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Abstract

Although radiotherapy is the second most effective cancer treatment, radiation injuries limit its use. About 80% of abdominal-pelvic radiotherapy patients develop acute radiation enteritis, with 20% discontinuing radiotherapy. The lack of effective mitigation measures restricts its clinical application. Recent studies have proposed gut microbiota as a potential biomarker for radiation injuries. However, the interaction between gut microbiota and radiation injuries remains poorly understood. This review summarizes two forms of interaction between gut microbiota and radiation injuries based on the location of the radiation field. One type of interaction, referred to as “direct interaction,” involves changes in the diversity and composition of gut microbiota, alterations in microbiota-derived metabolites, disruption of the intestinal barrier, activation of inflammatory responses within the intestine, and involvement of the host’s immune system. The second form, called “indirect interaction,” includes the influence of the gut microbiota on various body systems, such as gut microbiota–brain axis, gut microbiota–cardiopulmonary axis, and gut microbiota–oral axis. Additionally, we examine promising interventions aimed at reshaping the gut microbiota, including the use of probiotics, prebiotics, and fecal microbiota transplantation. The interaction between radiation injuries and gut microbiota is more complex than previously understood. Therefore, further clarification of the underlying mechanisms will facilitate the application of gut microbiota in preventing and alleviating radiation injuries.

Plain language summary

Exploring how gut bacteria may influence radiation damage

Cancer is a major health threat worldwide, and many patients undergo radiation therapy to treat tumors. However, radiation can also harm healthy organs, limiting the radiation dose that doctors can safely use. Currently, there are no specific treatments to prevent this type of damage, known as radiation-induced injury (RII). Recent research suggests that gut bacteria, also called gut microbiota (GM), may play a role in how radiation affects the body, but we do not yet fully understand this relationship. In this review, we explore two ways in which gut bacteria might interact with radiation damage. The first, known as “direct interaction”, occurs when radiation directly affects the gut microbiota. This can lead to changes in the types of bacteria present, affect substances produced by these bacteria, damage the gut barrier, trigger inflammation in the intestines, and influence the body’s immune system. The second, known as “indirect interaction”, involves the communication between the gut microbiota and other parts of the body, such as the brain, heart, lungs, and mouth. We also discuss potential treatments to help restore a healthy balance of gut bacteria, including probiotics (helpful bacteria), prebiotics (substances that help good bacteria grow), and fecal microbiota transplantation (a method of transferring bacteria from a healthy person’s stool). Understanding how gut bacteria and radiation-induced injury interact is more complex than previously thought, and further research could lead to better ways to protect patients from radiation damage during cancer treatment.

Keywords

dysbiosis gut microbiota mechanism radiation injuries

Introduction

Radiotherapy is a cornerstone of cancer treatment, with over half of cancer patients requiring this modality.¹ However, among patients receiving radiotherapy, radiation injuries of organs at risk are inevitable, with incidence rates reaching up to 77%.² Radiation injuries encompass various toxicities, including skin and oral mucosa damage, fibrosis, myelosuppression, gastrointestinal reactions, cardiopulmonary injuries, and cognitive dysfunction.^3
–5 The gut is particularly vulnerable to radiation during abdominal and pelvic cancer treatments, often leading to radiation-induced intestinal damage. Clinical manifestations include radiation enteritis, diarrhea, mucus discharge, tenesmus, abdominal pain, intestinal obstruction, gastrointestinal bleeding, and, in severe cases, intestinal perforation. Acute radiation enteritis affected over 80% of cervical cancer patients treated with radiotherapy,⁶ with 10%–20% developing debilitating symptoms requiring surgical intervention.⁷ However, effective prevention and treatment options for radiation injuries have remained elusive for decades, severely limiting the broader application of radiation regimens in cancer therapy. Interestingly, recent research showed that the gut microbiota played a critical role not only in inflammatory bowel diseases⁸ but also in the regulation of radiation injuries.⁹

The human intestinal microbiota comprises approximately 10¹⁴ microorganisms and is implicated in various conditions, including inflammatory, cardiovascular, metabolic, and autoimmune diseases.^10,11 In cancer research, gut microbiota had garnered increasing attention as a key factor in tumor development, diagnosis, treatment, and prognosis.^12,13 Additionally, gut microbiota had been shown to influence extra-intestinal malignant tumor, such as breast cancer.¹⁴ Moreover, chemotherapy-induced toxicity could be alleviated by targeting gut microbiota,¹⁵ and this therapeutic strategy had also been preliminarily validated in the context of radiation-induced organ damage.¹⁶

According to limited evidence with low grade, Chinese experts’ consensus on multidisciplinary diagnosis and treatment of radiation-induced rectal injury (2021 edition) referred to probiotics and fecal microbiota transplantation (FMT) as a new method to deal with radiation injuries.¹⁷ Nevertheless, we still face difficulties in the diagnosis and treatment of radiation injuries and lack of high-quality evidence to guide clinical practice.¹⁸ The specific interaction mechanisms between gut microbiota and radiation injuries in cancer remain poorly understood.

In this review, we summarize the current findings on the role of gut microbiota as a regulator of radiation injuries through direct and indirect interactions. We also highlight interventions targeting gut microbiota to mitigate radiation injuries, aiming to provide insights into potential therapeutic strategies for improving clinical outcomes in cancer patients undergoing radiotherapy.

The interaction and molecular mechanisms between gut microbiota and radiation injuries

Gut microbiota dysbiosis caused by ionizing radiation is a common phenomenon, and radiation changes the composition of beneficial and harmful bacteria in gut.^19,20 Gut microbiota also modulated the response and toxicity of radiation.^21,22 In this article, we classify the interaction between gut microbiota and radiation-induced intestinal injury caused by abdominal or pelvic radiation as “direct interaction.” Interestingly, gut microbiota dysbiosis was also observed when the head and chest organs were irradiated (with the intestines outside the radiation field). Moreover, non-intestinal organs affected by radiation-induced injuries are also regulated by gut microbiota. Whether the gut microbiota or the injured organs are in the irradiated field, mutual regulation between the two could be observed. Therefore, we classified the interaction between gut microbiota and non-intestinal organ injuries caused by radiation as “indirect interaction.” Figure 1 and Table 1 illustrate the two interaction patterns between gut microbiota and radiation injuries.

Figure 1.

The interaction between gut microbiota and radiation injuries: the red arrow represents “direct interaction” and the blue arrows represent “indirect interaction.”

Table 1.

Literature summary on the interaction mechanism between gut microbiota and radiation-induced injuries.

Interaction pattern	Mechanisms	Research objects	Irradiation site (dose)	Key results	Potential intervention strategies	References
Direct interaction	Gut microbiota homeostasis	C57BL/6J mice	Total body irradiation (9 Gy)	1. Radiation decreased α-diversity of gut microbiota.2. UroA mitigates radiation-induced apoptosis in intestinal epithelial cells by suppressing the p53 signaling pathway.	UroA	(24)
Direct interaction	Gut microbiota homeostasis	Patients with cervical cancer	Pelvic radiotherapy (NA)	1. In patients with chronic radiation enteritis, the proportion of Firmicutes decreased, and Proteobacteria increased, and the F/P ratio reflected the severity of radiation toxicity.2. The abundance of Shigella and Lachnospiraceae_Clostridium was relatively high in patients with severe enteritis.	Shigella Lachnospiraceae_Clostridium	(25)
Direct interaction	Gut microbiota homeostasisInflammatory response	C57BL/6 mice	Abdominal irradiation (15 Gy)	1. The species of bacteria, the alpha diversity, and the F/P ratio all decreased in feces.2. The expressions of inflammation-related proteins NF-κB p65, Cox-2, and NLRP-3 increased in jejunal tissues.3. TSA inhibited inflammatory mediators, alleviated gut dysbiosis, and promoted structural restoration of the irradiated intestine.	TSA	(26)
Direct interaction	Gut microbiota homeostasisInflammatory response	Wistar rats	Abdominal irradiation (22 Gy)	1. After irradiation, the F/B ratio, Trichospiraceae, and Streptococcus gastris decreased, while the abundances of Proteobacteria, Clostridium and Enterobacteriaceae increased.2. After the intervention of GRg3, the abundance of Ruminococcus, Lactobacillus, and other beneficial bacteria was significantly increased whereas those of Escherichia, Alloprevotella, and other harmful bacteria were decreased.3. GRg3 alleviated acute radiation proctitis by inhibiting the TLR4/MyD88/NF-κB pathway, down-regulating the expression of proinflammatory factors (IL-1β), up-regulating the expression of anti-inflammatory factors (IL-10).	GRg3	(27)
Direct interaction	Gut microbiota homeostasis	Chinese rhesus macaques, Macaca mulatta	Total body irradiation (7.4 Gy)	1. The ratio of F/B decreased and the Actinobacillus, Bacteroides, Prevotella (Paraprevotellaceae family), and Veillonella genera were significantly increased by more than 2-fold, whereas Acinetobacter and Aerococcus genus decreased by more than 10-fold post-irradiation.2. Low level of Lentisphaere and Verrucomicrobia phyla and Bacteroides genus at baseline before irradiation suggest a potential susceptibility to radiation-induced diarrhea.	The composition of the gut microbiota before irradiation was used to predict the occurrence of diarrhea	(28)
Direct interaction	Gut microbiota homeostasis	C57BL/6J mice	Total body irradiation (4, 8, or 12 Gy)	1. After radiation, the diversity of gut microbiota decreased as a whole, and the relative abundance of Proteobacteria and Bacteroides increased.2. Composition of gut microbiota was correlated with the radiation dose.3. Probiotics alleviated intestinal epithelial damage and partially restored the diversity of gut microbiota.	Probiotics	(29)
Direct interaction	Gut microbiota-derived metabolites	C57BL/6 mice	Abdominal irradiation (10 Gy)	The soluble dietary fiber pectin protected the terminal ileum against radiation-induced fibrosis via altering SCFAs concentration in the intestinal lumen.	Soluble dietary fiber pectinSCFAs	(33)
Direct interaction	Gut microbiota-derived metabolites	C57BL/6J mice	Abdominal irradiation (12 or 15 Gy)	Gut microbiota-derived butyrate alleviated radiation-induced intestinal injury via the activation of GPCRs and maintenance of the intestinal bacterial composition.	Butyrate	(35)
Direct interaction	Gut microbiota-derived metabolites	C57BL/6J miceBALB/c athymic nude mice	Abdominal irradiation (12 Gy)	1. Gut microbiota-derived IPA alleviated radiation-induced intestinal injury.2. FMT alleviated radiation-induced toxicity.	IPAFMT	(36)
Direct interaction	Gut microbiota-derived metabolites	Cervical and endometrial cancer	Pelvic radiotherapy (NA)	Erysipelatoclostridium and its related metabolite ptilosteroid A positively related to grade 2 radiation-induced intestinal injury.	Erysipelatoclostridium Ptilosteroid A	(37)
Direct interaction	Intestinal physical barrier	Caco-2 cells	10 Gy	Protein levels of tight junctions (ZO-1, occludin, claudin-3, and claudin-4) decreased in Caco-2 cell after irradiation.	Tight junctions	(41)
Direct interaction	Intestinal physical barrier	C57BL/6 mice	Abdominal irradiation (12 Gy)	1. Irradiation reduced levels of the tight-junction proteins Claudin-1, Occludin, and (ZO-1.2. Phycocyanin protects against radiation-induced intestinal injury by regulating the effect of the gut microbiota on the TLR4/Myd88/NF-κB pathway.	Phycocyanin	(42)
Direct interaction	Gut microbiota-derived metabolitesIntestinal physical barrier	C57BL/6 miceBALB/c mice	Total body irradiation (8 Gy)	1. The irradiation induced tight-junction damage (decreasing MECA32 and ZO-1), leading to the decrease of p38 MAPK and the increase of JNK MAPK.2. Acetic acid and valeric acid decreased while butyric acid not for its insensitive to irradiation.	Tight junctionsMAPK pathwayAcetic acid and valeric acid	(43)
Direct interaction	Intestinal physical barrier	C57 Bl/6 mice	Total body irradiation (7 Gy)	TSA could effectively control bacterial translocation as well as radiation-induced gastrointestinal injury.	TSA	(47)
Direct interaction	Intestinal inflammatory	C57BL/6 mice	Abdominal irradiation (13 Gy)	Rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression.	Rebamipide	(52)
Direct interaction	Intestinal inflammatory	C57BL/6 mice	Abdominal irradiation (12.5 Gy)	1. Abdominal irradiation led to an increase in the levels of intestinal inflammatory factors (TNF-α, IL-6, IL-1β).2. Sitagliptin restored radiation-induced changes in bacterial composition and reduced radiation-induced intestinal injury.	Sitagliptin	(53)
Direct interaction		C57BL/6J mice	Rectum (5.5 Gy)	Radiation-induced tissue injury involving microorganisms may mediated by IL-1β.	IL-1 receptor antagonist	(54)
Direct interaction	Intestinal inflammatory	C57BL/6 J mice	Abdominal irradiation (8 Gy)	Liriodendrin significantly inhibited the activation of Bcl-2/Bax/Caspase-3 and NF-κB signaling pathways and reduced the levels of pro-inflammatory cytokines (IL-6 and TNF-α).	Liriodendrin	(55)
Direct interaction	Intestinal inflammatory	ICR mice	Total body irradiation (4 Gy)	Furazolidone recovered the radiation-induced intestinal damage and decreased inﬂammatory cell inﬁltration.	Furazolidone	(57)
Direct interaction	Host immune system	Unspecified species of mice	The irradiated area was not mentioned (8 Gy)	The lymphocytes were damaged after irradiation, and the certain immunosuppression microenvironment was conducive to the growth of lactobacilli murinus which would induce the synthesis of FGA1.	FGA1	(59)
Indirect interaction	Gut microbiota-brain axis	C57BL/6 J mice	Head (15 Gy)	1. In the radiation-induced brain injury model, the gut microbiota was predominantly composed of Bacteroidales, Muribaculaceae, Erysipelotrichales, and Ruminococcus, and the levels of TNF-α and IL-6 in their blood increased.2. Gut microbiota-derived metabolites, such as SCFAs, participated in the gut microbiota–brain axis.3. The quercetin inclusion complexes gel alleviating radiation-induced brain injury relied heavily on the regulation of gut microbiota.	Quercetin inclusion complexes gel	(70)
Indirect interaction	Gut microbiota–brain axis	C57BL/6 mice	Head (10 Gy)	The gut microbiota-derived SCFAs aggravated radiation-induced brain injury by promoting the release of pro-inflammatory factors in brain tissue.	Gut microbiota	(71)
Indirect interaction	Gut microbiota–brain axis	C57BL/6J mice	Abdominal irradiation (10 Gy)	1. Irradiation elevated the expression level of miR-34a-5p in small intestine tissues and peripheral blood, which mediated distant cognitive impairment.2. Administration of miR-34a-5p antagomir intravenous retained the intestinal bacterial community after irradiation.	miR-34a-5p	(73)
Indirect interaction	Gut microbiota–brain axis	BALB/c mice	Abdominal irradiation (0.5 Gy)	Gut microbiota–plasma LPS and SCFAs-brain axis cause cognitive impairment through the regulation of LPS/Akt/mTOR signaling in the mouse hippocampus.	LPS/Akt/mTOR pathwaySCFAs-brain axis	(74)
Indirect interaction	Gut microbiota–cardiopulmonary axis	C57BL/6J mice	Total chest irradiation (15 Gy)	1. Gut microbiota-derived l-Histidine and its secondary metabolite ImP fought against radiation-induced cardiopulmonary injury in an enteric flora-dependent manner.2. Gut microbiota-derived PGF2α fights against radiation-induced lung toxicity through the FP/MAPK/NF-κB pathway.	l-HistidineImPPGF2α	(75)
Indirect interaction	Gut microbiota–oral axis	Wistar rats	Tongue (37.5 Gy)	1. Mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the intestinal injury caused by tongue irradiation.2. This kind of radiation-induced indirect injury could be alleviated by melatonin gel.	Melatonin gel	(80)
Indirect interaction	Gut microbiota–oral axis	SD rats	Snouts (20 Gy)	1. The gut microbiota promoted radiation-induced OM through the modulation of proinflammatory pathways.2. AIMD alleviated radiation-induced tongue injury.	Antibiotic treatment	(81)
Indirect interaction	Gut microbiota–oral axis	C57BL/6J mice	Abdominal irradiation (12 Gy)	1. Fusobacterium nucleatum translocating to the gut promoted radiotherapy resistance and aggravates radiation enteritis.2. After the oral microbiota transplantation from the non-irradiated mice in the irradiation group, the levels of TNF-α, IL-6, and IL-1 in the colon tissues of the irradiated mice increased.	F. nucleatum	(82)

AIMD, antibiotic-induced gut microbiota depletion; FMT, fecal microbiota transplantation; F/P, Firmicutes/Proteobacteria; F/B, Firmicutes/Bacteroides; GPCR, G-protein-coupled receptor; GRg3, Ginsenoside Rg3; ImP, imidazole propionate; IPA, indole-3-propionic acid; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; OM, oral mucositis; PGF2α, prostaglandin F2α; SCFA, short-chain fatty acid; SD, Sprague Dawley; TSA, Trichostatin A; ZO-1, zonula occludens-1; NA, not available.

Possible mechanisms of “direct interaction” between gut microbiota and radiation injuries

Compared with “indirect interaction,” the damage effect of “direct interaction” occurs in the radiation field. When the abdomen is exposed to radiation, both the intestines and gut microbiota are within the radiation field, and both are damaged by radiation. The disruption of internal environmental homeostasis and tissue damage promotes the interaction between gut microbiota and intestinal tissue. The possible mechanisms of the “direct interaction” between gut microbiota and radiation injuries are shown in Figure 2, which include: (1) changes in the diversity and composition of gut microbiota; (2) changes in gut microbiota-derived metabolites; (3) disruption of intestinal barrier integrity; (4) activation of the intestinal inflammatory response; and (5) involvement of the host immune system.

Figure 2.

Possible mechanisms of “direct interaction” between gut microbiota and radiation injuries.

Radiation-induced disruption of gut microbiota homeostasis

Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, which together make up 99% of the gut microbiota in the human intestine, are the primary members of the intestinal microbiota.²³ Ionizing radiation can easily disrupt the homeostasis of the gut microbiota.^16,23 For example, rats exposed to whole-body irradiation exhibited a significant decrease in gut microbiota abundance and α-diversity.²⁴ Fecal microbiota analysis of patients with chronic radiation enteritis following cervical cancer radiotherapy showed that patients with severe symptoms had lower α-diversity indices than those with mild or no symptoms. Furthermore, the proportion of Firmicutes in the severe group was significantly reduced, while the proportion of Proteobacteria increased.²⁵ Therefore, the composition of gut microbiota, especially the ratio of Firmicutes to Proteobacteria, reflects the severity of radiation toxicity. In animal models of radiation-induced intestinal injury, abdominal irradiation in mice altered the ratio of Firmicutes/Bacteroidetes and increased inflammatory markers such as NF-κB p65, Cox-2, and NLRP-3.²⁶ Dysbiosis was also observed in a rat model of acute radiation proctitis, where both the abundance of Firmicutes and the ratio of Firmicutes/Bacteroidetes decreased after abdominal irradiation, while the abundance of Proteobacteria increased. At the family level, the abundance of Clostridiaceae and Enterobacteriaceae increased, while Lachnospiraceae and Peptostreptococcaceae decreased.²⁷ Similarly, nonhuman primates exposed to radiation also showed a decrease in the Firmicutes/Bacteroidetes ratio.²⁸ In addition, a study showed that there was a time window for gut microbiota dysbiosis after radiation, with significant changes in microbiota composition and diversity observed from the acute injury phase to the recovery phase. Radiation-induced acute intestinal injury not only resulted in a decrease in the abundance of probiotics but also an increase in harmful bacteria. Interestingly, the abundance of certain gut microbiota taxa, such as Proteobacteria, Escherichia-Shigella genera, Eubacterium xylanophilum_group, and Lactobacillus murinus species, exhibited linear correlations with the radiation dose.²⁹

The oral cavity provides a suitable environment for bacteria. Radiation-induced oral mucositis is the most common complication in head and neck radiotherapy. Therefore, oral microbiota plays an important role in radiation-induced oral mucositis. Xiao et al.³⁰ confirmed the direct interaction between radiation-induced oral mucositis and oral microbiota in patients undergoing head and neck radiotherapy and in animal models. Their study found that both α and β-diversity decreased significantly after radiotherapy compared to pre-radiotherapy levels. Inflammatory factors such as IL-1, IL-6, and TNF-alpha in the tongue tissue of irradiated mice were significantly increased. However, these inflammatory markers decreased, bacterial species gradually increased, and radiation-induced alopecia and mucositis were significantly alleviated after transplantation of oral microbiota from healthy, unirradiated mice.

Gut microbiota-derived metabolites in mitigating radiation-induced intestinal injury

Short-chain fatty acids (SCFAs), the main metabolites of intestinal flora, play a role not only in colitis but also in regulating radiation-induced intestinal injury. Gut microbiota-derived SCFAs had been shown to alleviate intestinal inflammation in animal models of colitis.^31,32

Increasing the concentration of SCFAs in gut by regulating the composition of intestinal flora led to the significant reduction in submucosal thickness and collagen deposition. Thus, the degree of intestinal fibrosis in advanced radiation enteropathy was alleviated.³³ Additionally, butyrate played an important role in radiation injuries. The abundance of butyrate-producing intestinal microbiota decreased after exposure to radiation, which exacerbates radiation injuries.³⁴ Intestinal damage induced by abdominal irradiation could be alleviated through the supplementation of gut microbiota-derived butyrate.³⁵ Abdominal irradiation reduced gut microbiota-derived indole-3-propionic acid (IPA) and increased the relative abundance of Bacteroides and Rhodanobacter_thiooxydans. Supplementation with exogenous IPA not only restored the abundance of these microbiota, remodeling the intestinal microbiota, but also protected against radiation injuries by reversing the radiation-induced reduction of CoA-binding protein (ACBP) in the small intestine.³⁶

Some researchers observed that gut microbiota-derived Urolithin A (UroA) decreased when rats were exposed to whole-body irradiation.²⁴ In the radiation group, Escherichia shigella, Alphaproteobacteria, and Erysipelotrichaceae showed significantly increased abundances at the phylum, class, and family levels, respectively. Conversely, these levels were significantly reduced in the UroA-treated group. Additionally, intestinal histopathology showed that the number of P53+ cells significantly increased in the irradiation group compared to the control group, while it significantly decreased, as did apoptosis of intestinal epithelial cells, when UroA was administered. Therefore, UroA may reduce radiation injuries by inhibiting p53-mediated apoptosis of irradiated intestinal epithelial cells through remodeling the intestinal flora. Similarly, Erysipelatoclostridium and its metabolite Ptilosteroid A were related to radiation-induced intestinal injury in patients who received pelvic and abdominal radiation. The abundance of Erysipelatoclostridium was positively correlated with Ptilosteroid A.³⁷

Radiation-induced intestinal barrier damage and bacterial translocation

Intestinal barrier damage has been widely confirmed in inflammatory bowel disease. For example, the expression of Zonula Occludens-1 (ZO-1), Occludin, and Claudin-1 proteins was significantly reduced in disease models.^38
–40 The destruction of the tight junction structure is an important manifestation of radiation damage to intestinal epithelial cells.⁴¹ After abdominal irradiation, the levels of tight junction proteins such as Claudin-1, Occludin, and ZO-1 in the intestinal tissue of mice were decreased, indicating damage to the intestinal integrity.⁴² Similarly, Zhu et al.⁴³ observed intestinal barrier damage in C57 Bl/6 mice exposed to whole-body radiation. The role of reactive oxygen species (ROS) in disrupting the intestinal barrier caused by radiation would be beneficial. Ionizing radiation produces ROS, resulting in oxidative stress that can harm cellular components, including tight junction proteins like Occludin and ZO-1, thus increasing intestinal permeability.⁴⁴

As early as the late 20th century, a case of liver abscess and sepsis infected by Bacteroides fragilis was reported. The patient had received radiation therapy for cervical cancer and had severe radiation enteritis confirmed by colonoscopy. So, the author proposed that radiation enteritis should be included as one of the causes of sepsis.⁴⁵ B. fragilis is a kind of anaerobic symbiotic bacteria, and the necessary condition for its leak into the blood or translocation is to cross the intestinal barrier. Additionally, radiation-induced acute intestinal syndrome is a predisposing factor that can lead to sepsis via the translocation of Escherichia–faecalis.⁴⁶ Some researchers had also reported that gut microbiota can translocate to the mesenteric lymph nodes, spleen, and liver after total body irradiation in C57 Bl/6 mice.⁴⁷ Particularly, this creates an opportunity for Escherichia–Shigella to translocate across the intestinal barrier and into the bloodstream, causing enterogenous infection.⁴⁸ Therefore, radiation-induced intestinal barrier disruption facilitates the translocation of pathogenic bacteria, potentially causing systemic infections and altering host-microbiota equilibrium.

Radiation-induced proliferation of pathogenic bacteria, alongside the decline of beneficial bacteria, may be explained by several factors. Firstly, enterogenic pathogenic bacteria such as B. fragilis and Escherichia coli are more likely to survive in anaerobic or hypoxic intestinal environments. In contrast, beneficial bacteria, including Lactobacillus and Bifidobacterium, are more sensitive to environmental stressors and are more likely to be decreased due to radiation-induced oxidative damage. Furthermore, radiation changes the structure and function of intestinal epithelial cells and changes the intestinal microenvironment, such as pH and metabolites. Additionally, the immune system’s suppression reduces the competitive advantage of beneficial bacteria, allowing pathogenic bacteria to proliferate and translocate across the intestinal barrier.

Activation of the intestinal inflammatory response following radiation exposure

Gut microbiota and gut microbiota-derived metabolites maintained a balance of pro-inflammatory and inhibitory inflammatory responses in the host.^49,50 Supplementation with Prausnitzii Faecalibacterium⁵¹ could reduce the inflammatory response caused by radiation. The damage of intestine and its flora after abdominal irradiation was associated with inflammation,⁵² reflecting as the increase of INF-α, IL-6, IL-1β.^53,54 The mechanism of this phenomenon might be explained by the activating of Bcl-2/Bax/Caspase-3, TLR4/MyD88/NF-κB, or other NF-κB inflammatory signaling pathways.^27,55

After targeting the intestinal flora of mice with acute colitis, changes in the composition of intestinal flora were detected, and the abundance of Akkermansia decreased while the abundance of Parasutterella, Erysipelatclostridium, and Alistipes increased. Then, the symptoms of colitis were relieved, and the serum levels of IL-6, TNF-α, and IL-1β were significantly decreased. These recovery signs of inflammation were no longer observed when antibiotics were used to clear the intestinal flora before the experiment.⁵⁶ We got a new insight from this research which showed that the presence of intestinal flora was a prerequisite for regulating inflammation response caused by radiation damage. Interestingly, an another team discovered an inconsistent phenomenon. According to a study conducted by Ma et al.,⁵⁷ gut microbiota acted as a key driver in the process of intestinal inflammation induced by radiation, which showed that the intestinal injury induced by radiation was significantly reduced when mice were treated with antibacterial furazolidone before receiving whole body irradiation. The differential inflammatory effects observed between above the two studies may arise from fundamental distinctions between drug-induced and radiation-induced intestinal inflammatory mechanisms, combined with variations in antibiotic types, administration routes, and days of intervention.

In conclusion, the regulation of intestinal microecology on inflammatory response induced by radiation may be bidirectional, and the composition of gut microbiota may be the key factor in the direction of pro-inflammatory and anti-inflammatory regulation. Elucidating gut microbiota-mediated inflammatory mechanisms dramatically promotes clinical advancements. First, identification of NF-κB signaling targets and probiotic supplementation provides accessible strategies for mitigating radiation-induced enteritis. Second, understanding antibiotic-induced gut microbiota depletion effects informs precision antibiotic stewardship during radiotherapy. These insights facilitate the development of gut microbiota-targeted therapies to alleviate inflammatory effect in radiotherapy.

Involvement of the host immune system in radiation-induced injury

Gut microbiota and SCFAs derived from gut microbiota played a crucial role in regulating the host’s immune response.^49,58 The lymphocytes were damaged after irradiation in mice, leading to the weight loss of the thymus and spleen immune organs. And the certain immunosuppression microenvironment in vivo was conducive to the growth of lactobacilli murinus which would induce the synthesis of FGA1. Subsequent animal studies employing three immunodeficient models (nude, scid, and pIgR(−/−) mice) revealed that radiation exposure induced upregulation of small intestinal FGA1 expression in immunodeficient mice. However, this effect exhibited marked attenuation, demonstrating a 50% reduction in FGA1 elevation levels in irradiated immunodeficient mice relative to irradiated wild-type controls. Notably, wild-type mice subjected to both radiation and intestinal flora depletion via penicillin-streptomycin treatment demonstrated markedly reduced FGA1 expression levels in the small intestine compared to radiation-treated wild-type mice with intact microbiota.⁵⁹ This study suggested that gut microbiota was a key mediator in the regulation of host immune status when radiation-induced injury occurred.

As is well known, the gastrointestinal tract contains Gut-Associated Lymphoid Tissue (GALT), which includes lymphocytes scattered in the lamina propria of the intestinal mucosa, as well as organized lymphoid aggregates or follicles in the mucosa or submucosa. Peyer’s patches and lymphoid follicles in the small intestine as well as Isolated Lymphoid Follicles (ILFs) in the colon are also GALT.⁶⁰ GALT produced specific antibodies to resist the invasion of intestinal pathogens,⁶¹ and it was a part of the gastrointestinal immune system and mucosal repair system.⁶² Under moderate inflammatory conditions, the number, diameter, and density of ILFs increased.⁶³ Hence, radiation therapy may weaken intestinal mucosal immunity by disturbing local lymphoid tissues, thereby influencing systemic immune responses.

Possible mechanisms of indirect interaction between gut microbiota and radiation-induced injury

We introduce the concept of “indirect interaction” to explain how radiation impacts the host, particularly when the head or chest is exposed to radiation. Despite gut microbiota being distant from the radiation field, irradiation also disrupts gut microbiota homeostasis, which in turn affects the radiation injuries of organs within the radiation field. Therefore, gut microbiota functions as a mediator in regulating radiation injuries. The mechanisms underlying the “indirect interaction” between gut microbiota and radiation injuries are complex and multifaceted, including: (1) the gut microbiota–brain axis; (2) the gut microbiota–cardiopulmonary axis; and (3) the gut microbiota–oral axis.

The dysregulation of the gut-brain axis driven by microbial metabolites in radiation-induced brain injury

Several studies have demonstrated that gut microbiota plays a role in regulating brain function,^64
–67 with the gut microbiota–brain axis also contributing to cancer pathology.^68,69 It has been reported that radiation can activate the gut microbiota–brain axis universally, whether the brain, abdomen, or whole body is irradiated, to mitigate brain injury. Research by Hu et al.⁷⁰ indicated that in a radiation-induced brain injury model, the gut microbiota was predominantly composed of Bacteroidales, Muribaculaceae, Erysipelotrichales, and Ruminococcus, which differed significantly from the microbiota in the healthy control group. The mice in the model group had significantly elevated levels of TNF-α and IL-6 in their blood and decreased white blood cells. Additionally, gut microbiota-derived metabolites, such as SCFAs, participated in the gut microbiota–brain axis. Luo et al.⁷¹ demonstrated in a whole-brain irradiation mouse model that gut microbiota depletion via oral antibiotics attenuated radiation-induced brain injury. Their study revealed that whole-brain irradiation significantly elevated IL-6 and TNF-α levels in brain tissue, while pre-irradiation elimination of gut microbiota reduced neuroinflammation by suppressing the pro-inflammatory effects of SCFAs derived from gut microbial metabolism on brain.

Furthermore, supplementation with probiotics significantly reduced the damage to brain neurons.⁷² The mechanisms underlying cognitive impairment induced by such an “indirect interaction” between gut microbiota and radiation injuries involved the overexpression of miR-34a-5p⁷³ and the activation of the Akt/mTOR signaling pathway due to increased microbial-derived lipopolysaccharide (LPS) levels.⁷⁴

In conclusion, in the gut-brain axis regulation system, gut microbiota-derived metabolites (e.g., LPS and SCFAs) may exacerbate radiation-induced brain injury by activating the immune system, which subsequently triggers neuroinflammation through elevated pro-inflammatory cytokines (such as IL-6 and TNF-α). These cytokines penetrate blood–brain barrier, ultimately leading to neuronal damage. Therapeutic interventions targeting gut microbiota-derived metabolites combined with selective inhibition of neuroinflammatory signaling pathways may alleviate radiation-induced brain damage by simultaneously addressing gut dysbiosis, systemic inflammation, and blood–brain barrier disruption.

Gut microbiota–cardiopulmonary axis in radiation injury: Mechanistic insights

Radiation-induced cardiopulmonary damage resulting from chest irradiation is inevitable. Currently, there is no effective treatment to prevent or cure it. Notably, gut microbiota has been found to play an unexpected role in alleviating radiation-induced cardiopulmonary damage. In C57BL/6J mice receiving 15Gy chest irradiation, radiation-induced cardiopulmonary injury modulated in a gut microbiota-dependent manner. Supplementation with gut microbiota-derived l-Histidine restored gut microbiota α-diversity and alleviated structural damage to cardiopulmonary tissues following irradiation.⁷⁵ This team also found that chest irradiation altered the gut microbiota composition in mice, further supporting the protective role of gut microbiota in alleviating lung injury, as demonstrated by FMT in unirradiated mice. The underlying mechanism involved gut microbiota-derived prostaglandin F2α (PGF2α), penetrating the intestinal barrier, entering systemic circulation, and activating the FP/MAPK/NF-κB signaling axis.⁷⁶ Furthermore, after thoracic irradiation, the abundance of Firmicutes decreased, while Bacteroidetes increased.⁷⁷ Nie et al.⁷⁸ treated mice with antibiotics 2 weeks prior to chest irradiation to induce dysbiosis. Histopathological analysis of lung tissue revealed exacerbated radiation-induced lung injury. Furthermore, gut microbiota alleviated acute LPS-induced lung damage through the TLR4/NF-κB signaling pathway.⁷⁹

Although these studies have outlined the framework for the gut microbiota–cardiopulmonary axis in animal models, its relevance to humans still requires further investigation.

Bidirectional regulation of organ injury outside radiation field via gut microbiota–oral axis

In 2017, radiation-induced enterotoxicity (including changes to intestinal structure and function) in rats was first observed following tongue irradiation.⁸⁰ This kind of indirect damage far from the irradiation field has gradually attracted the attention of researchers. Similarly, Al-Qadami et al.⁸¹ found that gut microbiota played a pro-inflammatory role in snout irradiation of mice, exacerbating radiation-induced oral mucositis. When depleted the gut microbiota of radiation mice by antibiotics taking, tongue ulcer area of radiation mice was smaller, and the levels of IL-6, IL-1β, and TLR-4 were significantly lower compared to the radiation mice with normal gut microbiota. A recent study utilizing a mouse model with induced spontaneous colon cancer, followed by 12 Gy abdominal irradiation, demonstrated that the oral pathogen Fusobacterium nucleatum translocated to the intestine through the digestive tract to produce pro-inflammatory effects at intestine.⁸²

Although some researchers have noted that there seems to be a certain regulatory relationship between oral or intestinal microorganisms and the injury of target organs outside the radiation field, which may be linked by inflammatory factors, the exact regulatory mechanism of gut microbiota–oral axis is still unknown. Further clinical and basic research is required to address this issue.

Factors influencing the recovery of gut microbiota post-radiation

Previous studies have shown that dietary interventions (such as low-fat diets, avoiding dairy products, or low-residue diets) significantly alleviate clinical symptoms of radiation-induced enteritis in patients undergoing abdominal radiotherapy.⁸³ Compared to rats fed a normal diet, high-fat diet consumption induced significant alterations in gut microbiota composition, characterized by a marked elevation in Proteobacteria abundance accompanied by substantially increased circulating LPS levels.⁸⁴ High-fat diet administration induced diarrheal symptoms through TRAF6/IκB/p65 signaling pathway activation, which compromised intestinal mucosal barrier integrity.⁸⁵ In addition, high-fiber dietary intervention increased the abundance of Firmicutes phylum within the gut microbiota, concomitant with augmented biosynthesis of SCFAs as microbial metabolites.⁸⁶ Therefore, distinct dietary patterns may modulate radiation-induced intestinal injury by altering the metabolites of the gut microbiota and activating host inflammatory response pathway.

Low-intensity physical exercise has been shown to mitigate radiation-induced gut toxicity by reshaping the gut microbiota, including an increase in Akkermansia muciniphila, in abdominally irradiated mice.⁸⁷ Similarly to radiation injuries, changes in the intestinal flora following irradiation were dose-dependent.⁴³

A study focusing on rectal cancer patients of different racial backgrounds, including Island Hispanic Puerto Ricans and mainland non-Hispanic whites, found that although the gut microbiota α-diversity was similar before chemoradiotherapy, post-treatment differences were observed between the two groups.⁸⁸ Therefore, the dysbiosis of gut microbiota caused by abdominal and pelvic irradiation may be population-specific.

Sexual dimorphism in gut microbiota composition had been observed in mice after radiation exposure,⁸⁹ contributing to variations in radiation tolerance between genders and differences in host gene expression profiles.⁹⁰ Similarly, the effectiveness of restoring intestinal microbiota to reduce radiation-induced intestinal damage differs between male and female mice.⁹¹ In a recent study, female mice showed an increase in Lachnospiraceae, whereas male mice exhibited a decrease following a single 12 Gy abdominal irradiation. Furthermore, intravenous immunoglobulin alleviated radiation-induced damage through the Frichomyces/hypoxanthine/PLD1 axis in a sex-dependent and microbiota-dependent manner, alleviating hematopoietic and gastrointestinal toxicity in female mice but having no protective effect in male mice.⁹² Duan et al.⁹³ demonstrated that sexual dimorphism in gut microbiota composition resulted from testosterone-mediated regulation of the bile acid signaling pathway.

Briefly, multiple factors such as diet, exercise, race, and gender are involved in the interaction between the gut microbiota and radiation-induced injury. The mechanisms were complicated, which may involve metabolites of gut microbiota, inflammatory mediators, hormones, and the immune environment. Therefore, the development of therapeutic strategies aimed at reshaping gut microbiota to alleviate radiation-induced toxicity should incorporate multifactorial considerations.

Therapeutic interventions targeting gut microbiota to mitigate radiation-induced injury

High treatment-induced toxicity and injury can be alleviated by targeting gut microbiota, which acts as a mediator.^92,94,95 Furthermore, radiation injuries are regulated by gut microbiota and gut microbiota-derived metabolites.^96,97 Interventions that reshape the gut microbiota, including probiotics, prebiotics, and FMT, are expected to be effective in reducing radiation injuries.

Probiotics and prebiotics

A study showed that a combination of probiotics, such as Bifidobacterium, Lactobacillus acidophilus, and Saccharomyces boulardii, could prevent and alleviate chemoradiotherapy-induced mucositis.⁹⁸ In a randomized, double-blind, placebo-controlled clinical trial, continuous supplementation with mixed probiotics (including L. acidophilus LA-5 and Bifidobacterium animalis subsp. lactis BB-12) during radiotherapy in 54 cervical cancer patients receiving pelvic irradiation significantly reduced the incidence of diarrhea, from 82.1% in the control group to 53.8% in the treatment group.⁹⁹ Additionally, a high-quality meta-analysis of 23 randomized, placebo-controlled studies confirmed these findings, demonstrating that probiotic supplementation in patients undergoing abdominal or pelvic chemoradiotherapy effectively prevents chemoradiotherapy-induced diarrhea, with a particular reduction in the incidence of severe diarrhea.¹⁰⁰ The mechanism by which prebiotics and probiotics alleviate radiation injuries is believed to involve the restoration of intestinal microecology and the maintenance of intestinal barrier function.¹⁰¹

However, a phase II randomized controlled trial found that supplementation with prebiotics did not reduce the incidence of acute radiation enteritis in patients undergoing pelvic radiotherapy.¹⁰² The contrasting results across studies may be attributed to the heterogeneity of study designs, including the continuous impact of chemotherapy, which may severely affect probiotic growth. In this phase II clinical trial, the included sample size was small (n = 50), and concurrent chemotherapy during radiotherapy might exacerbate gut microbiota dysbiosis, leading to resistant starch supplementation failing to reduce radiation-induced diarrhea incidence.

Fecal microbiota transplantation

In 2023, the first reported case of FMT for the treatment of radiation-induced diarrhea involved a 59-year-old woman with cervical cancer who suffered from severe radiation enteritis. This patient received FMT from her 18-year-old son, successfully alleviating her diarrhea symptoms.¹⁰³ Recently, a large retrospective study of 15,000 intestinal dysfunction patients demonstrated the safety and efficacy of three main methods of FMT. Most patients (74.2%) received jejunal Enterobacter administration via nasoenteric tube, 24.4% oral capsules, and a minority via colonoscopy. The results showed that nasoenteric administration demonstrated the highest clinical improvement rates. Especially, subgroup analysis showed 77.3% symptom improvement in radiation enteritis at 3 months post-FMT.¹⁰⁴

Fundamental research on gut microbiota and radiation-induced intestinal injury has laid a theoretical foundation for the clinical application of FMT. When feces from healthy C57BL/6J mice were transplanted into mice irradiated with 9 Gy on the abdomen, radiation-induced intestinal damage was reduced, and the beneficial bacteria Lactobacillaceae and Lachnospiraceae were restored. Additionally, tryptophan pathway metabolites were involved in the repair of radiation injuries.¹⁰⁵ A preclinical study showed that supplementation with Faecalibacterium prausnitzii A2-165 strain in mice before and after abdominal irradiation reduced colon epithelial permeability, infiltration of inflammatory cells, and damage to crypt and stem cells. Therefore, F. prausnitzii played a protective role in maintaining the intestinal barrier and reducing intestinal epithelial damage after irradiation.⁵¹ When gut microbiota from a rectal irradiation model was transplanted into germ-free mice, the germ-free mice were more susceptible to radiation-induced intestinal injury, proving that the gut microbiota after radiation contains harmful bacteria which promoted radiation damage.⁵⁴

FMT offers potential strategies for combating radiation injuries through gut microbiota remodeling. Given the complexity of gut microbiota and safety considerations of FMT, the aspects of donor selection, extraction and processing of intestinal bacteria, quality control, and donor administration methods are still under exploration. Therefore, the clinical application of FMT is limited. Current consensus guidelines emphasize that rigorous donor screening constitutes the foundational requirement for FMT safety protocols. Established criteria mandate that donors be comprehensively healthy individuals undergoing standardized blood and stool testing to avoid infectious diseases. Nevertheless, standardization process differs in microbiota preparation protocols, particularly regarding quality assessment, necessitating continuous improvements toward establishing international consensus standards.^106
–109 Recent studies suggested that fecal bacteria-free filtrate transplantation may be a safer alternative to intensify radiation tolerance by remodeling gut microbiota.¹¹⁰

Therefore, identifying certain beneficial strains that alleviate radiation injuries is imperative and has a long way to go. FMT via nasoenteric tube may be a safe and efficient way of gut microbiota delivery, but it still requires further exploration through prospective clinical studies.

Other ways

Diet is a key factor influencing gut microbiota (gut microbiota) composition, which in turn affects radiation tolerance. A study found that a 30% caloric restriction diet enhanced intestinal radiation tolerance in irradiated mice by reducing pro-inflammatory microbes in females and increasing SCFA-producing bacteria in males.¹¹¹

Conclusion

In summary, the gut microbiota participates in regulating radiation injuries through direct or indirect interactions. The molecular mechanism is rather complex, involving gut microbiota-derived metabolites, intestinal biological and physical barriers, inflammatory factors, host immunity, and the gut microbiota–target organ axis, etc. The composition of gut microbiota exhibits sexual dimorphism and is influenced by multiple factors including dietary patterns, therapeutic interventions, and environmental conditions. Current studies demonstrate inconsistencies of beneficial and pathogenic gut microbiota in radiation-induced injuries. Furthermore, clinical studies targeted gut microbiota therapies for radiation-associated intestinal syndromes (e.g., diarrhea) also have yielded conflicting outcomes.

Key limitations in current research on gut microbiota and radiation injury include: (1) inadequate sample sizes, (2) significant heterogeneity in study designs (particularly regarding patient inclusion criteria, radiation dosage, type of drugs, and intervention timing/methods), and (3) demographic variables. So, it is urgent to design prospective, large-scale randomized controlled trials to systematically identify microbiota signatures associated with radiation-induced injury. Moreover, researchers should prioritize establishing standardized preparation protocols, quality control measures, and administration methods for FMT, thereby advancing precision-targeted microbiota-based therapeutic strategies.

Footnotes

Acknowledgements

Thanks to Laraib Nadeem who edited the language and improved the readability of the paper.

Declarations

ORCID iDs

Qiaoli Wang

Guoqiang Xu

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Radiation-induced injury and the gut microbiota: insights from a microbial perspective

Abstract

Plain language summary

Keywords

Introduction

The interaction and molecular mechanisms between gut microbiota and radiation injuries

Possible mechanisms of “direct interaction” between gut microbiota and radiation injuries

Radiation-induced disruption of gut microbiota homeostasis

Gut microbiota-derived metabolites in mitigating radiation-induced intestinal injury

Radiation-induced intestinal barrier damage and bacterial translocation

Activation of the intestinal inflammatory response following radiation exposure

Involvement of the host immune system in radiation-induced injury

Possible mechanisms of indirect interaction between gut microbiota and radiation-induced injury

The dysregulation of the gut-brain axis driven by microbial metabolites in radiation-induced brain injury

Gut microbiota–cardiopulmonary axis in radiation injury: Mechanistic insights

Bidirectional regulation of organ injury outside radiation field via gut microbiota–oral axis

Factors influencing the recovery of gut microbiota post-radiation

Therapeutic interventions targeting gut microbiota to mitigate radiation-induced injury

Probiotics and prebiotics

Fecal microbiota transplantation

Other ways

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References