Comparative Evaluation of PCR-Based, LAMP and RPA-CRISPR/Cas12a Assays for the Rapid Detection of Diaporthe aspalathi.

Southern stem canker (SSC) of soybean, attributable to the fungal pathogen Diaporthe aspalathi, results in considerable losses of soybean in the field and has damaged production in several of the main soybean-producing countries worldwide. Early and precise identification of the causal pathogen is imperative for effective disease management. In this study, we performed an RPA-CRISPR/Cas12a, as well as LAMP, PCR and real-time PCR assays to verify and compare their sensitivity, specificity and simplicity and the practicality of the reactions. We screened crRNAs targeting a specific single-copy gene, and optimized the reagent concentrations, incubation temperatures and times for the conventional PCR, real-time PCR, LAMP, RPA and Cas12a cleavage stages for the detection of D. aspalathi. In comparison with the PCR-based assays, two thermostatic detection technologies, LAMP and RPA-CRISPR/Cas12a, led to higher specificity and sensitivity. The sensitivity of the LAMP assay could reach 0.01 ng µL-1 genomic DNA, and was 10 times more sensitive than real-time PCR (0.1 ng µL-1) and 100 times more sensitive than conventional PCR assay (1.0 ng µL-1); the reaction was completed within 1 h. The sensitivity of the RPA-CRISPR/Cas12a assay reached 0.1 ng µL-1 genomic DNA, and was 10 times more sensitive than conventional PCR (1.0 ng µL-1), with a 30 min reaction time. Furthermore, the feasibility of the two thermostatic methods was validated using infected soybean leaf and seeding samples. The rapid, visual one-pot detection assay developed could be operated by non-expert personnel without specialized equipment. This study provides a valuable diagnostic platform for the on-site detection of SSC or for use in resource-limited areas.

Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability.

The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1ß that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.

Therapeutic Effect of Music Therapy on Patients with End-stage Cancer: A Retrospective Study.

OBJECTIVE: The aim of this study was to retrospectively analyze the effect of music therapy on patients with end-stage cancer in hospice care. METHODS: This retrospective cohort study included 195 patients with end-stage cancer from January 2021 to December 2023. The conventional group comprised patients who received routine hospice care, whereas the combination group comprised those who received routine hospice care and music therapy. The immune indicators, anxiety and depression scores, quality of life scores, and sleep quality scores of both groups were compared before and after management. RESULTS: Before management, no significant differences were observed in the immune indicators, anxiety and depression scores, quality of life scores, and sleep quality scores between both groups (P > 0.05). However, after management, the immune indicators lymphocytes CD3+ and CD4+ were significantly higher in the combination group than in the conventional group (P < 0.05); in contrast, anxiety and depression and the Pittsburgh Sleep Quality Index scores were lower in the combination group than in the conventional group (P < 0.05). Lastly, the World Health Organization Quality of Life Brief Version scores were significantly higher in all domains in the combination group than in those in the conventional group; furthermore, the degree of decline in the physical, psychological, and social relationship domain scores was smaller in the combination group than in the conventional group (P < 0.05). CONCLUSION: For patients with end-stage cancer, music therapy can improve their immune status, quality of life, and sleep and ameliorate their anxiety and depression.

Cas-OPRAD: a one-pot RPA/PCR CRISPR/Cas12 assay for on-site Phytophthora root rot detection.

Phytophthora sojae is a devastating plant pathogen that causes soybean Phytophthora root rot worldwide. Early on-site and accurate detection of the causal pathogen is critical for successful management. In this study, we have developed a novel and specific one-pot RPA/PCR-CRISPR/Cas12 assay for on-site detection (Cas-OPRAD) of Phytophthora root rot (P. sojae). Compared to the traditional RPA/PCR detection methods, the Cas-OPRAD assay has significant detection performance. The Cas-OPRAD platform has excellent specificity to distinguish 33 P. sojae from closely related oomycetes or fungal species. The PCR-Cas12a assay had a consistent detection limit of 100 pg. µL-1, while the RPA-Cas12a assay achieved a detection limit of 10 pg. µL-1. Furthermore, the Cas-OPRAD assay was equipped with a lateral flow assay for on-site diagnosis and enabled the visual detection of P. sojae on the infected field soybean samples. This assay provides a simple, efficient, rapid (<1 h), and visual detection platform for diagnosing Phytophthora root rot based on the one-pot CRISPR/Cas12a assay. Our work provides important methods for early and accurate on-site detection of Phytophthora root rot in the field or customs fields.

The effect of enhanced recovery after lung cancer surgery combined with fine surgical nursing on rehabilitation.

Objectives: To analyse the enhanced recovery after surgery approach combined with fine surgical nursing on recovery time, pain, sleep quality and satisfaction with care after lung cancer surgery. METHODS: The cross-sectional study was conducted at the Nanjing Chest Hospital, China, from October 2019 to March 2022, and comprised non-small cell lung cancer patients undergoing single-port video-assisted thoracoscopic surgery. Patients receiving fine surgical nursing in addition to conventional enhanced recovery after surgery formed the intervention group A, while those receiving the conventional enhanced recovery after surgery care alone formed control group B. Intraoperative blood loss, operative time, extubation time and length of stay values were noted for both the groups using standard scales. Nursing satisfaction and the incidence of adverse reactions in the two groups were also noted. Data was analysed using SPSS 23. RESULTS: Of the 99 patients, 46(46.5%) were in group A; 23(50%) males and 23(50%) females with mean age 70.3±4.8 years and mean body mass index 26.76±2.55kg/m2. There were 53(53.5%) patients in group B: 16(30.2%) males and 37(69.8%) females with mean age 69.9±4.4 years and mean body mass index 25.93±2.40kg/m2 (p>0.05). Intraoperative blood loss, operative time, postoperative extubation time and length of stay in group A were lower than those in group B (p<0.05). Pain and sleep quality values in group A were lower, while health status value was higher than group B (p<0.05). Group A had significantly higher nursing satisfaction compared to group B (p<0.05). Conclusion: The use of enhanced recovery after surgery combined with fine surgical nursing in patients with nonsmall cell lung cancer after video-assisted thoracoscopic surgery promoted postoperative recovery.

Roseburia intestinalis sensitizes colorectal cancer to radiotherapy through the butyrate/OR51E1/RALB axis.

The radioresistant signature of colorectal cancer (CRC) hampers the clinical utility of radiotherapy. Here, we find that fecal microbiota transplantation (FMT) potentiates the tumoricidal effects of radiation and degrades the intertwined adverse events in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. FMT cumulates Roseburia intestinalis (R. intestinalis) in the gastrointestinal tract. Oral gavage of R. intestinalis assembles at the CRC site and synthetizes butyrate, sensitizing CRC to radiation and alleviating intestinal toxicity in primary and CRC hepatic metastasis mouse models. R. intestinalis-derived butyrate activates OR51E1, a G-protein-coupled receptor overexpressing in patients with rectal cancer, facilitating radiogenic autophagy in CRC cells. OR51E1 shows a positive correlation with RALB in clinical rectal cancer tissues and CRC mouse model. Blockage of OR51E1/RALB signaling restrains butyrate-elicited autophagy in irradiated CRC cells. Our findings highlight that the gut commensal bacteria R. intestinalis motivates radiation-induced autophagy to accelerate CRC cell death through the butyrate/OR51E1/RALB axis and provide a promising radiosensitizer for CRC in a pre-clinical setting.

Biomodified Extracellular Vesicles Remodel the Intestinal Microenvironment to Overcome Radiation Enteritis.

Ionizing radiation (IR) is associated with the occurrence of enteritis, and protecting the whole intestine from radiation-induced gut injury remains an unmet clinical need. Circulating extracellular vesicles (EVs) are proven to be vital factors in the establishment of tissue and cell microenvironments. In this study, we aimed to investigate a radioprotective strategy mediated by small EVs (exosomes) in the context of irradiation-induced intestinal injury. We found that exosomes derived from donor mice exposed to total body irradiation (TBI) could protect recipient mice against TBI-induced lethality and alleviate radiation-induced gastrointestinal (GI) tract toxicity. To enhance the protective effect of EVs, profilings of mouse and human exosomal microRNAs (miRNAs) were performed to identify the functional molecule in exosomes. We found that miRNA-142-5p was highly expressed in exosomes from both donor mice exposed to TBI and patients after radiotherapy (RT). Moreover, miR-142 protected intestinal epithelial cells from irradiation-induced apoptosis and death and mediated EV protection against radiation enteritis by ameliorating the intestinal microenvironment. Then, biomodification of EVs was accomplished via enhancing miR-142 expression and intestinal specificity of exosomes, and thus improved EV-mediated protection from radiation enteritis. Our findings provide an effective approach for protecting against GI syndrome in people exposed to irradiation.

Nicotine Treatment Ameliorates Blood-Brain Barrier Damage After Acute Ischemic Stroke by Regulating Endothelial Scaffolding Protein Pdlim5.

Analysis of a National Institutes of Health (NIH) trial shows that cigarette smoking protected tissue plasminogen activator (tPA)-treated patients from hemorrhage transformation (HT); however, the underlying mechanism is not clear. Damage to the integrity of the blood-brain barrier (BBB) is the pathological basis of HT. Here, we investigated the molecular events of BBB damage after acute ischemic stroke (AIS) using in vitro oxygen-glucose deprivation (OGD) and in vivo mice middle cerebral artery occlusion (MCAO) models. Our results showed that the permeability of bEND.3 monolayer endothelial cells was significantly increased after being exposed to OGD for 2 h. Mice were subjected to 90-min ischemia with 45-min reperfusion, and BBB integrity was significantly damaged, accompanied by tight junction protein occludin degradation, downregulation of microRNA-21 (miR-21), transforming growth factor-ß (TGF-ß), phosphorylated Smad (p-Smad), plasminogen activator inhibitor-1 (PAI-1), and the upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that has been shown to regulate TGF-ß-Smad3 pathway. In addition, pretreatment with two-week nicotine significantly reduced AIS-induced BBB damage and its associated protein dysregulation via downregulating Pdlim5. Notably, AIS did not significantly induce BBB damage in Pdlim5 deficit mice, but overexpression of Pdlim5 in the striatum with adeno-associated virus produced BBB damage and associated protein dysregulation which could be ameliorated by two-week nicotine pretreatment. More important, AIS induced a significant miR-21 decrease, and miR-21 mimics treatment decreased AIS-induced BBB damage by decreasing Pdlim5. Together, these results demonstrate that nicotine treatment alleviates the AIS-compromised integrity of BBB by regulating Pdlim5.

Stable colonization of Akkermansia muciniphila educates host intestinal microecology and immunity to battle against inflammatory intestinal diseases.

Gut microbial preparations are widely used in treating intestinal diseases but show mixed success. In this study, we found that the therapeutic efficacy of A. muciniphila for dextran sodium sulfate (DSS)-induced colitis as well as intestinal radiation toxicity was ~50%, and mice experiencing a positive prognosis harbored a high frequency of A. muciniphila in the gastrointestinal (GI) tract. Stable GI colonization of A. muciniphila elicited more profound shifts in the gut microbial community structure of hosts. Coexisting with A. muciniphila facilitated proliferation and reprogrammed the gene expression profile of Lactobacillus murinus, a classic probiotic that overtly responded to A. muciniphila addition in a time-dependent manner. Then, a magnetic-drove, mannose-loaded nanophase material was designed and linked to the surface of A. muciniphila. The modified A. muciniphila exhibited enhancements in inflammation targeting and intestinal colonization under an external magnetic field, elevating the positive-response rate and therapeutic efficacy against intestinal diseases. However, the unlinked cocktail containing A. muciniphila and the delivery system only induced negligible improvement of therapeutic efficacy. Importantly, heat-inactivated A. muciniphila lost therapeutic effects on DSS-induced colitis and was even retained in the GI tract for a long time. Further investigations revealed that the modified A. muciniphila was able to drive M2 macrophage polarization by upregulating the protein level of IL-4 at inflammatory loci. Together, our findings demonstrate that stable colonization of live A. muciniphila at lesion sites is essential for its anti-inflammatory function.

Sexual dimorphism in gut microbiota dictates therapeutic efficacy of intravenous immunoglobulin on radiotherapy complications.

INTRODUCTION: With the mounting number of cancer survivors, the complications following cancer treatment become novel conundrums and starve for countermeasures. Intravenous immunoglobulin (IVIg) is a purified preparation for immune-deficient and autoimmune conditions. OBJECTIVES: Here, we investigated whether IVIg could be employed to fight against radiation injuries and explored the underlying mechanism. METHODS: Hematopoietic or gastrointestinal (GI) tract toxicity was induced by total body or abdominal local irradiation. High-throughput sequencing was performed to analyze the gut microbiota configurations and gene expression profile of small intestine. The untargeted metabolomics of gut microbiome was assessed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses. Hydrodynamic-based gene delivery was used to knockdown the target genes in vivo. RESULTS: Intravenous injection of IVIg protected against radiation-induced hematopoietic and GI tract toxicity in female mice but not in males. IVIg structured sex-characteristic gut microbiota configurations in abdominal irradiated mice. The irradiation enriched gut Lachnospiraceae in female mice but reduced those in males. IVIg injection combined with oral gavage of Lachnospiraceae or its metabolite hypoxanthine, alleviated radiation toxicity in male mice however, Lachnospiraceae or hypoxanthine alone failed to ameliorate the injuries. Abdominal local irradiation drove sex-distinct gene expression signatures in small intestine. Mechanistic investigation showed that replenishment of Lachnospiraceae or hypoxanthine offset abdominal radiation-reduced PLD1 expression in male mice. In females, irradiation elevated PLD1 expression. Deletion of PLD1 in GI tract of female mice erased the radioprotective effects of IVIg. CONCLUSION: IVIg battles against radiation injuries in a sex-specific, gut microbiome-dependent way through Lachnospiraceae/hypoxanthine/PLD1 axis. Our findings provide a sex-precise therapeutic avenue to improve the prognosis of cancer patients with radiotherapy in pre-clinical settings.

Development and comparison of 68Ga/18F/64Cu-labeled nanobody tracers probing Claudin18.2.

Claudin 18.2 (CLDN18.2) is an emerging target for the treatment of gastric cancers. We aim to develop tracers to image the expression of CLDN18.2. A humanized nanobody targeting CLDN18.2 (clone hu19V3) was produced and labeled with 68Ga, 64Cu, and 18F. The tracers were investigated in subcutaneous and metastatic models established using two different mouse types (nude and Balb/c mice) and two different cell lines (CHO-CLDN18.2 and CT26-CLDN18.2). Gastric cancer patient-derived xenograft (PDX) models were further established for validation experiments. Three novel CLDN18.2-targeted tracers (i.e., [68Ga]Ga-NOTA-hu19V3, [64Cu]Cu-NOTA-hu19V3, and [18F]F-hu19V3) were developed with good radiochemical yields and excellent radiochemical purities. [68Ga]Ga-NOTA-hu19V3 immuno-positron emission tomography (immunoPET) rapidly delineated subcutaneous CHO-CLDN18.2 lesions and CT26-CLDN18.2 tumors, as well as showing excellent diagnostic value in PDX models naturally expressing CLDN18.2. While [68Ga]Ga-NOTA-hu19V3 had high kidney accumulation, [64Cu]Cu-NOTA-hu19V3 showed reduced kidney accumulation and improved image contrast at late time points. Moreover, [18F]F-hu19V3 was developed via click chemistry reaction under mild conditions and precisely disseminated CHO-CLDN18.2 lesions in the lungs. Furthermore, region of interest analysis, biodistribution study, and histopathological staining results correlated well with the in vivo imaging results. Taken together, immunoPET imaging with the three tracers can reliably visualize CLDN18.2 expression.

Social Hierarchy Dictates Intestinal Radiation Injury in a Gut Microbiota-Dependent Manner.

Social hierarchy governs the physiological and biochemical behaviors of animals. Intestinal radiation injuries are common complications connected with radiotherapy. However, it remains unclear whether social hierarchy impacts the development of radiation-induced intestinal toxicity. Dominant mice exhibited more serious intestinal toxicity following total abdominal irradiation compared with their subordinate counterparts, as judged by higher inflammatory status and lower epithelial integrity. Radiation-elicited changes in gut microbiota varied between dominant and subordinate mice, being more overt in mice of higher status. Deletion of gut microbes by using an antibiotic cocktail or restructuring of the gut microecology of dominant mice by using fecal microbiome from their subordinate companions erased the difference in radiogenic intestinal injuries. Lactobacillus murinus and Akkermansia muciniphila were both found to be potential probiotics for use against radiation toxicity in mouse models without social hierarchy. However, only Akkermansia muciniphila showed stable colonization in the digestive tracts of dominant mice, and significantly mitigated their intestinal radiation injuries. Our findings demonstrate that social hierarchy impacts the development of radiation-induced intestinal injuries, in a manner dependent on gut microbiota. The results also suggest that the gut microhabitats of hosts determine the colonization and efficacy of foreign probiotics. Thus, screening suitable microbial preparations based on the gut microecology of patients might be necessary in clinical application.

Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers.

Claudin 18.2 (CLDN18.2), a tight junction (TJ) family protein controlling molecule exchange between cells, is frequently over-expressed in gastric cancer, pancreatic adenocarcinomas and in a fraction of non-small cell lung cancer cases. The tumor properties indicate that CLDN18.2 could be an attractive drug target for gastric and pancreatic cancers. In this study, we present effective strategies for developing anti-CLDN18.2 therapeutic candidates, based on variable domain of heavy chain of heavy chain antibodies (VHHs). CLDN18.2-specific VHHs were isolated by panning a phage display library from an alpaca immunized with a stable cell line highly expressing CLDN18.2. Humanized VHHs fused with human IgG1 Fc, as potential therapeutic candidates, exhibited desirable binding specificity and affinity to CLDN18.2. In vitro experiments showed that hu7v3-Fc was capable of eliciting both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) on CLDN18.2 positive tumor cells. In the mouse xenograft model, the anti-tumor efficacy of hu7v3-Fc was significantly more potent than Zolbetuximab, the benchmark anti-CLDN18.2 monoclonal antibody. Moreover, in vivo biodistribution using zirconium-89 (89Zr) labeled antibodies demonstrated that hu7v3-Fc (89Zr-hu7v3-Fc) exhibited a better tumor penetration and a faster tumor uptake than Zolbetuximab (89Zr-Zolbetuximab), which might be attributed to its smaller size and higher affinity. Taken together, anti-CDLN18.2 hu7v3-Fc is a promising therapeutic agent for human CLDN18.2 positive cancers. Furthermore, hu7v3 has emerged as a potential module for novel CLDN18.2 related therapeutics.

The Value of Serum Exosomal miR-184 in the Diagnosis of NSCLC.

Lung cancer has the highest morbidity rate (11.6%) and mortality rate (18.4%) among all current tumors. The morbidity rate in China accounts for approximately one-third, and it is still rising. Nonsmall cell lung cancer is the most common type of lung cancer, accounting for 80%-85% of all lung cancers, and approximately 57% of patients with advanced nonsmall cell lung cancer have distant metastases at the time of diagnosis. To explore the expression changes in microRNA-184 (miR-184) and its clinical value in serum exosomes of patients with nonsmall cell lung cancer (NSCLC). This study adopted a case-control study method, selecting 88 patients (NSCLC group) from June 2015 to June 2017 in our hospital who are confirmed to have NSCLC by fiber-optic bronchoscopy, and 90 patients who are confirmed to have benign lung diseases by pathological examination during the same period (control group). Fluorescence quantitative PCR technology is used to detect the levels of miR-184 in serum exosomes of the two groups, and the differences in the levels of miR-184 in serum exosomes of NSCLC patients with different pathological characteristics are analyzed. According to the results of the 3-year follow-up, the miR-184 levels in serum exosomes of NSCLC patients are grouped and compared. The expression level of miR-184 in serum exosomes in the NSCLC group is significantly higher than that in the control group, and the difference between the two groups is statistically significant (p < 0.05). The ROC curve is drawn with the expression level of miR-184 in serum exosomes of the two groups of patients. The results showed that the area under the ROC curve for the differential diagnosis of NSCLC and benign lung tumors with the expression level of miR-184 in serum exosomes is 0.927, and the sensitivity is 87.61%, while the specificity is 84.02%. The expression levels of miR-184 in serum exosomes of NSCLC patients with different pathological characteristics, in different TNM stages [(I+II) vs. (III+IV)], lymph node metastasis (yes vs. no), and different degrees of differentiation [(High + Medium) vs. Poorly differentiated] are compared and showed statistical significance (p < 0.05). In 88 NSCLC patients, after 3 years of follow-up, 33 survived, and 55 died, with a survival rate of 37.50%. The expression of miR-184 in serum exosomes of the 33 surviving patients is significantly lower than that of the nonsurviving group (p < 0.05). The expression level of miR-184 in serum exosomes of NSCLC patients is significantly increased, which has a certain value for the differential diagnosis of the nature of benign and malignant lung diseases and is closely related to the prognosis of patients.

Ambient temperature structures the gut microbiota of zebrafish to impact the response to radioactive pollution.

Potential nuclear accidents propel serious environmental pollution, and the resultant radionuclide release devastates severely the environment severely and threatens aquatic organism survival. Likewise, ongoing climate change coupled with the gradual increase in global surface temperatures can also adversely impact the aquatic ecosystems. In the present study, we preconditioned zebrafish (Danio rerio) at three different temperatures (18 °C, 26 °C and 34 °C) to investigate the effects of a temperature profile on their radiosensitivity (exposure to 20 Gy of gamma rays) to identify the potential biochemical mechanism responsible for influencing radiosensitivity. We found that preconditioning of zebrafish at different temperatures moulded specific gut microbiota configurations and impacted hepatic glycometabolism and sensitivity to subsequent radiation. Following antibiotic treatment to reduce gut bacteria, these observed differences in the expression of hepatic glycometabolism-related genes and radiation-induced intestinal toxicity were minimal, supporting the hypothesis that the gut bacteria reshaped by different ambient temperatures might be the key modulators of hepatic functions and radiosensitivity in zebrafish. Together, our findings provide novel insights into the connection of radiation injuries with temperature alterations in fish, and suggest that maintaining the stability of gram-positive bacteria may be efficacious to protect aquatic organisms against short or long-term radioactive contamination in the context of global climate change.

Low-Intensity Exercise Modulates Gut Microbiota to Fight Against Radiation-Induced Gut Toxicity in Mouse Models.

Radiation-induced gastrointestinal (GI) tract toxicity halts radiotherapy and degrades the prognosis of cancer patients. Physical activity defined as "any bodily movement produced by skeletal muscle that requires energy expenditure" is a beneficial lifestyle modification for health. Here, we investigate whether walking, a low-intensity form of exercise, could alleviate intestinal radiation injury. Short-term (15 days) walking protected against radiation-induced GI tract toxicity in both male and female mice, as judged by longer colons, denser intestinal villi, more goblet cells, and lower expression of inflammation-related genes in the small intestines. High-throughput sequencing and untargeted metabolomics analysis showed that walking restructured the gut microbiota configuration, such as elevated Akkermansia muciniphila, and reprogramed the gut metabolome of irradiated mice. Deletion of gut flora erased the radioprotection of walking, and the abdomen local irradiated recipients who received fecal microbiome from donors with walking treatment exhibited milder intestinal toxicity. Oral gavage of A. muciniphila mitigated the radiation-induced GI tract injury. Importantly, walking did not change the tumor growth after radiotherapy. Together, our findings provide novel insights into walking and underpin that walking is a safe and effective form to protect against GI syndrome of patients with radiotherapy without financial burden in a preclinical setting.

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.

Oral microbiota transplantation fights against head and neck radiotherapy-induced oral mucositis in mice.

Oral mucositis is a common radiotherapy-induced complication among nasal, oral and laryngeal cancer (NOALC) patients. This complication leads to decreased quality of life and has few treatments. Here, fractionated radiation was performed to mimic radiotherapy for NOALCs in mouse models. Oral microbiota transplantation (OMT) mitigated oral mucositis, as judged by reconstructed epithelium and tongue papillae, fewer infiltrated leukocytes and more proliferative cells in the oral epithelium. The gut microbiota impacted oral mucositis progression, and OMT restructured oral and gut bacteria configurations and reprogrammed the gene expression profile of tongue tissues. In vivo silencing of glossal S100 calcium binding protein A9 debilitated the radioprotection of OMT. In light of clinical samples, we identified that patients with different alteration trends of Lactobacillaceae frequency presented different primary lesions and prognoses of NOALC following radiotherapy. Together, our findings provide new insights into the oral-gut microbiota axis and underpin the suggestion that OMT might be harnessed as a novel remedy to fight against oral mucositis in NOALC patients following radiotherapy in preclinical settings. Of note, oral microorganisms, such as Lactobacillaceae, might be employed as biomarkers to predict the prognosis of NOALC with radiotherapy.

Oral microbiota affects the efficacy and prognosis of radiotherapy for colorectal cancer in mouse models.

Radiotherapy is inevitably intertwined with various side effects impairing the quality of life of cancer patients. Here, we report the possibility that alterations of the oral microbiota influence the therapeutic efficacy and prognosis of radiotherapy for primary rectal cancer and colorectal cancer (CRC) liver metastases that pathologically disrupt gastrointestinal integrity and function. 16S rRNA sequencing shows that oral microbiota alterations change the gut bacterial composition within tumors but not in adjacent peritumor tissues in CRC mouse models. Specifically, buccal Fusobacterium nucleatum migrates to the CRC locus and impairs the therapeutic efficacy and prognosis of radiotherapy. Administration of a specific antibiotic, metronidazole, abrogates the adverse effects of oral microbiome fluctuation on radiotherapy for CRC. The oral microbiota were also associated with radiation-induced intestinal injury via intestinal microbes. Our findings demonstrate that the oral microbiome in synergy with its intestinal counterparts impinges on the efficacy and prognosis of radiotherapy for CRC.