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1
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Giridhar P, Pradhan S, Dokania S, Venkatesulu B, Sarode R, Welsh JS. Microbiome and Abdominopelvic Radiotherapy Related Chronic Enteritis: A Microbiome-based Mechanistic Role of Probiotics and Antibiotics. Am J Clin Oncol 2024; 47:246-252. [PMID: 38193365 DOI: 10.1097/coc.0000000000001082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
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.
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Affiliation(s)
| | | | | | - Bhanuprasad Venkatesulu
- Department of Radiation Oncology, Loyola University Chicago, Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood
- Department of Radiation Oncology, MPMMCC/HBCH Varanasi Edward Hines Veteran Affairs Hospital, Chicago, IL
| | - Rahul Sarode
- Department of Microbiology, Mahamana Pandit Madanmohan Malaviya Cancer Centre/Homi Bhabha Cancer hospital, Tata Memorial Centre, Varanasi, India
| | - James S Welsh
- Department of Radiation Oncology, Loyola University Chicago, Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood
- Department of Radiation Oncology, MPMMCC/HBCH Varanasi Edward Hines Veteran Affairs Hospital, Chicago, IL
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2
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Liu X, Li Y, Gu M, Xu T, Wang C, Chang P. Radiation enteropathy-related depression: A neglectable course of disease by gut bacterial dysbiosis. Cancer Med 2024; 13:e6865. [PMID: 38457257 PMCID: PMC10923036 DOI: 10.1002/cam4.6865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 03/10/2024] Open
Abstract
Radiation enteropathy (RE) is common in patients treated with radiotherapy for pelvic-abdominal cancers. Accumulating data indicate that gut commensal bacteria determine intestinal radiosensitivity. Radiotherapy can result in gut bacterial dysbiosis. Gut bacterial dysbiosis contributes to the pathogenesis of RE. Mild to moderate depressive symptoms can be observed in patients with RE in clinical settings; however, the rate of these symptoms has not been reported. Studies have demonstrated that gut bacterial dysbiosis induces depression. In the state of comorbidity, RE and depression may be understood as local and abscopal manifestations of gut bacterial disorders. The ability of comorbid depression to worsen inflammatory bowel disease (IBD) has long been demonstrated and is associated with dysfunction of cholinergic neural anti-inflammatory pathways. There is a lack of direct evidence for RE comorbid with depression. It is widely accepted that RE shares similar pathophysiologic mechanisms with IBD. Therefore, we may be able to draw on the findings of the relationship between IBD and depression. This review will explore the relationship between gut bacteria, RE, and depression in light of the available evidence and indicate a method for investigating the mechanisms of RE combined with depression. We will also describe new developments in the treatment of RE with probiotics, prebiotics, and fecal microbial transplantation.
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Affiliation(s)
- Xinliang Liu
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
| | - Ying Li
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
| | - Meichen Gu
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
| | - Tiankai Xu
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
| | - Chuanlei Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Pengyu Chang
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
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3
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Klos B, Steinbach C, Ketel J, Lambert C, Penders J, Doré J, Enck P, Mack I. Effects of isolation and confinement on gastrointestinal microbiota-a systematic review. Front Nutr 2023; 10:1214016. [PMID: 37492598 PMCID: PMC10364611 DOI: 10.3389/fnut.2023.1214016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/21/2023] [Indexed: 07/27/2023] Open
Abstract
Purpose The gastrointestinal (GI) microbiota is a complex and dynamic ecosystem whose composition and function are influenced by many internal and external factors. Overall, the individual GI microbiota composition appears to be rather stable but can be influenced by extreme shifts in environmental exposures. To date, there is no systematic literature review that examines the effects of extreme environmental conditions, such as strict isolation and confinement, on the GI microbiota. Methods We conducted a systematic review to examine the effects of isolated and confined environments on the human GI microbiota. The literature search was conducted according to PRISMA criteria using PubMed, Web of Science and Cochrane Library. Relevant studies were identified based on exposure to isolated and confined environments, generally being also antigen-limited, for a minimum of 28 days and classified according to the microbiota analysis method (cultivation- or molecular based approaches) and the isolation habitat (space, space- or microgravity simulation such as MARS-500 or natural isolation such as Antarctica). Microbial shifts in abundance, alpha diversity and community structure in response to isolation were assessed. Results Regardless of the study habitat, inconsistent shifts in abundance of 40 different genera, mainly in the phylum Bacillota (formerly Firmicutes) were reported. Overall, the heterogeneity of studies was high. Reducing heterogeneity was neither possible by differentiating the microbiota analysis methods nor by subgrouping according to the isolation habitat. Alpha diversity evolved non-specifically, whereas the microbial community structure remained dissimilar despite partial convergence. The GI ecosystem returned to baseline levels following exposure, showing resilience irrespective of the experiment length. Conclusion An isolated and confined environment has a considerable impact on the GI microbiota composition in terms of diversity and relative abundances of dominant taxa. However, due to a limited number of studies with rather small sample sizes, it is important to approach an in-depth conclusion with caution, and results should be considered as a preliminary trend. The risk of dysbiosis and associated diseases should be considered when planning future projects in extreme environments. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022357589.
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Affiliation(s)
- Bea Klos
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - Christina Steinbach
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - Jasmin Ketel
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - Claude Lambert
- CIRI–Immunology Lab University Hospital, Saint-Étienne, France
- LCOMS/ENOSIS Université de Lorraine, Metz, France
| | - John Penders
- Department of Medical Microbiology, Infectious Diseases and Infection Prevention, Maastricht University Medical Center, CAPHRI Care and Public Health Research Institute, Maastricht, Netherlands
- Department of Medical Microbiology, Infectious Diseases and Infection Prevention, Maastricht University Medical Center, School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
| | - Joël Doré
- UMR Micalis Institut, INRA, Paris-Saclay University, Jouy-En-Josas, France
| | - Paul Enck
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - Isabelle Mack
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
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4
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Amit U, Facciabene A, Ben-Josef E. Radiation Therapy and the Microbiome; More Than a Gut Feeling. Cancer J 2023; 29:84-88. [PMID: 36957978 DOI: 10.1097/ppo.0000000000000650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
ABSTRACT It is increasingly recognized that heterogeneities in tumor response and severity of adverse effects in irradiated patients can be attributed to the tumor microenvironment and host-related factors. Among the latter, a growing body of literature in recent years has demonstrated the role of the patient's microbiome in modulating both tumor and normal tissue response to radiotherapy (RT). Upon contact with the environment after birth, the infant's gastrointestinal tract is rapidly colonized by microbiota, which is low in diversity and predominantly characterized by 2 dominant species, Actinobacteria and Proteobacteria. With time, intestinal microbiota diversity increases, and colonization of Firmicutes and Bacteroidetes becomes dominant. By the time a child reaches 3 years, the gut microbiota composition has been reshaped and is relatively similar to that of an adult. The microbiome colonizing the different body organs comprises various species and abundances, which may impact human health. Although the adult microbiome composition is thought to remain stable in health, microbiome diversity and composition respond to different environmental and pathological conditions, including pharmaceutical interventions and RT. Our review focuses on how the gut microbiota modulates normal tissue toxicity and tumor control. Readers who want to learn more about how RT shapes gut microbiome diversity and composition are referred to several excellent recently published reviews.
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Affiliation(s)
| | | | - Edgar Ben-Josef
- From the Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Nandi D, Parida S, Sharma D. The gut microbiota in breast cancer development and treatment: The good, the bad, and the useful! Gut Microbes 2023; 15:2221452. [PMID: 37305949 PMCID: PMC10262790 DOI: 10.1080/19490976.2023.2221452] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/26/2023] [Indexed: 06/13/2023] Open
Abstract
Regardless of the global progress in early diagnosis and novel therapeutic regimens, breast carcinoma poses a devastating threat, and the advances are somewhat marred by high mortality rates. Breast cancer risk prediction models based on the known risk factors are extremely useful, but a large number of breast cancers develop in women with no/low known risk. The gut microbiome exerts a profound impact on the host health and physiology and has emerged as a pivotal frontier in breast cancer pathogenesis. Progress in metagenomic analysis has enabled the identification of specific changes in the host microbial signature. In this review, we discuss the microbial and metabolomic changes associated with breast cancer initiation and metastatic progression. We summarize the bidirectional impact of various breast cancer-related therapies on gut microbiota and vice-versa. Finally, we discuss the strategies to modulate the gut microbiota toward a more favorable state that confers anticancer effects.
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Affiliation(s)
- Deeptashree Nandi
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Sheetal Parida
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Dipali Sharma
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
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6
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Devoy C, Flores Bueso Y, Tangney M. Understanding and harnessing triple-negative breast cancer-related microbiota in oncology. Front Oncol 2022; 12:1020121. [PMID: 36505861 PMCID: PMC9730816 DOI: 10.3389/fonc.2022.1020121] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 10/31/2022] [Indexed: 11/27/2022] Open
Abstract
Bacterial inhabitants of the body have the potential to play a role in various stages of cancer initiation, progression, and treatment. These bacteria may be distal to the primary tumour, such as gut microbiota, or local to the tissue, before or after tumour growth. Breast cancer is well studied in this context. Amongst breast cancer types, Triple Negative Breast Cancer (TNBC) is more aggressive, has fewer treatment options than receptor-positive breast cancers, has an overall worse prognosis and higher rates of reoccurrence. Thus, an in-depth understanding of the bacterial influence on TNBC progression and treatment is of high value. In this regard, the Gut Microbiota (GM) can be involved in various stages of tumour progression. It may suppress or promote carcinogenesis through the release of carcinogenic metabolites, sustenance of proinflammatory environments and/or the promotion of epigenetic changes in our genome. It can also mediate metastasis and reoccurrence through interactions with the immune system and has been recently shown to influence chemo-, radio-, and immune-therapies. Furthermore, bacteria have also been found to reside in normal and malignant breast tissue. Several studies have now described the breast and breast tumour microbiome, with the tumour microbiota of TNBC having the least taxonomic diversity among all breast cancer types. Here, specific conditions of the tumour microenvironment (TME) - low O2, leaky vasculature and immune suppression - are supportive of tumour selective bacterial growth. This innate bacterial ability could enable their use as delivery agents for various therapeutics or as diagnostics. This review aims to examine the current knowledge on bacterial relevance to TNBC and potential uses while examining some of the remaining unanswered questions regarding mechanisms underpinning observed effects.
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Affiliation(s)
- Ciaran Devoy
- Cancer Research@UCC, College of Medicine and Health, University College Cork, Cork, Ireland,SynBio Center, University College Cork, Cork, Ireland,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Yensi Flores Bueso
- Cancer Research@UCC, College of Medicine and Health, University College Cork, Cork, Ireland,SynBio Center, University College Cork, Cork, Ireland,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Mark Tangney
- Cancer Research@UCC, College of Medicine and Health, University College Cork, Cork, Ireland,SynBio Center, University College Cork, Cork, Ireland,APC Microbiome Ireland, University College Cork, Cork, Ireland,School of Pharmacy, College of Medicine and Health, University College Cork, Cork, Ireland,*Correspondence: Mark Tangney,
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7
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Fernandes D, Andreyev J. The Role of the Human Gut Microbiome in Inflammatory Bowel Disease and Radiation Enteropathy. Microorganisms 2022; 10:1613. [PMID: 36014031 PMCID: PMC9415405 DOI: 10.3390/microorganisms10081613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 12/04/2022] Open
Abstract
The human gut microbiome plays a key role in regulating host physiology. In a stable state, both the microbiota and the gut work synergistically. The overall homeostasis of the intestinal flora can be affected by multiple factors, including disease states and the treatments given for those diseases. In this review, we examine the relatively well-characterised abnormalities that develop in the microbiome in idiopathic inflammatory bowel disease, and compare and contrast them to those that are found in radiation enteropathy. We discuss how these changes may exert their effects at a molecular level, and the possible role of manipulating the microbiome through the use of a variety of therapies to reduce the severity of the underlying condition.
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Affiliation(s)
- Darren Fernandes
- The Department of Gastroenterology, United Lincolnshire NHS Trust, Lincoln County Hospital, Lincoln LN2 5QY, UK
| | - Jervoise Andreyev
- The Department of Gastroenterology, United Lincolnshire NHS Trust, Lincoln County Hospital, Lincoln LN2 5QY, UK
- The Biomedical Research Centre, Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
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8
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Teng NMY, Price CA, McKee AM, Hall LJ, Robinson SD. Exploring the impact of gut microbiota and diet on breast cancer risk and progression. Int J Cancer 2021; 149:494-504. [PMID: 33521932 PMCID: PMC8650995 DOI: 10.1002/ijc.33496] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/23/2020] [Accepted: 01/22/2021] [Indexed: 12/20/2022]
Abstract
There is emerging evidence that resident microbiota communities, that is, the microbiota, play a key role in cancer outcomes and anticancer responses. Although this has been relatively well studied in colorectal cancer and melanoma, other cancers, such as breast cancer (BrCa), have been largely overlooked to date. Importantly, many of the environmental factors associated with BrCa incidence and progression are also known to impact the microbiota, for example, diet and antibiotics. Here, we explore BrCa risk factors from large epidemiology studies and microbiota associations, and more recent studies that have directly profiled BrCa patients' gut microbiotas. We also discuss how in vivo studies have begun to unravel the immune mechanisms whereby the microbiota may influence BrCa responses, and finally we examine how diet and specific nutrients are also linked to BrCa outcomes. We also consider future research avenues and important considerations with respect to study design and implementation, and we highlight some of the important unresolved questions, which currently limit our overall understanding of the mechanisms underpinning microbiota-BrCa responses.
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Affiliation(s)
- Nancy M. Y. Teng
- Gut Microbes & HealthQuadram Institute Bioscience, Norwich Research ParkNorwichUK
| | - Christopher A. Price
- Gut Microbes & HealthQuadram Institute Bioscience, Norwich Research ParkNorwichUK
| | - Alastair M. McKee
- Gut Microbes & HealthQuadram Institute Bioscience, Norwich Research ParkNorwichUK
| | - Lindsay J. Hall
- Gut Microbes & HealthQuadram Institute Bioscience, Norwich Research ParkNorwichUK
- Norwich Medical SchoolUniversity of East Anglia, Norwich Research ParkNorwichUK
- Chair of Intestinal Microbiome, School of Life Sciences, ZIEL‐Institute for Food & HealthTechnical University of MunichFreisingGermany
| | - Stephen D. Robinson
- Gut Microbes & HealthQuadram Institute Bioscience, Norwich Research ParkNorwichUK
- School of Biological SciencesUniversity of East Anglia, Norwich Research ParkNorwichUK
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9
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Hollingsworth BA, Cassatt DR, DiCarlo AL, Rios CI, Satyamitra MM, Winters TA, Taliaferro LP. Acute Radiation Syndrome and the Microbiome: Impact and Review. Front Pharmacol 2021; 12:643283. [PMID: 34084131 PMCID: PMC8167050 DOI: 10.3389/fphar.2021.643283] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/04/2021] [Indexed: 12/12/2022] Open
Abstract
Study of the human microbiota has been a centuries-long endeavor, but since the inception of the National Institutes of Health (NIH) Human Microbiome Project in 2007, research has greatly expanded, including the space involving radiation injury. As acute radiation syndrome (ARS) is multisystemic, the microbiome niches across all areas of the body may be affected. This review highlights advances in radiation research examining the effect of irradiation on the microbiome and its potential use as a target for medical countermeasures or biodosimetry approaches, or as a medical countermeasure itself. The authors also address animal model considerations for designing studies, and the potential to use the microbiome as a biomarker to assess radiation exposure and predict outcome. Recent research has shown that the microbiome holds enormous potential for mitigation of radiation injury, in the context of both radiotherapy and radiological/nuclear public health emergencies. Gaps still exist, but the field is moving forward with much promise.
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Affiliation(s)
- Brynn A Hollingsworth
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, United States
| | - David R Cassatt
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, United States
| | - Andrea L DiCarlo
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, United States
| | - Carmen I Rios
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, United States
| | - Merriline M Satyamitra
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, United States
| | - Thomas A Winters
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, United States
| | - Lanyn P Taliaferro
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, United States
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10
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Lee HJ, Lee SH, Lee JH, Kim Y, Seong KM, Jin YW, Min KJ. Role of Commensal Microbes in the γ-Ray Irradiation-Induced Physiological Changes in Drosophila melanogaster. Microorganisms 2020; 9:microorganisms9010031. [PMID: 33374132 PMCID: PMC7824294 DOI: 10.3390/microorganisms9010031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/29/2022] Open
Abstract
Ionizing radiation induces biological/physiological changes and affects commensal microbes, but few studies have examined the relationship between the physiological changes induced by irradiation and commensal microbes. This study investigated the role of commensal microbes in the γ-ray irradiation-induced physiological changes in Drosophila melanogaster. The bacterial load was increased in 5 Gy irradiated flies, but irradiation decreased the number of operational taxonomic units. The mean lifespan of conventional flies showed no significant change by irradiation, whereas that of axenic flies was negatively correlated with the radiation dose. γ-Ray irradiation did not change the average number of eggs in both conventional and axenic flies. Locomotion of conventional flies was decreased after 5 Gy radiation exposure, whereas no significant change in locomotion activity was detected in axenic flies after irradiation. γ-Ray irradiation increased the generation of reactive oxygen species in both conventional and axenic flies, but the increase was higher in axenic flies. Similarly, the amounts of mitochondria were increased in irradiated axenic flies but not in conventional flies. These results suggest that axenic flies are more sensitive in their mitochondrial responses to radiation than conventional flies, and increased sensitivity leads to a reduced lifespan and other physiological changes in axenic flies.
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Affiliation(s)
- Hwa-Jin Lee
- Department of Biological Sciences, Inha University, Incheon 22212, Korea; (H.-J.L.); (S.-H.L.); (J.-H.L.)
| | - Shin-Hae Lee
- Department of Biological Sciences, Inha University, Incheon 22212, Korea; (H.-J.L.); (S.-H.L.); (J.-H.L.)
| | - Ji-Hyeon Lee
- Department of Biological Sciences, Inha University, Incheon 22212, Korea; (H.-J.L.); (S.-H.L.); (J.-H.L.)
| | - Yongjoong Kim
- Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (Y.K.); (K.M.S.); (Y.W.J.)
| | - Ki Moon Seong
- Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (Y.K.); (K.M.S.); (Y.W.J.)
| | - Young Woo Jin
- Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (Y.K.); (K.M.S.); (Y.W.J.)
| | - Kyung-Jin Min
- Department of Biological Sciences, Inha University, Incheon 22212, Korea; (H.-J.L.); (S.-H.L.); (J.-H.L.)
- Correspondence:
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11
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Mao A, Sun C, Katsube T, Wang B. A Minireview on Gastrointestinal Microbiota and Radiosusceptibility. Dose Response 2020; 18:1559325820963859. [PMID: 33239996 PMCID: PMC7672743 DOI: 10.1177/1559325820963859] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/20/2020] [Accepted: 09/09/2020] [Indexed: 12/13/2022] Open
Abstract
Gastrointestinal (GI) microbiota maintains a symbiotic relationship with the host and plays a key role in modulating many important biological processes and functions of the host, such as metabolism, inflammation, immune and stress response. It is becoming increasingly apparent that GI microbiota is susceptible to a wide range of environmental factors and insults, for examples, geographic location of birth, diet, use of antibiotics, and exposure to radiation. Alterations in GI microbiota link to various diseases, including radiation-induced disorders. In addition, GI microbiota composition could be used as a biomarker to estimate radiosusceptibility and radiation health risk in the host. In this minireview, we summarized the documented studies on radiation-induced alterations in GI microbiota and the relationship between GI microbiota and radiosusceptibility of the host, and mainly discussed the possible mechanisms underlying GI microbiota influencing the outcome of radiation response in humans and animal models. Furthermore, we proposed that GI microbiota manipulation may be used to reduce radiation injury and improve the health of the host.
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Affiliation(s)
- Aihong Mao
- Gansu Provincial Academic Institute for Medical Research, Lanzhou, People's Republic of China
| | - Chao Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, People's Republic of China
| | - Takanori Katsube
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Bing Wang
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
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12
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Shao L, Li M, Zhang B, Chang P. Bacterial dysbiosis incites Th17 cell revolt in irradiated gut. Biomed Pharmacother 2020; 131:110674. [PMID: 32866810 DOI: 10.1016/j.biopha.2020.110674] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 08/10/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022] Open
Abstract
Th17 cells are critical members in mediating immune responses of adaptive immunity. In humans and mice, gut is a main site where Th17 cells are resided, and Th17 cell polarization also occurs in the gut. This process can be mediated by many factors, such as commensal bacteria, dendritic cells and cytokines, such as TGF-β and IL-6. Physiologically, polarized Th17 cells function in anti-infection and maintaining the integrity of intestinal epithelium. However, Th17 cells are plastic. For example, they will become pro-inflammatory cells if being exposed to IL-23. The pathogenic roles of Th17 cells have been well documented in inflammatory bowel disease. Besides, Th17 cells can accumulate in irradiated gut as well. Critically, radiation enteritis and inflammatory bowel disease present several similarities in disease pathology and pathophysiology. Herein, bacterial dysbiosis highly correlates with the pathogenicity of Th17 cells in inflammatory bowel disease. To our knowledge, radiation serves as a factor in inducing bacterial dysbiosis. Using this action, can Th17 cells be incited to promote inflammation in irradiated gut? In this review, we will sequentially introduce polarization of Th17 cells at steady state, radiation-induced Th17 accumulation in the gut, and advances in the management of radiation enteritis by using pharmacological therapy for bacterial dysbiosis.
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Affiliation(s)
- Lihong Shao
- Department of Radiation Oncology & Therapy, Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Man Li
- Department of Radiation Oncology & Therapy, Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Boyin Zhang
- Department of Orthopedics Surgery, China-Japan Union Hospital of Jilin University, 130033, Changchun, China.
| | - Pengyu Chang
- Department of Radiation Oncology & Therapy, Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, Jilin, 130021, China; Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.
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Siddiqui R, Akbar N, Khan NA. Gut microbiome and human health under the space environment. J Appl Microbiol 2020; 130:14-24. [PMID: 32692438 DOI: 10.1111/jam.14789] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/10/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022]
Abstract
The gut microbiome is well recognized to have a pivotal role in regulation of the health and behaviour of the host, affecting digestion, metabolism, immunity, and has been linked to changes in bones, muscles and the brain, to name a few. However, the impact of microgravity environment on gut bacteria is not well understood. In space environments, astronauts face several health issues including stress, high iron diet, radiation and being in a closed system during extended space missions. Herein, we discuss the role of gut bacteria in the space environment, in relation to factors such as microgravity, radiation and diet. Gut bacteria may exact their effects by synthesis of molecules, their absorption, and through physiological effects on the host. Moreover we deliberate the role of these challenges in the dysbiosis of the human microbiota and possible dysregulation of the immune system.
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Affiliation(s)
- R Siddiqui
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, University City, Sharjah, United Arab Emirates
| | - N Akbar
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, University City, Sharjah, United Arab Emirates
| | - N A Khan
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, University City, Sharjah, United Arab Emirates
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14
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Gao YL, Shao LH, Dong LH, Chang PY. Gut commensal bacteria, Paneth cells and their relations to radiation enteropathy. World J Stem Cells 2020; 12:188-202. [PMID: 32266051 PMCID: PMC7118286 DOI: 10.4252/wjsc.v12.i3.188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/12/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent self-renewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein, the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.
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Affiliation(s)
- Yan-Li Gao
- Department of Pediatric Ultrasound, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Hong Shao
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Hua Dong
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Peng-Yu Chang
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China.
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15
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Eslami-S Z, Majidzadeh-A K, Halvaei S, Babapirali F, Esmaeili R. Microbiome and Breast Cancer: New Role for an Ancient Population. Front Oncol 2020; 10:120. [PMID: 32117767 PMCID: PMC7028701 DOI: 10.3389/fonc.2020.00120] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 01/22/2020] [Indexed: 12/11/2022] Open
Abstract
There are many risk factors associated with breast cancer (BC) such as the familial history of BC, using hormone replacement therapy, obesity, personal habits, and other clinical factors; however, not all BC cases are attributed to these risk factors. Recent researches show a correlation between patient microbiome and BC suggested as a new risk factor. The present review article aimed at evaluating the role of the microbiome as a risk factor in the occurrence of BC, investigating the proposed mechanisms of interaction between the microbiome and human genes involved in BC, and assessing the impact of the altered composition of breast, gut, and milk microbiome in the physiological status of normal breast as well as cancerous or non-cancerous breast lesions. The study also evaluated the growing evidence that these altered populations may hinder chemotherapeutic treatment. The role of microbiome in the development and maintenance of inflammation, estrogen metabolism, and epigenetic alterations was properly investigated. Finally, clinical and therapeutic applications of the microbiome- e.g., probiotics, microbiome genome modulation, and engineered microbiome enzymes in the management of BC were reviewed.
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Affiliation(s)
- Zahra Eslami-S
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.,Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, Montpellier, France
| | - Keivan Majidzadeh-A
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Sina Halvaei
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Fatemeh Babapirali
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.,University of Science and Culture, Basic Science and Advanced Technologies in Biology, Tehran, Iran
| | - Rezvan Esmaeili
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
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16
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Sahly N, Moustafa A, Zaghloul M, Salem TZ. Effect of radiotherapy on the gut microbiome in pediatric cancer patients: a pilot study. PeerJ 2019; 7:e7683. [PMID: 31579590 PMCID: PMC6761921 DOI: 10.7717/peerj.7683] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 08/16/2019] [Indexed: 12/17/2022] Open
Abstract
The incidence of pediatric cancer is lower than that of adult cancer worldwide. However, the former has detrimental side effects on the health of individuals, even after the cancer is cured, due to the impact of treatment on development. Recently, correlations have been made between the gut microbiome and cancer in several studies but only on adult participants. There is always a complication of dealing with pediatric cancer treatment protocols because they usually include a combination of chemotherapy, radiotherapy, and intensive prophylactic antibiotics. In the current study, a pilot study was conducted to analyze ten fecal samples from three pediatric cancer patients, suffering from rhabdomyosarcoma near their pelvic region, and two healthy individuals. A correlation between microbial composition and response to treatment was reported, in which the responders had generally a lower microbial diversity compared to non-responders. In addition, nucleotide changes and deletions in the tested 16S rRNA sequences post radiotherapy were detected. Despite the small sample size used in the experiments due to the uncommon rhabdomyosarcoma in children, the results can help in understanding the influence of radiotherapy on the gut microbiome in pediatric cancer patients. More work with larger sample size and different cancer types need to be conducted to understand the influence of radiotherapy on gut microbiome to mitigate the deleterious impact of radiation on treated children.
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Affiliation(s)
- Nourhan Sahly
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt
- Biotechnology Graduate Program, American University in Cairo, New Cairo, Egypt
| | - Ahmed Moustafa
- Biotechnology Graduate Program, American University in Cairo, New Cairo, Egypt
- Department of Biology, American University in Cairo, New Cairo, Egypt
| | - Mohamed Zaghloul
- Radiation Oncology Department, National Cancer Institute, Cairo, Egypt
- Children’s Cancer Hospital Egypt 57357 (CCHE 57357), Cairo, Egypt
| | - Tamer Z. Salem
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt
- Microbial Genetics Department, AGERI, ARC, Giza, Egypt
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17
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Food Supplements to Mitigate Detrimental Effects of Pelvic Radiotherapy. Microorganisms 2019; 7:microorganisms7040097. [PMID: 30987157 PMCID: PMC6518429 DOI: 10.3390/microorganisms7040097] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/21/2019] [Accepted: 03/28/2019] [Indexed: 12/12/2022] Open
Abstract
Pelvic radiotherapy has been frequently reported to cause acute and late onset gastrointestinal (GI) toxicities associated with significant morbidity and mortality. Although the underlying mechanisms of pelvic radiation-induced GI toxicity are poorly understood, they are known to involve a complex interplay between all cell types comprising the intestinal wall. Furthermore, increasing evidence states that the human gut microbiome plays a role in the development of radiation-induced health damaging effects. Gut microbial dysbiosis leads to diarrhea and fatigue in half of the patients. As a result, reinforcement of the microbiome has become a hot topic in various medical disciplines. To counteract GI radiotoxicities, apart from traditional pharmacological compounds, adjuvant therapies are being developed including food supplements like vitamins, prebiotics, and probiotics. Despite the easy, cheap, safe, and feasible approach to protect patients against acute radiation-induced toxicity, clinical trials have yielded contradictory results. In this review, a detailed overview is given of the various clinical, intestinal manifestations after pelvic irradiation as well as the role of the gut microbiome herein. Furthermore, whilst discussing possible strategies to prevent these symptoms, food supplements are presented as auspicious, prophylactic, and therapeutic options to mitigate acute pelvic radiation-induced GI injury by exploring their molecular mechanisms of action.
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18
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Kumagai T, Rahman F, Smith AM. The Microbiome and Radiation Induced-Bowel Injury: Evidence for Potential Mechanistic Role in Disease Pathogenesis. Nutrients 2018; 10:E1405. [PMID: 30279338 PMCID: PMC6213333 DOI: 10.3390/nu10101405] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 09/18/2018] [Accepted: 09/25/2018] [Indexed: 12/15/2022] Open
Abstract
Radiotherapy has played a major role in both the curative and palliative treatment of cancer patients for decades. However, its toxic effect to the surrounding normal healthy tissue remains a major drawback. In cases of intra-abdominal and/or pelvic malignancy, healthy bowel is inevitably included in the radiation field, causing undesirable consequences that subsequently manifest as radiation-induced bowel injury, which is associated with significant morbidity and mortality. The pathophysiology of radiation-induced bowel injury is poorly understood, although we now know that it derives from a complex interplay of epithelial injury and alterations in the enteric immune, nervous, and vascular systems in genetically predisposed individuals. Furthermore, evidence supporting a pivotal role for the gut microbiota in the development of radiation-induced bowel injury has been growing. In this review, we aim to appraise our current understanding of radiation-induced bowel injury and the role of the microbiome in its pathogenesis as well as prevention and treatment. Greater understanding of the relationship between the disease mechanism of radiation-induced bowel injury and gut microbiome might shed light on potential future prevention and treatment strategies through the modification of a patient's gut microbiome.
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Affiliation(s)
- Tomoko Kumagai
- UCL Eastman Dental Institute, University College London (UCL), Rayne Institute, 5 University Street, London WC1E 6JF, UK.
| | - Farooq Rahman
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK.
| | - Andrew M Smith
- UCL Eastman Dental Institute, University College London (UCL), Rayne Institute, 5 University Street, London WC1E 6JF, UK.
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Moussa L, Usunier B, Demarquay C, Benderitter M, Tamarat R, Sémont A, Mathieu N. Bowel Radiation Injury: Complexity of the Pathophysiology and Promises of Cell and Tissue Engineering. Cell Transplant 2018; 25:1723-1746. [PMID: 27197023 DOI: 10.3727/096368916x691664] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Ionizing radiation is effective to treat malignant pelvic cancers, but the toxicity to surrounding healthy tissue remains a substantial limitation. Early and late side effects not only limit the escalation of the radiation dose to the tumor but may also be life-threatening in some patients. Numerous preclinical studies determined specific mechanisms induced after irradiation in different compartments of the intestine. This review outlines the complexity of the pathogenesis, highlighting the roles of the epithelial barrier in the vascular network, and the inflammatory microenvironment, which together lead to chronic fibrosis. Despite the large number of pharmacological molecules available, the studies presented in this review provide encouraging proof of concept regarding the use of mesenchymal stromal cell (MSC) therapy to treat radiation-induced intestinal damage. The therapeutic efficacy of MSCs has been demonstrated in animal models and in patients, but an enormous number of cells and multiple injections are needed due to their poor engraftment capacity. Moreover, it has been observed that although MSCs have pleiotropic effects, some intestinal compartments are less restored after a high dose of irradiation. Future research should seek to optimize the efficacy of the injected cells, particularly with regard to extending their life span in the irradiated tissue. Moreover, improving the host microenvironment, combining MSCs with other specific regenerative cells, or introducing new tissue engineering strategies could be tested as methods to treat the severe side effects of pelvic radiotherapy.
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Affiliation(s)
- Lara Moussa
- Institut de Radioprotection et de SÛreté Nucléaire (IRSN), PRP-HOM/SRBE/LR2I, Fontenay-aux-Roses, France
| | - Benoît Usunier
- Institut de Radioprotection et de SÛreté Nucléaire (IRSN), PRP-HOM/SRBE/LR2I, Fontenay-aux-Roses, France
| | - Christelle Demarquay
- Institut de Radioprotection et de SÛreté Nucléaire (IRSN), PRP-HOM/SRBE/LR2I, Fontenay-aux-Roses, France
| | - Marc Benderitter
- Institut de Radioprotection et de SÛreté Nucléaire (IRSN), PRP-HOM/SRBE/LR2I, Fontenay-aux-Roses, France
| | - Radia Tamarat
- Institut de Radioprotection et de SÛreté Nucléaire (IRSN), PRP-HOM/SRBE/LR2I, Fontenay-aux-Roses, France
| | - Alexandra Sémont
- Institut de Radioprotection et de SÛreté Nucléaire (IRSN), PRP-HOM/SRBE/LR2I, Fontenay-aux-Roses, France
| | - Noëlle Mathieu
- Institut de Radioprotection et de SÛreté Nucléaire (IRSN), PRP-HOM/SRBE/LR2I, Fontenay-aux-Roses, France
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20
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Goudarzi M, Mak TD, Jacobs JP, Moon BH, Strawn SJ, Braun J, Brenner DJ, Fornace AJ, Li HH. An Integrated Multi-Omic Approach to Assess Radiation Injury on the Host-Microbiome Axis. Radiat Res 2016; 186:219-34. [PMID: 27512828 PMCID: PMC5304359 DOI: 10.1667/rr14306.1] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Medical responders to radiological and nuclear disasters currently lack sufficient high-throughput and minimally invasive biodosimetry tools to assess exposure and injury in the affected populations. For this reason, we have focused on developing robust radiation exposure biomarkers in easily accessible biofluids such as urine, serum and feces. While we have previously reported on urine and serum biomarkers, here we assessed perturbations in the fecal metabolome resulting from exposure to external X radiation in vivo. The gastrointestinal (GI) system is of particular importance in radiation biodosimetry due to its constant cell renewal and sensitivity to radiation-induced injury. While the clinical GI symptoms such as pain, bloating, nausea, vomiting and diarrhea are manifested after radiation exposure, no reliable bioindicator has been identified for radiation-induced gastrointestinal injuries. To this end, we focused on determining a fecal metabolomic signature in X-ray irradiated mice. There is overwhelming evidence that the gut microbiota play an essential role in gut homeostasis and overall health. Because the fecal metabolome is tightly correlated with the composition and diversity of the microorganism in the gut, we also performed fecal 16S rRNA sequencing analysis to determine the changes in the microbial composition postirradiation. We used in-house bioinformatics tools to integrate the 16S rRNA sequencing and metabolomic data, and to elucidate the gut integrated ecosystem and its deviations from a stable host-microbiome state that result from irradiation. The 16S rRNA sequencing results indicated that radiation caused remarkable alterations of the microbiome in feces at the family level. Increased abundance of common members of Lactobacillaceae and Staphylococcaceae families, and decreased abundances of Lachnospiraceae, Ruminococcaceae and Clostridiaceae families were found after 5 and 12 Gy irradiation. The metabolomic data revealed statistically significant changes in the microbial-derived products such as pipecolic acid, glutaconic acid, urobilinogen and homogentisic acid. In addition, significant changes were detected in bile acids such as taurocholic acid and 12-ketodeoxycholic acid. These changes may be associated with the observed shifts in the abundance of intestinal microbes, such as R. gnavus , which can transform bile acids.
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Affiliation(s)
- Maryam Goudarzi
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
| | - Tytus D. Mak
- Mass Spectrometry Data Center, National Institute of Standards and Technology, Gaithersburg, Maryland
| | - Jonathan P. Jacobs
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Bo-Hyun Moon
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
| | - Steven J. Strawn
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
| | - Jonathan Braun
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - David J. Brenner
- Center for Radiological Research, Columbia University, New York, New York
| | - Albert J. Fornace
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Heng-Hong Li
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
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21
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Probiotics to prevent gastrointestinal toxicity from cancer therapy: an interpretive review and call to action. Curr Opin Support Palliat Care 2016; 9:157-62. [PMID: 25872116 DOI: 10.1097/spc.0000000000000134] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW There is currently an unmet need for agents that can prevent the gastrointestinal toxicity (mucositis and enteritis) associated with chemotherapy and radiation therapy of abdominal and pelvic cancers. Herein we provide an overview of how manipulation of the gut microbiota by probiotic administration affects these gastrointestinal symptoms. We focus this review on published human trials and also provide suggestions on how the field can move forward. RECENT FINDINGS Several clinical trials of varying design, patient populations and probiotic products have been reported. Lactobacillus probiotics of adequate dosage demonstrate a potential to reduce gastrointestinal toxicity when administered prophylactically. Common study limitations prevent the widespread adoption of this practice at this point but are informative for rational design of future trials. SUMMARY No single probiotic strain or product has emerged from human clinical trials for this indication. Further human studies are required to address limitations in the current literature. Preclinical model data should be used to inform the rational design of these new clinical trials to adequately address this important question.
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22
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Pedroso SHSP, Vieira AT, Bastos RW, Oliveira JS, Cartelle CT, Arantes RME, Soares PMG, Generoso SV, Cardoso VN, Teixeira MM, Nicoli JR, Martins FS. Evaluation of mucositis induced by irinotecan after microbial colonization in germ-free mice. Microbiology (Reading) 2015. [DOI: 10.1099/mic.0.000149] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Silvia H. S. P. Pedroso
- Department of Microbiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Angélica T. Vieira
- Department of Microbiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Department of Biochemistry and Immunology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Rafael W. Bastos
- Department of Microbiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Jamil S. Oliveira
- Department of Biochemistry and Immunology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Christiane T. Cartelle
- Department of General Pathology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Rosa M. E. Arantes
- Department of General Pathology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Pedro M. G. Soares
- Department of Morphology, Medical School, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Simone V. Generoso
- Department of Basic Nursing, School of Nursing, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Valbert N. Cardoso
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Mauro M. Teixeira
- Department of Biochemistry and Immunology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Jacques R. Nicoli
- Department of Microbiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Flaviano S. Martins
- Department of Microbiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Chang PY, Qu YQ, Wang J, Dong LH. The potential of mesenchymal stem cells in the management of radiation enteropathy. Cell Death Dis 2015; 6:e1840. [PMID: 26247725 PMCID: PMC4558492 DOI: 10.1038/cddis.2015.189] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 06/02/2015] [Accepted: 06/08/2015] [Indexed: 12/20/2022]
Abstract
Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies.
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Affiliation(s)
- P-Y Chang
- 1] Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China [2] Electrochemical State Key Laboratory, Changchun Institute of Applied Chemistry Academy of Science, Changchun 130021, China
| | - Y-Q Qu
- Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China
| | - J Wang
- Electrochemical State Key Laboratory, Changchun Institute of Applied Chemistry Academy of Science, Changchun 130021, China
| | - L-H Dong
- Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China
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24
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Ritchie LE, Taddeo SS, Weeks BR, Lima F, Bloomfield SA, Azcarate-Peril MA, Zwart SR, Smith SM, Turner ND. Space Environmental Factor Impacts upon Murine Colon Microbiota and Mucosal Homeostasis. PLoS One 2015; 10:e0125792. [PMID: 26083373 PMCID: PMC4470690 DOI: 10.1371/journal.pone.0125792] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 03/26/2015] [Indexed: 01/01/2023] Open
Abstract
Astronaut intestinal health may be impacted by microgravity, radiation, and diet. The aim of this study was to characterize how high and low linear energy transfer (LET) radiation, microgravity, and elevated dietary iron affect colon microbiota (determined by 16S rDNA pyrosequencing) and colon function. Three independent experiments were conducted to achieve these goals: 1) fractionated low LET γ radiation (137Cs, 3 Gy, RAD), high Fe diet (IRON) (650 mg/kg diet), and a combination of low LET γ radiation and high Fe diet (IRON+RAD) in male Sprague-Dawley rats; 2) high LET 38Si particle exposure (0.050 Gy), 1/6 G partial weight bearing (PWB), and a combination of high LET38Si particle exposure and PWB in female BalbC/ByJ mice; and 3) 13 d spaceflight in female C57BL/6 mice. Low LET radiation, IRON and spaceflight increased Bacteroidetes and decreased Firmicutes. RAD and IRON+RAD increased Lactobacillales and lowered Clostridiales compared to the control (CON) and IRON treatments. Low LET radiation, IRON, and spaceflight did not significantly affect diversity or richness, or elevate pathogenic genera. Spaceflight increased Clostridiales and decreased Lactobacillales, and similar trends were observed in the experiment using a ground-based model of microgravity, suggesting altered gravity may affect colonic microbiota. Although we noted no differences in colon epithelial injury or inflammation, spaceflight elevated TGFβ gene expression. Microbiota and mucosal characterization in these models is a first step in understanding the impact of the space environment on intestinal health.
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Affiliation(s)
- Lauren E. Ritchie
- Intercollegiate Faculty of Genetics, Texas A&M University, College Station, Texas, United States of America
| | - Stella S. Taddeo
- Nutrition & Food Science Department, Texas A&M University, College Station, Texas, United States of America
| | - Brad R. Weeks
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, United States of America
| | - Florence Lima
- Division of Nephrology, Department of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
| | - Susan A. Bloomfield
- Department of Health and Kinesiology, Texas A&M University, College Station, Texas, United States of America
| | - M. Andrea Azcarate-Peril
- Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Sara R. Zwart
- Human Health and Performance Directorate, NASA Lyndon B. Johnson Space Center, Houston, Texas, United States of America
| | - Scott M. Smith
- Human Health and Performance Directorate, NASA Lyndon B. Johnson Space Center, Houston, Texas, United States of America
| | - Nancy D. Turner
- Intercollegiate Faculty of Genetics, Texas A&M University, College Station, Texas, United States of America
- Nutrition & Food Science Department, Texas A&M University, College Station, Texas, United States of America
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Ratikan JA, Micewicz ED, Xie MW, Schaue D. Radiation takes its Toll. Cancer Lett 2015; 368:238-45. [PMID: 25819030 DOI: 10.1016/j.canlet.2015.03.031] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Revised: 03/19/2015] [Accepted: 03/20/2015] [Indexed: 12/13/2022]
Abstract
The ability to recognize and respond to universal molecular patterns on invading microorganisms allows our immune system to stay on high alert, sensing danger to our self-integrity. Our own damaged cells and tissues in pathological situations activate similar warning systems as microbes. In this way, the body is able to mount a response that is appropriate to the danger. Toll-like receptors are at the heart of this pattern recognition system that initiates innate pro-oxidant, pro-inflammatory signaling cascades and ultimately bridges recognition of danger to adaptive immunity. The acute inflammatory lesions that are formed segue into resolution of inflammation, repair and healing or, more dysfunctionally, into chronic inflammation, autoimmunity, excessive tissue damage and carcinogenesis. Redox is at the nexus of this decision making process and is the point at which ionizing radiation initially intercepts to trigger similar responses to self-damage. In this review we discuss our current understanding of how radiation-damaged cells interact with Toll-like receptors and how the immune systems interprets these radiation-induced danger signals in the context of whole-body exposures and during local tumor irradiation.
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Affiliation(s)
- Josephine A Ratikan
- Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
| | - Ewa D Micewicz
- Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
| | - Michael W Xie
- Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
| | - Dörthe Schaue
- Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA.
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26
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Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, Bruley des Varannes S, Le Vacon F, de La Cochetière MF. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications. Aliment Pharmacol Ther 2014; 40:409-21. [PMID: 25040088 DOI: 10.1111/apt.12878] [Citation(s) in RCA: 212] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 12/21/2013] [Accepted: 06/25/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND Gastrointestinal mucositis is defined as inflammation and/or ulcers of the gastrointestinal tract occurring as a complication of chemotherapy and radiation therapy, and affects about 50% of all cancer patients. AIM To assess the role of gut microbiota in the pathogenesis of gastrointestinal mucositis and the potential for manipulations of the microbiota to prevent and to treat mucositis. METHODS Search of the literature published in English using Medline, Scopus and the Cochrane Library, with main search terms 'intestinal microbiota', 'bacteremia', 'mucositis', 'chemotherapy-induced diarrhoea', 'chemotherapy-induced mucositis', 'radiotherapy-induced mucositis'. RESULTS The gut microbiota plays a major role in the maintenance of intestinal homoeostasis and integrity. Patients receiving cytotoxic and radiation therapy exhibit marked changes in intestinal microbiota, with most frequently, decrease in Bifidobacterium, Clostridium cluster XIVa, Faecalibacterium prausnitzii, and increase in Enterobacteriaceae and Bacteroides. These modifications may contribute to the development of mucositis, particularly diarrhoea and bacteraemia. The prevention of cancer therapy-induced mucositis by probiotics has been investigated in randomised clinical trials with some promising results. Three of six trials reported a significantly decreased incidence of diarrhoea. One trial reported a decrease in infectious complications. CONCLUSIONS The gut microbiota may play a major role in the pathogenesis of mucositis through the modification of intestinal barrier function, innate immunity and intestinal repair mechanisms. Better knowledge of these effects may lead to new therapeutic approaches and to the identification of predictive markers of mucositis.
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Affiliation(s)
- Y Touchefeu
- Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire de Nantes, Nantes, France
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27
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Abstract
The etiology of colon cancer is complex, yet it is undoubtedly impacted by intestinal microbiota. Whether the contribution to colon carcinogenesis is generated through the presence of an overall dysbiosis or by specific pathogens is still a matter for debate. However, it is apparent that interactions between microbiota and the host are mediated by a variety of processes, including signaling cascades, the immune system, host metabolism, and regulation of gene transcription. To fully appreciate the role of microbiota in colon carcinogenesis, it will be necessary to expand efforts to define populations in niche environments, such as colonic crypts, explore cross talk between the host and the microbiota, and more completely define the metabolomic profile of the microbiota. These efforts must be pursued with appreciation that dietary substrates and other environmental modifiers mediate changes in the microbiota, as well as their metabolism and functional characteristics.
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Williams JP, McBride WH. After the bomb drops: a new look at radiation-induced multiple organ dysfunction syndrome (MODS). Int J Radiat Biol 2011; 87:851-68. [PMID: 21417595 PMCID: PMC3314299 DOI: 10.3109/09553002.2011.560996] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE There is increasing concern that, since the Cold War era, there has been little progress regarding the availability of medical countermeasures in the event of either a radiological or nuclear incident. Fortunately, since much is known about the acute consequences that are likely to be experienced by an exposed population, the probability of survival from the immediate hematological crises after total body irradiation (TBI) has improved in recent years. Therefore focus has begun to shift towards later down-stream effects, seen in such organs as the gastrointestinal tract (GI), skin, and lung. However, the mechanisms underlying therapy-related normal tissue late effects, resulting from localised irradiation, have remained somewhat elusive and even less is known about the development of the delayed syndrome seen in the context of whole body exposures, when it is likely that systemic perturbations may alter tissue microenvironments and homeostasis. CONCLUSIONS The sequence of organ failures observed after near-lethal TBI doses are similar in many ways to that of multiple organ dysfunction syndrome (MODS), leading to multiple organ failure (MOF). In this review, we compare the mechanistic pathways that underlie both MODS and delayed normal tissue effects since these may impact on strategies to identify radiation countermeasures.
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Affiliation(s)
- Jacqueline P Williams
- Department of Radiation Oncology, University of Rochester Medical Center Rochester, NY 14642, USA.
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29
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30
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DiCarlo AL, Maher C, Hick JL, Hanfling D, Dainiak N, Chao N, Bader JL, Coleman CN, Weinstock DM. Radiation injury after a nuclear detonation: medical consequences and the need for scarce resources allocation. Disaster Med Public Health Prep 2011; 5 Suppl 1:S32-44. [PMID: 21402810 DOI: 10.1001/dmp.2011.17] [Citation(s) in RCA: 176] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A 10-kiloton (kT) nuclear detonation within a US city could expose hundreds of thousands of people to radiation. The Scarce Resources for a Nuclear Detonation Project was undertaken to guide community planning and response in the aftermath of a nuclear detonation, when demand will greatly exceed available resources. This article reviews the pertinent literature on radiation injuries from human exposures and animal models to provide a foundation for the triage and management approaches outlined in this special issue. Whole-body doses >2 Gy can produce clinically significant acute radiation syndrome (ARS), which classically involves the hematologic, gastrointestinal, cutaneous, and cardiovascular/central nervous systems. The severity and presentation of ARS are affected by several factors, including radiation dose and dose rate, interindividual variability in radiation response, type of radiation (eg, gamma alone, gamma plus neutrons), partial-body shielding, and possibly age, sex, and certain preexisting medical conditions. The combination of radiation with trauma, burns, or both (ie, combined injury) confers a worse prognosis than the same dose of radiation alone. Supportive care measures, including fluid support, antibiotics, and possibly myeloid cytokines (eg, granulocyte colony-stimulating factor), can improve the prognosis for some irradiated casualties. Finally, expert guidance and surge capacity for casualties with ARS are available from the Radiation Emergency Medical Management Web site and the Radiation Injury Treatment Network.
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Affiliation(s)
- Andrea L DiCarlo
- Radiation/Nuclear Countermeasures Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA
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31
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Abstract
The body senses "danger" from "damaged self" molecules through members of the same receptor superfamily it uses for microbial "non-self", triggering canonical signaling pathways that lead to the generation of acute inflammatory responses. For this reason, the biology of normal tissue responses to moderate and clinically relevant doses of radiation is inextricably connected to innate immunity. The complex sequence of inflammatory events that ensues causes further cell and tissue damage to eliminate potential invaders but also leads to cytoprotective responses that limit the spread of damage and to wound healing through tissue regeneration or replacement. These sequential processes are orchestrated through multiple feedback control mechanisms involving cyclical production of free radicals and cytokines that are common to both radiation and immune signaling. This requires a concerted effort by resident tissue and inflammatory cell types, with macrophages apparently leading the way. The initial response to moderate doses of radiation therefore feeds into a pro-inflammatory paradigm whose eventual outcome is critically dependent upon the properties of the immune cells that are involved in tissue damage, regeneration and repair and that are in part under genetic influence. Importantly, these canonical pathways provide targets for interventions aimed at modifying normal tissue radiation responses. In this review, we examine areas of intersection between innate immunity and normal tissue radiobiology.
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Affiliation(s)
- Dörthe Schaue
- Division of Molecular and Cellular Oncology, Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1714
| | - William H. McBride
- Division of Molecular and Cellular Oncology, Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1714
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32
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Williams JP, Brown SL, Georges GE, Hauer-Jensen M, Hill RP, Huser AK, Kirsch DG, Macvittie TJ, Mason KA, Medhora MM, Moulder JE, Okunieff P, Otterson MF, Robbins ME, Smathers JB, McBride WH. Animal models for medical countermeasures to radiation exposure. Radiat Res 2010; 173:557-78. [PMID: 20334528 PMCID: PMC3021126 DOI: 10.1667/rr1880.1] [Citation(s) in RCA: 335] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Since September 11, 2001, there has been the recognition of a plausible threat from acts of terrorism, including radiological or nuclear attacks. A network of Centers for Medical Countermeasures against Radiation (CMCRs) has been established across the U.S.; one of the missions of this network is to identify and develop mitigating agents that can be used to treat the civilian population after a radiological event. The development of such agents requires comparison of data from many sources and accumulation of information consistent with the "Animal Rule" from the Food and Drug Administration (FDA). Given the necessity for a consensus on appropriate animal model use across the network to allow for comparative studies to be performed across institutions, and to identify pivotal studies and facilitate FDA approval, in early 2008, investigators from each of the CMCRs organized and met for an Animal Models Workshop. Working groups deliberated and discussed the wide range of animal models available for assessing agent efficacy in a number of relevant tissues and organs, including the immune and hematopoietic systems, gastrointestinal tract, lung, kidney and skin. Discussions covered the most appropriate species and strains available as well as other factors that may affect differential findings between groups and institutions. This report provides the workshop findings.
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Affiliation(s)
- Jacqueline P Williams
- Department of Radiation Oncology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 647, Rochester, NY 14642, USA.
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33
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Abstract
PURPOSE OF REVIEW Injury to the small bowel from ionizing radiation occurs commonly in patients undergoing cancer therapy and less commonly in instances of accidental radiation overexposure. Several lines of evidence now suggest that dynamic interactions between the host's enteric microbiota and innate immune system are important in modulating the intestinal response to radiation. Here, we will review recent developments in the area of acute radiation enteropathy and examine the current state of knowledge regarding the impact of host-microbial interactions in the process. RECENT FINDINGS There is promise in the development and testing of new clinical biomarkers including serum citrulline. Toll-like receptor agonists and innate immune system signaling pathways including nuclear factor-kappa B profoundly alter intestinal epithelial cell apoptosis and crypt survival after radiation exposure. Germ-free conditions, probiotics and antibiotics are each identified as modifiers of disease development and course. A human study suggested that luminal microbiota composition may influence the host's intestinal response to radiation and may change in those developing postradiation diarrhea. SUMMARY New knowledge implies that investigations aimed at deciphering the microbiome-host interactions before and after small bowl radiation injury may eventually allow prediction of disease course and offer opportunities for the development of novel therapeutic or prophylactic strategies.
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34
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Abstract
We describe a method for treating germ-free (GF) mice with gamma-irradiation and transplanting them with normal or genetically manipulated bone marrow while maintaining their GF status. This approach revealed that GF mice are markedly resistant to lethal radiation enteritis. Furthermore, administering lethal doses of total body irradiation to GF mice produces markedly fewer apoptotic endothelial cells and lymphocytes in the mesenchymal cores of their small intestinal villi, compared with conventionally raised animals that have acquired a microbiota from birth. Analysis of GF and conventionally raised Rag1-/- mice disclosed that mature lymphocytes are not required for the development of lethal radiation enteritis or the microbiota-associated enhancement of endothelial radiosensitivity. Studies of gnotobiotic knockout mice that lack fasting-induced adipose factor (Fiaf), a fibrinogen/angiopoietin-like protein normally secreted from the small intestinal villus epithelium and suppressed by the microbiota, showed that Fiaf deficiency results in loss of resistance of villus endothelial and lymphocyte populations to radiation-induced apoptosis. Together, these findings provide insights about the cellular and molecular targets involved in microbial regulation of intestinal radiosensitivity.
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Affiliation(s)
- Peter A Crawford
- Center for Genome Sciences and Department of Molecular Biology, Washington University School of Medicine, St. Louis, MO 63108, USA
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35
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Tanaka K, Watanabe K, Yamaguchi S, Hasegawa M, Kitagawa M, Aizawa S. Cytological basis for enhancement of radiation-induced mortality by Friend leukaemia virus infection. Int J Radiat Biol 2005; 80:673-81. [PMID: 15586887 DOI: 10.1080/09553000400005502] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
PURPOSE To analyse the cytological basis for enhancement of radiation-induced mortality by Friend leukaemia virus infection. MATERIALS AND METHODS Cellularity in haematopoietic tissues of C3H mice infected with FLV and/or whole-body irradiation was examined. RESULTS When mice were treated with a sublethal dose (3 Gy) of irradiation at 1 week after virus infection, most manifested a severe loss of cellularity in the spleen, bone marrow and peripheral blood 2 weeks after irradiation. More than 90% of the mice died within 1 month post-irradiation. However, this deleterious effect of virus infection on the survival of irradiated mice was observed only when they were irradiated at around 1 week after virus inoculation. Strain differences in the sensitivity to this effect were observed among virus-sensitive strains of mice. CONCLUSIONS The results indicate that Friend leukaemia virus infection can cause enhancement of radiation sensitivity of haematopoietic cells in host animals in a restricted manner in terms of genetic background and the interval between infection and irradiation.
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Affiliation(s)
- K Tanaka
- Radiation Hazards Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage, Chiba 263-8555, Japan
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36
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Nose M, Wang B, Itsukaichi H, Yukawa O, Hayata I, Yamada T, Ohyama H. Rescue of lethally irradiated mice from hematopoietic death by pre-exposure to 0.5 Gy X rays without recovery from peripheral blood cell depletion and its modification by OK432. Radiat Res 2001; 156:195-204. [PMID: 11448241 DOI: 10.1667/0033-7587(2001)156[0195:rolimf]2.0.co;2] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Exposing mice to 0.5 Gy X rays 2 weeks before lethal irradiation has been reported to induce marked radioresistance and to rescue them from hematopoietic death. Here we examined effects of the 0.5-Gy pre-exposure on hematological changes in C57BL mice that were lethally irradiated with 6.5 Gy X rays. Approximately 77% of pre-exposed mice survived 30 days after this irradiation, whereas 80% of mice that did not receive this pre-exposure died by day 20. However, regardless of the pre-exposure, peripheral blood cell counts decreased markedly by day 3 and reached a nadir at day 20. CFU-S in femur and CFU-GM in spleen had started to recover at day 10 and 14, respectively, but recovery of functional peripheral blood cells occurred later. The effect of pre-exposure on survival was altered by OK432, a bioresponse modifier; the effect depended on the timing of its administration. OK432 given 2 days before 0.5 Gy enhanced the protective effect of pre-exposure, resulting in the survival of 97% of the mice. In contrast, injection of OK432 1 day before or 2 days after pre-exposure led to 100% mortality. Thus the survival-promoting effect of 0.5 Gy could be altered by OK432. The OK432-induced changes in the survival of mice could not be attributed solely to hematological changes, as shown by blood cell counts and progenitor cell contents. These results suggest that radioresistance induced by pre-exposure to 0.5 Gy X rays is not stable, but rather varies with the physiological conditions, and can be modulated by factors such as OK432.
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Affiliation(s)
- M Nose
- Radiation Hazards Research Group, National Institute of Radiological Sciences, Chiba, 263-8555, Japan
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37
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van der Waaij D. History of recognition and measurement of colonization resistance of the digestive tract as an introduction to selective gastrointestinal decontamination. Epidemiol Infect 1992; 109:315-26. [PMID: 1468517 PMCID: PMC2271937 DOI: 10.1017/s0950268800050317] [Citation(s) in RCA: 29] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Selective decontamination of the digestive tract was developed following the observation that the digestive tract normally has considerable resistance to colonization by newly ingested bacteria. The research that eventually led to selective decontamination was performed because in the late 1960s and early 1970s, the need for prophylaxis against Gram-negative infections in immuno-compromized patients became evident. At that time, the relatively small number of antibiotics available for therapy of serious infections often lead to treatment failure. To introduce the subject of selective decontamination, this paper, therefore, starts with a short historical overview of the kind of infectious agents as well as the antibiotics available in the 1960s; particularly regarding the type and treatment of infections in severely compromised patients. The fact that the possibilities in infectious diseases were limited was the reason for our experimental search for ways of successful prophylactic treatment with minimal risk of development of resistance.
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Affiliation(s)
- D van der Waaij
- Laboratory for Medical Microbiology, University of Groningen, The Netherlands
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Abstract
The first principle of infection prevention in neutropenic patients is to ensure that every effort is made to prevent impairment of the host's defences or any disturbance of the ecological balance of the patient's microbial flora. The second principle is that potential or established sources of infection should be sought and ideally treated before any immunosuppressive therapy is instituted. The third principle is to define the extent to which a particular patient can be expected to benefit from special measures such as protective isolation, sterile or low-pathogen food, decontamination, granulocyte transfusions, passive or active immunization, or antimicrobial prophylaxis aimed at a specific micro-organism such as Pneumocystis carinii or Mycobacterium tuberculosis. A programme for the prevention of infections in neutropenic patients will fail if any of these three principles is ignored.
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Affiliation(s)
- P J van den Broek
- Department of Infectious Diseases, Leiden University Hospital, The Netherlands
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Bhartiya HC, Srivastava PN. Cell migration in the intestine of Indian desert gerbil (Meriones hurrianae Jerdon) and its relationship with the radiosensitivity of the animal. EXPERIENTIA 1974; 30:1397-8. [PMID: 4442524 DOI: 10.1007/bf01919656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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40
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Donati RM, McLaughlin MM, Stromberg LR. Combined surgical and radiation injury. 8. The effect of the gnotobiotic state on wound closure. EXPERIENTIA 1973; 29:1388-90. [PMID: 4761250 DOI: 10.1007/bf01922835] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Miller I, Mandel L, Morávek F, Kruml J, Klepalová J. Course of the post-irradiation syndrome after irradiation with lethal doses in newborn conventional, germ-free and Escherichia coli-monoassociated piglets. Folia Microbiol (Praha) 1972; 17:291-9. [PMID: 4115943 DOI: 10.1007/bf02880204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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42
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Donati RM, Frank DW, Stromberg LR, McLaughlin MM. The effect of the germfree state on wound healing. J Surg Res 1971; 11:163-72. [PMID: 5573776 DOI: 10.1016/0022-4804(71)90056-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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43
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The Effect of Intestinal Flora on Toxicity of Nitrogen Mustard. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 1969. [DOI: 10.1007/978-1-4899-6495-3_26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Levenson SM, Kan D, Lev M, Doft F. Influence of microorganisms on mammalian metabolism and nutrition, with specific reference to oxygen, consumption, carbon dioxide production, and colonic temperature. Ann N Y Acad Sci 1968; 150:788-91. [PMID: 4302616 DOI: 10.1111/j.1749-6632.1968.tb14730.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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45
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Patt HM. CELL TURNOVER AND MAMMALIAN RADIOSENSITIVITY. Cell Prolif 1968. [DOI: 10.1111/j.1365-2184.1968.tb00195.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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46
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EVANS TITUSC. THE ACUTE EFFECTS OF RADIATION ON INTACT MAMMALS. Radiol Clin North Am 1965. [DOI: 10.1016/s0033-8389(22)00784-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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