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Mallick R, Basak S, Das RK, Banerjee A, Paul S, Pathak S, Duttaroy AK. Roles of the gut microbiota in human neurodevelopment and adult brain disorders. Front Neurosci 2024; 18:1446700. [PMID: 39659882 PMCID: PMC11628544 DOI: 10.3389/fnins.2024.1446700] [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: 06/15/2024] [Accepted: 11/05/2024] [Indexed: 12/12/2024] Open
Abstract
Growing evidence demonstrates the connection between gut microbiota, neurodevelopment, and adult brain function. Microbial colonization occurs before the maturation of neural systems and its association with brain development. The early microbiome interactions with the gut-brain axis evolved to stimulate cognitive activities. Gut dysbiosis can lead to impaired brain development, growth, and function. Docosahexaenoic acid (DHA) is critically required for brain structure and function, modulates gut microbiota, and impacts brain activity. This review explores how gut microbiota influences early brain development and adult functions, encompassing the modulation of neurotransmitter activity, neuroinflammation, and blood-brain barrier integrity. In addition, it highlights processes of how the gut microbiome affects fetal neurodevelopment and discusses adult brain disorders.
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Affiliation(s)
- Rahul Mallick
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Sanjay Basak
- Molecular Biology Division, ICMR-National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India
| | - Ranjit K. Das
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai, India
| | - Sujay Paul
- Tecnologico de Monterrey, School of Engineering and Sciences, Queretaro, Mexico
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai, India
| | - Asim K. Duttaroy
- Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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Vuralli D, Ceren Akgor M, Dagidir HG, Onat P, Yalinay M, Sezerman U, Bolay H. Microbiota alterations are related to migraine food triggers and inflammatory markers in chronic migraine patients with medication overuse headache. J Headache Pain 2024; 25:192. [PMID: 39516813 PMCID: PMC11546420 DOI: 10.1186/s10194-024-01891-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
OBJECTIVE Chronic migraine (CM) patients with medication overuse headache (MOH) were recently shown to be associated with leaky gut and inflammation. We aimed to investigate gut microbiota profiles of CM patients with MOH, and their correlations with inflammatory serum parameters, migraine food triggers, and comorbid anxiety and depression. MATERIALS AND METHODS The study included women participants (32 CM patients with NSAID overuse headache, and 16 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, presence of irritable bowel syndrome symptoms, and HADS-D and HADS-A scores were recorded. Serum samples were collected to measure circulating LPS, HMGB1, HIF-1α, and IL-6. The gut microbiota profiles of the patients were evaluated using fecal samples. RESULTS Serum LPS, HMGB1, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the healthy controls. HADS-A and HADS-D scores were considerably higher in the CM + MOH group compared to the healthy controls. In the microbiota analysis, alpha and beta diversities were similar between the two groups. The class Clostridia, the order Eubacteriales, and the genus Ruminococcus were less abundant in the CM + NSAID overuse headache group compared to the control group. At the genus level Desulfovibrio, Gemmiger, and Dialister and at the species level, Clostridium fessum, Blautia luti, Dorea longicatena, Eubacterium coprostanoligenes, and Gemmiger formicilis were more abundant in the CM + NSAID overuse headache group compared to the control group. Desulfovibrio, Gemmiger, Dialister, Ethanoligenens harbinense, Eubacterium coprostanoligenes, Dorea longicatena, and Thermoclostridium stercorarium showed positive correlations and Clostridia bacteria showed negative correlations with migraine food triggers. Positive correlations were found between LPS and Hapalosiphonaceae, HMGB1 and Melghirimyces, HIF1-α and Rouxeilla and Blautia luti, IL-6 and Melghirimyces and Ruminococcus. CONCLUSION In CM patients with MOH, we have revealed the presence of dysbiosis towards an inflammatory state, and positive correlations were shown between altered gut microbiota and inflammatory serum parameters and migraine food triggers.
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Affiliation(s)
- Doga Vuralli
- Department of Neurology and Algology, Gazi University Faculty of Medicine, Ankara, Türkiye
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Türkiye
- Neuropsychiatry Center, Gazi University, Ankara, Türkiye
| | - Merve Ceren Akgor
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Türkiye
| | - Hale Gok Dagidir
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Türkiye
| | - Pınar Onat
- Epigenetiks Genetic Bioinformatics Software Inc., Istanbul, Türkiye
| | - Meltem Yalinay
- Department of Clinical Microbiology, Gazi University Faculty of Medicine, Ankara, Türkiye
| | - Ugur Sezerman
- Department of Biostatistics and Medical Informatics, Acibadem University Faculty of Medicine, Istanbul, Türkiye
| | - Hayrunnisa Bolay
- Department of Neurology and Algology, Gazi University Faculty of Medicine, Ankara, Türkiye.
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Türkiye.
- Neuropsychiatry Center, Gazi University, Ankara, Türkiye.
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Al-Akayleh F, Agha ASAA, Al-Remawi M, Al-Adham ISI, Daadoue S, Alsisan A, Khattab D, Malath D, Salameh H, Al-Betar M, AlSakka M, Collier PJ. What We Know About the Actual Role of Traditional Probiotics in Health and Disease. Probiotics Antimicrob Proteins 2024; 16:1836-1856. [PMID: 38700762 DOI: 10.1007/s12602-024-10275-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2024] [Indexed: 10/02/2024]
Abstract
The complex relationship between probiotics and human health goes beyond their traditional function in gut health, generating considerable interest for their broad potential in disease treatment. This review explores the various functions of probiotics, highlighting their impact on the immune system, their benefits for gut and oral health, their effects on metabolic and neurological disorders, and their emerging potential in cancer therapy. We give significant importance to studying the effects of probiotics on the gut-brain axis, revealing new and non-invasive therapeutic approaches for complex neurological disorders. In addition, we expand the discussion to encompass the impact of probiotics on the gut-liver and gut-lung axes, recognizing their systemic effects and potential in treating respiratory and hepatic conditions. The use of probiotic "cocktails" to improve cancer immunotherapy outcomes indicates a revolutionary approach to oncological treatments. The review explores the specific benefits associated with various strains and the genetic mechanisms that underlie them. This study sets the stage for precision medicine, where probiotic treatments can be tailored to meet the unique needs of each patient. Recent developments in delivery technologies, including microencapsulation and nanotechnology, hold great potential for enhancing the effectiveness and accuracy of probiotic applications in therapeutic settings. This study provides a strong basis for future scientific research and clinical use, promoting the incorporation of probiotics into treatment plans for a wide range of diseases. This expands our understanding of the potential benefits of probiotics in modern medicine.
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Affiliation(s)
- Faisal Al-Akayleh
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan.
| | - Ahmed S A Ali Agha
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
- Faculty of Pharmacy, The University of Jordan, Amman, 11942, Jordan
| | - Mayyas Al-Remawi
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Ibrahim S I Al-Adham
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Saifeddin Daadoue
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Anagheem Alsisan
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Dana Khattab
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Doha Malath
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Haneen Salameh
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Maya Al-Betar
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Motaz AlSakka
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan
| | - Phillip J Collier
- Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, 11196, Jordan.
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Ke F, Dong ZH, Bu F, Li CN, He QT, Liu ZC, Lu J, Yu K, Wang DG, Xu HN, Ye CT. Clostridium difficile infection following colon subtotal resection in a patient with gallstones: A case report and review of literature. World J Gastrointest Surg 2024; 16:3048-3056. [PMID: 39351567 PMCID: PMC11438826 DOI: 10.4240/wjgs.v16.i9.3048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/02/2024] [Accepted: 07/10/2024] [Indexed: 09/18/2024] Open
Abstract
BACKGROUND Clostridium difficile (C. difficile) infection (CDI) is a rare clinical disease caused by changes in the intestinal microenvironment, which has a variety of causes and a poor prognosis, and for which there is no standardized clinical treatment. CASE SUMMARY A patient experienced recurrent difficulty in bowel movements over the past decade. Recently, symptoms worsened within the last ten days, leading to a clinic visit due to constipation. The patient was subsequently referred to our department. Preoperatively, the patient was diagnosed with obstructed colon accompanied by gallstones. Empirical antibiotics were administered both before and after surgery to prevent infection. On the fourth day post-surgery, symptoms of CDI emerged. Stool cultures confirmed the presence of C. difficile DNA. Treatment involved a combination of vancomycin and linezolid, resulting in the patient's successful recovery upon discharge. However, the patient failed to adhere to the prescribed medication after discharge and was discovered deceased during a follow-up two months later. CONCLUSION CDI is the leading cause of nosocomial post-operative care, with limited clinical cases and poor patient prognosis, and comprehensive clinical treatment guidelines are still lacking. This infection can be triggered by a variety of factors, including intestinal hypoxia, inappropriate antibiotic use, and bile acid circulation disorders. In patients with chronic bowel disease and related etiologies, prompt preoperative attention to possible CDI and preoperative bowel preparation is critical. Adequate and prolonged medication should be maintained in the treatment of CDI to prevent recurrence of the disease.
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Affiliation(s)
- Feng Ke
- Department of General Surgery, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130000, Jilin Province, China
| | - Zhen-Hua Dong
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Fan Bu
- Department of Plastic and Aesthetic Surgery, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Cheng-Nan Li
- Department of Encephalopathy Rehabilitation, Chaoyi Hospital, Yanbian Korean Autonomous Prefecture, Yanji 133000, Jilin Province, China
| | - Qi-Tong He
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Zhi-Cheng Liu
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Ji Lu
- Department of Urology, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Kai Yu
- Department of Urology, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Da-Guang Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - He-Nan Xu
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Chang-Tao Ye
- Department of Urology, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
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Lucas JH, Wang Q, Meehan-Atrash J, Pang C, Rahman I. Developmental PFOS exposure alters lung inflammation and barrier integrity in juvenile mice. Toxicol Sci 2024; 201:48-60. [PMID: 38830033 PMCID: PMC11347778 DOI: 10.1093/toxsci/kfae073] [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] [Indexed: 06/05/2024] Open
Abstract
Emerging epidemiological evidence indicates perfluorooctane sulfonic acid (PFOS) is increasingly associated with asthma and respiratory viral infections. Animal studies suggest PFOS disrupts lung development and immuno-inflammatory responses, but little is known about the potential consequences on respiratory health and disease risk. Importantly, PFOS exposure during the critical stages of lung development may increase disease risk later in life. Thus, we hypothesized that developmental PFOS exposure will affect lung inflammation and alveolar/airway development in a sex-dependent manner. To address this knowledge gap, timed pregnant Balb/cJ dams were orally dosed with a PFOS (1.0 or 2.0 mg/kg/d) injected mealworm or a vehicle control daily from gestational day (GD) 0.5 to postnatal day (PND) 21, and offspring were sacrificed at PND 22-23. PFOS-exposed male offspring displayed increased alveolar septa thickness. Occludin was also downregulated in the lungs after PFOS exposure in mice, indicative of barrier dysfunction. BALF macrophages were significantly elevated at 2.0 mg/kg/d PFOS in both sexes compared with vehicles, whereas BALF cytokines (TNF-α, IL-6, KC, MIP-1α, MIP-1β, and MCP-1) were suppressed in PFOS-exposed male offspring compared with vehicle controls. Multiplex nucleic acid hybridization assay showed male-specific downregulation of cytokine gene expression in PFOS-exposed mice compared with vehicle mice. Overall, these results demonstrate PFOS exposure exhibits male-specific adverse effects on lung development and inflammation in juvenile offspring, possibly predisposing them to later-in-life respiratory disease. Further research is required to elucidate the mechanisms underlying the sex-differentiated pulmonary toxicity of PFOS.
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Affiliation(s)
- Joseph H Lucas
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States
| | - Qixin Wang
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States
| | - Jiries Meehan-Atrash
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States
| | - Cortney Pang
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States
| | - Irfan Rahman
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States
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Liu Y, Yang C, Zhang J, Ihsan A, Ares I, Martínez M, Lopez-Torres B, Martínez-Larrañaga MR, Wang X, Anadón A, Martínez MA. Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts. Expert Opin Drug Metab Toxicol 2024:1-21. [PMID: 38980754 DOI: 10.1080/17425255.2024.2378885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 07/08/2024] [Indexed: 07/11/2024]
Abstract
INTRODUCTION Carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) are extensively used worldwide due to their antipyretic, analgesic, and anti-inflammatory effects. CBA-NSAIDs have reasonable margin of safety at therapeutic doses, and in the current climate, do not possess addiction potential like opioid drugs. Studies have revealed that various adverse events of CBA-NSAIDs are related mitochondrial dysfunction and oxidative stress. AREAS COVERED This review article summarizes adverse events induced by CBA-NSAIDs, mechanisms of mitochondrial damage, oxidative stress, and metabolic interactions. Meanwhile, this review discusses the treatment and prevention of CBA-NSAIDs damage by natural plant extracts based on antioxidant effects. EXPERT OPINION CBA-NSAIDs can induce reactive oxygen species (ROS) production, mediate DNA, protein and lipid damage, lead to imbalance of cell antioxidant status, change of mitochondrial membrane potential, activate oxidative stress signal pathway, thus leading to oxidative stress and cell damage. Adverse events caused by CBA-NSAIDs often exhibit dose and time dependence. In order to avoid adverse events caused by CBA-NSAIDs, it is necessary to provide detailed patient consultation and eliminate influencing factors. Moreover, constructive research studies on the organ-specific toxicity and mechanism of natural plant extracts in preventing and treating metabolic abnormalities of CBA-NSAIDs, will provide important value for warning and guidance for use of CBA-NSAIDs.
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Affiliation(s)
- Yanan Liu
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Chao Yang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Jieying Zhang
- MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Awais Ihsan
- Department of Biosciences, COMSATS University Islamabad, Sahiwal Campus, Islamabad, Pakistan
| | - Irma Ares
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Marta Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Bernardo Lopez-Torres
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - María-Rosa Martínez-Larrañaga
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Xu Wang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Arturo Anadón
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - María-Aránzazu Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
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Sánchez-Trigueros MI, Martínez-Vieyra IA, Pineda-Peña EA, Castañeda-Hernández G, Perez-Cruz C, Cerecedo D, Chávez-Piña AE. Role of antioxidative activity in the docosahexaenoic acid's enteroprotective effect in the indomethacin-induced small intestinal injury model. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4275-4285. [PMID: 38085291 DOI: 10.1007/s00210-023-02881-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/30/2023] [Indexed: 05/23/2024]
Abstract
Therapeutic effect of non-steroidal anti-inflammatory drugs (NSAIDs) has been related with gastrointestinal injury. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), can prevent gastric and small intestinal damage. Nonetheless, contribution of antioxidative action in the protective effect of DHA has not been evaluated before in the small intestine injury after indomethacin treatment. Pathogenesis of NSAID-induced small intestinal injury is multifactorial, and reactive oxidative species have been related to indomethacin's small intestinal damage. The present work aimed to evaluate antioxidative activity in the protective action of DHA in the indomethacin-induced small intestinal damage. Female Wistar rats were gavage with DHA (3 mg/kg) or omeprazole (3 mg/kg) for 10 days. Each rat received indomethacin (3 mg/kg, orally) daily to induce small intestinal damage. The total area of intestinal ulcers and histopathological analysis were performed. In DHA-treated rats, myeloperoxidase and superoxide dismutase activity, glutathione, malondialdehyde, leukotriene, and lipopolysaccharide (LPS) levels were measured. Furthermore, the relative abundance of selective bacteria was assessed. DHA administration (3 mg/kg, p.o.) caused a significant decrease in indomethacin-induced small intestinal injury in Wistar rats after 10 days of treatment. DHA's enteroprotection resulted from the prevention of an increase in myeloperoxidase activity, and lipoperoxidation, as well as an improvement in the antioxidant defenses, such as glutathione levels and superoxide dismutase activity in the small intestine. Furthermore, we showed that DHA's enteroprotective effect decreased significantly LPS levels in indomethacin-induced injury in small intestine. Our data suggest that DHA's enteroprotective might be attributed to the prevention of oxidative stress.
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Affiliation(s)
- Martha Ivonne Sánchez-Trigueros
- Laboratorio de Farmacología, Doctorado en Ciencias en Biotecnología, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, Mexico City, México
| | - Ivette Astrid Martínez-Vieyra
- Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City, México
| | - Elizabeth Arlen Pineda-Peña
- Unidad Multidisciplinaria de Investigación Experimental (UMIEZ), Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de mayo esquina Fuerte de Loreto, Ejército de Oriente, Iztapalapa, 0930, Mexico City, México
| | | | - Claudia Perez-Cruz
- Departamento de Farmacología, Centro de Investigaciones y Estudios Avanzados, CINVESTAV, Mexico City, México
| | - Doris Cerecedo
- Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City, México
- Maestría en Ciencias en Biomedicina Molecular, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, ermo Massieu Helguera No. 239, Fraccionamiento "La Escalera", Ticomán, CDMX. C.P. 07320, México City, México
| | - Aracely Evangelina Chávez-Piña
- Laboratorio de Farmacología, Doctorado en Ciencias en Biotecnología, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, Mexico City, México.
- Maestría en Ciencias en Biomedicina Molecular, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, ermo Massieu Helguera No. 239, Fraccionamiento "La Escalera", Ticomán, CDMX. C.P. 07320, México City, México.
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Sharpton TJ, Alexiev A, Tanguay RL. Defining the environmental determinants of dysbiosis at scale with zebrafish. CURRENT OPINION IN TOXICOLOGY 2023; 36:100430. [PMID: 38486798 PMCID: PMC10938905 DOI: 10.1016/j.cotox.2023.100430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2024]
Abstract
The gut microbiome, critical to maintaining vertebrate homeostasis, is susceptible to a various exposures. In some cases, these exposures induce dysbiosis, wherein the microbiome changes into a state conducive to disease progression. To better prevent, manage, and treat health disorders, we need to define which exposures induce dysbiosis. Contemporary methods face challenges due to the immense diversity of the exposome and the restricted throughput of conventional experimental tools used for dysbiosis evaluation. We propose integrating high-throughput model systems as an augment to traditional techniques for rapid identification of dysbiosis-inducing agents. Although high-throughput screening tools revolutionized areas such as pharmacology and toxicology, their incorporation in gut microbiome research remains limited. One particularly powerful high-throughput model system is the zebrafish, which affords access to scalable in vivo experimentation involving a complex gut microbiome. Numerous studies have employed this model to identify potential dysbiosis triggers. However, its potential could be further harnessed via innovative study designs, such as evaluation of synergistic effects from combined exposures, expansions to the methodological toolkit to discern causal effects of microbiota, and efforts to assess and improve the translational relevance of the model. Ultimately, this burgeoning experimental resource can accelerate the discovery of agents that underlie dysbiotic disorders.
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Affiliation(s)
- Thomas J Sharpton
- Department of Microbiology, Oregon State University, Corvallis, OR
- Department of Statistics, Oregon State University, Corvallis, OR
| | | | - Robyn L Tanguay
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR
- Sinnhuber Aquatic Research Center, Oregon State University, Corvallis, OR
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Mohamed DI, Abo Nahas HH, Elshaer AM, El-Waseef DAEDA, El-Kharashi OA, Mohamed SMY, Sabry YG, Almaimani RA, Almasmoum HA, Altamimi AS, Ibrahim IAA, Alshawwa SZ, Jaremko M, Emwas AH, Saied EM. Unveiling the interplay between NSAID-induced dysbiosis and autoimmune liver disease in children: insights into the hidden gateway to autism spectrum disorders. Evidence from ex vivo, in vivo, and clinical studies. Front Cell Neurosci 2023; 17:1268126. [PMID: 38026692 PMCID: PMC10644687 DOI: 10.3389/fncel.2023.1268126] [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: 07/27/2023] [Accepted: 09/28/2023] [Indexed: 12/01/2023] Open
Abstract
Autism spectrum disorders (ASD) represent a diverse group of neuropsychiatric conditions, and recent evidence has suggested a connection between ASD and microbial dysbiosis. Immune and gastrointestinal dysfunction are associated with dysbiosis, and there are indications that modulating the microbiota could improve ASD-related behaviors. Additionally, recent findings highlighted the significant impact of microbiota on the development of autoimmune liver diseases, and the occurrence of autoimmune liver disease in children with ASD is noteworthy. In the present study, we conducted both an in vivo study and a clinical study to explore the relationship between indomethacin-induced dysbiosis, autoimmune hepatitis (AIH), and the development of ASD. Our results revealed that indomethacin administration induced intestinal dysbiosis and bacterial translocation, confirmed by microbiological analysis showing positive bacterial translocation in blood cultures. Furthermore, indomethacin administration led to disturbed intestinal permeability, evidenced by the activation of the NLRP3 inflammasomes pathway and elevation of downstream biomarkers (TLR4, IL18, caspase 1). The histological analysis supported these findings, showing widened intestinal tight junctions, decreased mucosal thickness, inflammatory cell infiltrates, and collagen deposition. Additionally, the disturbance of intestinal permeability was associated with immune activation in liver tissue and the development of AIH, as indicated by altered liver function, elevated ASMA and ANA in serum, and histological markers of autoimmune hepatitis. These results indicate that NSAID-induced intestinal dysbiosis and AIH are robust triggers for ASD existence. These findings were further confirmed by conducting a clinical study that involved children with ASD, autoimmune hepatitis (AIH), and a history of NSAID intake. Children exposed to NSAIDs in early life and complicated by dysbiosis and AIH exhibited elevated serum levels of NLRP3, IL18, liver enzymes, ASMA, ANA, JAK1, and IL6. Further, the correlation analysis demonstrated a positive relationship between the measured parameters and the severity of ASD. Our findings suggest a potential link between NSAIDs, dysbiosis-induced AIH, and the development of ASD. The identified markers hold promise as indicators for early diagnosis and prognosis of ASD. This research highlights the importance of maintaining healthy gut microbiota and supports the necessity for further investigation into the role of dysbiosis and AIH in the etiology of ASD.
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Affiliation(s)
- Doaa I. Mohamed
- Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Asmaa M. Elshaer
- Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Omnyah A. El-Kharashi
- Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Soha M. Y. Mohamed
- Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Yasmine Gamal Sabry
- Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Riyad A. Almaimani
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Hussain A. Almasmoum
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abdulmalik S. Altamimi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Ibrahim Abdel Aziz Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Samar Z. Alshawwa
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Mariusz Jaremko
- Smart-Health Initiative and Red Sea Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Abdul-Hamid Emwas
- Advanced Nanofabrication Imaging and Characterization Center, King Abdullah University of Science and Technology, Core Labs, Thuwal, Saudi Arabia
| | - Essa M. Saied
- Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
- Institute for Chemistry, Humboldt Universität zu Berlin, Berlin, Germany
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10
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Bailey S, Fraser K. Advancing our understanding of the influence of drug induced changes in the gut microbiome on bone health. Front Endocrinol (Lausanne) 2023; 14:1229796. [PMID: 37867525 PMCID: PMC10588641 DOI: 10.3389/fendo.2023.1229796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 08/07/2023] [Indexed: 10/24/2023] Open
Abstract
The gut microbiome has been implicated in a multitude of human diseases, with emerging evidence linking its microbial diversity to osteoporosis. This review article will explore the molecular mechanisms underlying perturbations in the gut microbiome and their influence on osteoporosis incidence in individuals with chronic diseases. The relationship between gut microbiome diversity and bone density is primarily mediated by microbiome-derived metabolites and signaling molecules. Perturbations in the gut microbiome, induced by chronic diseases can alter bacterial diversity and metabolic profiles, leading to changes in gut permeability and systemic release of metabolites. This cascade of events impacts bone mineralization and consequently bone mineral density through immune cell activation. In addition, we will discuss how orally administered medications, including antimicrobial and non-antimicrobial drugs, can exacerbate or, in some cases, treat osteoporosis. Specifically, we will review the mechanisms by which non-antimicrobial drugs disrupt the gut microbiome's diversity, physiology, and signaling, and how these events influence bone density and osteoporosis incidence. This review aims to provide a comprehensive understanding of the complex interplay between orally administered drugs, the gut microbiome, and osteoporosis, offering new insights into potential therapeutic strategies for preserving bone health.
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Affiliation(s)
- Stacyann Bailey
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, United States
- Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, United States
| | - Keith Fraser
- Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, United States
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United States
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11
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Soto Ocaña J, Bayard NU, Hart JL, Thomas AK, Furth EE, Lacy DB, Aronoff DM, Zackular JP. Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin-mediated mitochondrial damage. SCIENCE ADVANCES 2023; 9:eadh5552. [PMID: 37467340 PMCID: PMC10355836 DOI: 10.1126/sciadv.adh5552] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 06/15/2023] [Indexed: 07/21/2023]
Abstract
Clostridioides difficile damages the colonic mucosa through the action of two potent exotoxins. Factors shaping C. difficile pathogenesis are incompletely understood but are likely due to the ecological factors in the gastrointestinal ecosystem, mucosal immune responses, and environmental factors. Little is known about the role of pharmaceutical drugs during C. difficile infection (CDI), but recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI. The mechanism underlying this phenomenon remains unclear. Here, we show that NSAIDs exacerbate CDI by disrupting colonic epithelial cells (CECs) and sensitizing cells to C. difficile toxin-mediated damage independent of their canonical role of inhibiting cyclooxygenase (COX) enzymes. Notably, we find that NSAIDs and C. difficile toxins target the mitochondria of CECs and enhance C. difficile toxin-mediated damage. Our results demonstrate that NSAIDs exacerbate CDI by synergizing with C. difficile toxins to damage host cell mitochondria. Together, this work highlights a role for NSAIDs in exacerbating microbial infection in the colon.
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Affiliation(s)
- Joshua Soto Ocaña
- Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nile U. Bayard
- Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Jessica L. Hart
- Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Audrey K. Thomas
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Emma E. Furth
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - D. Borden Lacy
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - David M. Aronoff
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Joseph P. Zackular
- Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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12
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Ramírez-Tejero JA, Durán-González E, Martínez-Lara A, Lucena Del Amo L, Sepúlveda I, Huancas-Díaz A, Carvajal M, Cotán D. Microbiota and Mitochondrial Sex-Dependent Imbalance in Fibromyalgia: A Pilot Descriptive Study. Neurol Int 2023; 15:868-880. [PMID: 37489361 PMCID: PMC10366818 DOI: 10.3390/neurolint15030055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/23/2023] [Accepted: 06/25/2023] [Indexed: 07/26/2023] Open
Abstract
Fibromyalgia is a widespread chronic condition characterized by pain and fatigue. Among the long list of physiological disturbances linked to this syndrome, mitochondrial imbalance and oxidative stress stand out. Recently, the crosstalk between mitochondria and intestinal microbiota has caught the attention of biomedical researchers, who have found connections between this axis and several inflammatory and pain-related conditions. Hence, this pilot descriptive study focused on characterizing the mitochondrial mass/mitophagy ratio and total antioxidant capacity in PBMCs, as well as some microbiota components in feces, from a Peruvian cohort of 19 females and 7 males with FM. Through Western blotting, electrochemical oxidation, ELISA, and real-time qPCR, we determined VDAC1 and MALPLC3B protein levels; total antioxidant capacity; secretory immunoglobulin A (sIgA) levels; and Firmicutes/Bacteroidetes, Bacteroides/Prevotella, and Roseburia/Eubacterium ratios; as well as Ruminococcus spp., Pseudomonas spp., and Akkermansia muciniphila levels, respectively. We found statistically significant differences in Ruminococcus spp. and Pseudomonas spp. levels between females and males, as well as a marked polarization in mitochondrial mass in both groups. Taken together, our results point to a mitochondrial imbalance in FM patients, as well as a sex-dependent difference in intestinal microbiota composition.
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Affiliation(s)
| | | | | | | | | | | | - Marco Carvajal
- Instituto de Medicina Funcional e Integral de Perú, Lima 15073, Peru
| | - David Cotán
- Pronacera Therapeutics S.L., 41015 Sevilla, Spain
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13
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Cheng JKJ, Unnikrishnan M. Clostridioides difficile infection: traversing host-pathogen interactions in the gut. MICROBIOLOGY (READING, ENGLAND) 2023; 169. [PMID: 36848200 DOI: 10.1099/mic.0.001306] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
C. difficile is the primary cause for nosocomial infective diarrhoea. For a successful infection, C. difficile must navigate between resident gut bacteria and the harsh host environment. The perturbation of the intestinal microbiota by broad-spectrum antibiotics alters the composition and the geography of the gut microbiota, deterring colonization resistance, and enabling C. difficile to colonize. This review will discuss how C. difficile interacts with and exploits the microbiota and the host epithelium to infect and persist. We provide an overview of C. difficile virulence factors and their interactions with the gut to aid adhesion, cause epithelial damage and mediate persistence. Finally, we document the host responses to C. difficile, describing the immune cells and host pathways that are associated and triggered during C. difficile infection.
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Affiliation(s)
- Jeffrey K J Cheng
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
| | - Meera Unnikrishnan
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
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14
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Comparison between Symptomatic and Asymptomatic Mice after Clostridioides difficile Infection Reveals Novel Inflammatory Pathways and Contributing Microbiota. Microorganisms 2022; 10:microorganisms10122380. [PMID: 36557633 PMCID: PMC9782979 DOI: 10.3390/microorganisms10122380] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/23/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022] Open
Abstract
Clostridioides difficile causes the highest number of nosocomial infections. Currently, treatment options for C. difficile infection (CDI) are very limited, resulting in poor treatment outcomes and high recurrence rates. Although the disease caused by CDI is inflammatory in nature, the role of inflammation in the development of CDI symptoms is contradictory and not completely understood. Hence, the use of anti-inflammatory medication is debatable in CDI. In the current study, we evaluated the genetic and microbiome profiles of mice after infection with C. difficile. These mice were categorized based on the severity of CDI and the results were viewed accordingly. Our results indicate that certain genes are upregulated in severe CDI more than in the moderate case. These include oncostatin-M (OSM), matrix metalloprotease 8 (MMP8), triggering receptor expressed on myeloid cells 1 (Trem-1), and dual oxidase 2 (Duox2). We also investigated the microbiome composition of CDI mice before and after infecting with C. difficile. The results show that C. difficile abundance is not indicative of diseases severity. Certain bacterial species (e.g., Citrobacter) were enriched while others (e.g., Turicibacter) were absent in severe CDI. This study identifies novel inflammatory pathways and bacterial species with a potential role in determining the severity of CDI.
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15
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Chen J, Li Y, Wang S, Zhang H, Du Y, Wu Q, Wang H. Targeting Clostridioides difficile: New uses for old drugs. Drug Discov Today 2022; 27:1862-1873. [PMID: 35390545 DOI: 10.1016/j.drudis.2022.03.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/03/2021] [Accepted: 03/30/2022] [Indexed: 12/30/2022]
Abstract
Clostridioides difficile bacteria can cause life-threatening diarrhea and colitis owing to limited treatment options and unacceptably high recurrence rates among infected patients. This necessitates the development of alternative routes for C. difficile treatment. Drug repurposing with new indications represents a proven shortcut. Here, we present a refined focus on 16 FDA-approved drugs that would be suitable for further development as potential anti-C. difficile drugs. Of these drugs, clinical trials have been conducted on five currently used drugs; however, ursodeoxycholic acid is the only drug to enter Phase IV clinical trials to date. Thus, drug repurposing promotes the study of mechanistic and therapeutic strategies, providing new options for the development of next-generation anti-C. difficile agents.
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Affiliation(s)
- Jianwei Chen
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China; Macau University of Science and Technology, State Key Laboratory of Quality Research in Chinese Medicines, Macao
| | - Yasheng Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University & Anhui Center for Surveillance of Bacterial Resistance, Hefei, China
| | - Siqi Wang
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Hongfang Zhang
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Yujie Du
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Qiang Wu
- Macau University of Science and Technology, State Key Laboratory of Quality Research in Chinese Medicines, Macao.
| | - Hong Wang
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China.
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16
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Soto Ocaña J, Bayard NU, Zackular JP. Pain killers: the interplay between nonsteroidal anti-inflammatory drugs and Clostridioides difficile infection. Curr Opin Microbiol 2022; 65:167-174. [PMID: 34894543 PMCID: PMC9058983 DOI: 10.1016/j.mib.2021.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 02/03/2023]
Abstract
Clostridioides difficile is one of the leading causes of nosocomial infections worldwide. Increases in incidence, severity, and healthcare cost associated with C. difficile infection (CDI) have made this pathogen an urgent public health threat worldwide. The factors shaping the evolving epidemiology of CDI and impacting clinical outcomes of infection are not well understood, but involve tripartite interactions between the host, microbiota, and C. difficile. In addition to this, emerging data suggests an underappreciated role for environmental factors, such as diet and pharmaceutical drugs, in CDI. In this review, we discuss the role of nonsteroidal anti-inflammatory drugs (NSAIDs) and eicosanoids in CDI.
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Affiliation(s)
- Joshua Soto Ocaña
- Division of Protective Immunity, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Nile U. Bayard
- Division of Protective Immunity, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Joseph P. Zackular
- Division of Protective Immunity, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States;,Corresponding author:
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17
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Melnik LI, Guha S, Ghimire J, Smither AR, Beddingfield BJ, Hoffmann AR, Sun L, Ungerleider NA, Baddoo MC, Flemington EK, Gallaher WR, Wimley WC, Garry RF. Ebola virus delta peptide is an enterotoxin. Cell Rep 2022; 38:110172. [PMID: 34986351 DOI: 10.1016/j.celrep.2021.110172] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/27/2021] [Accepted: 12/03/2021] [Indexed: 12/21/2022] Open
Abstract
During the 2013-2016 West African (WA) Ebola virus (EBOV) outbreak, severe gastrointestinal symptoms were common in patients and associated with poor outcome. Delta peptide is a conserved product of post-translational processing of the abundant EBOV soluble glycoprotein (sGP). The murine ligated ileal loop model was used to demonstrate that delta peptide is a potent enterotoxin. Dramatic intestinal fluid accumulation follows injection of biologically relevant amounts of delta peptide into ileal loops, along with gross alteration of villous architecture and loss of goblet cells. Transcriptomic analyses show that delta peptide triggers damage response and cell survival pathways and downregulates expression of transporters and exchangers. Induction of diarrhea by delta peptide occurs via cellular damage and regulation of genes that encode proteins involved in fluid secretion. While distinct differences exist between the ileal loop murine model and EBOV infection in humans, these results suggest that delta peptide may contribute to EBOV-induced gastrointestinal pathology.
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Affiliation(s)
- Lilia I Melnik
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Shantanu Guha
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Jenisha Ghimire
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Allison R Smither
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Brandon J Beddingfield
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Andrew R Hoffmann
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Leisheng Sun
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | | | - Melody C Baddoo
- Tulane Cancer Center, Tulane University, New Orleans, LA 70112, USA
| | | | - William R Gallaher
- Department of Microbiology, Immunology and Parasitology, LSU Health Sciences Center, New Orleans, LA 70112, USA; Mockingbird Nature Research Group, Pearl River, LA 70452, USA
| | - William C Wimley
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
| | - Robert F Garry
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Zalgen Labs, Germantown, MD 20876, USA.
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18
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Azimirad M, Noori M, Raeisi H, Yadegar A, Shahrokh S, Asadzadeh Aghdaei H, Bentivegna E, Martelletti P, Petrosillo N, Zali MR. How Does COVID-19 Pandemic Impact on Incidence of Clostridioides difficile Infection and Exacerbation of Its Gastrointestinal Symptoms? Front Med (Lausanne) 2021; 8:775063. [PMID: 34966759 PMCID: PMC8710593 DOI: 10.3389/fmed.2021.775063] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/22/2021] [Indexed: 12/19/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) has rapidly spread all over the world with a very high rate of mortality. Different symptoms developed by COVID-19 infection and its impacts on various organs of the human body have highlighted the importance of both coinfections and superinfections with other pathogens. The gastrointestinal (GI) tract is vulnerable to infection with COVID-19 and can be exploited as an alternative transmission route and target for virus entry and pathogenesis. The GI manifestations of COVID-19 disease are associated with severe disease outcomes and death in all age groups, in particular, elderly patients. Empiric antibiotic treatments for microbial infections in hospitalized patients with COVID-19 in addition to experimental antiviral and immunomodulatory drugs may increase the risk of antibiotic-associated diarrhea (AAD) and Clostridioides difficile infection (CDI). Alterations of gut microbiota are associated with depletion of beneficial commensals and enrichment of opportunistic pathogens such as C. difficile. Hence, the main purpose of this review is to explain the likely risk factors contributing to higher incidence of CDI in patients with COVID-19. In addition to lung involvement, common symptoms observed in COVID-19 and CDI such as diarrhea, highlight the significance of bacterial infections in COVID-19 patients. In particular, hospitalized elderly patients who are receiving antibiotics might be more prone to CDI. Indeed, widespread use of broad-spectrum antibiotics such as clindamycin, cephalosporins, penicillin, and fluoroquinolones can affect the composition and function of the gut microbiota of patients with COVID-19, leading to reduced colonization resistance capacity against opportunistic pathogens such as C. difficile, and subsequently develop CDI. Moreover, patients with CDI possibly may have facilitated the persistence of SARS-CoV-2 viral particles in their feces for approximately one month, even though the nasopharyngeal test turned negative. This coinfection may increase the potential transmissibility of both SARS-CoV-2 and C. difficile by fecal materials. Also, CDI can complicate the outcome of COVID-19 patients, especially in the presence of comorbidities or for those patients with prior exposure to the healthcare setting. Finally, physicians should remain vigilant for possible SARS-CoV-2 and CDI coinfection during the ongoing COVID-19 pandemic and the excessive use of antimicrobials and biocides.
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Affiliation(s)
- Masoumeh Azimirad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Noori
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamideh Raeisi
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Enrico Bentivegna
- Internal Medicine and Emergency Medicine, St'Andrea Hospital, Sapienza University, Rome, Italy
| | - Paolo Martelletti
- Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy
| | - Nicola Petrosillo
- Infectious Diseases Service, University Hospital Campus Bio-Medico, Rome, Italy
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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19
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Adjunctive Probiotics Alleviates Asthmatic Symptoms via Modulating the Gut Microbiome and Serum Metabolome. Microbiol Spectr 2021; 9:e0085921. [PMID: 34612663 PMCID: PMC8510161 DOI: 10.1128/spectrum.00859-21] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Asthma is a multifactorial disorder, and microbial dysbiosis enhances lung inflammation and asthma-related symptoms. Probiotics have shown anti-inflammatory effects and could regulate the gut-lung axis. Thus, a 3-month randomized, double-blind, and placebo-controlled human trial was performed to investigate the adjunctive efficacy of probiotics in managing asthma. Fifty-five asthmatic patients were randomly assigned to a probiotic group (n = 29; received Bifidobacterium lactis Probio-M8 powder and Symbicort Turbuhaler) and a placebo group (n = 26; received placebo and Symbicort Turbuhaler), and all 55 subjects provided details of their clinical history and demographic data. However, only 31 patients donated a complete set of fecal and blood samples at all three time points for further analysis. Compared with those of the placebo group, co-administering Probio-M8 with Symbicort Turbuhaler significantly decreased the fractional exhaled nitric oxide level at day 30 (P = 0.049) and improved the asthma control test score at the end of the intervention (P = 0.023). More importantly, the level of alveolar nitric oxide concentration decreased significantly among the probiotic receivers at day 30 (P = 0.038), and the symptom relief effect was even more obvious at day 90 (P = 0.001). Probiotic co-administration increased the resilience of the gut microbiome, which was reflected by only minor fluctuations in the gut microbiome diversity (P > 0.05, probiotic receivers; P < 0.05, placebo receivers). Additionally, the probiotic receivers showed significantly changes in some species-level genome bins (SGBs), namely, increases in potentially beneficial species Bifidobacterium animalis, Bifidobacterium longum, and Prevotella sp. CAG and decreases in Parabacteroides distasonis and Clostridiales bacterium (P < 0.05). Compared with that of the placebo group, the gut metabolic potential of probiotic receivers exhibited increased levels of predicted microbial bioactive metabolites (linoleoyl ethanolamide, adrenergic acid, erythronic acid) and serum metabolites (5-dodecenoic acid, tryptophan, sphingomyelin) during/after intervention. Collectively, our results suggested that co-administering Probio-M8 synergized with conventional therapy to alleviate diseases associated with the gut-lung axis, like asthma, possibly via activating multiple anti-inflammatory pathways. IMPORTANCE The human gut microbiota has a potential effect on the pathogenesis of asthma and is closely related to the disease phenotype. Our trial has demonstrated that co-administering Probio-M8 synergized with conventional therapy to alleviate asthma symptoms. The findings of the present study provide new insights into the pathogenesis and treatment of asthma, mechanisms of novel therapeutic strategies, and application of probiotics-based therapy.
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20
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Cibulková I, Řehořová V, Hajer J, Duška F. Fecal Microbial Transplantation in Critically Ill Patients-Structured Review and Perspectives. Biomolecules 2021; 11:1459. [PMID: 34680092 PMCID: PMC8533499 DOI: 10.3390/biom11101459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 09/25/2021] [Accepted: 10/01/2021] [Indexed: 12/18/2022] Open
Abstract
The human gut microbiota consists of bacteria, archaea, fungi, and viruses. It is a dynamic ecosystem shaped by several factors that play an essential role in both healthy and diseased states of humans. A disturbance of the gut microbiota, also termed "dysbiosis", is associated with increased host susceptibility to a range of diseases. Because of splanchnic ischemia, exposure to antibiotics, and/or the underlying disease, critically ill patients loose 90% of the commensal organisms in their gut within hours after the insult. This is followed by a rapid overgrowth of potentially pathogenic and pro-inflammatory bacteria that alter metabolic, immune, and even neurocognitive functions and that turn the gut into the driver of systemic inflammation and multiorgan failure. Indeed, restoring healthy microbiota by means of fecal microbiota transplantation (FMT) in the critically ill is an attractive and plausible concept in intensive care. Nonetheless, available data from controlled studies are limited to probiotics and FMT for severe C. difficile infection or severe inflammatory bowel disease. Case series and observational trials have generated hypotheses that FMT might be feasible and safe in immunocompromised patients, refractory sepsis, or severe antibiotic-associated diarrhea in ICU. There is a burning need to test these hypotheses in randomized controlled trials powered for the determination of patient-centered outcomes.
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Affiliation(s)
- Ivana Cibulková
- Third Faculty of Medicine, Charles University, 11000 Prague, Czech Republic; (I.C.); (V.Ř.); (J.H.)
- Department of Medicine, FNKV University Hospital, 10034 Prague, Czech Republic
| | - Veronika Řehořová
- Third Faculty of Medicine, Charles University, 11000 Prague, Czech Republic; (I.C.); (V.Ř.); (J.H.)
- Department of Anesthesiology and Intensive Care Medicine, FNKV University Hospital, 10034 Prague, Czech Republic
| | - Jan Hajer
- Third Faculty of Medicine, Charles University, 11000 Prague, Czech Republic; (I.C.); (V.Ř.); (J.H.)
- Department of Medicine, FNKV University Hospital, 10034 Prague, Czech Republic
| | - František Duška
- Third Faculty of Medicine, Charles University, 11000 Prague, Czech Republic; (I.C.); (V.Ř.); (J.H.)
- Department of Anesthesiology and Intensive Care Medicine, FNKV University Hospital, 10034 Prague, Czech Republic
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21
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Ressler AM, Patel A, Rao K. Non-steroidal anti-inflammatory drugs are not associated with increased risk of Clostridioides difficile infection: A propensity-score-matched case-control study. Anaerobe 2021; 72:102444. [PMID: 34506930 DOI: 10.1016/j.anaerobe.2021.102444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 09/03/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022]
Abstract
Prior research identified an increased risk for Clostridioides difficile infection (CDI) following exposure to certain non-steroidal anti-inflammatory drugs (NSAIDs). We conducted a retrospective case-control study to evaluate the risk for CDI associated with NSAID use. NSAID use was not associated with an increased risk of CDI.
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Affiliation(s)
- Adam M Ressler
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
| | - Alieysa Patel
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Krishna Rao
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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Goncuoglu C, Guven GS, Sener B, Demirkan K. Effect of gastric acid suppression on Clostridioides difficile-induced diarrhea and appropriateness of gastric acid suppressors in hospitalized patients: A matched case-control study. Arab J Gastroenterol 2021; 22:292-296. [PMID: 34531136 DOI: 10.1016/j.ajg.2021.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 05/05/2021] [Accepted: 06/30/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND AND STUDY AIMS The effects of gastric acid suppressors (GASs) on Clostridioides difficile infection remain controversial. Moreover, studies have shown that GASs are overused. This study was designed to evaluate the effects of GAS use on the risk of C. difficile-induced diarrhea (CDID) development and to investigate the appropriate use of GASs. PATIENTS AND METHODS In this observational case-control study, patients hospitalized between January 2010 and December 2016 who had diarrhea after 3 days of hospitalization were included. The study (n = 122) and control (n = 122) groups were matched according to the patients' hospitalization dates and departments. RESULTS No significant difference in CDID development was observed between the study and control groups. However, GAS use was excessive in the study and control groups (usage rates were 90.2% and 91.8%, respectively) (p > 0.05). Most proton pump inhibitors and histamine-2 receptor antagonists were used without an appropriate indication. Surprisingly, the use of nonsteroidal anti-inflammatory drugs for 7 days and longer showed a significant difference between the study and control groups (p < 0.05). Additionally, significant differences in enteral feeding, oral nutritional support products, carbapenem, penicillin, glycopeptide antibiotics, antifungals, hypoalbuminemia, and increased leukocyte levels were observed between the study and control groups (p < 0.05). CONCLUSION A significant difference in CDID development was not detected. The use of non-steroidal anti-inflammatory drugs for 7 days and longer was a risk factor for CDID development. Additionally, an excessive inappropriate use of GASs was observed. Clinicians should be cautious of all these factors, which may increase the risk of CDID development.
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Affiliation(s)
- Cansu Goncuoglu
- Hacettepe University, Faculty of Pharmacy, Department of Clinical Pharmacy, P.O. Box 06100, Sıhhiye, Ankara, Turkey.
| | - Gulay Sain Guven
- Hacettepe University, Faculty of Medicine, Department of Internal Medicine, P.O. Box 06100, Sıhhiye, Ankara, Turkey
| | - Burcin Sener
- Hacettepe University, Faculty of Medicine, Department of Medical Microbiology, P.O. Box 06100, Sıhhiye, Ankara, Turkey
| | - Kutay Demirkan
- Hacettepe University, Faculty of Pharmacy, Department of Clinical Pharmacy, P.O. Box 06100, Sıhhiye, Ankara, Turkey
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23
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Dietert RR. Microbiome First Medicine in Health and Safety. Biomedicines 2021; 9:biomedicines9091099. [PMID: 34572284 PMCID: PMC8468398 DOI: 10.3390/biomedicines9091099] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/16/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Microbiome First Medicine is a suggested 21st century healthcare paradigm that prioritizes the entire human, the human superorganism, beginning with the microbiome. To date, much of medicine has protected and treated patients as if they were a single species. This has resulted in unintended damage to the microbiome and an epidemic of chronic disorders [e.g., noncommunicable diseases and conditions (NCDs)]. Along with NCDs came loss of colonization resistance, increased susceptibility to infectious diseases, and increasing multimorbidity and polypharmacy over the life course. To move toward sustainable healthcare, the human microbiome needs to be front and center. This paper presents microbiome-human physiology from the view of systems biology regulation. It also details the ongoing NCD epidemic including the role of existing drugs and other factors that damage the human microbiome. Examples are provided for two entryway NCDs, asthma and obesity, regarding their extensive network of comorbid NCDs. Finally, the challenges of ensuring safety for the microbiome are detailed. Under Microbiome-First Medicine and considering the importance of keystone bacteria and critical windows of development, changes in even a few microbiota-prioritized medical decisions could make a significant difference in health across the life course.
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Affiliation(s)
- Rodney R Dietert
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA
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Voicu MN, Popescu F, Florescu DN, Rogoveanu I, Turcu-Stiolica A, Gheonea DI, Iovanescu VF, Iordache S, Cazacu SM, Ungureanu BS. Clostridioides difficile Infection among Cirrhotic Patients with Variceal Bleeding. Antibiotics (Basel) 2021; 10:731. [PMID: 34204307 PMCID: PMC8233718 DOI: 10.3390/antibiotics10060731] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022] Open
Abstract
Clostridioides difficile infection (CDI) stands as the leading cause of nosocomial infection with high morbidity and mortality rates, causing a major burden on the healthcare system. Driven by antibiotics, it usually affects older patients with chronic disease or immunosuppressed or oncologic management. Variceal bleeding secondary to cirrhosis requires antibiotics to prevent bacterial translocation, and thus patients become susceptible to CDI. We aimed to investigate the risk factors for CDI in cirrhotic patients with variceal bleeding following ceftriaxone and the mortality risk in this patient's population. We retrospectively screened 367 cirrhotic patients with variceal bleeding, from which 25 patients were confirmed with CDI, from 1 January 2017 to 31 December 2019. We found MELD to be the only multivariate predictor for mortality (odds ratio, OR = 1.281, 95% confidence interval, CI: 0.098-1.643, p = 0.042). A model of four predictors (age, days of admission, Charlson index, Child-Pugh score) was generated (area under the receiver operating characteristics curve, AUC = 0.840, 95% CI: 0.758-0.921, p < 0.0001) to assess the risk of CDI exposure. Determining the probability of getting CDI for cirrhotic patients with variceal bleeding could be a tool for doctors in taking decisions, which could be integrated in sustainable public health programs.
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Affiliation(s)
- Mirela Nicoleta Voicu
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (M.N.V.); (F.P.)
| | - Florica Popescu
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (M.N.V.); (F.P.)
| | - Dan Nicolae Florescu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (I.R.); (D.I.G.); (V.F.I.); (S.I.); (S.M.C.); (B.S.U.)
| | - Ion Rogoveanu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (I.R.); (D.I.G.); (V.F.I.); (S.I.); (S.M.C.); (B.S.U.)
| | - Adina Turcu-Stiolica
- Department of Pharmacoeconomics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dan Ionut Gheonea
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (I.R.); (D.I.G.); (V.F.I.); (S.I.); (S.M.C.); (B.S.U.)
| | - Vlad Florin Iovanescu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (I.R.); (D.I.G.); (V.F.I.); (S.I.); (S.M.C.); (B.S.U.)
| | - Sevastita Iordache
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (I.R.); (D.I.G.); (V.F.I.); (S.I.); (S.M.C.); (B.S.U.)
| | - Sergiu Marian Cazacu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (I.R.); (D.I.G.); (V.F.I.); (S.I.); (S.M.C.); (B.S.U.)
| | - Bogdan Silviu Ungureanu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (I.R.); (D.I.G.); (V.F.I.); (S.I.); (S.M.C.); (B.S.U.)
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25
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Hutka B, Lázár B, Tóth AS, Ágg B, László SB, Makra N, Ligeti B, Scheich B, Király K, Al-Khrasani M, Szabó D, Ferdinandy P, Gyires K, Zádori ZS. The Nonsteroidal Anti-Inflammatory Drug Ketorolac Alters the Small Intestinal Microbiota and Bile Acids Without Inducing Intestinal Damage or Delaying Peristalsis in the Rat. Front Pharmacol 2021; 12:664177. [PMID: 34149417 PMCID: PMC8213092 DOI: 10.3389/fphar.2021.664177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/19/2021] [Indexed: 01/02/2023] Open
Abstract
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce significant damage to the small intestine, which is accompanied by changes in intestinal bacteria (dysbiosis) and bile acids. However, it is still a question of debate whether besides mucosal inflammation also other factors, such as direct antibacterial effects or delayed peristalsis, contribute to NSAID-induced dysbiosis. Here we aimed to assess whether ketorolac, an NSAID lacking direct effects on gut bacteria, has any significant impact on intestinal microbiota and bile acids in the absence of mucosal inflammation. We also addressed the possibility that ketorolac-induced bacterial and bile acid alterations are due to a delay in gastrointestinal (GI) transit. Methods: Vehicle or ketorolac (1, 3 and 10 mg/kg) were given to rats by oral gavage once daily for four weeks, and the severity of mucosal inflammation was evaluated macroscopically, histologically, and by measuring the levels of inflammatory proteins and claudin-1 in the distal jejunal tissue. The luminal amount of bile acids was measured by liquid chromatography-tandem mass spectrometry, whereas the composition of microbiota by sequencing of bacterial 16S rRNA. GI transit was assessed by the charcoal meal method. Results: Ketorolac up to 3 mg/kg did not cause any signs of mucosal damage to the small intestine. However, 3 mg/kg of ketorolac induced dysbiosis, which was characterized by a loss of families belonging to Firmicutes (Paenibacillaceae, Clostridiales Family XIII, Christensenellaceae) and bloom of Enterobacteriaceae. Ketorolac also changed the composition of small intestinal bile by decreasing the concentration of conjugated bile acids and by increasing the amount of hyodeoxycholic acid (HDCA). The level of conjugated bile acids correlated negatively with the abundance of Erysipelotrichaceae, Ruminococcaceae, Clostridiaceae 1, Muribaculaceae, Bacteroidaceae, Burkholderiaceae and Bifidobacteriaceae. Ketorolac, under the present experimental conditions, did not change the GI transit. Conclusion: This is the first demonstration that low-dose ketorolac disturbed the delicate balance between small intestinal bacteria and bile acids, despite having no significant effect on intestinal mucosal integrity and peristalsis. Other, yet unidentified, factors may contribute to ketorolac-induced dysbiosis and bile dysmetabolism.
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Affiliation(s)
- Barbara Hutka
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Bernadette Lázár
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - András S Tóth
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Bence Ágg
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Szilvia B László
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Nóra Makra
- Department of Medical Microbiology, Semmelweis University, Budapest, Hungary
| | - Balázs Ligeti
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
| | - Bálint Scheich
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Kornél Király
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Mahmoud Al-Khrasani
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Dóra Szabó
- Department of Medical Microbiology, Semmelweis University, Budapest, Hungary
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Klára Gyires
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Zoltán S Zádori
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
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26
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Lázár B, László SB, Hutka B, Tóth AS, Mohammadzadeh A, Berekméri E, Ágg B, Balogh M, Sajtos V, Király K, Al-Khrasani M, Földes A, Varga G, Makra N, Ostorházi E, Szabó D, Ligeti B, Kemény Á, Helyes Z, Ferdinandy P, Gyires K, Zádori ZS. A comprehensive time course and correlation analysis of indomethacin-induced inflammation, bile acid alterations and dysbiosis in the rat small intestine. Biochem Pharmacol 2021; 190:114590. [PMID: 33940029 DOI: 10.1016/j.bcp.2021.114590] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/13/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023]
Abstract
It has been proposed that changes in microbiota due to nonsteroidal anti-inflammatory drugs (NSAIDs) alter the composition of bile, and elevation of hydrophobic secondary bile acids contributes to small intestinal damage. However, little is known about the effect of NSAIDs on small intestinal bile acids, and whether bile alterations correlate with mucosal injury and dysbiosis. Here we determined the ileal bile acid metabolome and microbiota 24, 48 and 72 h after indomethacin treatment, and their correlation with each other and with tissue damage in rats. In parallel with the development of inflammation, indomethacin increased the ileal proportion of glycine and taurine conjugated bile acids, but not bile hydrophobicity. Firmicutes decreased with time, whereas Gammaproteobacteria increased first, but declined later and were partially replaced by Bilophila, Bacteroides and Fusobacterium. Mucosal injury correlated negatively with unconjugated bile acids and Gram-positive bacteria, and positively with taurine conjugates and some Gram-negative taxa. Strong positive correlation was found between Lactobacillaceae, Ruminococcaceae, Clostridiaceae and unconjugated bile acids. Indomethacin-induced dysbiosis was not likely due to direct antibacterial effects or alterations in luminal pH. Here we provide the first detailed characterization of indomethacin-induced time-dependent alterations in small intestinal bile acid composition, and their associations with mucosal injury and dysbiosis. Our results suggest that increased bile hydrophobicity is not likely to contribute to indomethacin-induced small intestinal damage.
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Affiliation(s)
- Bernadette Lázár
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Szilvia B László
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Barbara Hutka
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - András S Tóth
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Amir Mohammadzadeh
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Eszter Berekméri
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; Department of Ecology, University of Veterinary Medicine, 1078 Budapest, Hungary
| | - Bence Ágg
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; Pharmahungary Group, 6722 Szeged, Hungary
| | - Mihály Balogh
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Viktor Sajtos
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Kornél Király
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Mahmoud Al-Khrasani
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Anna Földes
- Department of Oral Biology, Semmelweis University, 1089 Budapest, Hungary
| | - Gábor Varga
- Department of Oral Biology, Semmelweis University, 1089 Budapest, Hungary
| | - Nóra Makra
- Department of Medical Microbiology, Semmelweis University, 1089 Budapest, Hungary
| | - Eszter Ostorházi
- Department of Medical Microbiology, Semmelweis University, 1089 Budapest, Hungary
| | - Dóra Szabó
- Department of Medical Microbiology, Semmelweis University, 1089 Budapest, Hungary
| | - Balázs Ligeti
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, 1083 Budapest, Hungary
| | - Ágnes Kemény
- Department of Medical Biology, University of Pécs, 7624 Pécs, Hungary; Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; Pharmahungary Group, 6722 Szeged, Hungary
| | - Klára Gyires
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
| | - Zoltán S Zádori
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary.
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27
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Brennan CA, Nakatsu G, Gallini Comeau CA, Drew DA, Glickman JN, Schoen RE, Chan AT, Garrett WS. Aspirin Modulation of the Colorectal Cancer-Associated Microbe Fusobacterium nucleatum. mBio 2021; 12:e00547-21. [PMID: 33824205 PMCID: PMC8092249 DOI: 10.1128/mbio.00547-21] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 03/04/2021] [Indexed: 12/14/2022] Open
Abstract
Aspirin is a chemopreventive agent for colorectal adenoma and cancer (CRC) that, like many drugs inclusive of chemotherapeutics, has been investigated for its effects on bacterial growth and virulence gene expression. Given the evolving recognition of the roles for bacteria in CRC, in this work, we investigate the effects of aspirin with a focus on one oncomicrobe-Fusobacterium nucleatum We show that aspirin and its primary metabolite salicylic acid alter F. nucleatum strain Fn7-1 growth in culture and that aspirin can effectively kill both actively growing and stationary Fn7-1. We also demonstrate that, at levels that do not inhibit growth, aspirin influences Fn7-1 gene expression. To assess whether aspirin modulation of F. nucleatum may be relevant in vivo, we use the ApcMin/+ mouse intestinal tumor model in which Fn7-1 is orally inoculated daily to reveal that aspirin-supplemented chow is sufficient to inhibit F. nucleatum-potentiated colonic tumorigenesis. We expand our characterization of aspirin sensitivity across other F. nucleatum strains, including those isolated from human CRC tissues, as well as other CRC-associated microbes, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli Finally, we determine that individuals who use aspirin daily have lower fusobacterial abundance in colon adenoma tissues, as determined by quantitative PCR performed on adenoma DNA. Together, our data support that aspirin has direct antibiotic activity against F. nucleatum strains and suggest that consideration of the potential effects of aspirin on the microbiome holds promise in optimizing risk-benefit assessments for use of aspirin in CRC prevention and management.IMPORTANCE There is an increasing understanding of the clinical correlations and potential mechanistic roles of specific members of the gut and tumoral microbiota in colorectal cancer (CRC) initiation, progression, and survival. However, we have yet to parlay this knowledge into better CRC outcomes through microbially informed diagnostic, preventive, or therapeutic approaches. Here, we demonstrate that aspirin, an established CRC chemopreventive, exhibits specific effects on the CRC-associated Fusobacterium nucleatum in culture, an animal model of intestinal tumorigenesis, and in human colonic adenoma tissues. Our work proposes a potential role for aspirin in influencing CRC-associated bacteria to prevent colorectal adenomas and cancer, beyond aspirin's canonical anti-inflammatory role targeting host tissues. Future research, such as studies investigating the effects of aspirin on fusobacterial load in patients, will help further elucidate the prospect of using aspirin to modulate F. nucleatumin vivo for improving CRC outcomes.
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Affiliation(s)
- Caitlin A Brennan
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
- Harvard T. H. Chan Microbiome in Public Health Center, Boston, Massachusetts, USA
| | - Geicho Nakatsu
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
- Harvard T. H. Chan Microbiome in Public Health Center, Boston, Massachusetts, USA
| | - Carey Ann Gallini Comeau
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
| | - David A Drew
- Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Jonathan N Glickman
- Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Robert E Schoen
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Andrew T Chan
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
- Harvard T. H. Chan Microbiome in Public Health Center, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
| | - Wendy S Garrett
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
- Harvard T. H. Chan Microbiome in Public Health Center, Boston, Massachusetts, USA
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
- Department and Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
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28
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Wang X, Tang Q, Hou H, Zhang W, Li M, Chen D, Gu Y, Wang B, Hou J, Liu Y, Cao H. Gut Microbiota in NSAID Enteropathy: New Insights From Inside. Front Cell Infect Microbiol 2021; 11:679396. [PMID: 34295835 PMCID: PMC8290187 DOI: 10.3389/fcimb.2021.679396] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/10/2021] [Indexed: 12/15/2022] Open
Abstract
As a class of the commonly used drugs in clinical practice, non-steroidal anti-inflammatory drugs (NSAIDs) can cause a series of adverse events including gastrointestinal injuries. Besides upper gastrointestinal injuries, NSAID enteropathy also attracts attention with the introduction of capsule endoscopy and double balloon enteroscopy. However, the pathogenesis of NSAID enteropathy remains to be entirely clarified. Growing evidence from basic and clinical studies presents that gut microbiota is a critical factor in NSAID enteropathy progress. We have reviewed the recent data about the interplay between gut microbiota dysbiosis and NSAID enteropathy. The chronic medication of NSAIDs could change the composition of the intestinal bacteria and aggravate bile acids cytotoxicity. Meanwhile, NSAIDs impair the intestinal barrier by inhibiting cyclooxygenase and destroying mitochondria. Subsequently, intestinal bacteria translocate into the mucosa, and then lipopolysaccharide released from gut microbiota combines to Toll-like receptor 4 and induce excessive production of nitric oxide and pro-inflammatory cytokines. Intestinal injuries present in the condition of intestinal inflammation and oxidative stress. In this paper, we also have reviewed the possible strategies of regulating gut microbiota for the management of NSAID enteropathy, including antibiotics, probiotics, prebiotics, mucosal protective agents, and fecal microbiota transplant, and we emphasized the adverse effects of proton pump inhibitors on NSAID enteropathy. Therefore, this review will provide new insights into a better understanding of gut microbiota in NSAID enteropathy.
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Affiliation(s)
- Xianglu Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qiang Tang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Huiqin Hou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Wanru Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Mengfan Li
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Danfeng Chen
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yu Gu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Jingli Hou
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
| | - Yangping Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
- *Correspondence: Hailong Cao, ; Jingli Hou, ; Yangping Liu,
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Lisowska B, Jakubiak J, Siewruk K, Sady M, Kosson D. Which idea is better with regard to immune response? Opioid anesthesia or opioid free anesthesia. J Inflamm Res 2020; 13:859-869. [PMID: 33177861 PMCID: PMC7652233 DOI: 10.2147/jir.s275986] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022] Open
Abstract
The stress of surgery is characterized by an inflammatory response with immune suppression resulting from many factors, including the type of surgery and the kind of anesthesia, linked with the drugs that are used and the underlying disease of the patient. The trauma of surgery triggers a cascade of reactions involving the immune response and nociception. As strong analgesics, opioids provide the analgesic component of general anesthesia with bi-directional effect on the immune system. Opioids influence almost all aspects of the immune response in regards to leukocytes, macrophages, mast cells, lymphocytes, and NK cells. The suppressive effect of opioids on the immune system is limiting their use, especially in patients with impaired immune response, so the possibility of using multimodal anesthesia without opioids, known as opioid-free anesthesia (OFA), is gaining more and more sympathizers. The idea of OFA is to eliminate opioid analgesia in the treatment of acute pain and to replace it with drugs from other groups that are assumed to have a comparable analgesic effect without affecting the immune system. Here, we present a review on the impact of anesthesia, with and without the use of opioids, on the immune response to surgical stress.
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Affiliation(s)
- Barbara Lisowska
- Department Anesthesiology and Intensive Medical Care, National Geriatrics, Rheumatology and Rehabilitation Institute, Warsaw 02-637, Poland
| | - Jakub Jakubiak
- Department of Anesthesiology and Intensive Care, John Paul II Western Hospital, Grodzisk Mazowiecki 05-825, Poland
| | - Katarzyna Siewruk
- Faculty of Veterinary Medicine, Department of Large Animal Diseases with Clinic, Warsaw University of Life Sciences, Warsaw 02-797, Poland
| | - Maria Sady
- Faculty of Veterinary Medicine, Department of Large Animal Diseases with Clinic, Warsaw University of Life Sciences, Warsaw 02-797, Poland
| | - Dariusz Kosson
- Department of Anaesthesiology and Intensive Care, Division of Teaching, Medical University of Warsaw, Warsaw 02-005, Poland
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30
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Hernández Del Pino RE, Barbero AM, Español LÁ, Morro LS, Pasquinelli V. The adaptive immune response to Clostridioides difficile: A tricky balance between immunoprotection and immunopathogenesis. J Leukoc Biol 2020; 109:195-210. [PMID: 32829520 DOI: 10.1002/jlb.4vmr0720-201r] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
Clostridioides difficile (C. difficile) is the major cause of hospital-acquired gastrointestinal infections in individuals following antibiotics treatment. The pathogenesis of C. difficile infection (CDI) is mediated mainly by the production of toxins that induce tissue damage and host inflammatory responses. While innate immunity is well characterized in human and animal models of CDI, adaptive immune responses remain poorly understood. In this review, the current understanding of adaptive immunity is summarized and its influence on pathogenesis and disease outcome is discussed. The perspectives on what we believe to be the main pending questions and the focus of future research are also provided. There is no doubt that the innate immune response provides a first line of defense to CDI. But, is the adaptive immune response a friend or a foe? Probably it depends on the course of the disease. Adaptive immunity is essential for pathogen eradication, but may also trigger uncontrolled or pathological inflammation. Most of the understanding of the role of T cells is based on findings from experimental models. While they are a very valuable tool for research studies, more studies in human are needed to translate these findings into human disease. Another main challenge is to unravel the role of the different T cell populations on protection or induction of immunopathogenesis.
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Affiliation(s)
- Rodrigo Emanuel Hernández Del Pino
- Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Buenos Aires, Argentina.,Centro de Investigaciones y Transferencias del Noroeste de la Provincia de Buenos Aires (CIT NOBA), UNNOBA-Universidad Nacional de San Antonio de Areco (UNSAdA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Angela María Barbero
- Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Buenos Aires, Argentina.,Centro de Investigaciones y Transferencias del Noroeste de la Provincia de Buenos Aires (CIT NOBA), UNNOBA-Universidad Nacional de San Antonio de Areco (UNSAdA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Laureano Ángel Español
- Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Buenos Aires, Argentina
| | - Lorenzo Sebastián Morro
- Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Buenos Aires, Argentina
| | - Virginia Pasquinelli
- Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Buenos Aires, Argentina.,Centro de Investigaciones y Transferencias del Noroeste de la Provincia de Buenos Aires (CIT NOBA), UNNOBA-Universidad Nacional de San Antonio de Areco (UNSAdA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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Smith AB, Soto Ocana J, Zackular JP. From Nursery to Nursing Home: Emerging Concepts in Clostridioides difficile Pathogenesis. Infect Immun 2020; 88:IAI.00934-19. [PMID: 32122939 PMCID: PMC7309631 DOI: 10.1128/iai.00934-19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Clostridioides difficile is a Gram-positive, spore-forming, anaerobic bacterium that infects the human gastrointestinal tract, causing a wide range of disorders that vary in severity from mild diarrhea to toxic megacolon and/or death. Over the past decade, incidence, severity, and costs associated with C. difficile infection (CDI) have increased dramatically in both the pediatric and adult populations. The factors driving this rapidly evolving epidemiology remain largely unknown but are likely due in part to previously unappreciated host, microbiota, and environmental factors. In this review, we will cover the risks and challenges of CDI in adult and pediatric populations and examine asymptomatic colonization in infants. We will also discuss the emerging role of diet, pharmaceutical drugs, and pathogen-microbiota interactions in C. difficile pathogenesis, as well as the impact of host-microbiota interactions in the manifestation of C. difficile-associated disease. Finally, we highlight new areas of research and novel strategies that may shed light on this complex infection and provide insights into the future of microbiota-based therapeutics for CDI.
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Affiliation(s)
- Alexander B Smith
- Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joshua Soto Ocana
- Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joseph P Zackular
- Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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32
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Liu H, Wang HH. Impact of Microbiota Transplant on Resistome of Gut Microbiota in Gnotobiotic Piglets and Human Subjects. Front Microbiol 2020; 11:932. [PMID: 32508773 PMCID: PMC7248251 DOI: 10.3389/fmicb.2020.00932] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/20/2020] [Indexed: 12/20/2022] Open
Abstract
Microbiota transplant is becoming a popular process to restore or initiate “healthy” gut microbiota and immunity. But, the potential risks of the related practices need to be carefully evaluated. This study retrospectively examined the resistomes of donated fecal microbiota for treating intestinal disorders, vaginal microbiota of pregnant women, and infant fecal microbiota from rural and urban communities, as well as the impact of transplants on the fecal resistome of human and animal recipients. Antibiotic resistance (AR) genes were found to be abundant in all donor microbiota. An overall surge of resistomes with higher prevalence and abundance of AR genes was observed in the feces of all transplanted gnotobiotic pigs as well as in the feces of infant subjects, compared to those in donor fecal and maternal vaginal microbiota. Surprisingly, transplants using rural Amish microbiota led to more instead of less AR genes in the fecal microbiota of gnotobiotic pigs than did transplants using urban microbiota. New AR gene subtypes undetected originally also appeared in gnotobiotic pigs, in Crohn’s Disease (CD) patients after transplant, and in feces of infant subjects. The data illustrated the key role of the host gastrointestinal tract system in amplifying the ever-increasing AR gene pool, even without antibiotic exposure. The data further suggest that the current approaches of microbiota transplant can introduce significant health risk factor(s) to the recipients, and newborn human and animal hosts with naïve gut microbiota were especially susceptible. Given the illustrated public health risks of microbiota transplant, minimizing massive and unnecessary damages to gut microbiota by oral antibiotics and other gut impacting drugs becomes important. Since eliminating risk factors including AR bacteria and opportunistic pathogens directly from donor microbiota is still difficult to achieve, developing microbial cocktails with defined organisms and functions has further become an urgent need, should microbiota transplantation become necessary.
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Affiliation(s)
- Hu Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China.,Department of Food Science and Technology, The Ohio State University, Columbus, OH, United States
| | - Hua H Wang
- Department of Food Science and Technology, The Ohio State University, Columbus, OH, United States.,Department of Microbiology, The Ohio State University, Columbus, OH, United States
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33
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Affiliation(s)
- Robert W. P. Glowacki
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Eric C. Martens
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
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34
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Antonelli M, Martin-Loeches I, Dimopoulos G, Gasbarrini A, Vallecoccia MS. Clostridioides difficile (formerly Clostridium difficile) infection in the critically ill: an expert statement. Intensive Care Med 2020; 46:215-224. [PMID: 31938827 DOI: 10.1007/s00134-019-05873-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/16/2019] [Indexed: 02/07/2023]
Abstract
Clostridioides difficile (formerly Clostridium difficile) infection (CDI) represents a worrisome condition, often underestimated, with severe clinical presentations, frequently requiring intensive care unit (ICU) admission. The aim of the present expert statement was to give an overview of the management of CDI in critically ill patients, for whom CDI represents a redoubtable problem, in large part related to the use and abuse of antibiotics. The available knowledge about pathophysiology, risk factors, diagnosis and treatment concerning critical care patients affected by CDI has been reviewed, even though most of the existing information come from studies performed outside the ICU and the evidence on several issues in this specific context is scarce. The adoption of potential preventive and therapeutic strategies aimed to stem the phenomenon were discussed, including the faecal microbiota transplantation. This possibility could represent a highly interesting option in critically ill patients, but current evidence is limited and future well designed studies are needed. A special insight on the specific challenges that the ICU physicians may face caring for the critically ill patients with CDI was also proposed.
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Affiliation(s)
- Massimo Antonelli
- Department of Anesthesiology, Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
- Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Ignacio Martin-Loeches
- Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St. James's Hospital, St James Street, Dublin 8, Dublin, Ireland
- Hospital Clinic, IDIBAPS, Universidad de Barcelona, Ciberes, Barcelona, Spain
| | - George Dimopoulos
- Critical Care Department, ATTIKON University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonio Gasbarrini
- Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Maria Sole Vallecoccia
- Department of Anesthesiology, Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
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35
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Reply to Noori et al., "A Complex Scenario of Nonsteroidal Anti-inflammatory Drugs Induced Prostaglandin E2 Production and Gut Microbiota Alteration in Clostridium difficile-Infected Mice". mBio 2020; 11:mBio.03142-19. [PMID: 31992624 PMCID: PMC6989112 DOI: 10.1128/mbio.03142-19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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36
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Noori M, Yadegar A, Zali MR. A Complex Scenario of Nonsteroidal Anti-inflammatory Drugs Induced Prostaglandin E2 Production and Gut Microbiota Alteration in Clostridium difficile-Infected Mice. mBio 2020; 11:e02596-19. [PMID: 31937640 PMCID: PMC6960283 DOI: 10.1128/mbio.02596-19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Affiliation(s)
- Maryam Noori
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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37
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Khan MF, Wang H. Environmental Exposures and Autoimmune Diseases: Contribution of Gut Microbiome. Front Immunol 2020; 10:3094. [PMID: 31998327 PMCID: PMC6970196 DOI: 10.3389/fimmu.2019.03094] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 12/18/2019] [Indexed: 12/12/2022] Open
Abstract
Environmental agents have been gaining more attention in recent years for their role in the pathogenesis of autoimmune diseases (ADs). Increasing evidence has linked environmental exposures, including trichloroethene (TCE), silica, mercury, pristane, pesticides, and smoking to higher risk for ADs. However, potential mechanisms by which these environmental agents contribute to the disease pathogenesis remains largely unknown. Dysbiosis of the gut microbiome is another important environmental factor that has been linked to the onset of different ADs. Altered microbiota composition is associated with impaired intestinal barrier function and dysregulation of mucosal immune system, but it is unclear if gut dysbiosis is a causal factor or an outcome of ADs. In this review article, we first describe the recent epidemiological and mechanistic evidences linking environmental/occupational exposures with various ADs (especially SLE). Secondly, we discuss how changes in the gut microbiome composition (dysbiosis) could contribute to the disease pathogenesis, especially in response to exposure to environmental chemicals.
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Affiliation(s)
- M. Firoze Khan
- Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
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38
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Maseda D, Ricciotti E. NSAID-Gut Microbiota Interactions. Front Pharmacol 2020; 11:1153. [PMID: 32848762 PMCID: PMC7426480 DOI: 10.3389/fphar.2020.01153] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAID)s relieve pain, inflammation, and fever by inhibiting the activity of cyclooxygenase isozymes (COX-1 and COX-2). Despite their clinical efficacy, NSAIDs can cause gastrointestinal (GI) and cardiovascular (CV) complications. Moreover, NSAID use is characterized by a remarkable individual variability in the extent of COX isozyme inhibition, therapeutic efficacy, and incidence of adverse effects. The interaction between the gut microbiota and host has emerged as a key player in modulating host physiology, gut microbiota-related disorders, and metabolism of xenobiotics. Indeed, host-gut microbiota dynamic interactions influence NSAID disposition, therapeutic efficacy, and toxicity. The gut microbiota can directly cause chemical modifications of the NSAID or can indirectly influence its absorption or metabolism by regulating host metabolic enzymes or processes, which may have consequences for drug pharmacokinetic and pharmacodynamic properties. NSAID itself can directly impact the composition and function of the gut microbiota or indirectly alter the physiological properties or functions of the host which may, in turn, precipitate in dysbiosis. Thus, the complex interconnectedness between host-gut microbiota and drug may contribute to the variability in NSAID response and ultimately influence the outcome of NSAID therapy. Herein, we review the interplay between host-gut microbiota and NSAID and its consequences for both drug efficacy and toxicity, mainly in the GI tract. In addition, we highlight progress towards microbiota-based intervention to reduce NSAID-induced enteropathy.
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Affiliation(s)
- Damian Maseda
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, United States
| | - Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, and Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
- *Correspondence: Emanuela Ricciotti,
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Type 3 Immunity during Clostridioides difficile Infection: Too Much of a Good Thing? Infect Immun 2019; 88:IAI.00306-19. [PMID: 31570564 DOI: 10.1128/iai.00306-19] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Clostridioides (formerly known as Clostridium) difficile is the leading cause of hospital-acquired gastrointestinal infections in the United States and one of three urgent health care threats identified by the Centers for Disease Control and Prevention. C. difficile disease is mediated by the production of toxins that disrupt the epithelial barrier and cause a robust host inflammatory response. Studies in humans as well as animal models of disease have shown that the type of immune response generated against the infection dictates the outcome of disease, often irrespective of bacterial burden. Much of the focus on immunity during C. difficile infection (CDI) has been on type 3 immunity because of the established role for this arm of the immune system in other gastrointestinal inflammatory conditions such as inflammatory bowel disease (IBD). For example, interleukin-22 (IL-22) production by group 3 innate lymphoid cells (ILC3s) protects against pathobionts translocating across the epithelium during CDI. On the other hand, interleukin-17 (IL-17) production by Th17 cells increases CDI-associated mortality. Additionally, neutropenia has been associated with increased susceptibility to CDI in humans, but increased neutrophilia in mouse models correlates with host pathology. Taking the data together, these findings suggest dual roles for type 3 immune responses during infection. Here, we review the complex role of type 3 immunity during CDI and delineate what is known about innate and adaptive cellular immunity as well as the downstream effector cytokines known to be important during this infection.
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40
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Patel H, Makker J, Vakde T, Shaikh D, Badipatla K, Dunne J, Mantri N, Nayudu SK, Glandt M, Balar B, Chilimuri S. Nonsteroidal Anti-Inflammatory Drugs Impact on the Outcomes of Hospitalized Patients with Clostridium difficile Infection. Clin Exp Gastroenterol 2019; 12:449-456. [PMID: 31849510 PMCID: PMC6911331 DOI: 10.2147/ceg.s223886] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/21/2019] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Mouse model experiments have demonstrated an increased Clostridium difficile infection (CDI) severity with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) use. We aim to evaluate the impact of NSAIDs in humans after a diagnosis of CDI on primary outcomes defined as I) all-cause mortality and II) toxic mega-colon attributable to CDI. PATIENTS AND METHODS All hospitalized patients with a diagnosis of CDI were divided into two groups; those with NSAIDs administered up to 10 days after onset of CDI versus no NSAIDs use. The primary outcomes were analyzed between the groups, while controlling for severity of CDI. A logistic regression analysis was performed to identify the predictors of worse outcomes. RESULTS NSAIDs were administered in 14% (n=80) of the 568 hospitalized visits for an average of 2.5 days after the CDI diagnosis. All-cause mortality was high in patients who did not receive NSAIDs as compared to those who did receive NSAIDs (16.6% vs 12.5%, p 0.354). Patients who were prescribed NSAIDs were more likely to have toxic mega-colon as compared to those who were not prescribed NSAIDs (2.5% vs 0.6%, p 0.094). Results were not statistically significant, even after controlling for CDI severity. Logistic regression analysis did not identify NSAIDs administration as a significant factor for all-cause mortality in CDI patients. CONCLUSION This retrospective study results, contrary to mouse model, did not show association between NSAID use and CDI related mortality and toxic mega-colon. Shorter duration of NSAIDs use, younger people in study group, and timely CDI treatment may have resulted in contrasting results.
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Affiliation(s)
- Harish Patel
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
- Division of Gastroenterology, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Jasbir Makker
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
- Division of Gastroenterology, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Trupti Vakde
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
- Division of Pulmonary and Critical Care Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Danial Shaikh
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
- Division of Gastroenterology, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Kanthi Badipatla
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
- Division of Gastroenterology, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - James Dunne
- Support Service and Operation, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Nikhitha Mantri
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Suresh Kumar Nayudu
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
- Division of Gastroenterology, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Mariela Glandt
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Bhavna Balar
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
- Division of Gastroenterology, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
| | - Sridhar Chilimuri
- Department of Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
- Division of Gastroenterology, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA
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41
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Maseda D, Ricciotti E, Crofford LJ. Prostaglandin regulation of T cell biology. Pharmacol Res 2019; 149:104456. [PMID: 31553935 DOI: 10.1016/j.phrs.2019.104456] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/06/2019] [Accepted: 09/13/2019] [Indexed: 12/26/2022]
Abstract
Prostaglandins (PG) are pleiotropic bioactive lipids involved in the control of many physiological processes, including key roles in regulating inflammation. This links PG to the modulation of the quality and magnitude of immune responses. T cells, as a core part of the immune system, respond readily to inflammatory cues from their environment, and express a diverse array of PG receptors that contribute to their function and phenotype. Here we put in context our knowledge about how PG affect T cell biology, and review advances that bring light into how specific T cell functions that have been newly discovered are modulated through PG. We will also comment on drugs that target PG metabolism and sensing, their effect on T cell function during disease, and we will finally discuss how we can design new approaches that modulate PG in order to maximize desired therapeutic T cell effects.
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Affiliation(s)
- Damian Maseda
- Department of Microbiology, University of Pennsylvania School of Medicine, 8-138 Smillow Center for Translational Research, Philadelphia, PA, USA.
| | - Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
| | - Leslie J Crofford
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
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42
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Zackular JP, Kirk L, Trindade BC, Skaar EP, Aronoff DM. Misoprostol protects mice against severe Clostridium difficile infection and promotes recovery of the gut microbiota after antibiotic perturbation. Anaerobe 2019; 58:89-94. [PMID: 31220605 PMCID: PMC6697607 DOI: 10.1016/j.anaerobe.2019.06.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 06/15/2019] [Indexed: 01/13/2023]
Abstract
Clostridium difficile infection (CDI) is one of the most common nosocomial infections worldwide and an urgent public health threat. Epidemiological and experimental studies have demonstrated an association between nonsteroidal anti-inflammatory drug (NSAID) exposure and enhanced susceptibility to, and severity of, CDI. NSAIDs target cyclooxygenase enzymes and inhibit the production of prostaglandins (PGs), but the therapeutic potential of exogenous introduction of PGs for the treatment of CDI has not been explored. In this study, we report that treatment with the FDA-approved stable PGE1 analogue, misoprostol, protects mice against C. difficile-associated mortality, intestinal pathology, and CDI-mediated intestinal permeability. Furthermore, we report that the effect of misoprostol on the gastrointestinal tract contributes to increased recovery of the gut microbiota following antibiotic perturbation. Together, these data implicate PGs as an important host-factor associated with recovery to C. difficile-associated disease and demonstrate the potential for misoprostol in the treatment of CDI. Further studies to explore the safety and efficacy of misoprostol treatment of CDI in humans is needed.
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Affiliation(s)
- Joseph P Zackular
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Leslie Kirk
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Bruno C Trindade
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Eric P Skaar
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - David M Aronoff
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.
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Host⁻Microbe Interactions and Gut Health in Poultry-Focus on Innate Responses. Microorganisms 2019; 7:microorganisms7050139. [PMID: 31100860 PMCID: PMC6560434 DOI: 10.3390/microorganisms7050139] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 05/14/2019] [Accepted: 05/14/2019] [Indexed: 01/14/2023] Open
Abstract
Commercial poultry are continually exposed to, frequently pathogenic, microorganisms, usually via mucosal surfaces such as the intestinal mucosa. Thus, understanding host–microbe interactions is vital. Many of these microorganisms may have no or limited contact with the host, while most of those interacting more meaningfully with the host will be dealt with by the innate immune response. Fundamentally, poultry have evolved to have immune responses that are generally appropriate and adequate for their acquired microbiomes, although this is challenged by commercial production practices. Innate immune cells and their functions, encompassing inflammatory responses, create the context for neutralising the stimulus and initiating resolution. Dysregulated inflammatory responses can be detrimental but, being a highly conserved biological process, inflammation is critical for host defence. Heterogeneity and functional plasticity of innate immune cells is underappreciated and offers the potential for (gut) health interventions, perhaps including exogenous opportunities to influence immune cell metabolism and thus function. New approaches could focus on identifying and enhancing decisive but less harmful immune processes, improving the efficiency of innate immune cells (e.g., targeted, efficient microbial killing) and promoting phenotypes that drive resolution of inflammation. Breeding strategies and suitable exogenous interventions offer potential solutions to enhance poultry gut health, performance and welfare.
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