The Role of Microbiome and Probiotics in Chemo-Radiotherapy-Induced Diarrhea: A Narrative Review of the Current Evidence.

BACKGROUND: In this article, we review the most recent research on probiotics effects on diarrhea in both human and animal models of the condition along with the therapeutic potential of these compounds based on their findings. RECENT FINDINGS: Nearly 50%-80% of cancer patients experience chemotherapy-induced diarrhea (CID), serious gastrointestinal toxicity of chemotherapeutic and radiation regimens that leads to prolonged hospitalizations, cardiovascular problems, electrolyte imbalances, disruptions in cancer treatment, poor cancer prognosis, and death. CID is typically categorized as osmotic diarrhea. The depletion of colonic crypts and villi by radiotherapy and chemotherapy agents interferes with the absorptive function of the intestine, thereby decreasing the absorption of chloride and releasing water into the intestinal lumen. Probiotic supplements have been found to be able to reverse the intestinal damage caused by chemo-radiation therapy by promoting the growth of crypt and villi and reducing inflammatory pathways. In addition, they support the modulation of immunological and angiogenesis responses in the gut as well as the metabolism of certain digestive enzymes by altering the gut microbiota. CONCLUSION: Beyond the benefits of probiotics, additional clinical research is required to clarify the most effective strain combinations and dosages for preventing chemotherapy and radiotherapy diarrhea.

Polystyrene microplastics aggravate radiation-induced intestinal injury in mice.

Radiotherapy is a common treatment for abdominal and pelvic tumors, while the radiation-induced intestinal injury (RIII) is one of the major side-effects of radiotherapy, which reduces the life quality and impedes the treatment completion of cancer patients. Previous studies have demonstrated that environmental pollutant microplastics led to various kinds of injury in the gut, but its effects on RIII are still uncovered. In this study, we fed the C57BL/6J mice with distilled water or 50 µg/d polystyrene microplastics (PSMPs) for 17 days and exposed the mice to total abdominal irradiation (TAI) at day 14. Then the severity of RIII was examined by performing histopathological analysis and microbial community analysis. The results demonstrated that PSMPs significantly aggravated RIII in small intestine rather than colon of mice upon TAI. PSMPs increased levels of the histopathological damage and the microbial community disturbance in mice small intestine, shown by the overabundance of Akkermansiaceae and the decrease of microflora including Lactobacillaceae, Muribaculaceae and Bifidobacteriaceae. In conclusion, our results suggested that more microplastics exposure might led to more severe RIII, which should be considered in patients' daily diet adjustment and clinical radiotherapy plan evaluation. Furthermore, this study also called for the further researches to uncover the underlying mechanism and develop novel strategies to attenuate RIII in mice intestine.

MICROBIOME AND INFLAMMASOME ALTERATIONS FOUND DURING RADIATION DOSE FINDING IN A SINCLAIR MINIPIG MODEL OF GASTROINTESTINAL ACUTE RADIATION SYNDROME.

ABSTRACT: Both abdominal radiotherapy and a nuclear event can result in gastrointestinal symptoms, including acute radiation syndrome (GI-ARS). GI-ARS is characterized by compromised intestinal barrier integrity increasing the risk for infectious complications. Physiologically relevant animal models are crucial for elucidating host responses and therapeutic targets. We aimed to determine the radiation dose requirements for creating GI-ARS in the Sinclair minipig. Male, sexually mature swine were randomly divided into sham (n = 6) and three lower hemibody radiation dosage groups of 8, 10, and 12 Gy (n = 5/group) delivered using linear accelerator-derived x-rays (1.9 Gy/min). Animals were monitored for GI-ARS symptoms for 14 days with rectal swab and blood collection at days 0-3, 7, 10, and 14 followed by necropsy for western blotting and histology. Dose-dependent increases in weight loss, diarrhea severity, and mortality (log-rank test, P = 0.041) were seen. Villi length was significantly reduced in all irradiated animals compared to controls ( P < 0.001). Serum citrulline decreased and bacterial translocation increased after irradiation compared to controls. Increased NLRP3 levels in post-mortem jejunum were seen ( P = 0.0043) as well as increased IL-1ß levels in the 12 Gy group ( P = 0.041). Radiation dose and survival were associated with significant gut microbial community shifts in beta diversity. Moreover, decedents had increased Porphyromonas, Campylobacter, Bacteroides , Parvimonas , and decreased Fusobacterium and decreased Aerococcus, Lactobacillus, Prevotella, and Streptococcus . Our novel Sinclair minipig model showed dose-dependent clinical symptoms of GI-ARS. These findings provide invaluable insights into the intricate interplay between GI-ARS, intestinal inflammation, and gut microbiota alterations offering potential targets for therapeutic and diagnostic interventions after radiation exposure.

Intestinal microbiota composition is predictive of radiotherapy-induced acute gastrointestinal toxicity in prostate cancer patients.

BACKGROUND: The search for factors beyond the radiotherapy dose that could identify patients more at risk of developing radio-induced toxicity is essential to establish personalised treatment protocols for improving the quality-of-life of survivors. To investigate the role of the intestinal microbiota in the development of radiotherapy-induced gastrointestinal toxicity, the MicroLearner observational cohort study characterised the intestinal microbiota of 136 (discovery) and 79 (validation) consecutive prostate cancer patients at baseline radiotherapy. METHODS: Gastrointestinal toxicity was assessed weekly during RT using CTCAE. An average grade >1.3 over time points was used to identify patients suffering from persistent acute toxicity (endpoint). The microbiota of patients was quantified from the baseline faecal samples using 16S rRNA gene sequencing technology and the Ion Reporter metagenomic pipeline. Statistical techniques and computational and machine learning tools were used to extract, functionally characterise, and predict core features of the bacterial communities of patients who developed acute gastrointestinal toxicity. FINDINGS: Analysis of the core bacterial composition in the discovery cohort revealed a cluster of patients significantly enriched for toxicity, displaying a toxicity rate of 60%. Based on selected high-risk microbiota compositional features, we developed a clinical decision tree that could effectively predict the risk of toxicity based on the relative abundance of genera Faecalibacterium, Bacteroides, Parabacteroides, Alistipes, Prevotella and Phascolarctobacterium both in internal and external validation cohorts. INTERPRETATION: We provide evidence showing that intestinal bacteria profiling from baseline faecal samples can be effectively used in the clinic to improve the pre-radiotherapy assessment of gastrointestinal toxicity risk in prostate cancer patients. FUNDING: Italian Ministry of Health (Promotion of Institutional Research INT-year 2016, 5 × 1000, Ricerca Corrente funds). Fondazione Regionale per la Ricerca Biomedica (ID 2721017). AIRC (IG 21479).

Microbiome in radiotherapy: an emerging approach to enhance treatment efficacy and reduce tissue injury.

Radiotherapy is a widely used cancer treatment that utilizes powerful radiation to destroy cancer cells and shrink tumors. While radiation can be beneficial, it can also harm the healthy tissues surrounding the tumor. Recent research indicates that the microbiota, the collection of microorganisms in our body, may play a role in influencing the effectiveness and side effects of radiation therapy. Studies have shown that specific species of bacteria living in the stomach can influence the immune system's response to radiation, potentially increasing the effectiveness of treatment. Additionally, the microbiota may contribute to adverse effects like radiation-induced diarrhea. A potential strategy to enhance radiotherapy outcomes and capitalize on the microbiome involves using probiotics. Probiotics are living microorganisms that offer health benefits when consumed in sufficient quantities. Several studies have indicated that probiotics have the potential to alter the composition of the gut microbiota, resulting in an enhanced immune response to radiation therapy and consequently improving the efficacy of the treatment. It is important to note that radiation can disrupt the natural balance of gut bacteria, resulting in increased intestinal permeability and inflammatory conditions. These disruptions can lead to adverse effects such as diarrhea and damage to the intestinal lining. The emerging field of radiotherapy microbiome research offers a promising avenue for optimizing cancer treatment outcomes. This paper aims to provide an overview of the human microbiome and its role in augmenting radiation effectiveness while minimizing damage.

Dietary restriction and fasting alleviate radiation-induced intestinal injury by inhibiting cGAS/STING activation.

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy, limiting the clinical application of this treatment. Evidence shows the potential benefits of dietary restriction in improving metabolic profiles and age-related diseases. The present study investigated the effects and mechanisms of dietary restriction in radiation-induced intestinal injury. The mice were randomly divided into the control group, 10 Gy total abdominal irradiation (TAI) group, and groups pretreated with 30% caloric restriction (CR) for 7 days or 24 h fasting before TAI. After radiation, the mice were returned to ad libitum. The mice were sacrificed 3.5 days after radiation, and tissue samples were collected. CR and fasting reduced radiation-induced intestinal damage and promoted intestinal recovery by restoring the shortened colon length, improving the impaired intestinal structure and permeability, and remodeling gut microbial structure. CR and fasting also significantly reduced mitochondrial damage and DNA damage, which in turn reduced activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) pathway and the production of type I interferon and other chemokines in the jejunum. Since the cGAS/STING pathway is linked with innate immunity, we further showed that CR and fasting induced polarization to immunosuppressive M2 macrophage, decreased CD8+ cytotoxic T lymphocytes, and downregulated proinflammatory factors in the jejunum. Our findings indicated that CR and fasting alleviate radiation-induced intestinal damage by reducing cGAS/STING-mediated harmful immune responses.

Lactobacillus rhamnosus GG alleviates radiation-induced intestinal injury by modulating intestinal immunity and remodeling gut microbiota.

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10 Gy total abdominal irradiation (TAI) group, or a group pretreated with 108 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.

Effects of combined ciprofloxacin and Neulasta therapy on intestinal pathology and gut microbiota after high-dose irradiation in mice.

Introduction: Treatments that currently exist in the strategic national stockpile for acute radiation syndrome (ARS) focus on the hematopoietic subsyndrome, with no treatments on gastrointestinal (GI)-ARS. While the gut microbiota helps maintain host homeostasis by mediating GI epithelial and mucosal integrity, radiation exposure can alter gut commensal microbiota which may leave the host susceptible to opportunistic pathogens and serious sequelae such as sepsis. To mitigate the effects of hematopoietic ARS irradiation, currently approved treatments exist in the form of colony stimulating factors and antibiotics: however, there are few studies examining how these therapeutics affect GI-ARS and the gut microbiota. The aim of our study was to examine the longitudinal effects of Neulasta and/or ciprofloxacin treatment on the gut microbiota after exposure to 9.5 Gy 60Co gamma-radiation in mice. Methods: The gut microbiota of vehicle and drug-treated mice exposed to sham or gamma-radiation was characterized by shotgun sequencing with alpha diversity, beta diversity, and taxonomy analyzed on days 2, 4, 9, and 15 post-irradiation. Results: No significant alpha diversity differences were observed following radiation, while beta diversity shifts and taxonomic profiles revealed significant alterations in Akkermansia, Bacteroides, and Lactobacillus. Ciprofloxacin generally led to lower Shannon diversity and Bacteroides prevalence with increases in Akkermansia and Lactobacillus compared to vehicle treated and irradiated mice. While Neulasta increased Shannon diversity and by day 9 had more similar taxonomic profiles to sham than ciprofloxacin-or vehicle-treated irradiated animals. Combined therapy of Neulasta and ciprofloxacin induced a decrease in Shannon diversity and resulted in unique taxonomic profiles early post-irradiation, returning closer to vehicle-treated levels over time, but persistent increases in Akkermansia and Bacteroides compared to Neulasta alone. Discussion: This study provides a framework for the identification of microbial elements that may influence radiosensitivity, biodosimetry and the efficacy of potential therapeutics. Moreover, increased survival from H-ARS using these therapeutics may affect the symptoms and appearance of what may have been subclinical GI-ARS.

Photobiomodulation Therapy: A Novel Therapeutic Approach to Alzheimer's Disease Made Possible by the Evidence of a Brain-Gut Interconnection.

The evidence of brain-gut interconnections in Alzheimer's disease (AD) opens novel avenues for the treatment of a pathology for which no definitive treatment exists. Gut microbiota and bacterial translocation may produce peripheral inflammation and immune modulation, contributing to brain amyloidosis, neurodegeneration, and cognitive deficits in AD. The gut microbiota can be used as a potential therapeutic target in AD. In particular, photobiomodulation (PBM) can affect the interaction between the microbiota and the immune system, providing a potential explanation for its restorative properties in AD-associated dysbiosis. PBM is a safe, non-invasive, non-ionizing, and non-thermal therapy that uses red or near-infrared light to stimulate the cytochrome c oxidase (CCO, complex IV), the terminal enzyme of the mitochondrial electron transport chain, resulting in adenosine triphosphate synthesis. The association of the direct application of PBM to the head with an abscopal and a systemic treatment through simultaneous application to the abdomen provides an innovative therapeutic approach to AD by targeting various components of this highly complex pathology. As a hypothesis, PBM might have a significant role in the therapeutic options available for the treatment of AD.

Intestinal microecological transplantation for a patient with chronic radiation enteritis: A case report.

BACKGROUND: The gut microbiota is strongly associated with radiation-induced gut damage. This study aimed to assess the effectiveness and safety of intestinal microecological transplantation for treating patients with chronic radiation enteritis. CASE SUMMARY: A 64-year-old female with cervical cancer developed abdominal pain, diarrhea, and blood in the stool 1 year after radiotherapy. An electronic colonoscopy was performed to diagnose chronic radiation enteritis. Two courses of intestinal microecological transplantation and full-length 16S rRNA microbiological analysis were performed. The patient experienced short- and long-term relief from symptoms without adverse effects. Whole 16S rRNA sequencing revealed significant differences in the intestinal flora's composition between patient and healthy donors. Pathogenic bacteria, such as Escherichia fergusonii and Romboutsia timonensis, were more in the patient. Beneficial bacteria such as Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans, Ruminococcus bromii, and Bifidobacterium longum were more in the healthy donors. Intestinal microbiota transplantation resulted in a significant change in the patient's intestinal flora composition. The composition converged with the donor's flora, with an increase in core beneficial intestinal bacteria, such as Eubacterium rectale, and a decrease in pathogenic bacteria. Changes in the intestinal flora corresponded with the patients' alleviating clinical symptoms. CONCLUSION: Intestinal microecological transplantation is an effective treatment for relieving the clinical symptoms of chronic radiation enteritis by altering the composition of the intestinal flora. This study provides a new approach for treating patients with chronic radiation enteritis.

Comparison of gut toxicity and microbiome effects in zebrafish exposed to polypropylene microplastics: Interesting effects of UV-weathering on microbiome.

Weathered microplastics (MPs) exhibit different physicochemical properties compared to pristine MPs, thus, their effects on the environment and living organisms may also differ. In the present study, we investigated the gut-toxic effects of virgin polypropylene MPs (PP) and UV-weathered PP MPs (UV-PP) on zebrafish. The zebrafish were exposed to the two types of PP MPs at a concentration of 50 mg/L each for 14 days. After exposure, MPs accumulated primarily within the gastrointestinal tract, with UV-PP exhibiting a higher accumulation than PP. The ingestion of PP and UV-PP induced gut damage in zebrafish and increased the gene expression and levels of enzymes related to oxidative stress and inflammation, with no significant differences between the two MPs. Analysis of the microbial community confirmed alterations in the abundance and diversity of zebrafish gut microorganisms in the PP and UV-PP groups, with more pronounced changes in the PP-exposed group. Moreover, the Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the association between changes in the gut microorganisms at the phylum and genus levels with cellular responses, such as oxidative stress, inflammation, and tissue damage. This study provides valuable insights regarding the environmental impact of MPs on organisms.

Disrupted gut microecology after high-dose 131I therapy and radioprotective effects of arachidonic acid supplementation.

BACKGROUND: Despite the potential radiotoxicity in differentiated thyroid cancer (DTC) patients with high-dose 131I therapy, the alterations and regulatory mechanisms dependent on intestinal microecology remain poorly understood. We aimed to identify the characteristics of the gut microbiota and metabolites in DTC patients suffering from high-dose 131I therapy and explore the radioprotective mechanisms underlying arachidonic acid (ARA) treatment. METHODS: A total of 102 patients with DTC were recruited, with fecal samples collected before and after 131I therapy for microbiome and untargeted and targeted metabolomic analyses. Mice were exposed to total body irradiation with ARA replenishment and antibiotic pretreatment and were subjected to metagenomic, metabolomic, and proteomic analyses. RESULTS: 131I therapy significantly changed the structure of gut microbiota and metabolite composition in patients with DTC. Lachnospiraceae were the most dominant bacteria after 131I treatment, and metabolites with decreased levels and pathways related to ARA and linoleic acid were observed. In an irradiation mouse model, ARA supplementation not only improved quality of life and recovered hematopoietic and gastrointestinal systems but also ameliorated oxidative stress and inflammation and preserved enteric microecology composition. Additionally, antibiotic intervention eliminated the radioprotective effects of ARA. Proteomic analysis and ursolic acid pretreatment showed that ARA therapy greatly influenced intestinal lipid metabolism in mice subjected to irradiation by upregulating the expression of hydroxy-3-methylglutaryl-coenzyme A synthase 1. CONCLUSION: These findings highlight that ARA, as a key metabolite, substantially contributes to radioprotection. Our study provides novel insights into the pivotal role that the microbiota-metabolite axis plays in radionuclide protection and offers effective biological targets for treating radiation-induced adverse effects.

Fecal Microbiota Transplantation Repairs Radiation Enteritis Through Modulating the Gut Microbiota-Mediated Tryptophan Metabolism.

Radiation enteritis is a common complication of abdominal and pelvic radiotherapy. Several previous studies showed that fecal microbiota transplantation (FMT) could alleviate radiation enteritis. In this study, we investigated the efficacy of FMT in alleviating radiation enteritis and explored the mechanisms by multi-omics approaches. Briefly, C57BL/6J mice were subjected to 9 Gy irradiation to the localized abdominal field, and randomized received FMT from healthy donor mice or saline. H&E staining of harvested small intestine showed FMT decreased epithelial injury. Radiation-induced microbiota dysbiosis, characterized by a decrease in beneficial bacteria Lactobacillaceae and Lachnospiraceae, while these bacteria were restored by FMT. Fecal metabolomics analysis revealed that FMT modulated metabolic dysregulation. Two tryptophan pathway metabolites, indole-3-acetaldehyde and N-Acetyl-5-hydroxytryptamine were decreased after irradiation, whereas these metabolites showed a pronounced recovery in mice receiving FMT. Proteomics analysis of small intestine indicated that radiation enteritis triggered immune-inflammatory responses, which were potentially mitigated by FMT. In 21 patients receiving pelvic radiotherapy for cervical cancer, those who developed enteritis (n = 15) had higher abundance in Lachnospiraceae. Moreover, Indole-3-acetaldehyde was reduced after irradiation. These findings provide insights into the therapeutic effects of FMT in radiation enteritis and highlight Lachnospiraceae and the tryptophan metabolite, Indole-3-acetaldehyde may protect against radiation enteritis.

Microbiome and Abdominopelvic Radiotherapy Related Chronic Enteritis: A Microbiome-based Mechanistic Role of Probiotics and Antibiotics.

Chronic diarrhea and abdominal pain after radiotherapy continue to be a problem in cancer survivors. Gut microbiomes are essential for preventing intestinal inflammation, maintaining intestinal integrity, maintaining enterohepatic circulation, regulating bile acid metabolism, and absorption of nutrients, including fat-soluble vitamins. Gut microbiome dysbiosis is expected to cause inflammation, bile acid malabsorption, malnutrition, and associated symptoms. Postradiotherapy, Firmicutes and Bacteroidetes phylum are significantly decreased while Fusobacteria and other unclassified bacteria are increased. Available evidence suggests harmful bacteria Veillonella, Erysipelotrichaceae, and Ruminococcus are sensitive to Metronidazole or Ciprofloxacin. Beneficial bacteria lactobacillus and Bifidobacterium are relatively resistant to metronidazole. We hypothesize and provide an evidence-based review that short-course targeted antibiotics followed by specific probiotics may lead to alleviation of radiation enteritis.

Enteric α-Defensin Contributes to Recovery of Radiation-Induced Intestinal Injury by Modulating Gut Microbiota and Fecal Metabolites.

The effect of ionizing radiation on the gastrointestinal tract is a common complication of abdominal and pelvic radiotherapy. However, the pathological features of radiation enteropathy and its effective medical intervention regimen is still a global challenge. Here, we explored the role and mechanism of enteric alpha-defensins (EαDs) in protecting against radiation enteropathy. To address this, we utilized EαDs-deficiency mice, in which the matrix metallopeptidase 7 to activate Paneth cell α-defensins was knockout (KO) mice, and the complementary wild-type (WT) control mice for this study. Remarkably, the KO mice were more susceptible to 5.0 Gy total-body irradiation, resulting in worse clinic scores and lower survival rate, compared with the wild-type mice. Histological examination indicated that the KO mice were subjected to slow recovery of intestinal villus and mucosa function, characterized by the reduced expression of TFF3, Glut1 and Muc2. In addition, compared with the wild-type controls, the KO mice experienced serious inflammation response in intestinal tissue, indicated by the remarkably increased expression level of IL-1ß, IL-6 and IL-12. Using high-throughput sequencing analysis, we found that the intestinal bacterial community of the KO mice was more prone to dysbiosis than that of the WT mice, with significantly increased abundance of opportunistic pathogenic bacteria, such as Streptococcus sp. and Escherichia-Shigella sp., whereas remarkably decreased probiotics harboring Lactobacillus sp., Desulfovibrio sp. etc. Fecal metabolomics analysis indicated that the relative abundance of 31 metabolites arose significantly different between WT and KO mice on day 10 after radiation exposure. A subset of differential metabolites to regulate host metabolism and immunity, such as acetic acid, acetate, butanoic acid, was negatively correlated with the alteration of gut microbiota in the irradiated KO mice. This study provides new insight into EαDs contribution to the recovery of radiation-induced intestinal damage, and suggests a potential novel target to prevent the adverse effects of radiotherapy.

Mitigative and anti-inflammatory effects of Trichostatin A against radiation-induced gastrointestinal toxicity and gut microbiota alteration in mice.

PURPOSE: Radiation-induced gastrointestinal injury (RIGI) is a serious side effect of abdominal and pelvic radiotherapy, which often limits the treatment of gastrointestinal and gynaecological cancers. RIGI is also observed during accidental radiological or nuclear scenarios with no approved agents available till date to prevent or mitigate RIGI in humans. Trichostatin A (TSA), an epigenetic modulator, has been currently in clinical trials for cancer treatment and is also well known for its antibiotic and antifungal properties. METHODS: In this study, partial body (abdominal) irradiation mice model was used to investigate the mitigative effect of TSA against gastrointestinal toxicity caused by gamma radiation. Mice were checked for alterations in mean body weight, diarrheal incidence, disease activity index and survival against 15 Gy radiation. Structural abnormalities in intestine and changes in microbiota composition were studied by histopathology and 16S rRNA sequencing of fecal samples respectively. Immunoblotting and biochemical assays were performed to check protein nitrosylation, expression of inflammatory mediators, infiltration of inflammatory cells and changes in pro-inflammatory cytokine. RESULTS: TSA administration to C57Bl/6 mice improved radiation induced mean body weight loss, maintained better health score, reduced disease activity index and promoted survival. The 16S rRNA sequencing of fecal DNA demonstrated that TSA influenced the fecal microbiota dynamics with significant alterations in the Firmicutes/Bacteriodetes ratio. TSA effectively mitigated intestinal injury, down-regulated NF-κB, Cox-2, iNOS expression, inhibited PGE2 and protein nitrosylation levels in irradiated intestine. The upregulation of NLRP3-inflammasome complex and infiltrations of inflammatory cells in the inflamed intestine were also prevented by TSA. Subsequently, the myeloperoxidase activity in intestine alongwith serum IL-18 levels was found reduced. CONCLUSION: These findings provide evidence that TSA inhibits inflammatory mediators, alleviates gut dysbiosis, and promotes structural restoration of the irradiated intestine. TSA, therefore, can be considered as a potential agent for mitigation of RIGI in humans.

Long-term LDR exposure may induce cognitive impairments: A possible association through targeting gut microbiota-gut-brain axis.

Environmental and occupational low-dose radiation (LDR) exposure may be harmful for health but the previous reports regarding effect of LDR on cognition are contradictory. Here we investigated the effect of long-term LDR exposure on cognition. In this study, male Balb/c mice' cognitive functions were tested at 15 weeks after being exposed to 0.5 Gy LDR in 10 fractions at each dose of 0.05 Gy. The results demonstrated that long-term LDR exposure increases escape latency and the time spent in finding exits in mice compared with non LDR exposure. Meanwhile, the inflammation-related proteins including NFκB and p38 also increased. Lipopolysaccharide (LPS) increased and short-chain fatty acid (SCFA) levels decreased following long term LDR exposure. Treatment with microbiota-derived LPS and SCFAs reversed these effects in mice. Furthermore, the gut barrier integrity was damaged in a time-dependent manner with the decreased expression of intestinal epithelial-related biomarkers such as ZO-1 and occludin. Mechanistically, long after exposure to LDR, increased LPS levels may cause cognitive impairment through the regulation of Akt/mTOR signaling in the mouse hippocampus. These findings provide new insight into the clinical applications of LDR and suggest that the gut microbiota-plasma LPS and SCFAs-brain axis may underlie long-term LDR-induced cognition effects.

New Insights into the Relationship between Gut Microbiota and Radiotherapy for Cancer.

Cancer is the second most common cause of death among humans in the world, and the threat that it presents to human health is becoming more and more serious. The mechanisms of cancer development have not yet been fully elucidated, and new therapies are changing with each passing day. Evidence from the literature has validated the finding that the composition and modification of gut microbiota play an important role in the development of many different types of cancer. The results also demonstrate that there is a bidirectional interaction between the gut microbiota and radiotherapy treatments for cancer. In a nutshell, the modifications of the gut microbiota caused by radiotherapy have an effect on tumor radiosensitivity and, as a result, affect the efficacy of radiotherapy and show a certain radiation toxicity, which leads to numerous side effects. What is of new research significance is that the "gut-organ axis" formed by the gut microbiota may be one of the most interesting potential mechanisms, although the relevant research is still very limited. In this review, we combine new insights into the relationship between the gut microbiota, cancer, and radiotherapy. Based on our current comprehensive understanding of this relationship, we give an overview of the new cancer treatments based on the gut microbiota.

Gut Microbiota-Derived l-Histidine/Imidazole Propionate Axis Fights against the Radiation-Induced Cardiopulmonary Injury.

Radiation-induced cardiopulmonary injuries are the most common and intractable side effects that are entwined with radiotherapy for thorax cancers. However, the therapeutic options for such complications have yielded disappointing results in clinical applications. Here, we reported that gut microbiota-derived l-Histidine and its secondary metabolite imidazole propionate (ImP) fought against radiation-induced cardiopulmonary injury in an entiric flora-dependent manner in mouse models. Local chest irradiation decreased the level of l-Histidine in fecal pellets, which was increased following fecal microbiota transplantation. l-Histidine replenishment via an oral route retarded the pathological process of lung and heart tissues and improved lung respiratory and heart systolic function following radiation exposure. l-Histidine preserved the gut bacterial taxonomic proportions shifted by total chest irradiation but failed to perform radioprotection in gut microbiota-deleted mice. ImP, the downstream metabolite of l-Histidine, accumulated in peripheral blood and lung tissues following l-Histidine replenishment and protected against radiation-induced lung and heart toxicity. Orally gavaged ImP could not enter into the circulatory system in mice through an antibiotic cocktail treatment. Importantly, ImP inhibited pyroptosis to nudge lung cell proliferation after radiation challenge. Together, our findings pave a novel method of protection against cardiopulmonary complications intertwined with radiotherapy in pre-clinical settings and underpin the idea that gut microbiota-produced l-Histidine and ImP are promising radioprotective agents.

Gut metabolite Urolithin A mitigates ionizing radiation-induced intestinal damage.

Ionizing radiation (IR)-induced intestinal damage is the major and common injury of patients receiving radiotherapy. Urolithin A (UroA) is a metabolite of the intestinal flora of ellagitannin, a compound found in fruits and nuts such as pomegranates, strawberries and walnuts. UroA shows the immunomodulatory and anti-inflammatory capacity in various metabolic diseases. To evaluate the radioprotective effects, UroA(0.4, 2 and 10 mg/kg) were intraperitoneally injected to C57BL/6 male mice 48, 24, 1 h prior to and 24 h after 9.0Gy TBI. The results showed that UroA markedly upregulated the survival of irradiated mice, especially at concentration of 2 mg/kg. UroA improved the intestine morphology architecture and the regeneration ability of enterocytes in irradiated mice. Then, UroA significantly decreased the apoptosis of enterocytes induced by radiation. Additionally, 16S rRNA sequencing analysis showed the effect of UroA is associated with the recovery of the IR-induced intestinal microbacteria profile changes in mice. Therefore, our results determinated UroA could be developed as a potential candidate for radiomitigators in radiotherapy and accidental nuclear exposure. And the beneficial functions of UroA might be associated with the inhibition of p53-mediated apoptosis and remodelling of the gut microbes.