Year: 2026
Type: erratum
Abstract: Abdominopelvic malignancies are lesions that occur in the abdomen and pelvis, originating from various organs and tissues in this region. According to the latest cancer statistics published in 2024, gynecological cancers, colorectal cancer, and prostate cancer rank highest in both incidence and mortality among abdominopelvic malignancies [1] . Currently, surgery, chemotherapy, radiotherapy, immunotherapy, targeted therapy, and endocrine therapy are the main treatment modalities for abdominopelvic malignancies [2] . Radiotherapy exerts its antitumor effects primarily by utilizing high-energy radiation to directly damage the DNA structure of cancer cells. Additionally, radiation interacts with intracellular water molecules to generate free radicals, inducing extensive DNA damage [3] . It is particularly indicated for patients ineligible for surgery, as postoperative adjuvant treatment, or for recurrent cases [4][5][6] , holding a significant position in the comprehensive management of abdominopelvic malignancies. Notably, radiotherapy directed at the abdominopelvic region, which includes the gastrointestinal tract, can significantly disrupt gut microbiota homeostasis, leading to dysbiosis [7] . This dysbiosis not only contributes to the development of radiotherapy-related side effects but also diminishes the radiosensitivity of tumor tissues [8,9] . Over 97% of human commensal bacteria reside within the digestive tract, predominantly in the colon, collectively forming the gut microbiota [10] . Eckburg et al. [11] demonstrated that 98% of the gut microbiota belongs to four dominant phyla: Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. These commensal microorganisms play crucial roles in essential physiological processes, including regulating intestinal epithelial cell proliferation and differentiation, activating innate immune responses, and participating in metabolic homeostasis regulation [12] . They can also modulate the efficacy of various cancer therapies, including radiotherapy [13,14] .Gut microbiota-derived short-chain fatty acids (SCFAs) promote the production of tight junction proteins and mucins, thereby maintaining intestinal barrier integrity following radiotherapy [15] . Outer membrane vesicles (OMVs) secreted by the gut microbiota contain various bacterial-associated molecular patterns and serve as potent mediators for enhancing anti-tumor immunity [16] . Furthermore, the anaerobic or facultative anaerobic characteristics of gut microbiota enable their effective targeting of hypoxic tumor regions. Combined with bioengineering technologies, they can ameliorate hypoxia within the tumor microenvironment (TME), consequently enhancing radiosensitivity. In summary, a close interaction exists between the gut microbiota and radiotherapy. Understanding the mechanisms underlying the interplay between abdominopelvic radiotherapy and the gut microbiota will provide a theoretical foundation for developing microbiota-modulating adjuvant strategies for radiotherapy. This approach aims to achieve the dual goals of mitigating adverse effects and enhancing anti-tumor efficacy.The gut microbiota is influenced by numerous factors, among which abdominopelvic radiotherapy is one that significantly alters its diversity and abundance. A systematic review incorporating 11 studies demonstrated that exposure to radiation induces changes in intestinal bacterial composition, characterized by a reduction in beneficial bacteria and an increase in potentially harmful bacteria [17] . Due to such alterations, the gut microbiota may serve as a novel biomarker for radiation exposure [18] .In animal models, the Zhao team [19] confirmed that abdominal irradiation disrupts gut microbiota balance in mice and significantly reduces the alpha-diversity index.Following radiation exposure, the abundance of the Bacteroidetes, Firmicutes, and Actinobacteria decreased in the gut, while the abundance of Proteobacteria, which is enriched with pathogenic bacteria, significantly increased. Duan et al. [20] further revealed a pathogen-probiotic dynamic imbalance in the gut microbiota of irradiated mice: the abundance of opportunistic pathogens such as Escherichia and Shigella (Proteobacteria) increased, whereas the abundance of beneficial bacteria including Romboutsia (Firmicutes) and Bacteroides (Bacteroidetes) decreased. Lu et al. [21] also found that abdominal irradiation induces a "pathogenic remodeling" of the intestinal microenvironment, leading to Enterobacteriaceae becoming the dominant bacterial family. Collectively, these findings indicate that abdominal radiation exposure induces gut microbial dysbiosis in animal models.Clinically, alterations in the gut microbiota following abdominopelvic radiotherapy exhibit consistent trends among patients, irrespective of the presence of radiation-induced intestinal injury. He et al. [15] observed that, compared to cervical cancer patients who did not receive radiotherapy, patients undergoing radiotherapy exhibited a significant reduction in fecal microbiota alpha-diversity, increased abundance of Proteobacteria, and decreased abundance of Firmicutes and Bacteroidetes. Nam et al. [22] compared fecal microbiota changes before and after pelvic radiotherapy in nine gynecological cancer patients, reporting a 10% decrease in Firmicutes and a 3% increase in Fusobacterium. Bacteroidetes, which typically confer beneficial functions within the gut [23] , exhibit variable abundance changes across studies. While most studies observed a decrease in its abundance [15,24,25] , a minority reported an increase [26] . Furthermore, in patients developing radiation-induced intestinal injury post-radiotherapy, some studies also observed an elevated abundance of Actinobacteria [27] . Collectively, these findings reveal characteristic alterations associated with radiotherapy-induced gut microbiota dysbiosis: diminished alpha-diversity accompanied by an imbalance in the ratio of pathogenic to beneficial bacteria.In summary, current research indicates that radiotherapy reduces the alpha-diversity and alters the abundance of the gut microbiota in patients with abdominopelvic malignancies (Table 1). The abundance of the Firmicutes and Bacteroidetes decreases.These phyla predominantly comprise probiotic bacteria whose exposed peptidoglycan structures are highly susceptible to degradation by radiation-generated reactive oxygen species (ROS) [28] . Conversely, the abundance of the Proteobacteria and Actinobacteria increases. These phyla encompass various opportunistic pathogens, exemplified by Escherichia coli, which can activate the RecA-mediated SOS DNA damage response system [29] . This activation enhances their capacity for repairing radiation-induced double-strand breaks, thereby conferring a competitive advantage within the intestinal microenvironment. The subsequent overproliferation of these harmful bacteria further suppresses the colonization and growth of beneficial bacterial populations, ultimately establishing a vicious cycle.A stable gut microbiota is essential for maintaining the intestinal epithelial barrier, suppressing inflammation, and preserving host immune homeostasis. Dysbiosis of the gut microbiota not only compromises intestinal epithelial barrier function but also promotes the expression of inflammatory cytokines and activates systemic inflammatory responses. These pathological changes can lead to the development of various radiotherapy-induced adverse effects, among which radiation enteritis (RE) is the most prevalent.RE represents the most prevalent adverse effect of abdominopelvic radiotherapy. This pathology is characterized by persistent intestinal tissue damage and extensive pathological alterations, manifesting with complex clinical presentations and a protracted clinical course. RE significantly impairs patients' quality of life and compromises comprehensive cancer treatment efficacy [30][31][32] . Characteristic symptoms include diarrhea, abdominal pain, constipation, and hematochezia [33] . Gut microbiota dysbiosis is closely associated with RE development. Wang et al. [34] analyzed fecal samples from cervical cancer patients undergoing pelvic radiotherapy, identifying distinct dysbiosis signatures in RE patients. Compared to patients without RE, those developing RE exhibited significantly reduced alpha-diversity, increased beta-diversity, elevated relative abundance of Proteobacteria, and decreased relative abundance of Bacteroidetes and Firmicutes. This disparity became more pronounced with increasing RE severity. Bacterial genera such as Bifidobacterium, Bacteroides, Lactobacillus, and Akkermansia muciniphila maintain intestinal epithelial barrier integrity by producing SCFAs that stimulate gut cells to secrete tight junction proteins (ZO-1, occludin, and claudin-3) and mucin MUC2 [15,[35][36][37] . Furthermore, bacteria including Faecalibacterium prausnitzii, Ruminococcus, Coprococcus, Dorea, Lachnospira, Roseburia, Bifidobacterium, and Clostridium alleviate intestinal inflammation by suppressing the NF-κB pathway, thereby reducing the expression of inflammatory cytokines such as TNF-α , IL-8, and IL-1 β [38][39][40] . Abdominopelvic radiotherapy substantially reduces the abundance of these barrier-protective and anti-inflammatory bacterial populations. Consequently, intestinal barrier function becomes compromised, permitting overgrowth of harmful bacteria. This leads to accumulation of endotoxins in the bloodstream, elevation of inflammatory cytokines, and ultimately culminates in the pathogenesis of radiation enteritis.Beyond gastrointestinal symptoms, patients with RE frequently experience concomitant fatigue [41] . Clinical studies reveal that, compared to patients without fatigue symptoms at the end of radiotherapy, those reporting fatigue exhibit significant enrichment of the genera Eubacterium, Streptococcus, Adlercreutzia, and Actinomyces in their gut microbiota [42] . Furthermore, among fatigued patients, those in the high-fatigue group demonstrate significantly reduced abundance of genera such as Subdoligranulum, Faecalibacterium, Bifidobacterium, and Agathobacter compared to the low-fatigue group [43] . Notably, these diminished bacterial taxa serve as primary producers of SCFAsmetabolites with well-established anti-inflammatory properties [44] . Existing evidence indicates that a lower abundance of SCFA-producing bacterial taxa contributes to a pro-inflammatory state associated with post-radiotherapy fatigue [45] . Further functional analyses suggest that inflammatory cytokines entering the systemic circulation act upon the central nervous system, thereby activating the gut-brain axis. This mechanism may represent one key pathway underlying the development of radiotherapy-related fatigue [43,46] .Therefore, restoring intestinal microbiota balance represents a significant potential approach for alleviating radiotherapy side effects. Currently, oral probiotics and fecal microbiota transplantation are the two main strategies. Novel oral delivery systems for probiotics, such as microfluidic strategies [47] and single-cell encapsulation [48] , aim to ensure precise targeting and stable colonization of probiotics. However, their limited range of bacterial species makes it difficult to compensate for complex microecological imbalances. Although fecal microbiota transplantation can deliver a more complete spectrum of microbiota, the heterogeneity and unpredictability of its efficacy constrain its broad clinical application [49] . Integrating multi-omics data for precise donor-recipient matching and focusing on the restoration of core functional microbial communities may be a feasible direction for achieving effective personalized interventions in the future.Gut microbiota dysbiosis not only contributes to radiotherapy-induced adverse effects but also negatively correlates with therapeutic response to radiation. Xiao et al.demonstrated that melanoma-bearing mice treated with a broad-spectrum antibiotic cocktail exhibited significantly diminished radiotherapeutic efficacy [50] . Clinically, head and neck cancer patients receiving broad-spectrum antibiotics show substantially reduced radiation response rates [51] . These findings suggest that antibiotic-mediated gut dysbiosis may underlie this phenomenon. Furthermore, the Sims TT team observed that radiotherapy-induced reduction in gut microbiota alpha-diversity significantly correlates with decreased chemo-radiotherapy response rates and reduced overall survival in cervical cancer patients [52] . Yang et al. additionally reported that Shengmai turmeric powder enhances radiotherapeutic efficacy by preserving gut microbiota against radiation-induced dysbiosis, indirectly supporting the inverse relationship between microbial imbalance and treatment outcomes [53] .An intact gut microbiota enhances anti-tumor immune responses through immunomodulation, thereby indirectly improving radiosensitivity. Paulos et al.demonstrated that whole-body irradiation in mice induces translocation of gut microbesincluding Enterobacter cloacae, Escherichia coli, Lactobacillus, and Bifidobacteriumto mesenteric lymph nodes, augmenting anti-tumor effects [54] .Bacterial components (e.g., lipopolysaccharides, flagellin, DNA) and metabolites from these anaerobic or facultative anaerobic gut microbes serve as pathogen-associated molecular patterns (PAMPs). These PAMPs activate immune cells via Toll-Like Receptors (TLRs), significantly amplifying anti-tumor immunity [16,55] . Consequently, depletion or dysbiosis of the gut microbiota compromises therapeutic responsiveness to radiotherapy. Notably, bacterial depletion may further provoke intestinal fungal overgrowth. Such overgrowth can suppress anti-tumor immunity by activating the Dectin-1 receptor pathway [50] , exerting dual inhibitory effects on radiotherapeutic efficacy. Although fecal microbiota transplantation (FMT) or probiotic administration may restore microbial balance and demonstrate potential in mitigating radiotherapy-induced adverse effects [56][57][58] ,conclusive evidence for their efficacy in improving radiotherapeutic outcomes remains lacking. Thus, harnessing gut microbiota-mediated immunomodulation may constitute a pivotal strategy for enhancing radiotherapeutic efficacy.In summary, although the gut microbiota shows potential value in alleviating complications associated with radiotherapy, the direct mechanisms by which it influences radiotherapy efficacy have not yet been fully elucidated. There remains a lack of sufficient clinical evidence to systematically clarify the specific role of gut microbiota in radioresistance, which is undoubtedly an area worthy of further exploration in radiation medicine. In addition, the theory that the gut microbiota indirectly affects radiotherapy efficacy by modulating anti-tumor immune responses has been substantiated. Based on this characteristic of the gut microbiota, combining emerging engineered bacteria and nanotechnology in the future may represent one of the key pathways to achieving its clinical translation.As the most frequent complication of abdominopelvic radiotherapy, RE has emerged as a critical limiting factor in the advancement of radiation oncology [59] .Radiotherapy-induced gut microbiota dysbiosis constitutes an underlying mechanism of radiation-associated intestinal injury. Previous studies indicate that oral administration of multi-strain probiotics [60] and FMT [61,62] effectively mitigate radiation-related tissue damage. The mechanistic basis involves synergistic actions through which the gut microbiota alleviates radiation-induced intestinal injury via multiple pathways (Figure 2).SCFAs and indole metabolites in microbial metabolic products exhibit significant intestinal barrier protective functions. Guo et al. found that "elite survivor" mice, which are tolerant to high doses of radiation, have an enrichment of Lachnospiraceae and Enterococcaceae in their intestines. The high levels of SCFAs and tryptophan metabolites produced by these microbial groups alleviate hematopoietic and gastrointestinal syndromes and suppress inflammatory responses, thereby providing long-term radioprotection for the mice [63] . SCFAs are produced by anaerobic microbiota in the gut (such as Bacteroidetes, Firmicutes, etc. ) through the fermentation of dietary fibers [64] . They exert their protective roles via specific receptors. Clinical studies have demonstrated that butyrate enemas can significantly alleviate radiation-induced intestinal injury in the abdominopelvic region [65,66] ,possibly via modulation of GPR41/43 receptors on the surface of intestinal epithelial cells [67] . Propionic acid produced by Akkermansia muciniphila binds to the GPR43 receptor, activating histone acetyltransferases (HAT) while inhibiting histone deacetylases (HDAC). This elevates histone acetylation levels, leading to chromatin structure loosening. Consequently, it enhances transcription of tight junction proteins (occludin, ZO-1) and mucin MUC2, ultimately contributing to the maintenance of intestinal epithelial barrier integrity following radiotherapy [15,68] . Additionally, valeric acid may activate the AML1/KRT1 signaling pathway through specific transporters or GPCRs, upregulating the expression of cytoskeleton-associated proteins, thereby enhancing intracellular mechanical stability, which could represent one of the mechanisms underlying its radioprotective effects [69] . The generation of another important class of metabolites -indole derivatives -relies on the tryptophan metabolic enzyme systems of Lactobacillus, Bifidobacterium, and other gut microbiota [70] . Studies indicate that indole-3-propionic acid (IPA) reduces oxidative stress levels via the PXR/ACBP pathway, thereby ameliorating radiation-induced hematopoietic and gastrointestinal toxicity [71,72] . Indole-3-carboxaldehyde (I3A)activates the aryl hydrocarbon receptor (AhR) in intestinal epithelial cells, promoting expression of the anti-inflammatory cytokine IL-10, which facilitates differentiation of intestinal stem cells into functional cells through mediation of the signaling pathway, ultimately enhancing intestinal barrier function and repairing radiation-induced damage . Furthermore, contributes to intestinal radioprotection by maintaining the and functions of intestinal stem cells, mitigating radiation-associated DNA and activating the pathway to alleviate oxidative stress . SCFAs and indole metabolites maintain intestinal epithelial and both intestinal inflammation and oxidative factor levels following radiotherapy through various thereby exerting radioprotective from metabolic the components of the microbiota also radioprotective potential (Table The cell acid of activates the receptor on the of the which binds to the receptor on stem cells This interaction their from the of the intestinal to the and by the pathway, of epithelial stem cells and promotes thereby the from radiation-induced damage . from the membrane of Escherichia a protective effect through activation of the receptor . Furthermore, the from flagellin, can activate the receptor on intestinal epithelial cells, NF-κB to the production of protective . These studies indicate that components of the microbiota, through specific activation of the receptor that ultimately on the of intestinal epithelial on the molecular mechanisms by which gut microbiota-derived products radioprotection via multiple signaling pathways the synergistic effects of microbiota modulation and metabolic this strategy may be more effective in maintaining intestinal homeostasis radiotherapy, thereby forming a intestinal barrier However, further clinical research is to development of tumor involves tumor cell properties such as DNA pathway and metabolic as as within the including hypoxia and . Radiotherapy not only leads to treatment and reduced quality of life but also compromises tissue function and the of malignancies or long-term complications . 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Furthermore, A a bacterial secreted by Enterobacteriaceae (e.g., Escherichia also induces cell . on et al. engineered Escherichia to bacteria which with into a administration of in mice its accumulation at tumor and precise of enhancing radiotherapy efficacy . bacterial from pathogens, with bioengineering technologies, can into effective strategies to radiotherapy tumor cells, it can also cell This activates anti-tumor immunity and an effect of in this leads to the accumulation of the . 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Collectively, these studies indicate that from and engineered gut microbiota-derived bacteria can significantly the radiotherapy-induced providing novel for achieving hypoxic prevalent within the constitute another critical barrier to the system tumor cell the hypoxic characteristics of the are closely associated with have that the hypoxic can increase the radiation of tumor cells by activating signaling pathways such as and . the anaerobic properties of specific gut microbiota in with bioengineering targeted of this critical the anaerobic of Escherichia and the of its et al. a the of the within the hypoxic of it tumor into This alleviates hypoxia in the and consequently enhances tumor radiosensitivity et al. membrane vesicles to hypoxic tumor these and by of their and significantly tumor . the hypoxic of et al. a to that in tumor hypoxic this approach disrupts the hypoxic microenvironment while activating immune responses, thereby inducing an anti-tumor effect . 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Such enable precise modulation of tumor and the immune microenvironment, and for interaction between abdominopelvic radiotherapy and the gut microbiota is a critical both therapeutic efficacy and significantly alters the structure of the gut microbiota, and these alterations are closely associated with the of radiotherapy-related and the development of Gut microbiota, with their metabolites and can activate various intestinal protective their properties and with bioengineering the gut microbiota can also serve as an effective to This interaction mechanism the theoretical foundation for developing synergistic strategies. upon microecological as dietary modulation (e.g., increasing of and oral probiotics, and gut microbiota modulation is to a core of radiotherapy synergistic it the potential to efficacy while reducing in abdominopelvic cancer
Source: Frontiers in Microbiology
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7126089149
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