Radiation-induced Enteropathy Research Articles

Prevention of Radiotherapy-Induced Enteropathy by Probiotics (PREP): Double-Blind Randomized Placebo-Controlled Trial.

Probiotics are thought to be effective in the treatment of radiation-induced enteropathy (RIE). However, little is known regarding their efficacy in preventing RIE. In this prospective, randomized, double-blinded, placebo-controlled, single-center study, the incidence of grade 2 acute RIE was compared and the safety of probiotics was evaluated. Patients receiving pelvic radiotherapy for a minimum of 40 Gy at the pelvic level were randomized into two groups: (i) a probiotic group receiving Bacillus licheniformis from two weeks before radiotherapy until the end and (ii) a control group receiving a placebo with the same schedule. The toxicities of 234 patients were graded according to the Common Terminology Criteria for Adverse Events v5.0. Grade 1 RIE was observed in 65 (56%) of the probiotics group compared with 75 (64%) of the placebo group. Grade 2 RIE occurred in 30 patients (26%) in the probiotics group compared with 26 (22%) in the placebo group, indicating that probiotics failed in their preventive role compared with placebo (p = 0.493). Medication adherence rates were good, and no difference was observed between the two arms. These findings suggest that B. licheniformis does not significantly prevent RIE.

Gastroprotective and microbiome-modulating effects of ubiquinol in rats with radiation-induced enteropathy

Radiation enteritis is a frequently encountered issue for patients receiving radiotherapy and has a significant impact on cancer patients' quality of life. The gut microbiota plays a pivotal role in intestinal function, yet the impact of irradiation on gut microorganisms is not fully understood. This study explores the gastroprotective effect and gut microbiome-modulating potential of ubiquinol (Ubq), the reduced form of the powerful antioxidant CoQ-10. For this purpose, male albino rats were randomly assigned to four groups: Control, IRR (acute 7 Gy γ-radiation), Ubq_Post (Ubq for 7 days post-irradiation), and Ubq_Pre/Post (Ubq for 7 days pre and 7 days post-irradiation). The fecal microbiomes of all groups were profiled by 16S rRNA amplicon sequencing followed by bioinformatics and statistical analysis. Histopathological examination of intestinal tissue indicated severe damage in the irradiated group, which was mitigated by ubiquinol with enhanced regeneration, goblet cells, and intestinal alkaline phosphatase expression. Compared to the irradiated group, the Ubq-treated groups had a significant recovery of intestinal interleukin-1β, caspase-3, nitric oxide metabolites, and thio-barbituric reactive substances to near-healthy levels. Ubq_Pre/Post group displayed elevated peroxisome proliferator-activated receptor (PPAR-γ) level, suggesting heightened benefits. Serum insulin reduction in irradiated rats improved post-Ubq treatment, with a possible anti-inflammatory effect on the pancreatic tissue. Fecal microbiota profiling revealed a dysbiosis state with a reduction of bacterial diversity post-irradiation, which was re-modulated in the Ubq treated groups to profiles that are indistinguishable from the control group. These findings underscore Ubq's gastroprotective effects against radiation-induced enteritis and its potential in restoring the gut microbiota’s diversity and balance.

Microbiota-derived I3A protects the intestine against radiation injury by activating AhR/IL-10/Wnt signaling and enhancing the abundance of probiotics

ABSTRACT The intestine is prone to radiation damage in patients undergoing radiotherapy for pelvic tumors. However, there are currently no effective drugs available for the prevention or treatment of radiation-induced enteropathy (RIE). In this study, we aimed at investigating the impact of indole-3-carboxaldehyde (I3A) derived from the intestinal microbiota on RIE. Intestinal organoids were isolated and cultivated for screening radioprotective tryptophan metabolites. A RIE model was established using 13 Gy whole-abdominal irradiation in male C57BL/6J mice. After oral administration of I3A, its radioprotective ability was assessed through the observation of survival rates, clinical scores, and pathological analysis. Intestinal stem cell survival and changes in the intestinal barrier were observed through immunofluorescence and immunohistochemistry. Subsequently, the radioprotective mechanisms of I3A was investigated through 16S rRNA and transcriptome sequencing, respectively. Finally, human colon cancer cells and organoids were cultured to assess the influence of I3A on tumor radiotherapy. I3A exhibited the most potent radioprotective effect on intestinal organoids. Oral administration of I3A treatment significantly increased the survival rate in irradiated mice, improved clinical and histological scores, mitigated mucosal damage, enhanced the proliferation and differentiation of Lgr5+ intestinal stem cells, and maintained intestinal barrier integrity. Furthermore, I3A enhanced the abundance of probiotics, and activated the AhR/IL-10/Wnt signaling pathway to promote intestinal epithelial proliferation. As a crucial tryptophan metabolite, I3A promotes intestinal epithelial cell proliferation through the AhR/IL-10/Wnt signaling pathway and upregulates the abundance of probiotics to treat RIE. Microbiota-derived I3A demonstrates potential clinical application value for the treatment of RIE.

A Review of the Efficacy of the Low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols (FODMAP) Diet in Managing Gastrointestinal Symptoms Related to Cancer Treatment.

The low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet, designed to alleviate symptoms in individuals with irritable bowel syndrome (IBS), focuses on limiting the consumption of poorly absorbed fermentable carbohydrates known as FODMAP. These FODMAP are believed to be the primary triggers for food-related gastrointestinal symptoms in functional gastrointestinal disorders. However, there is currently insufficient direct evidence investigating the role of low FODMAP diets in cancer patients undergoing treatment. This review aims to summarize the current evidence on the low FODMAP diet and its potential implications for cancer patients in terms of treatment outcomes, alleviating gastrointestinal symptoms, and overall health. A systematic literature search was conducted using databases, including PubMed, Scopus, Google Scholar, Web of Science, and Cochrane. Five studies met the criteria for inclusion in the review, and these studies covered rectal toxicity during radiotherapy, gastrointestinal symptoms in colorectal cancer patients, acute gastrointestinal toxicity during pelvic external beam radiotherapy, symptoms in patients with radiation-induced enteropathy, and chronic gastrointestinal sequelae resulting from pelvic organ cancer treatment. The available evidence suggests that a low FODMAP diet may offer advantages in reducing rectal gas and volume during radiotherapy, alleviating diarrhea symptoms, reducing symptom deterioration, and improving quality of life. However, these studies highlight the need for large-scale randomized trials, long-term follow-up, and guidelines to establish the efficacy, safety, and implementation strategies of the low FODMAP diet in different cancer contexts and patient populations. While preliminary findings reported some possible benefits of a low FODMAP diet for certain cancer patients, rigorous studies with large sample sizes are needed to provide more robust evidence. Further research is warranted to optimize the utilization of this diet as an adjunctive intervention for managing gastrointestinal symptoms in this population.

Combined Administration of Pravastatin and Metformin Attenuates Acute Radiation-Induced Intestinal Injury in Mouse and Minipig Models

Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury.

Metformin Protects the Intestinal Barrier by Activating Goblet Cell Maturation and Epithelial Proliferation in Radiation-Induced Enteropathy.

Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/β-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/β-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.

Autophagy Induced by Micheliolide Alleviates Acute Irradiation-Induced Intestinal Injury via Inhibition of the NLRP3 Inflammasome.

Radiation-induced enteropathy (RIE) is one of the most common and fatal complications of abdominal radiotherapy, with no effective interventions available. Pyroptosis, a form of proinflammatory regulated cell death, was recently found to play a vital role in radiation-induced inflammation and may represent a novel therapeutic target for RIE. To investigate this, we found that micheliolide (MCL) exerted anti-radiation effects in vitro. Therefore, we investigated both the therapeutic effects of MCL in RIE and the possible mechanisms by which it may be therapeutic. We developed a mouse model of RIE by exposing C57BL/6J mice to abdominal irradiation. MCL treatment significantly ameliorated radiation-induced intestinal tissue damage, inflammatory cell infiltration, and proinflammatory cytokine release. In agreement with these observations, the beneficial effects of MCL treatment in RIE were abolished in Becn1 +/− mice. Furthermore, super-resolution microscopy revealed a close association between NLR pyrin domain three and lysosome-associated membrane protein/light chain 3-positive vesicles following MCL treatment, suggesting that MCL facilitates phagocytosis of the NLR pyrin domain three inflammasome. In summary, MCL-mediated induction of autophagy can ameliorate RIE by NLR pyrin domain three inflammasome degradation and identify MCL as a novel therapy for RIE.

Metallothionein 2 activation by pravastatin reinforces epithelial integrity and ameliorates radiation-induced enteropathy.

BackgroundRadiotherapy or accidental exposure to ionizing radiation causes severe damage of healthy intestinal tissues. Intestinal barrier function is highly sensitive to ionizing radiation, and loss of epithelial integrity results in mucosal inflammation, bacterial translocation, and endotoxemia. Few studies have of epithelial integrity as a therapeutic target to treat radiation toxicity. Here, we examined the effects of pravastatin (PS) and the molecular mechanisms underlying epithelial integrity on radiation-induced enteropathy.MethodsThe radio-mitigative effects of PS were evaluated in a minipig model by quantifying clinical symptoms, and performing histological and serological analyses and mRNA sequencing in intestinal tissues. To evaluate the role of intercellular junctions on radiation damage, we used tight junction regulator and metallothionein 2 (MT2) as treatments in a mouse model of radiation-induced enteropathy. Caco-2 monolayers were used to examine functional epithelial integrityand intercellular junction expression.FindingUsing a minipig model of pharmaceutical oral bioavailability, we found that PS mitigated acute radiation-induced enteropathy. PS-treated irradiated minipigs had mild clinical symptoms, lower intestinal inflammation and endotoxin levels, and improved gastrointestinal integrity, compared with control group animals. The results of mRNA sequencing analysis indicated that PS treatment markedly influenced intercellular junctions by inhibiting p38 MAPK signaling in the irradiated intestinal epithelium. The PS-regulated gene MT2 improved the epithelial barrier via enhancement of intercellular junctions in radiation-induced enteropathy.InterpretationPS regulated epithelial integrity by modulating MT2 in radiation-damaged epithelial cells. These findings suggested that maintenance of epithelial integrity is a novel therapeutic target for treatment of radiation-induced gastrointestinal damage.FundingAs stated in the Acknowledgments

Prevention of radiotherapy induced enteropathy by probiotics (PREP): protocol for a double-blind randomized placebo-controlled trial

BackgroundRadiation induced enteropathy is a common complication of radiotherapy for pelvic tumors and adversely affects patient quality of life. Probiotics are thought to restore bowel microflora to optimal levels and reinforce intestinal barrier capacity. Although probiotics are effective in the treatment of radiation induced enteropathy, less is known about their efficacy to prevent radiation induced enteropathy.MethodsThis double-blind randomized placebo-controlled study will investigate the efficacy of probiotics to prevent radiation-induced enteropathy in patients with gynecologic or urologic cancer who received pelvic radiotherapy. The study is designed to enroll 248 eligible patients, who will be randomized 1:1 to a probiotic or placebo group. Toxicities will be evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v5.0.DiscussionThe primary aim of this study is to provide high level evidence for the ability of probiotics to prevent acute radiation induced enteropathy. The secondary aims are to determine the effects of probiotics on the incidence of chronic radiation induced enteropathy and the safety of probiotics in patients with gynecologic or urologic cancer.Trial registrationClinicalTrials.gov (NCT03978949, Registered on 7 June 2019).

Synthesis, characterization and evaluation of resveratrol-loaded functionalized carbon nanotubes as a novel delivery system in radiation enteropathy

Radiation-induced enteropathy is a major clinical challenge during radiotherapy. Resveratrol displays beneficial pharmacological activities; however, low oral bioavailability limits its effectiveness. This study aims at preparing methacrylic acid (MAAc) functionalized multi-walled carbon nanotubes (MWCNTs-MAAc) as carriers for pH triggered controlled release of resveratrol in an effort to improve the drug therapeutic potential. MWCNTs-MAAc were prepared using radiation technique and then characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), scanning electron microscope (SEM), X-ray diffraction (XRD) and Fourier transform-infrared (FT-IR) spectroscopy. In vitro drug release profile at different pH values was analyzed. Furthermore, the designed RES-MWCNTs-MAAc nanocomplex was evaluated against radiation-induced enteropathy in rats. Oral administration of RES-MWCNTs-MAAc restored colonic redox state and elevated antioxidant enzymes activities glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) and reduced colonic inflammatory mediators tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interferone-γ (IFN-γ) contents in addition to declining the intrinsic apoptotic pathway as evidenced by down-regulation of Bax and caspase-3 proteins expression accompanied by up-regulation of Bcl-2 protein expression. RES-MWCNTs-MAAc was more efficient than free resveratrol due to the delivery system that allowed prolonged resveratrol release at target site. Thus, this formulation could serve as a beneficial anti-inflammatory approach for patients during radiotherapy.

Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy.

Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.

Ghrelin reverts intestinal stem cell loss associated with radiation-induced enteropathy by activating Notch signaling

BackgroudExposure to high-dose radiation, such as after a nuclear accident or radiotherapy, elicits severe intestinal damage and is associated with a high mortality rate. In treating patients exhibiting radiation-induced intestinal dysfunction, countermeasures to radiation are required. In principle, the cellular event underlying radiation-induced gastrointestinal syndrome is intestinal stem cell (ISC) apoptosis in the crypts. High-dose irradiation induces the loss of ISCs and impairs intestinal barrier function, including epithelial regeneration and integrity. Notch signaling plays a critical role in the maintenance of the intestinal epithelium and regulates ISC self-renewal. Ghrelin, a hormone produced mainly by enteroendocrine cells in the gastrointestinal tract, has diverse physiological and biological functions. PurposeWe investigate whether ghrelin mitigates radiation-induced enteropathy, focusing on its role in maintaining epithelial function. MethodsTo investigate the effect of ghrelin in radiation-induced epithelial damage, we analyzed proliferation and Notch signaling in human intestinal epithelial cell. And we performed histological analysis, inflammatory response, barrier functional assays, and expression of notch related gene and epithelial stem cell using a mouse model of radiation-induced enteritis. ResultsIn this study, we found that ghrelin treatment accelerated the reversal of radiation-induced epithelial damage including barrier dysfunction and defective self-renewing property of ISCs by activating Notch signaling. Exogenous injection of ghrelin also attenuated the severity of radiation-induced intestinal injury in a mouse model. ConclusionThese data suggest that ghrelin may be used as a potential therapeutic agent for radiation-induced enteropathy.

The Emerging Role of Eosinophils as Multifunctional Leukocytes in Health and Disease.

Eosinophils are terminally differentiated cytotoxic effector cells that have a role in parasitic infections and allergy by releasing their granule-derived cytotoxic proteins. However, an increasing number of recent observations indicate that eosinophils are not only associated with the pathogenesis of a wide range of diseases, but also contribute to the maintenance of homeostatic responses in previously underappreciated diverse tissues, such as the gastrointestinal (GI) tract and adipose tissue. In this review, we describe biological characteristics of eosinophils, as their developmental properties, permissive proliferation and survival, degranulation activity, and migration properties enable them to distribute to both homeostatic and inflamed tissues. We describe pathologic aspects of eosinophils with a role in asthma and in various GI diseases, including eosinophilic GI disorders, inflammatory bowel disease, and radiation-induced enteropathy. Finally, we discuss the beneficial role of eosinophils, which contribute to the resolution of pathogenic conditions and to the modulation of homeostatic biologic responses.

Photobiomodulation Enhances the Angiogenic Effect of Mesenchymal Stem Cells to Mitigate Radiation-Induced Enteropathy.

Radiation-induced enteropathy remains a major complication after accidental or therapeutic exposure to ionizing radiation. Recent evidence suggests that intestinal microvascular damage significantly affects the development of radiation enteropathy. Mesenchymal stem cell (MSC) therapy is a promising tool to regenerate various tissues, including skin and intestine. Further, photobiomodulation (PBM), or low-level light therapy, can accelerate wound healing, especially by stimulating angiogenesis, and stem cells are particularly susceptible to PBM. Here, we explored the effect of PBM on the therapeutic potential of MSCs for the management of radiation enteropathy. In vitro, using human umbilical cord blood-derived MSCs, PBM increased proliferation and self-renewal. Intriguingly, the conditioned medium from MSCs treated with PBM attenuated irradiation-induced apoptosis and impaired tube formation in vascular endothelial cells, and these protective effects were associated with the upregulation of several angiogenic factors. In a mouse model of radiation-induced enteropathy, treatment with PBM-preconditioned MSCs alleviated mucosal destruction, improved crypt cell proliferation and epithelial barrier functions, and significantly attenuated the loss of microvascular endothelial cells in the irradiated intestinal mucosa. This treatment also significantly increased angiogenesis in the lamina propria. Together, we suggest that PBM enhances the angiogenic potential of MSCs, leading to improved therapeutic efficacy for the treatment of radiation-induced enteropathy.

Pravastatin Attenuates Acute Radiation-Induced Enteropathy and Improves Epithelial Cell Function.

Background and Aim: Radiation-induced enteropathy is frequently observed after radiation therapy for abdominal and pelvic cancer or occurs secondary to accidental radiation exposure. The acute effects of irradiation on the intestine might be attributed to inhibition of mitosis in the crypts, as the loss of proliferative functions impairs development of the small intestinal epithelium and its barrier function. Especially, oxidative damage to intestinal epithelial cells is a key event in the initiation and progression of radiation-induced enteropathy. Pravastatin is widely used clinically to lower serum cholesterol levels and has been reported to have anti-inflammatory effects on endothelial cells. Here, we investigated the therapeutic effects of pravastatin on damaged epithelial cells after radiation-induced enteritis using in vitro and in vivo systems.Materials and Methods: To evaluate the effects of pravastatin on intestinal epithelial cells, we analyzed proliferation and senescence, oxidative damage, and inflammatory cytokine expression in an irradiated human intestinal epithelial cell line (InEpC). In addition, to investigate the therapeutic effects of pravastatin in mice, we performed histological analysis, bacterial translocation assays, and intestinal permeability assays, and also assessed inflammatory cytokine expression, using a radiation-induced enteropathy model.Results: Histological damage such as shortening of villi length and impaired intestinal crypt function was observed in whole abdominal-irradiated mice. However, damage was attenuated in pravastatin-treated animals, in which normalization of intestinal epithelial cell differentiation was also observed. Using in vitro and in vivo systems, we also showed that pravastatin improves the proliferative properties of intestinal epithelial cells and decreases radiation-induced oxidative damage to the intestine. In addition, pravastatin inhibited levels of epithelial-derived inflammatory cytokines including IL-6, IL-1β, and TNF-α in irradiated InEpC cells. We also determined that pravastatin could rescue intestinal barrier dysfunction via anti-inflammatory effects using the mouse model.Conclusion: Pravastatin has a therapeutic effect on intestinal lesions and attenuates radiation-induced epithelial damage by suppressing oxidative stress and the inflammatory response.

Protective Effects of Flagellin A N/C Against Radiation-Induced NLR Pyrin Domain Containing 3 Inflammasome-Dependent Pyroptosis in Intestinal Cells

Toinvestigate changes induced in mouse intestines after irradiation and to explore the potential radioprotective effects of flagellin AN/C (FlaAN/C). A mouse model of radiation-induced enteropathy was used in this study. A 10-Gy abdominal irradiation was performed on FlaAN/C- and vehicle-injected mice to explore the role of FlaAN/C in intestinal radiation injury and to study the molecular mechanism in this process. In the intestinal tissue, pathologic changes were investigated by hematoxylin and eosin staining, TUNEL staining, and immunohistochemistry; Western blotting and quantitative reverse transcription-polymerase chain reaction were used to determine the changes in protein and messenger RNA levels, respectively; and an enzyme-linked immunosorbent assay was performed to determine protein concentration in serum. The involvement of the reactive oxygen species pathway was investigated by determining superoxide dismutase, glutathione (GSH) peroxidase, GSH reductase, and GSH disulfide (GSSG) plus GSH activities. Flagellin A N/C inhibited radiation-induced reactive oxygen species production, decreased NLRP3 activity, and reduced the occurrence of caspase-1-dependent pyroptosis. The results revealed that oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in radiation-induced intestinal injury. Flagellin A N/C exerted a protective effect by blunting the activation of NLRP3 inflammasome signaling, thereby reducing the inflammatory response and occurrence of caspase-1-dependent pyroptosis in the intestine. Therefore, treatment of mice with FlaAN/C reduced radiation-induced intestinal injury. Reactive oxygen species-induced NLRP3 inflammasomes mediated radiation-induced pyroptosis of the intestinal cells, and FlaAN/C suppressed pyroptosis to protect the intestinal tissue. These results provide novel insights into the mechanisms underlying radiation-induced cytotoxicity, and FlaAN/C might be a potential preventive therapy for radiation-induced intestinal injury in patients with cancer.

Does the low FODMAP diet improve symptoms of radiation-induced enteropathy? A pilot study

Rationale: Patients with radiation-induced enteropathy (RE) after cancer treatment show similar symptoms as patients with irritable bowel syndrome (IBS). The low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet (LFD) is a widespread management strategy for IBS. We aimed to investigate if there may be a positive effect of LFD on symptoms and health-related quality of life (HRQOL) in patients with RE.Methods: In an open non-controlled pilot study, 11 patients (all female) with RE-related IBS symptoms were recruited largely based on own initiative. All followed LFD for four weeks. IBS Severity Scoring System (IBS-SSS) and IBS Symptom Questionnaire (IBS-SQ) were used to assess symptoms. Short Form Nepean Dyspepsia Index (SF-NDI) and 12-item Short Form Health Survey (SF-12) evaluated HRQOL. A three day food record was used to estimate baseline intake of FODMAPs and to reveal dietary changes.Results: FODMAP intake was successfully reduced, although LFD was found a burdensome intervention. IBS symptoms improved significantly based on mean total score of IBS-SSS and IBS-SQ, which changed from 310.2 ± 60.7 to 171.4 ± 107.2 (p = .001) and 27.4 ± 4.1 to 15.7 ± 10.1 (p = .002). HRQOL improved based on SF-NDI total score (30.5 ± 9.4 to 18.3 ± 8.2, p = .001) and based on mental (p = .047) and physical (p = .134) score of SF-12. Main additional dietary changes were reduced intake of energy, carbohydrates, and fiber.Conclusion: Our findings from this small-scaled pilot study indicate that the LFD may alleviate symptoms and improve HRQOL in patients with RE. Further controlled studies with larger sample size should be conducted to verify our results and hopefully enable implementation of LFD as a future part of the management strategy for RE.

Chronic Radiation Gastroenteropathy Diagnosed by Small Bowel Capsule Endoscopy: A Case Report

Radiation therapy plays an important role in a vast array of both benign and malignant disease processes. However, gastrointestinal toxicity limits the total radiation dose that can be prescribed. Chronic radiation gastroenteropathy may arise as early as 6 months to as late as several decades after the initial exposure. Microvascular sclerosis, mucosal atrophy, and intestinal wall fibrosis lead to altered intestinal transit, gut dysmotility, malabsorption, and potentially intestinal obstruction, fistulization, and perforation. We present a case of chronic radiation gastroenteropathy diagnosed by small bowel capsule endoscopy. A 56 year old man presented to the gastroenterology clinic for evaluation of chronic refractory iron-deficiency anemia (IDA). He had a history of Hodgkin lymphoma 30 years prior treated at that time with chemoradiation therapy with which he achieved remission; he then suffered from complications of radiation including mild pulmonary fibrosis, cardiomyopathy, coronary artery disease, and myelopathy resulting in paraplegia. As part of the workup for IDA, prior esophagogastroduodenoscopy (EGD) and colonoscopy had been remarkable for diffuse duodenal lymphangiectasias and a benign traversable transverse colon stricture attributed to radiation therapy. At our institution repeat EGD showed a bleeding gastric Dieulafoy lesion treated with bipolar electrocoagulation leading to hemostasis, and repeat colonoscopy was unremarkable except for the colonic stricture. Postprandial bloating, distention, and flatulence responded to a short course of ciprofloxacin, supporting a presumptive diagnosis of small intestinal bacterial overgrowth; recurrent symptoms were treated with a second course of ciprofloxacin and subsequently amoxicillin/clavulanic acid. Given persistent IDA he underwent small bowel capsule endoscopy, which showed mucosal atrophy interspersed with mucosal congestion and erythema as well as diffuse lymphangiectasias throughout the small bowel; these findings were consistent with chronic radiation enteropathy. Despite the decreasing incidence of radiation-induced enteropathy, we continue to encounter patients who present with significant complications after a prolonged latency period. A presumptive diagnosis is often made clinically, although small bowel capsule endoscopy remains a valuable and minimally invasive method to confirm this clinical entity.FigureFigureFigure

Silibinin attenuates radiation-induced intestinal fibrosis and reverses epithelial-to-mesenchymal transition.

Radiotherapy is a common treatment for cancer patients, but its use is often restricted by the tolerance of normal tissue. As cancer patients live longer, delayed radiation effects on normal tissue have become a concern. Radiation-induced enteropathy, including inflammatory bowel disease and fibrosis, are major issues for long-term cancer survivors. To investigate whether silibinin attenuates delayed radiation-induced intestinal injury in mice, we focused on intestinal fibrotic changes. Silibinin improved delayed radiation injuries in mice in association with decreased collagen deposition within the intestines and deceased transforming growth factor (TGF)-β1 levels in the intestine and plasma. Treating mice bearing CT26 mouse colon cancer tumors with both silibinin and radiation stimulated tumor regression more than radiation alone. We also investigated the effect of silibinin on the radiation-induced epithelial-to-mesenchymal transition (EMT), the primary mechanism of fibrosis. We assessed changes in E-cadherin, N-cadherin, and α-smooth muscle actin expression, and demonstrated that silibinin attenuates radiation-induced EMT. Irradiating intestinal epithelial cells increased TGF-β1 levels, but silibinin suppressed TGF-β1 expression by inhibiting Smad2/3 phosphorylation. These results suggest silibinin has the potential to serve as a useful therapeutic agent in patients with radiation-induced intestinal fibrosis.

The efficacy of human placenta-derived mesenchymal stem cells on radiation enteropathy along with proteomic biomarkers predicting a favorable response

BackgroundRadiation enteropathy is a common complication in patients with abdominopelvic cancer, but no treatment has yet been established. Stem cell therapy may be a viable therapeutic option because intestinal stem cells are highly vulnerable to ionizing radiation (IR) and stem cell loss explains its intractability to general treatment. Here, we investigated either prophylactic or therapeutic efficacy of human placenta-derived mesenchymal stem cells (hPDSCs) against radiation enteropathy and could identify biomarkers predicting a favorable response to stem cell therapy.MethodsWe challenged a radiation-induced enteropathy model with hPDSCs. After sacrifice, we checked the gross anatomy of small intestine, histology gross, and analyzed that, accompanied with molecular changes implicated in this model.ResultshPDSCs significantly improved the outcome of mice induced with either radiation enteropathy or lethal radiation syndrome (P < 0.01). hPDSCs exerted inhibitory actions on inflammatory cytokines, the re-establishment of epithelium homeostasis was completed with increasing endogenous restorative processes as assessed with increased levels of proliferative markers in the hPDSCs group, and a significant inhibition of IR-induced apoptosis. The preservation of cells expressing lysozyme, and Musashi-1 were significantly increased in the hPDSC treatment group. Both preventive and therapeutic efficacies of hPDSCs were noted against IR-induced enteropathy. Label-free quantification was used to identify biomarkers which predict favorable responses after hPDSC treatment, and finally glutathione S-transferase-mu type, interleukin-10, and peroxiredoxin-2 were validated as proteomic biomarkers predicting a favorable response to hPDSCs in radiation enteropathy.ConclusionshPDSCs may be a useful prophylactic and therapeutic cell therapy for radiation enteropathy.