaling and supports intraepithelial lymphocyte survival; and Angptl7 may participate in vascular remodeling during injury repair.

The most striking result emerged when the researchers overlaid the two datasets. Spearman correlations between the top 50 altered microbial taxa and differentially expressed host genes suggested meaningful associations involving Lachnospiraceae NK4A136 group, Mucispirillum and Desulfovibrio, although the authors caution that after false discovery rate correction these links weakened and should be treated as exploratory and hypothesis-generating. Redundancy analysis flagged angptl7, ciart, Igkv6-17 and Igkv1-132 as the genes most strongly tied to microbial variation, and Procrustes analysis again demonstrated coordinated variation between the transcriptomic profile of colonic injury and the structure of the gut microbiome. Linear regression between individual genes and beta diversity indices quantified how much each gene contributed to community structure. Together, these analyses construct an integrated molecular network in which microbial dysbiosis and host transcriptional responses move in lockstep during the development of iodine-125-induced colitis, rather than operating as independent phenomena.

The authors are careful to frame their conclusions within the study’s limits. The inflammatory response was measured at the mRNA level without protein validation, causality between microbial changes and tissue injury was not established, the sample size was small at five mice per group, and only a single observational timepoint was captured, precluding dynamic analysis. The gut microbiota health and dysbiosis indices, originally built from human datasets, were applied to mice in a strictly exploratory fashion. The unexpected rise in Bifidobacterium alongside inflammation may reflect that organism’s relative tolerance of radiation-induced oxidative stress, allowing its proportional expansion as more sensitive obligate anaerobes died off, a question requiring absolute quantification. Future work with fecal microbiota transplantation from irradiated to non-irradiated recipients, germ-free models, mono-colonization experiments and IL-17 signaling blockade will be needed to confirm causal roles. Even so, the study marks a conceptual advance: radiation colitis after seed brachytherapy appears to arise not only from direct cytotoxic injury but from a coupled ecological and transcriptional perturbation, and that reframing suggests that protecting or restoring beneficial gut bacteria could one day become a practical strategy to shield patients from one of brachytherapy’s most burdensome complications.

Subject of Research: How gut microbiota dysbiosis mediates radiation colitis induced by iodine-125 seed brachytherapy through host transcriptional regulation

Article Title: Gut Microbiota Dysbiosis Mediates 125I‐Induced Radiation Colitis via Host Transcriptional Regulation

Article References: Liu, P., Zeng, X., Liu, W., Xie, H., Fang, Y., Yang, E., Tang, X., Fan, C., & Chen, Y. (2026). Gut Microbiota Dysbiosis Mediates 125 I‐Induced Radiation Colitis via Host Transcriptional Regulation. Immunity, Inflammation and Disease, 14(9), Article e70523. https://doi.org/10.1002/iid3.70523

Image Credits: AI Generated

DOI: 10.1002/iid3.70523

Keywords: gut microbiota, radiation colitis, iodine-125 brachytherapy, dysbiosis, 16S rRNA sequencing, RNA-Seq, IL-17 signaling, intestinal barrier, Lachnospiraceae, pro-inflammatory cytokines, transcriptomics, mouse model