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Choi G, Bessman NJ. Iron at the crossroads of host-microbiome interactions in health and disease. Nat Microbiol 2025:10.1038/s41564-025-02001-y. [PMID: 40399686 DOI: 10.1038/s41564-025-02001-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 03/31/2025] [Indexed: 05/23/2025]
Abstract
Iron is an essential dietary micronutrient for both humans and microorganisms. Disruption of iron homeostasis is closely linked, as both a cause and an effect, to the development and progression of gut microbiota dysbiosis and multiple diseases. Iron absorption in humans is impacted by diverse environmental factors, including diet, medication and microbiota-derived molecules. Accordingly, treatment outcomes for iron-associated diseases may depend on an individual patient's microbiome. Here we describe various iron acquisition strategies used by the host, commensal microorganisms and pathogens to benefit or outcompete each other in the complex gut environment. We further explore recently discovered microbial species and metabolites modulating host iron absorption, which represent potential effectors of disease and therapeutic targets. Finally, we discuss the need for mechanistic studies on iron-host-microbiome interactions that can affect disease and treatment outcomes, with the ultimate aim of supporting the development of microbiome-based personalized medicine.
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Affiliation(s)
- Garam Choi
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Nicholas J Bessman
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA.
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA.
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Medjbeur T, Sardo U, Perrier P, Cormier K, Roy M, Dumay A, Kautz L. Comparative analysis of dietary iron deprivation and supplementation in a murine model of colitis. FASEB Bioadv 2025; 7:e70007. [PMID: 40330433 PMCID: PMC12050954 DOI: 10.1096/fba.2025-00022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 05/08/2025] Open
Abstract
Inflammatory bowel diseases are chronic inflammatory conditions with growing prevalence in western populations. Iron is an essential component of erythrocytes hemoglobin. Under the influence of elevated hepcidin production, iron is sequestered in cells during inflammation which, in turn, leads to iron restriction for red blood cell synthesis. As a consequence, iron deficiency and anemia of inflammation are the most prevalent extraintestinal complications in IBD patients. Iron deficiency is commonly treated with oral iron supplements, with limited efficacy as iron absorption is blunted during intestinal inflammation. Moreover, iron supplementation can cause intestinal complications, as previous studies have shown that it can worsen the inflammatory response. However, a comparative analysis of the effects of low, adequate, and high dietary iron content matching the iron supplementation given to patients has not been performed in mice. We therefore tested the impact of dietary iron deprivation and supplementation in a murine model of colitis induced by dextran sodium sulfate. We found that both dietary iron deprivation and supplementation were accompanied by a more severe inflammation with earlier signs of gastrointestinal bleeding compared to mice fed an iron-adequate diet. The manipulation of dietary iron led to a profound dysbiosis in the colon of control mice that differed depending on the dietary iron content. Analysis of this dysbiosis is in line with a pronounced susceptibility to colonic inflammation, thus questioning the benefit/risk balance of oral iron supplementation for IBD patients.
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Affiliation(s)
- Thanina Medjbeur
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III – Paul Sabatier (UPS)ToulouseFrance
| | - Ugo Sardo
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III – Paul Sabatier (UPS)ToulouseFrance
| | - Prunelle Perrier
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III – Paul Sabatier (UPS)ToulouseFrance
| | - Kevin Cormier
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III – Paul Sabatier (UPS)ToulouseFrance
| | - Maryline Roy
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche Sur l'Inflammation, Inflamex Laboratory of ExcellenceParisFrance
| | - Anne Dumay
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche Sur l'Inflammation, Inflamex Laboratory of ExcellenceParisFrance
| | - Léon Kautz
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III – Paul Sabatier (UPS)ToulouseFrance
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Juul S, German K. Iron supplementation for infants in the NICU: What preparation, how much, and how long is optimal? Semin Fetal Neonatal Med 2025; 30:101612. [PMID: 40016057 DOI: 10.1016/j.siny.2025.101612] [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] [Indexed: 03/01/2025]
Abstract
Infants born preterm or with other perinatal risk factors are at added risk for both iron deficiency and overload. Insufficient iron supplementation in the perinatal period is associated with long-term neurodevelopmental effects. Based on this, iron supplements must be targeted to infants' individual iron needs to avoid the adverse effects of both iron deficiency and overload. Enteral iron supplements have been the gold standard in iron supplementation of neonates for many years. However, emerging parenteral formulations may provide an alternative for some infants, such as those who are unable to tolerate oral supplements or who are refractory to enteral supplementation. Optimal dosing and timing of supplementation is an area of ongoing research. In this review, we will summarize available enteral and parenteral iron formulations, review iron measurement parameters, and identify outstanding questions and ongoing research.
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Affiliation(s)
- Sandra Juul
- Department of Pediatrics, Division of Neonatology, USA; Institute on Human Development and Disability, University of Washington, 1959 NE Pacific St., Box 356320, RR542 HSB, Seattle, WA, 98195-6320, USA.
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Dutta AK, Chinthala H, George JT, Thomas DM, Joseph Joseph A. Anemia in inflammatory bowel disease-A comprehensive review. Indian J Gastroenterol 2025:10.1007/s12664-024-01735-7. [PMID: 39954228 DOI: 10.1007/s12664-024-01735-7] [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: 11/04/2024] [Accepted: 12/21/2024] [Indexed: 02/17/2025]
Abstract
Anemia is a frequent complication in inflammatory bowel disease (IBD) patients. The etiology is multifactorial, with iron deficiency and anemia of chronic disease being the main reasons. Other causes include vitamin B12 and folate deficiency, hemolytic anemia and medications such as azathioprine and sulfasalazine. Apart from physical symptoms, it is associated with several negative outcomes, including poor quality of life, increased risk of hospital admission, increased risk of surgery and higher treatment costs. Diagnostic evaluation aims to identify the underlying cause and severity to determine the appropriate therapeutic strategy. Investigations include a complete blood count, iron indices, inflammatory markers and vitamin B12 and folate levels. Patients with iron deficiency need adequate replacement therapy to improve hemoglobin and replenish iron stores. Those with moderate to severe anemia and/or active disease need intravenous iron, while mild anemia can be treated with oral iron. Multiple parenteral iron formulations are available which differ in dose and frequency of administration. Traditional oral iron supplements are available in ferrous forms, which, although effective, are associated with gastrointestinal side effects. Newer oral iron formulations have helped reduce these adverse effects but are expensive. Anemia of chronic disease is mainly driven by the effects of inflammatory mediators on iron metabolism and erythropoiesis and treatment requires control of disease activity. Relapse of anemia after therapy is frequent; hence, patients need to be closely followed up for early detection and appropriate management. Significant advances have been made in understanding the pathophysiology of anemia in IBD and better and safer iron formulations are available. However, a significant proportion of IBD patients with anemia go undetected or untreated and there is a need for improved recognition and better management practices. This review discusses various aspects of anemia in IBD and the current approach to diagnosis and management.
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Affiliation(s)
- Amit Kumar Dutta
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India.
| | - Hemanth Chinthala
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India
| | - John Titus George
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India
| | - David Mathew Thomas
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India
| | - Anjilivelil Joseph Joseph
- Department of Gastroenterology, Christian Medical College Vellore, Ranipet Campus, Vellore, 632 517, India
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Xing Y, Wang MM, Zhang F, Xin T, Wang X, Chen R, Sui Z, Dong Y, Xu D, Qian X, Lu Q, Li Q, Cai W, Hu M, Wang Y, Cao JL, Cui D, Qi J, Wang W. Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe 2+ through TRPML1 channel. Nat Commun 2025; 16:985. [PMID: 39856099 PMCID: PMC11760952 DOI: 10.1038/s41467-025-56403-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe2+-prolyl hydroxylase domain enzymes (PHDs)-NF-κB-interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages. Mechanistically, the suppression of IL1B transcription caused by TRPML1 activation results from its modulation on the release of lysosomal Fe2+, which subsequently activates PHDs. The activated PHDs then represses transcriptional activity of NF-κB, ultimately resulting in suppressed IL1B transcription. More importantly, in vivo stimulation of TRPML1 ameliorates multiple clinical signs of Dextran sulfate sodium-induced colitis in mice, suggesting TRPML1 has potential in treating inflammatory bowel disease.
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Affiliation(s)
- Yanhong Xing
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Meng-Meng Wang
- Department of Otolaryngology and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Feifei Zhang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Tianli Xin
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xinyan Wang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Rong Chen
- The First People's Hospital of Yancheng, Yancheng, China
| | - Zhongheng Sui
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, Hong Kong, China
| | - Yawei Dong
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Dongxue Xu
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xingyu Qian
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qixia Lu
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qingqing Li
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Weijie Cai
- New Cornerstone Science Laboratory, Liangzhu Laboratory & School of Basic Medical Sciences, Zhejiang University, Hangzhou, China
| | - Meiqin Hu
- New Cornerstone Science Laboratory, Liangzhu Laboratory & School of Basic Medical Sciences, Zhejiang University, Hangzhou, China
- Department of Neurology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yuqing Wang
- Department of Medicine and Biosystemic Science, Faculty of Medicine, Kyushu University, Fukuoka, Kyushu, Japan
| | - Jun-Li Cao
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Derong Cui
- Department of Anesthesiology, The Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jiansong Qi
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
| | - Wuyang Wang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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K M M, Ghosh P, Nagappan K, Palaniswamy DS, Begum R, Islam MR, Tagde P, Shaikh NK, Farahim F, Mondal TK. From Gut Microbiomes to Infectious Pathogens: Neurological Disease Game Changers. Mol Neurobiol 2025; 62:1184-1204. [PMID: 38967904 DOI: 10.1007/s12035-024-04323-0] [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] [Received: 04/02/2024] [Accepted: 06/19/2024] [Indexed: 07/06/2024]
Abstract
Gut microbiota and infectious diseases affect neurological disorders, brain development, and function. Compounds generated in the gastrointestinal system by gut microbiota and infectious pathogens may mediate gut-brain interactions, which may circulate throughout the body and spread to numerous organs, including the brain. Studies shown that gut bacteria and disease-causing organisms may pass molecular signals to the brain, affecting neurological function, neurodevelopment, and neurodegenerative diseases. This article discusses microorganism-producing metabolites with neuromodulator activity, signaling routes from microbial flora to the brain, and the potential direct effects of gut bacteria and infectious pathogens on brain cells. The review also considered the neurological aspects of infectious diseases. The infectious diseases affecting neurological functions and the disease modifications have been discussed thoroughly. Recent discoveries and unique insights in this perspective need further validation. Research on the complex molecular interactions between gut bacteria, infectious pathogens, and the CNS provides valuable insights into the pathogenesis of neurodegenerative, behavioral, and psychiatric illnesses. This study may provide insights into advanced drug discovery processes for neurological disorders by considering the influence of microbial communities inside the human body.
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Affiliation(s)
- Muhasina K M
- Department of Pharmacognosy, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India.
| | - Puja Ghosh
- Department of Pharmacognosy, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India
| | - Krishnaveni Nagappan
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India
| | | | - Rahima Begum
- Department of Microbiology, Gono Bishwabidyalay, Dhaka, Bangladesh
| | - Md Rabiul Islam
- Tennessee State University Chemistry department 3500 John A Merritt Blvd, Nashville, TN, 37209, USA
| | - Priti Tagde
- PRISAL(Pharmaceutical Royal International Society), Branch Office Bhopal, Bhopal, Madhya Pradesh, 462042, India
| | - Nusrat K Shaikh
- Department of Quality Assurance, Smt. N. M, Padalia Pharmacy College, Navapura, Ahmedabad, 382 210, Gujarat, India
| | - Farha Farahim
- Department of Nursing, King Khalid University, Abha, 61413, Kingdom of Saudi Arabia
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Iriarte-Gahete M, Tarancon-Diez L, Garrido-Rodríguez V, Leal M, Pacheco YM. Absolute and functional iron deficiency: Biomarkers, impact on immune system, and therapy. Blood Rev 2024; 68:101227. [PMID: 39142965 DOI: 10.1016/j.blre.2024.101227] [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] [Received: 06/14/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 08/16/2024]
Abstract
Iron is essential for numerous physiological processes and its deficiency often leads to anemia. Iron deficiency (ID) is a global problem, primarily affecting reproductive-age women and children, especially in developing countries. Diagnosis uses classical biomarkers like ferritin or transferrin saturation. Recent advancements include using soluble transferrin receptor (sTfR) or hepcidin for improved detection and classification of absolute and functional iron deficiencies, though mostly used in research. ID without anemia may present symptoms like asthenia and fatigue, even without relevant clinical consequences. ID impacts not only red-blood cells but also immune system cells, highlighting its importance in global health and immune-related comorbidities. Managing ID, requires addressing its cause and selecting appropriate iron supplementation. Various improved oral and intravenous products are available, but further research is needed to refine treatment strategies. This review updates on absolute and functional iron deficiencies, their relationships with the immune system and advancements in diagnosis and therapies.
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Affiliation(s)
- Marianela Iriarte-Gahete
- Immunology Service, Unit of Clinical Laboratories, Institute of Biomedicine of Seville, IBiS / Virgen del Rocío University Hospital / CSIC / University of Seville, Seville, Spain
| | - Laura Tarancon-Diez
- Group of Infections in the Pediatric Population, Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Vanesa Garrido-Rodríguez
- Immunology Service, Unit of Clinical Laboratories, Institute of Biomedicine of Seville, IBiS / Virgen del Rocío University Hospital / CSIC / University of Seville, Seville, Spain
| | - Manuel Leal
- Internal Medicine Service, Viamed Santa Ángela de la Cruz Hospital, Seville, Spain
| | - Yolanda María Pacheco
- Immunology Service, Unit of Clinical Laboratories, Institute of Biomedicine of Seville, IBiS / Virgen del Rocío University Hospital / CSIC / University of Seville, Seville, Spain; Universidad Loyola Andalucía, Facultad de Ciencias de la Salud, Campus Sevilla, 41704, Dos Hermanas, Sevilla, Spain.
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EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Bohn T, Castenmiller J, de Henauw S, Hirsch‐Ernst K, Knutsen HK, Maciuk A, Mangelsdorf I, McArdle HJ, Pentieva K, Siani A, Thies F, Tsabouri S, Vinceti M, Aggett P, Fairweather‐Tait S, de Sesmaisons Lecarré A, Fabiani L, Karavasiloglou N, Saad RM, Sofroniou A, Titz A, Naska A. Scientific opinion on the tolerable upper intake level for iron. EFSA J 2024; 22:e8819. [PMID: 38868106 PMCID: PMC11167337 DOI: 10.2903/j.efsa.2024.8819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024] Open
Abstract
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for iron. Systematic reviews were conducted to identify evidence regarding high iron intakes and risk of chronic diseases, adverse gastrointestinal effects and adverse effects of iron supplementation in infancy, young childhood and pregnancy. It is established that systemic iron overload leads to organ toxicity, but no UL could be established. The only indicator for which a dose-response could be established was black stools, which reflect the presence of large amounts of unabsorbed iron in the gut. This is a conservative endpoint among the chain of events that may lead to systemic iron overload but is not adverse per se. Based on interventions in which black stools did not occur at supplemental iron intakes of 20-25 mg/day (added to a background intake of 15 mg/day), a safe level of intake for iron of 40 mg/day for adults (including pregnant and lactating women) was established. Using allometric scaling (body weight0.75), this value was scaled down to children and adolescents and safe levels of intakes between 10 mg/day (1-3 years) and 35 mg/day (15-17 years) were derived. For infants 7-11 months of age who have a higher iron requirement than young children, allometric scaling was applied to the supplemental iron intakes (i.e. 25 mg/day) and resulted in a safe level of supplemental iron intake of 5 mg/day. This value was extended to 4-6 month-old infants and refers to iron intakes from fortified foods and food supplements, not from infant and follow-on formulae. The application of the safe level of intake is more limited than a UL because the intake level at which the risk of adverse effects starts to increase is not defined.
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Loveikyte R, Duijvestein M, Mujagic Z, Goetgebuer RL, Dijkstra G, van der Meulen-de Jong AE. Predicting response to iron supplementation in patients with active inflammatory bowel disease (PRIme): a randomised trial protocol. BMJ Open 2024; 14:e077511. [PMID: 38296290 PMCID: PMC10828887 DOI: 10.1136/bmjopen-2023-077511] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/15/2024] [Indexed: 02/03/2024] Open
Abstract
INTRODUCTION Iron deficiency anaemia (IDA) is the most common systemic manifestation of inflammatory bowel disease (IBD) that has detrimental effects on quality of life (QoL) and disease outcomes. Iron deficiency (ID), with or without anaemia, poses a diagnostic and therapeutic challenge in patients with IBD due to the multifactorial nature of ID(A) and its frequent recurrence. Elevated hepcidin-a systemic iron regulator that modulates systemic iron availability and intestinal iron absorption-has been associated with oral iron malabsorption in IBD. Therefore, hepcidin could assist in therapeutic decision-making. In this study, we investigate whether hepcidin can predict response to oral and intravenous iron supplementation in patients with active IBD undergoing anti-inflammatory treatment. METHODS AND ANALYSIS PRIme is an exploratory, multicentre, open-label and randomised trial. All adult patients with active IBD and ID(A) will be assessed for eligibility. The participants (n=90) will be recruited at five academic hospitals within the Netherlands and randomised into three groups (1:1:1): oral ferrous fumarate, oral ferric maltol or intravenous iron. Clinical and biochemical data will be collected at the baseline and after 6, 14 and 24 weeks. Blood samples will be collected to measure hepcidin and other biomarkers related to iron status. In addition, patient-reported outcomes regarding QoL and disease burden will be evaluated. The primary outcome is the utility of hepcidin as a predictive biomarker for response to iron therapy, which will be assessed using receiver operating curve analysis. ETHICS AND DISSEMINATION The study has been approved by the Institutional Review Board at the Leiden University Medical Center (IRB No. P21.109) and other study sites. All participants will provide written informed consent to enrol in the study. The findings will be published in a peer-reviewed journal and disseminated at scientific conferences; the dataset will be available on reasonable request. TRIAL REGISTRATION Prospectively registered in the https://clinicaltrials.gov/ and the Eudra registries. First submitted on 10 May 2022 to the ClinicalTrials.gov (ID: NCT05456932) and on 3 March 2022 to the European Union Drug Regulating Authorities Clinical Trials Database (ID: 2022-000894-16).
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Affiliation(s)
- Roberta Loveikyte
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Marjolijn Duijvestein
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Zlatan Mujagic
- Department of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Rogier L Goetgebuer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
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Usman D, Abubakar MB, Ibrahim KG, Imam MU. Iron chelation and supplementation: A comparison in the management of inflammatory bowel disease using drosophila. Life Sci 2024; 336:122328. [PMID: 38061132 DOI: 10.1016/j.lfs.2023.122328] [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] [Received: 09/23/2023] [Revised: 11/20/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023]
Abstract
AIMS Inflammatory Bowel Disease (IBD) is associated with systemic iron deficiency and has been managed with iron supplements which cause adverse side effects. Conversely, some reports highlight iron depletion to ameliorate IBD. The underlying intestinal response and comparative benefit of iron depletion and supplementation in IBD is unknown. The aims of this work were to characterize and compare the effects of iron supplementation and iron depletion in IBD. MAIN METHODS IBD was induced in Drosophila melanogaster using 3 % dextran sodium sulfate (DSS) in diet for 7 days. Using this model, we investigated the impacts of acute iron depletion (using bathophenanthroline disulfonate, BPS) and supplementation (using ferrous sulphate, FS), before and after IBD induction, on gut iron homeostasis, cell death, gut permeability, inflammation, antioxidant defence, antimicrobial response and several fly phenotypes. KEY FINDINGS DSS decreased fly mass (p < 0.001), increased gut permeability (p < 0.001) and shortened lifespan (p = 0.035) compared to control. The DSS-fed flies also showed significantly elevated lipid peroxidation (p < 0.001), and the upregulated expression of apoptotic marker- drice (p < 0.001), tight junction protein - bbg (p < 0.001), antimicrobial peptide - dpta (p = 0.002) and proinflammatory cytokine - upd2 (p < 0.001). BPS significantly (p < 0.05) increased fly mass and lifespan, decreased gut permeability, decreased lipid peroxidation and decreased levels of drice, bbg, dpta and upd2 in IBD flies. This iron chelation (using BPS) showed better protection from DSS-induced IBD than iron supplementation (using FS). Preventive and curative interventions, by BPS or FS, also differed in outcomes. SIGNIFICANCE This may inform precise management strategies aimed at tackling IBD and its recurrence.
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Affiliation(s)
- Dawoud Usman
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University Sokoto, Nigeria; Department of Physiology, College of Health Sciences, Usmanu Danfodiyo University Sokoto, Nigeria
| | - Murtala Bello Abubakar
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University Sokoto, Nigeria; Department of Physiology, College of Health Sciences, Usmanu Danfodiyo University Sokoto, Nigeria; Department of Physiology, College of Medicine and Health Sciences, Baze University, Abuja, Nigeria
| | - Kasimu Ghandi Ibrahim
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University Sokoto, Nigeria; Department of Physiology, College of Health Sciences, Usmanu Danfodiyo University Sokoto, Nigeria; Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, P. O. Box 2000, Zarqa 13110, Jordan; School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, Johannesburg, South Africa
| | - Mustapha Umar Imam
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University Sokoto, Nigeria; Department of Medical Biochemistry, College of Health Sciences, Usmanu Danfodiyo University Sokoto, Nigeria.
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Loveikyte R, Bourgonje AR, van Goor H, Dijkstra G, van der Meulen-de Jong AE. The effect of iron therapy on oxidative stress and intestinal microbiota in inflammatory bowel diseases: A review on the conundrum. Redox Biol 2023; 68:102950. [PMID: 37918126 PMCID: PMC10643537 DOI: 10.1016/j.redox.2023.102950] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 10/28/2023] [Indexed: 11/04/2023] Open
Abstract
One in five patients with Inflammatory Bowel Disease (IBD) suffers from anemia, most frequently caused by iron deficiency. Anemia and iron deficiency are associated with worse disease outcomes, reduced quality of life, decreased economic participation, and increased healthcare costs. International guidelines and consensus-based recommendations have emphasized the importance of treating anemia and iron deficiency. In this review, we draw attention to the rarely discussed effects of iron deficiency and iron therapy on the redox status, the intestinal microbiota, and the potential interplay between them, focusing on the clinical implications for patients with IBD. Current data are scarce, inconsistent, and do not provide definitive answers. Nevertheless, it is imperative to rule out infections and discern iron deficiency anemia from other types of anemia to prevent untargeted oral or intravenous iron supplementation and potential side effects, including oxidative stress. Further research is necessary to establish the clinical significance of changes in the redox status and the intestinal microbiota following iron supplementation.
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Affiliation(s)
- R Loveikyte
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands; Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - A R Bourgonje
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - H van Goor
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - G Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - A E van der Meulen-de Jong
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
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12
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Faqerah N, Walker D, Gerasimidis K. Review article: The complex interplay between diet and Escherichia coli in inflammatory bowel disease. Aliment Pharmacol Ther 2023; 58:984-1004. [PMID: 37771255 DOI: 10.1111/apt.17720] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/23/2022] [Accepted: 09/05/2023] [Indexed: 09/30/2023]
Abstract
BACKGROUND Although no causative microbe has been yet identified or successfully targeted in the treatment of inflammatory bowel disease (IBD), the role of Escherichia coli in the pathogenesis of Crohn's disease has attracted considerable interest. AIM In this review, we present a literature overview of the interactions between diet and E. coli and other Proteobacteria in the aetiology, outcomes and management of IBD and suggest future research directions. METHODS An extensive literature search was performed to identify in vitro studies and research in animal models that explored mechanisms by which dietary components can interact with E. coli or Proteobacteria to initiate or propagate gut inflammation. We also explored the effect diet and dietary therapies have on the levels of E. coli or Proteobacteria in patients with IBD. RESULTS Preclinical data suggest that the Western diet and its components influence the abundance, colonisation and phenotypic behaviour of E. coli in the gut, which may in turn initiate or contribute to gut inflammation. In contrast, the Mediterranean diet and specific dietary fibres may abrogate these effects and protect from inflammation. There are limited data from clinical trials, mostly from patients with Crohn's disease during treatment with exclusive enteral nutrition, with findings often challenging observations from preclinical research. Data from patients with ulcerative colitis are sparse. CONCLUSIONS Preclinical and some clinical trial data suggest that E. coli and other Proteobacteria interact with certain dietary components to promote gut inflammation. Well-designed clinical trials are required before dietary recommendations for disease management can be made.
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Affiliation(s)
- Nojoud Faqerah
- Human Nutrition, School of Medicine, Dentistry and Life Sciences, University of Glasgow, New Lister Building, Glasgow Royal Infirmary, Glasgow, UK
- School of Infection and Immunity, University of Glasgow, Glasgow, UK
- Microbiology, Rabigh Medical College, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Daniel Walker
- School of Infection and Immunity, University of Glasgow, Glasgow, UK
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Konstantinos Gerasimidis
- Human Nutrition, School of Medicine, Dentistry and Life Sciences, University of Glasgow, New Lister Building, Glasgow Royal Infirmary, Glasgow, UK
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13
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Tarancon-Diez L, Iriarte-Gahete M, Sanchez-Mingo P, Perez-Cabeza G, Romero-Candau F, Pacheco YM, Leal M, Muñoz-Fernández MÁ. Real-world experience of intravenous iron sucrose supplementation and dynamics of soluble transferrin receptor and hepcidin in a Spanish cohort of absolute iron deficient patients. Biomed Pharmacother 2023; 167:115510. [PMID: 37757490 DOI: 10.1016/j.biopha.2023.115510] [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] [Received: 05/23/2023] [Revised: 09/01/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
The study evaluated the safety and effectiveness of the generic intravenous (IV) iron treatment (Feriv®), in a Spanish cohort with absolute iron deficiency (ID) (serum ferritin <50 ng/ml, with or without anaemia) (n = 122; 91% women; median age of 44 years [IQR: 33.7-54]). Iron-related biomarkers were measured before treatment (baseline), 2 weeks after beginning the protocol (intermediate control, IC) and between 7 and 10 days after treatment completion (final time-point). Primary efficacy endpoints were ferritin levels ≥ 50 ng/ml, anaemia restoration or an increase in haemoglobin (Hb) of at least one point in patients without baseline anaemia. After treatment, iron-related biomarkers improved, including ferritin, Hb, sideremia, transferrin, transferrin saturation index, soluble transferrin receptor (sTfR), and hepcidin. Baseline ferritin concentration (13.5 ng/ml [IQR: 8-24.2]) increased at the IC and continued rising at the final time-point, reaching a median ferritin of 222 ng/ml and 97.3% of patients ≥ 50 ng/ml. At the final time-point, anaemia prevalence decreased from 26.2% to 5%, while the 34.1% without baseline anaemia showed an increase in Hb of at least one point. Headache was the only drug-adverse event recorded in 2.3% of patients. At a late time-point (27.5 median weeks after ending therapy [IQR: 22-40]), evaluated in a subgroup of 66 patients, 18% had ferritin levels < 50 ng/ml. Multivariate analysis showed that low baseline ferritin and high sTfR/hepcidin ratio tended to be independently associated with ID recurrence. Feriv® is a safe, effective first-line treatment for absolute ID, with improvement of serum ferritin and Hb. ID recurrence was associated with the baseline degree of iron stores depletion, indicated by serum ferritin, and sTfR/hepcidin ratio.
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Affiliation(s)
- Laura Tarancon-Diez
- Molecular Immunology Laboratory, Hospital General Universitario Gregorio Marañón, Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Marianela Iriarte-Gahete
- Immunology Service, Unit of Clinical Laboratories, Institute of Biomedicine of Seville, IBiS / Virgen del Rocío University Hospital / CSIC / University of Seville, Seville, Spain
| | | | | | | | - Yolanda M Pacheco
- Immunology Service, Unit of Clinical Laboratories, Institute of Biomedicine of Seville, IBiS / Virgen del Rocío University Hospital / CSIC / University of Seville, Seville, Spain
| | - Manuel Leal
- Internal Medicine Service, Hospital Santa Ángela de la Cruz, Seville, Spain
| | - Maria Ángeles Muñoz-Fernández
- Molecular Immunology Laboratory, Hospital General Universitario Gregorio Marañón, Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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14
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Fan L, Xia Y, Wang Y, Han D, Liu Y, Li J, Fu J, Wang L, Gan Z, Liu B, Fu J, Zhu C, Wu Z, Zhao J, Han H, Wu H, He Y, Tang Y, Zhang Q, Wang Y, Zhang F, Zong X, Yin J, Zhou X, Yang X, Wang J, Yin Y, Ren W. Gut microbiota bridges dietary nutrients and host immunity. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2466-2514. [PMID: 37286860 PMCID: PMC10247344 DOI: 10.1007/s11427-023-2346-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 04/05/2023] [Indexed: 06/09/2023]
Abstract
Dietary nutrients and the gut microbiota are increasingly recognized to cross-regulate and entrain each other, and thus affect host health and immune-mediated diseases. Here, we systematically review the current understanding linking dietary nutrients to gut microbiota-host immune interactions, emphasizing how this axis might influence host immunity in health and diseases. Of relevance, we highlight that the implications of gut microbiota-targeted dietary intervention could be harnessed in orchestrating a spectrum of immune-associated diseases.
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Affiliation(s)
- Lijuan Fan
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Yaoyao Xia
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Youxia Wang
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Dandan Han
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yanli Liu
- College of Animal Science and Technology, Northwest A&F University, Xi'an, 712100, China
| | - Jiahuan Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Jie Fu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Leli Wang
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
| | - Zhending Gan
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Bingnan Liu
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Jian Fu
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Congrui Zhu
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Zhenhua Wu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Jinbiao Zhao
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Hui Han
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Hao Wu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Yiwen He
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Yulong Tang
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
| | - Qingzhuo Zhang
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Yibin Wang
- College of Animal Science and Technology, Northwest A&F University, Xi'an, 712100, China
| | - Fan Zhang
- College of Animal Science and Technology, Northwest A&F University, Xi'an, 712100, China
| | - Xin Zong
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Jie Yin
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China.
| | - Xihong Zhou
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.
| | - Xiaojun Yang
- College of Animal Science and Technology, Northwest A&F University, Xi'an, 712100, China.
| | - Junjun Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
| | - Yulong Yin
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China.
| | - Wenkai Ren
- Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
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15
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Rieg T, Xue J, Stevens M, Thomas L, White J, Dominguez Rieg J. Intravenous ferric carboxymaltose and ferric derisomaltose alter the intestinal microbiome in female iron-deficient anemic mice. Biosci Rep 2023; 43:BSR20231217. [PMID: 37671923 PMCID: PMC10520285 DOI: 10.1042/bsr20231217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/31/2023] [Accepted: 09/06/2023] [Indexed: 09/07/2023] Open
Abstract
Iron deficiency anemia (IDA) is a leading global health concern affecting approximately 30% of the population. Treatment for IDA consists of replenishment of iron stores, either by oral or intravenous (IV) supplementation. There is a complex bidirectional interplay between the gut microbiota, the host's iron status, and dietary iron availability. Dietary iron deficiency and supplementation can influence the gut microbiome; however, the effect of IV iron on the gut microbiome is unknown. We studied how commonly used IV iron preparations, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), affected the gut microbiome in female iron-deficient anemic mice. At the phylum level, vehicle-treated mice showed an expansion in Verrucomicrobia, mostly because of the increased abundance of Akkermansia muciniphila, along with contraction in Firmicutes, resulting in a lower Firmicutes/Bacteroidetes ratio (indicator of dysbiosis). Treatment with either FCM or FDI restored the microbiome such that Firmicutes and Bacteroidetes were the dominant phyla. Interestingly, the phyla Proteobacteria and several members of Bacteroidetes (e.g., Alistipes) were expanded in mice treated with FCM compared with those treated with FDI. In contrast, several Clostridia class members were expanded in mice treated with FDI compared with FCM (e.g., Dorea spp., Eubacterium). Our data demonstrate that IV iron increases gut microbiome diversity independently of the iron preparation used; however, differences exist between FCM and FDI treatments. In conclusion, replenishing iron stores with IV iron preparations in clinical conditions, such as inflammatory bowel disease or chronic kidney disease, could affect gut microbiome composition and consequently contribute to an altered disease outcome.
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Affiliation(s)
- Timo Rieg
- Department of Molecular Pharmacology and Physiology, Hypertension and Kidney Research Center, University of South Florida, Tampa, FL 33612, U.S.A
- James A. Haley Veterans’ Hospital, Tampa, FL 33612, U.S.A
| | - Jianxiang Xue
- Department of Molecular Pharmacology and Physiology, Hypertension and Kidney Research Center, University of South Florida, Tampa, FL 33612, U.S.A
| | - Monica Stevens
- Department of Molecular Pharmacology and Physiology, Hypertension and Kidney Research Center, University of South Florida, Tampa, FL 33612, U.S.A
| | - Linto Thomas
- Department of Molecular Pharmacology and Physiology, Hypertension and Kidney Research Center, University of South Florida, Tampa, FL 33612, U.S.A
| | | | - Jessica A. Dominguez Rieg
- Department of Molecular Pharmacology and Physiology, Hypertension and Kidney Research Center, University of South Florida, Tampa, FL 33612, U.S.A
- James A. Haley Veterans’ Hospital, Tampa, FL 33612, U.S.A
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16
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Song WX, Yu ZH, Ren XF, Chen JH, Chen X. Role of micronutrients in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2023; 31:711-731. [DOI: 10.11569/wcjd.v31.i17.711] [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: 08/08/2023] [Revised: 08/28/2023] [Accepted: 09/01/2023] [Indexed: 09/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an autoimmune intestinal disease that includes ulcerative colitis, Crohn's disease, and indeterminate colitis. Patients with IBD are often at risk for malnutrition, including micronutrient deficiencies, due to dietary restrictions and poor intestinal absorption. Micronutrients, including vitamins and minerals, play an important role in the human body's metabolism and maintenance of tissue functions. This article reviews the role of micronutrients in IBD. Micronutrients can affect the occurrence and progression of IBD by regulating immunity, intestinal flora, oxidative stress, intestinal barrier function, and other aspects. Monitoring and timely supplementation of micronutrients are important to delay progression and improve clinical symptoms in IBD patients.
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Affiliation(s)
- Wen-Xuan Song
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zi-Han Yu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xiang-Feng Ren
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Ji-Hua Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
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17
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Liu S, Dong Z, Tang W, Zhou J, Guo L, Gong C, Liu G, Wan D, Yin Y. Dietary iron regulates intestinal goblet cell function and alleviates Salmonella typhimurium invasion in mice. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2006-2019. [PMID: 37340176 DOI: 10.1007/s11427-022-2298-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 01/31/2023] [Indexed: 06/22/2023]
Abstract
Iron is an important micronutrient that plays a vital role in host defenses and bacterial pathogenicity. As iron treatments increase the risk of infection by stimulating the growth and virulence of bacterial pathogens, their roles in anti-infection immunity have frequently been underestimated. To estimate whether adequate dietary iron intake would help defend against pathogenic bacterial infection, mice were fed iron-deficient (2 mg kg-1 feed), iron-sufficient (35 mg kg-1 feed), or iron-enriched diet (350 mg kg-1 feed) for 12 weeks, followed by oral infection with Salmonella typhimurium. Our results revealed that dietary iron intake improved mucus layer function and decelerated the invasion of the pathogenic bacteria, Salmonella typhimurium. Positive correlations between serum iron and the number of goblet cells and mucin2 were found in response to total iron intake in mice. Unabsorbed iron in the intestinal tract affected the gut microbiota composition, and the abundance of Bacteroidales, family Muribaculaceae, was positively correlated with their mucin2 expression. However, the results from antibiotic-treated mice showed that the dietary iron-regulated mucin layer function was not microbial-dependent. Furthermore, in vitro studies revealed that ferric citrate directly induced mucin2 expression and promoted the proliferation of goblet cells in both ileal and colonic organoids. Thus, dietary iron intake improves serum iron levels, regulates goblet cell regeneration and mucin layer function, and plays a positive role in the prevention of pathogenic bacteria.
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Affiliation(s)
- Shuan Liu
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Zhenlin Dong
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
| | - Wenjie Tang
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- Animal Breeding and Genetics Key Laboratory of Sichuan Province, Livestock and Poultry Biological Products Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu, 610066, China
| | - Jian Zhou
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Liu Guo
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Chengyan Gong
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Guang Liu
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
| | - Dan Wan
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.
| | - Yulong Yin
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.
- University of Chinese Academy of Sciences, Beijing, 101408, China.
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18
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Xia JY, Hepler C, Tran P, Waldeck NJ, Bass J, Prindle A. Engineered calprotectin-sensing probiotics for IBD surveillance in humans. Proc Natl Acad Sci U S A 2023; 120:e2221121120. [PMID: 37523538 PMCID: PMC10410751 DOI: 10.1073/pnas.2221121120] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 06/07/2023] [Indexed: 08/02/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a spectrum of autoimmune diseases affecting the gastrointestinal tract characterized by a relapsing and remitting course of gut mucosal inflammation. Disease flares can be difficult to predict, and the current practice of IBD disease activity surveillance through endoscopy is invasive and requires medical expertise. Recent advancements in synthetic biology raise the possibility that symbiotic microbes can be engineered to selectively detect disease biomarkers used in current clinical practice. Here, we introduce an engineered probiotic capable of detecting the clinical gold standard IBD biomarker, calprotectin, with sensitivity and specificity in IBD patients. Specifically, we identified a bacterial promoter in the probiotic strain Escherichia coli Nissle 1917 (EcN) which exhibits a specific expression increase in the presence of calprotectin. Using murine models of colitis, we show that the reporter signal is activated in vivo during transit of the GI tract following oral delivery. Furthermore, our engineered probiotic can successfully discriminate human patients with active IBD from those in remission and without IBD using patient stool samples, where the intensity of reporter signal quantitatively tracks with clinical laboratory-measured levels of calprotectin. Our pilot study sets the stage for probiotics that can be engineered to detect fecal calprotectin for precise noninvasive disease activity monitoring in IBD patients.
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Affiliation(s)
- Jonathan Y. Xia
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Chelsea Hepler
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Peter Tran
- Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL60208
| | - Nathan J. Waldeck
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Joseph Bass
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Arthur Prindle
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
- Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL60208
- Center for Synthetic Biology, Northwestern University, Evanston, IL60208
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19
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Djoko KY. Control of nutrient metal availability during host-microbe interactions: beyond nutritional immunity. J Biol Inorg Chem 2023:10.1007/s00775-023-02007-z. [PMID: 37464157 PMCID: PMC10368554 DOI: 10.1007/s00775-023-02007-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/28/2023] [Indexed: 07/20/2023]
Abstract
The control of nutrient availability is an essential ecological function of the host organism in host-microbe systems. Although often overshadowed by macronutrients such as carbohydrates, micronutrient metals are known as key drivers of host-microbe interactions. The ways in which host organisms control nutrient metal availability are dictated by principles in bioinorganic chemistry. Here I ponder about the actions of metal-binding molecules from the host organism in controlling nutrient metal availability to the host microbiota. I hope that these musings will encourage new explorations into the fundamental roles of metals in the ecology of diverse host-microbe systems.
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Affiliation(s)
- Karrera Y Djoko
- Department of Biosciences, Durham University, Durham, DH1 3LE, UK.
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20
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Lynch KT, Hassinger TE. Preoperative Identification and Management of Anemia in the Colorectal Surgery Patient. Clin Colon Rectal Surg 2023; 36:161-166. [PMID: 37113284 PMCID: PMC10125282 DOI: 10.1055/s-0043-1760868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Preoperative anemia is a common finding in patients undergoing colorectal surgery, particularly those with cancer. While often multifactorial, iron deficiency anemia remains the most common cause of anemia in this patient population. Although seemingly innocuous, preoperative anemia is associated with an increased risk of perioperative complications and need for allogenic blood transfusions, both of which may worsen cancer-specific survival. Preoperative correction of anemia and iron deficiency is thus necessary to diminish these risks. Current literature supports preoperative screening for anemia and iron deficiency in patients slated to undergo colorectal surgery for malignancy or for benign conditions with associated patient- or procedure-related risk factors. Accepted treatment regimens include iron supplementation-either oral or intravenous-as well as erythropoietin therapy. Autologous blood transfusion should not be utilized as a treatment for preoperative anemia when there is time to implement other corrective strategies. Additional study is still needed to better standardize preoperative screening and optimize treatment regimens.
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Affiliation(s)
- Kevin T. Lynch
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Taryn E. Hassinger
- Division of Colon and Rectal Surgery, Allegheny Health Network, Pittsburgh, Pennsylvania
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21
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Lin D, Medeiros DM. The microbiome as a major function of the gastrointestinal tract and its implication in micronutrient metabolism and chronic diseases. Nutr Res 2023; 112:30-45. [PMID: 36965327 DOI: 10.1016/j.nutres.2023.02.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/22/2023] [Accepted: 02/25/2023] [Indexed: 03/06/2023]
Abstract
The composition and function of microbes harbored in the human gastrointestinal lumen have been underestimated for centuries because of the underdevelopment of nucleotide sequencing techniques and the lack of humanized gnotobiotic models. Now, we appreciate that the gut microbiome is an integral part of the human body and exerts considerable roles in host health and diseases. Dietary factors can induce changes in the microbial community composition, metabolism, and function, thereby altering the host immune response, and consequently, may influence disease risks. An imbalance of gut microbiome homeostasis (i.e., dysbiosis) has been linked to several chronic diseases, such as inflammatory bowel diseases, obesity, and diabetes. Remarkable progress has recently been made in better understanding the extent to which the influence of the diet-microbiota interaction on host health outcomes in both animal models and human participants. However, the exact causality of the gut microbiome on the development of diseases is still controversial. In this review, we will briefly describe the general structure and function of the intestine and the process of nutrient absorption in humans. This is followed by a summarization of the recent updates on interactions between gut microbiota and individual micronutrients, including carotenoids, vitamin A, vitamin D, vitamin C, folate, iron, and zinc. In the opinion of the authors, these nutrients were identified as representative of vitamins and minerals with sufficient research on their roles in the microbiome. The host responses to the gut microbiome will also be discussed. Future direction in microbiome research, for example, precision microbiome, will be proposed.
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Affiliation(s)
- Dingbo Lin
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK 74078.
| | - Denis M Medeiros
- Division of Molecular Biology and Biochemistry, University of Missouri-Kansas City, Kansas City, MO 64108
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22
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Li H, Kazmi JS, Lee S, Zhang D, Gao X, Maryanovich M, Torres L, Verma D, Kelly L, Ginzburg YZ, Frenette PS, Manwani D. Dietary iron restriction protects against vaso-occlusion and organ damage in murine sickle cell disease. Blood 2023; 141:194-199. [PMID: 36315910 PMCID: PMC10023724 DOI: 10.1182/blood.2022016218] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 10/14/2022] [Accepted: 10/15/2022] [Indexed: 11/07/2022] Open
Abstract
Sickle cell disease (SCD) is an inherited disorder resulting from a β-globin gene mutation, and SCD patients experience erythrocyte sickling, vaso-occlusive episodes (VOE), and progressive organ damage. Chronic hemolysis, inflammation, and repeated red blood cell transfusions in SCD can disrupt iron homeostasis. Patients who receive multiple blood transfusions develop iron overload, and another subpopulation of SCD patients manifest iron deficiency. To elucidate connections between dietary iron, the microbiome, and SCD pathogenesis, we treated SCD mice with an iron-restricted diet (IRD). IRD treatment reduced iron availability and hemolysis, decreased acute VOE, and ameliorated chronic organ damage in SCD mice. Our results extend previous studies indicating that the gut microbiota regulate disease in SCD mice. IRD alters microbiota load and improves gut integrity, together preventing crosstalk between the gut microbiome and inflammatory factors such as aged neutrophils, dampening VOE, and organ damage. These findings provide strong evidence for the therapeutic potential of manipulating iron homeostasis and the gut microbiome to ameliorate SCD pathophysiology. Many treatments, which are under development, focus on lowering the systemic iron concentration to relieve disease complications, and our data suggest that iron-induced changes in microbiota load and gut integrity are related- and novel-therapeutic targets.
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Affiliation(s)
- Huihui Li
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Jacob S. Kazmi
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Sungkyun Lee
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Dachuan Zhang
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Xin Gao
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Maria Maryanovich
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Lidiane Torres
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Divij Verma
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Libusha Kelly
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY
| | - Yelena Z. Ginzburg
- The Tisch Cancer Institute, Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Paul S. Frenette
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Deepa Manwani
- The Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY
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23
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Wolf PG, Bernabe BP, Oliveira ML, Hamm A, McLeod A, Olender S, Castellanos K, Loman BR, Gaskins HR, Fitzgibbon M, Tussing-Humphreys L. Effect of Diets Varying in Iron and Saturated Fat on the Gut Microbiota and Intestinal Inflammation: A Crossover Feeding Study among Older Females with Obesity. Nutr Cancer 2023; 75:876-889. [PMID: 36625531 PMCID: PMC10023443 DOI: 10.1080/01635581.2022.2163668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 12/23/2022] [Accepted: 12/23/2022] [Indexed: 01/11/2023]
Abstract
Obesity is considered an independent risk factor for colorectal cancer (CRC). Altered nutrient metabolism, particularly changes to digestion and intestinal absorption, may play an important role in the development of CRC. Iron can promote the formation of tissue-damaging and immune-modulating reactive oxygen species. We conducted a crossover, controlled feeding study to examine the effect of three, 3-week diets varying in iron and saturated fat content on the colonic milieu and systemic markers among older females with obesity. Anthropometrics, fasting venous blood and stool were collected before and after each diet. There was a minimum 3-week washout period between diets. Eighteen participants consumed the three diets (72% Black; mean age 60.4 years; mean body mass index 35.7 kg/m2). Results showed no effect of the diets on intestinal inflammation (fecal calprotectin) or circulating iron, inflammation, and metabolic markers. Pairwise comparisons revealed less community diversity between samples (beta diversity, calculated from 16S rRNA amplicon sequences) among participants when consuming a diet low in iron and high in saturated fat vs. when consuming a diet high in iron and saturated fat. More studies are needed to investigate if dietary iron represents a salient target for CRC prevention among individuals with obesity.
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Affiliation(s)
- Patricia G. Wolf
- Institute for Health Research and Policy, University of Illinois Chicago, Chicago, IL, USA
- University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, USA
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
| | | | - Manoela Lima Oliveira
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, Illinois, USA
| | - Alyshia Hamm
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, Illinois, USA
| | - Andrew McLeod
- Institute for Health Research and Policy, University of Illinois Chicago, Chicago, IL, USA
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, Illinois, USA
| | - Sarah Olender
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, Illinois, USA
| | - Karla Castellanos
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Brett R. Loman
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - H. Rex Gaskins
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, Urbana, IL, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Marian Fitzgibbon
- Institute for Health Research and Policy, University of Illinois Chicago, Chicago, IL, USA
- University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, USA
- Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA
| | - Lisa Tussing-Humphreys
- University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, USA
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, Illinois, USA
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24
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Aksoyalp ZŞ, Temel A, Erdogan BR. Iron in infectious diseases friend or foe?: The role of gut microbiota. J Trace Elem Med Biol 2023; 75:127093. [PMID: 36240616 DOI: 10.1016/j.jtemb.2022.127093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 09/13/2022] [Accepted: 10/05/2022] [Indexed: 12/07/2022]
Abstract
Iron is a trace element involved in metabolic functions for all organisms, from microorganisms to mammalians. Iron deficiency is a prevalent health problem that affects billions of people worldwide, and iron overload could have some hazardous effect. The complex microbial community in the human body, also called microbiota, influences the host immune defence against infections. An imbalance in gut microbiota, dysbiosis, changes the host's susceptibility to infections by regulating the immune system. In recent years, the number of studies on the relationship between infectious diseases and microbiota has increased. Gut microbiota is affected by different parameters, including mode of delivery, hygiene habits, diet, drugs, and plasma iron levels during the lifetime. Gut microbiota may influence iron levels in the body, and iron overload and deficiency can also affect gut microbiota composition. Novel researches on microbiota shed light on the fact that the bidirectional interactions between gut microbiota and iron play a role in the pathogenesis of many diseases, especially infections. A better understanding of these interactions may help us to comprehend the pathogenesis of many infectious and metabolic diseases affecting people worldwide and following the development of more effective preventive and/or therapeutic strategies. In this review, we aimed to present the iron-mediated host-gut microbiota interactions, susceptibility to bacterial infections, and iron-targeted therapy approaches for infections.
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Affiliation(s)
- Zinnet Şevval Aksoyalp
- Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmacology, Izmir, Turkey.
| | - Aybala Temel
- Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, Izmir, Turkey.
| | - Betul Rabia Erdogan
- Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmacology, Izmir, Turkey.
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25
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Qu S, Zheng Y, Huang Y, Feng Y, Xu K, Zhang W, Wang Y, Nie K, Qin M. Excessive consumption of mucin by over-colonized Akkermansia muciniphila promotes intestinal barrier damage during malignant intestinal environment. Front Microbiol 2023; 14:1111911. [PMID: 36937258 PMCID: PMC10018180 DOI: 10.3389/fmicb.2023.1111911] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/13/2023] [Indexed: 03/06/2023] Open
Abstract
Gut microbiota disorders damage the intestinal barrier, which causes intestinal disease. Thus, we screened the microbiota with significant changes using an in situ malignant colorectal cancer (CRC) model. Among the colonies with increased abundance, Akkermansia muciniphila (A. muciniphila) is known for its characteristic of breaking down mucin, which is an essential component of the intestinal barrier. The role of A. muciniphila remains controversial. To investigate the effect of excess A. muciniphila on the intestinal barrier, we established an over-colonized A. muciniphila mouse model by administering a live bacterial suspension after disrupting the original gut microbiome with antibiotics. The results showed that over-colonization of A. muciniphila decreased intestinal mucin content. The mRNA and protein expression levels of tight junction proteins also decreased significantly in the over-colonized A. muciniphila mouse model. Our findings reveal that excess colonization by A. muciniphila breaks the dynamic balance between mucin secretion and degradation, reduces the thickness of the intestinal mucus layer, and damages the intestinal barrier, which would eventually aggravate the development of colitis and CRC. These results will raise awareness about the safety of A. muciniphila serving as a probiotic.
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26
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Singh K, Sethi Chopra D, Singh D, Singh N. Nano-formulations in treatment of iron deficiency anaemia: An overview. Clin Nutr ESPEN 2022; 52:12-19. [PMID: 36513444 DOI: 10.1016/j.clnesp.2022.08.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 08/20/2022] [Accepted: 08/30/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Iron deficiency anaemia (IDA) is a significant challenge to global health. The absorption and bioavailability depend on the delivery vehicle being used. Ferrous sulphate is a drug of choice for IDA but leads to frequent gastrointestinal tract side effects that force the patient to discontinue the treatment. Gastrointestinal side effects result from converting bivalent iron into trivalent iron accompanied by reactive oxygen species (ROS) formation. Due to lower absorption, oral preparations of trivalent iron are recommended in patients with intolerance to ferrous sulphate. Nanosized iron preparation can resolved these concerns. The particle size of iron salts has been observed to have a significant impact on iron absorption. The surface area of iron compounds is increased by reducing their particle size, which improves their solubility in gastric juice and boosts their absorption. Sucrosomial iron, ferric citrate complexes, and ferric maltol are some of the novel iron preparations that ensure high bioavailability and good tolerance in chronic kidney disease, congestive heart failure, and inflammatory bowel disease. However, the parenteral route of administration of iron is unacceptable to most patients. Moreover, it leads to high free iron levels in circulation, resulting in ROS generation. CONCLUSION This article provides an informative summary of iron deficiency anaemia causes and treatment through nanoformulations and literature and in-depth patent analysis.
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Affiliation(s)
- Kuldeep Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India
| | - Dimple Sethi Chopra
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India.
| | - Dhandeep Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India
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27
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The role of iron in chronic inflammatory diseases: from mechanisms to treatment options in anemia of inflammation. Blood 2022; 140:2011-2023. [PMID: 35994752 DOI: 10.1182/blood.2021013472] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/09/2022] [Indexed: 11/20/2022] Open
Abstract
Anemia of inflammation (AI) is a highly prevalent comorbidity in patients affected by chronic inflammatory disorders, such as chronic kidney disease, inflammatory bowel disease, or cancer, that negatively affect disease outcome and quality of life. The pathophysiology of AI is multifactorial, with inflammatory hypoferremia and iron-restricted erythropoiesis playing a major role in the context of disease-specific factors. Here, we review the recent progress in our understanding of the molecular mechanisms contributing to iron dysregulation in AI, the impact of hypoferremia and anemia on the course of the underlying disease, and (novel) therapeutic strategies applied to treat AI.
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28
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Malesza IJ, Bartkowiak-Wieczorek J, Winkler-Galicki J, Nowicka A, Dzięciołowska D, Błaszczyk M, Gajniak P, Słowińska K, Niepolski L, Walkowiak J, Mądry E. The Dark Side of Iron: The Relationship between Iron, Inflammation and Gut Microbiota in Selected Diseases Associated with Iron Deficiency Anaemia—A Narrative Review. Nutrients 2022; 14:nu14173478. [PMID: 36079734 PMCID: PMC9458173 DOI: 10.3390/nu14173478] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 12/21/2022] Open
Abstract
Iron is an indispensable nutrient for life. A lack of it leads to iron deficiency anaemia (IDA), which currently affects about 1.2 billion people worldwide. The primary means of IDA treatment is oral or parenteral iron supplementation. This can be burdened with numerous side effects such as oxidative stress, systemic and local-intestinal inflammation, dysbiosis, carcinogenic processes and gastrointestinal adverse events. Therefore, this review aimed to provide insight into the physiological mechanisms of iron management and investigate the state of knowledge of the relationship between iron supplementation, inflammatory status and changes in gut microbiota milieu in diseases typically complicated with IDA and considered as having an inflammatory background such as in inflammatory bowel disease, colorectal cancer or obesity. Understanding the precise mechanisms critical to iron metabolism and the awareness of serious adverse effects associated with iron supplementation may lead to the provision of better IDA treatment. Well-planned research, specific to each patient category and disease, is needed to find measures and methods to optimise iron treatment and reduce adverse effects.
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Affiliation(s)
- Ida J. Malesza
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | | | - Jakub Winkler-Galicki
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Aleksandra Nowicka
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | | | - Marta Błaszczyk
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Paulina Gajniak
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Karolina Słowińska
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Leszek Niepolski
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Jarosław Walkowiak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Edyta Mądry
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
- Correspondence:
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29
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Argüelles-Arias F, Bermejo F, Borrás-Blasco J, Domènech E, Sicilia B, Huguet JM, de Arellano AR, Valentine WJ, Hunt B. Cost-effectiveness analysis of ferric carboxymaltose versus iron sucrose for the treatment of iron deficiency anemia in patients with inflammatory bowel disease in Spain. Therap Adv Gastroenterol 2022; 15:17562848221086131. [PMID: 35574429 PMCID: PMC9092579 DOI: 10.1177/17562848221086131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 02/21/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD) and can result in reduced quality of life and increased healthcare costs. IDA is treated with iron supplementation, commonly with intravenous iron formulations, such as ferric carboxymaltose (FCM), and iron sucrose (IS). METHODS This study assessed the cost-effectiveness of FCM compared with IS, in terms of additional cost per additional responder in patients with IDA subsequent to IBD in the Spanish setting. An economic model was developed to assess the additional cost per additional responder, defined as normalization or an increase of ⩾2 g/dl in hemoglobin levels, for FCM versus IS from a Spanish healthcare payer perspective. Efficacy inputs were taken from a randomized controlled trial comparing the two interventions (FERGIcor). Costs of treatment were calculated in 2021 Euros (EUR) using a microcosting approach and included the costs of intravenous iron, healthcare professional time, and consumables. Cost-effectiveness was assessed over one cycle of treatment, with a series of sensitivity analyses performed to test the robustness of the results. RESULTS FCM was more effective than IS, with 84% of patients achieving a response compared with 76%. When expressed as number needed to treat, 13 patients would need to switch treatment from IS to FCM in order to achieve one additional responder. Costs of treatment were EUR 323 with FCM compared with EUR 470 with IS, a cost saving of EUR 147 with FCM. Cost savings with FCM were driven by the reduced number of infusions required, resulting in a reduced requirement for healthcare professional time and use of consumables compared with the IS arm. CONCLUSION The present analysis suggests that FCM is less costly and more effective than IS for the treatment of IDA subsequent to IBD in Spain and therefore was considered dominant.
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Affiliation(s)
- Federico Argüelles-Arias
- Hospital Universitario Virgen Macarena,
Seville, Spain; Facultad de Medicina, Universidad de Sevilla, Seville,
Spain
| | - Fernando Bermejo
- Hospital Universitario de Fuenlabrada,
Instituto de Investigación Sanitaria del Hospital La Paz (IdiPAZ), Madrid,
Spain
| | | | - Eugeni Domènech
- Hospital Universitari Germans Trias i Pujol,
Badalona, Spain; CIBEREHD, Madrid, Spain
| | | | - José M. Huguet
- Hospital General Universitario de Valencia,
Valencia, Spain
| | | | | | - Barnaby Hunt
- Ossian Health Economics and Communications
GmbH, Bäumleingasse 20, 4051 Basel, Switzerland
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30
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Spagnuolo R, Abenavoli L, Larussa T, Iannelli C, Pellicano R, Fagoonee S, Doldo P, Luzza F. Safety profile of intravenous iron in inflammatory bowel disease: an up-to-date overview. Minerva Gastroenterol (Torino) 2022; 68:111-118. [PMID: 33267572 DOI: 10.23736/s2724-5985.20.02819-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Up to 30-70% of patients may experience mild and moderate side effects during iron therapy and this is often associated with a poor adherence to therapy. Anemia is frequent in patients with active inflammatory bowel disease (IBD), due to both iron deficiency and chronic inflammation, therefore iron supplementation is frequently needed. Considering that gastrointestinal disorders are the most common side effects with oral iron, in IBD patients intravenous administration must be preferred. Although intravenous iron supplementation remains the most effective therapy of IBD-associated iron deficiency anemia, the perception of risk related to intravenous administration by clinicians could limit this successful strategy. In this narrative review we provided an up to date on the safety of the different iron formulations for intravenous administration, by reporting the most recent studies in IBD patients.
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Affiliation(s)
- Rocco Spagnuolo
- Department of Clinical and Experimental Medicine, "Magna Graecia" University, Catanzaro, Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy -
| | - Tiziana Larussa
- Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Chiara Iannelli
- Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette Hospital, Città della Salute e della Scienza, Turin, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, Turin, Italy
| | - Patrizia Doldo
- Department of Clinical and Experimental Medicine, "Magna Graecia" University, Catanzaro, Italy
| | - Francesco Luzza
- Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
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31
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Liang L, Xiong Q, Kong J, Tian C, Miao L, Zhang X, Du H. Intraperitoneal supplementation of iron alleviates dextran sodium sulfate-induced colitis by enhancing intestinal barrier function. Biomed Pharmacother 2021; 144:112253. [PMID: 34607106 DOI: 10.1016/j.biopha.2021.112253] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/15/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023] Open
Abstract
Iron supplementation is necessary for the treatment of anemia, one of the most frequent complications in inflammatory bowel disease (IBD). However, oral iron supplementation leads to an exacerbation of intestinal inflammation. Gut barrier plays a key role in the pathogenesis of IBD. The aim of this study was to characterize the interrelationship between systemic iron, intestinal barrier and the development of intestinal inflammation in a dextran sulfate sodium (DSS) induced experimental colitis mice model. We found that DSS-treated mice developed severe inflammation of colon, but became much healthy when intraperitoneal injection with iron. Iron supplementation alleviated colonic and systemic inflammation by lower histological scores, restorative morphology of colonic villi, and reduced expression of pro-inflammatory cytokines. Moreover, intraperitoneal supplementation of iron enhanced intestinal barrier function by upregulating the colonic expressions of tight junction proteins, restoring intestinal immune homeostasis by regulating immune cell infiltration and T lymphocyte subsets, and increasing mucous secretion of goblet cells in the colon. High-throughput sequencing of fecal 16 S rRNA showed that iron injection significantly increased the relative abundance of Bacteroidetes, which was suppressed in the gut microbiota of DSS-induced colitis mice. These results provided evidences supporting the protective effects of systemic iron repletion by intraperitoneal injection of iron on intestinal barrier functions. The finding highlights a novel approach for the treatment of IBD with iron injection therapy.
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Affiliation(s)
- Li Liang
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Qingqing Xiong
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Jingxia Kong
- Department of Investment and Insurance, Zhejiang Financial College, Hangzhou, China
| | - Chenying Tian
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Linfeng Miao
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Xiaofeng Zhang
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Huahua Du
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, China.
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32
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German KR, Juul SE. Iron and Neurodevelopment in Preterm Infants: A Narrative Review. Nutrients 2021; 13:nu13113737. [PMID: 34835993 PMCID: PMC8624708 DOI: 10.3390/nu13113737] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022] Open
Abstract
Iron is critical for brain development, playing key roles in synaptogenesis, myelination, energy metabolism and neurotransmitter production. NICU infants are at particular risk for iron deficiency due to high iron needs, preterm birth, disruptions in maternal or placental health and phlebotomy. If deficiency occurs during critical periods of brain development, this may lead to permanent alterations in brain structure and function which is not reversible despite later supplementation. Children with perinatal iron deficiency have been shown to have delayed nerve conduction speeds, disrupted sleep patterns, impaired recognition memory, motor deficits and lower global developmental scores which may be present as early as in the neonatal period and persist into adulthood. Based on this, ensuring brain iron sufficiency during the neonatal period is critical to optimizing neurodevelopmental outcomes and iron supplementation should be targeted to iron measures that correlate with improved outcomes.
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Sagar P, Singh V, Gupta R, Kaul S, Sharma S, Kaur S, Bhunia RK, Kondepudi KK, Singhal NK. pH-Triggered, Synbiotic Hydrogel Beads for In Vivo Therapy of Iron Deficiency Anemia and Reduced Inflammatory Response. ACS APPLIED BIO MATERIALS 2021; 4:7467-7484. [PMID: 35006707 DOI: 10.1021/acsabm.1c00720] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Iron deficiency anemia (IDA) is the most common nutritional disorder worldwide nearly affecting two billion people. The efficacies of conventional oral iron supplements are mixed, intravenous iron administration acquaintances with finite but crucial risks. Usually, only 5-20% iron is absorbed in the duodenum while the remaining fraction reaches the colon, affecting the gut microbes and can significantly impact intestinal inflammatory responses. Therefore, administration of gut bacterial modulators such as probiotics, prebiotics, and any other dietary molecules that can stimulate healthy gut bacteria can enhance iron absorption without any adverse side effects. In this study, we have prepared an iron supplement to avoid the side effects of conventional oral iron supplements. The formulation includes co-encapsulation of iron with anti-inflammatory probiotic bacteria within alginate/starch hydrogels (B + I-Dex (H)), which has been demonstrated to be efficient in mitigating IDA in vivo. As intestinal pH increases, the pore size of hydrogel increases due to ionic interactions and thus releases the encapsulated bacteria and iron. The field emission scanning electron microscopy (FESEM) analysis confirmed the porous structure of hydrogel beads, and in vitro release studies showed a sustained release of iron and bacteria at intestinal pH. The hydrogel was found to be nontoxic and biocompatible in Caco2 cell lines. The formulation showed efficient in vitro and in vivo iron bioavailability in Fe depletion-repletion studies. B + I-Dex (H) was observed to generate less inflammatory response than FeSO4 or nonencapsulated iron dextran (I-Dex) in vivo. We entrust that this duly functional hydrogel formulation could be further utilized or modified for the development of oral therapeutics for IDA.
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Affiliation(s)
- Poonam Sagar
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India.,Department of Biotechnology, Panjab University Chandigarh, Sector 25, Chandigarh 160014, Punjab, India
| | - Vishal Singh
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India
| | - Ritika Gupta
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India.,Department of Biotechnology, Panjab University Chandigarh, Sector 25, Chandigarh 160014, Punjab, India
| | - Sunaina Kaul
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India.,Department of Biotechnology, Panjab University Chandigarh, Sector 25, Chandigarh 160014, Punjab, India
| | - Shikha Sharma
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India.,Department of Biotechnology, Panjab University Chandigarh, Sector 25, Chandigarh 160014, Punjab, India
| | - Simranjit Kaur
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India
| | - Rupam Kumar Bhunia
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India
| | - Kanthi Kiran Kondepudi
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India
| | - Nitin Kumar Singhal
- National Agri-Food Biotechnology Institute, Sector-81 Mohali, Sahibzada Ajit Singh Nagar 140306, Punjab, India
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Apte A, Kapoor M, Naik S, Lubree H, Khamkar P, Singh D, Agarwal D, Roy S, Kawade A, Juvekar S, Banerjee R, Bavdekar A. Efficacy of transdermal delivery of liposomal micronutrients through body oil massage on neurodevelopmental and micronutrient deficiency status in infants: results of a randomized placebo-controlled clinical trial. BMC Nutr 2021; 7:48. [PMID: 34493339 PMCID: PMC8524365 DOI: 10.1186/s40795-021-00458-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/29/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Micronutrient deficiency is a known cause of adverse neurodevelopment and growth. Poor adherence to oral regimes of micronutrient supplements is a known challenge during the implementation of supplementation programs. The present study evaluates the benefits of liposomal encapsulated micronutrient fortified body oils (LMF oil) that can be used for infant body massage in terms of neurodevelopment and prevention of deficiency. STUDY DESIGN Double-blind randomized clinical trial. METHODS A total of 444 healthy infants aged 4-7 weeks were randomized to receive either LMF oil (containing iron, vitamin D, folate, and vitamin B12) or placebo oil for gentle body massage till 12 months of age. Blood samples were collected at 6 and 12 months for transferrin saturation (TSAT), hemoglobin, and 25-hydroxy vitamin (25-OH-D) levels. Mental and motor development was assessed at 12 months using developmental assessment for Indian Infants (DASII). RESULTS A total of 391 infants completed the study. There was no significant improvement in the hemoglobin in the intervention group at 12 months of age as compared to the placebo group [- 0.50 vs.-0.54 g%]. There was a marginally significant improvement in 25-OH-D at 12 months in the LMF oil group [+ 1.46vs.-0.18 ng/ml, p = 0.049]. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age [adjusted mean change + 0.11vs.-0.51 g%, p = 0.043]. The mental or motor developmental quotients in the intervention group were not significantly different from those in the placebo group. CONCLUSION Use of LMF oil for prevention of nutritional deficiency did not offer significant protection against nutritional anemia but prevented vitamin D deficiency to some extent with improvement in 25-OH-D at 12 months. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age. The intervention did not result in significant improvement in mental or motor development. Further evaluation with increased doses needs to be undertaken. TRIAL REGISTRATION CTRI no: CTRI/2017/11/010710 ; dated 30/11/2017.
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Affiliation(s)
- Aditi Apte
- Department of Biosciences and Bioengineering, Nanomedicine Laboratory, Indian Institute of Technology Bombay, Powai, Mumbai, India. .,PRERNA Young Scientist, KEM Hospital Research Centre, Pune, India.
| | - Mudra Kapoor
- Department of Biosciences and Bioengineering, Nanomedicine Laboratory, Indian Institute of Technology Bombay, Powai, Mumbai, India
| | | | - Himangi Lubree
- Vadu Rural Health Program, KEM Hospital Research Centre, Pune, India
| | - Pooja Khamkar
- Vadu Rural Health Program, KEM Hospital Research Centre, Pune, India
| | - Diksha Singh
- Vadu Rural Health Program, KEM Hospital Research Centre, Pune, India
| | - Dhiraj Agarwal
- Vadu Rural Health Program, KEM Hospital Research Centre, Pune, India
| | - Sudipto Roy
- PRERNA Young Scientist, KEM Hospital Research Centre, Pune, India
| | - Anand Kawade
- Vadu Rural Health Program, KEM Hospital Research Centre, Pune, India
| | - Sanjay Juvekar
- Vadu Rural Health Program, KEM Hospital Research Centre, Pune, India
| | - Rinti Banerjee
- Department of Biosciences and Bioengineering, Nanomedicine Laboratory, Indian Institute of Technology Bombay, Powai, Mumbai, India
| | - Ashish Bavdekar
- Vadu Rural Health Program, KEM Hospital Research Centre, Pune, India
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Zou J, Liu C, Jiang S, Qian D, Duan J. Cross Talk between Gut Microbiota and Intestinal Mucosal Immunity in the Development of Ulcerative Colitis. Infect Immun 2021; 89:e0001421. [PMID: 33526559 PMCID: PMC8370674 DOI: 10.1128/iai.00014-21] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC), a nonspecific inflammatory disease, is characterized by inflammation and mucosal damage in the colon, and its prevalence in the world is increasing. Nevertheless, the exact pathogenesis of UC is still unclear. Accumulating data have suggested that its pathogenesis is multifactorial, involving genetic predisposition, environmental factors, microbial dysbiosis, and dysregulated immune responses. Generally, UC is aroused by inappropriate immune activation based on the interaction of host and intestinal microbiota. The relationship between microbiota and host immune system in the pathogenesis of UC is complicated. However, increasing evidence indicates that the shift of microbiota composition can substantially influence intestinal immunity. In this review, we primarily focus on the delicate balance between microbiota and gut mucosal immunity during UC progression.
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Affiliation(s)
- Junfeng Zou
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Chen Liu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Shu Jiang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Dawei Qian
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Jinao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
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Anemia Severity Associated with Increased Healthcare Utilization and Costs in Inflammatory Bowel Disease. Dig Dis Sci 2021; 66:2555-2563. [PMID: 32892260 DOI: 10.1007/s10620-020-06590-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Anemia is a common systemic complication of inflammatory bowel disease (IBD) and is associated with worse disease outcomes, quality of life, and higher healthcare costs. AIMS The purpose of this study was to determine how anemia severity impacts healthcare resource utilization and if treatment of anemia was associated with reduced utilization and costs. METHODS Retrospective chart review of adult patients managed by gastroenterology between 2014 and 2018 at a tertiary referral center. RESULTS The records of 1763 patients with IBD were included in the analysis, with 966 (55%) patients with CD, 799 (44%) with UC, and 18 (1%) with unspecified IBD. Of these patients, 951 (54%) had anemia. Patients with anemia had significantly more hospitalizations, increased length of stays, more ER, GI, and PCP visits, as well as higher costs when compared to patients with IBD without anemia. Patients with more severe anemia had more healthcare utilization and incurred even higher total costs. Treatment with IV or oral iron did not lower overall utilization or costs, when compared to patients with anemia who did not receive treatment (p < 0.0001). CONCLUSIONS Our results demonstrate that the presence of anemia is correlated with increased resource utilization in patients with IBD, with increase in anemia severity associated with higher utilization and costs. Anemia has been associated with increased disease activity and could represent a marker of more severe disease, possibly explaining these associations. Our results suggest that treating anemia is associated with increased resource utilization; however, further research is needed to investigate this relationship.
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Cococcioni L, Pensabene L, El-Khouly S, Chadokufa S, McCartney S, Saliakellis E, Kiparissi F, Borrelli O. Ferric carboxymaltose treatment for iron deficiency anemia in children with inflammatory bowel disease: Efficacy and risk of hypophosphatemia. Dig Liver Dis 2021; 53:830-834. [PMID: 33775573 DOI: 10.1016/j.dld.2021.02.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/23/2021] [Accepted: 02/16/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although intravenous ferric carboxymaltose (FCM) is effective in treating iron deficiency anemia (IDA) in paediatric inflammatory bowel disease (pIBD), no data are available on its post-infusion related risks. AIMS We assessed the efficacy of FCM and the rate of post-infusion hypophosphatemia in a large cohort of children with IBD and IDA. METHODS All children with IBD with IDA treated with FCM over 5-year period were reviewed. Disease activity, biohumoral assessment and treatments were evaluated at baseline, 4-6 and 12 weeks after each infusion. RESULTS 128 patients [median age at first infusion: 13 years] were identified, 81 (63.3%) were <14 years, 10 (7.8%) <6 years. Eighty-three children (64.8%) received one infusion, whilst 45 (35.2%) repeated infusions. A significant increase in Hb (p<0.001), iron (p<0.001) and ferritin (p<0.001) was observed 4-6 and 12 weeks post-infusion. Hb gain was unrelated to disease severity. Low baseline iron was the main predicting factor for repeated infusions (p<0.05). Three patients reported infusion reactions, none <6 years. Twenty-five children had low post-infusion serum phosphate (11 were <14 years, 3 <6 years). Two children developed severe hypophosphatemia. CONCLUSIONS FCM administration is effective for IDA management in pIBD, including children <6 years. Due to the high prevalence of post-infusion hypophosphatemia, serum phosphate monitoring should be mandatory.
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Affiliation(s)
- Lucia Cococcioni
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK; Paediatric Department, "V. Buzzi" Children's Hospital, University of Milan, Milan, Italy
| | - Licia Pensabene
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK; Department of Surgical and Medical Sciences, Pediatric Unit, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Sara El-Khouly
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK
| | - Sibongile Chadokufa
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK
| | - Sara McCartney
- Gastroenterology Department, University College London Hospital, London, UK
| | - Efstratios Saliakellis
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK
| | - Fevronia Kiparissi
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK
| | - Osvaldo Borrelli
- Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3HZ London, UK; Stem Cells and Regenerative Medicine, UCL Institute of Child Health, 30 Guilford Street, London, UK.
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Mahalhal A, Frau A, Burkitt MD, Ijaz UZ, Lamb CA, Mansfield JC, Lewis S, Pritchard DM, Probert CS. Oral Ferric Maltol Does Not Adversely Affect the Intestinal Microbiome of Patients or Mice, But Ferrous Sulphate Does. Nutrients 2021; 13:2269. [PMID: 34209042 PMCID: PMC8308237 DOI: 10.3390/nu13072269] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 06/28/2021] [Accepted: 06/28/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND AND AIMS Altering dietary ferrous sulphate (FS) consumption exacerbates a murine model of colitis and alters the intestinal microbiome. We investigated the impact of oral ferric maltol (FM) and FS on mice with dextran sodium sulphate (DSS) induced colitis, and the microbiome of patients with iron deficiency. METHODS Mice had acute colitis induced, with 2% DSS for 5 days, followed by water. During this period, groups of mice were fed standard chow (200 ppm iron, SC, n = 8), or SC with 200ppm FS supplementation (n = 16, FSS), or SC with 200 ppm FM supplementation (n = 16, FMS). Clinical, pathological and microbiome assessments were compared at days 1 and 10. Fecal bacterial gDNA was extracted and the microbiome assessed by sequencing. Statistical inferences were made using MacQIIME. Principal Coordinates Analysis were used to visualize beta-diversity cluster analysis. Ten patients with IDA were treated with FS, and six with inactive inflammatory bowel disease received FM, supplements for four weeks: pre- and mid-treatment fecal samples were collected: the microbiome was assessed (see above). RESULTS In mice, after DSS treatment, there was a decrease in many genera in the SC and FSS groups: Lactobacillales increased in mice that received FMS. In humans, FS treatment led to an increase in five genera, but FM was not associated with any measurable change. The severity of DSS-induced colitis was greater with FSS than FMS. CONCLUSIONS This study demonstrates differential and unique influences of ferric maltol and ferrous sulphate supplements on intestinal microbiota. These differences might contribute to the different side effects associated with these preparations.
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Affiliation(s)
- Awad Mahalhal
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK; (A.F.); (D.M.P.); (C.S.P.)
| | - Alessandra Frau
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK; (A.F.); (D.M.P.); (C.S.P.)
| | - Michael D. Burkitt
- Division of Diabetes endocrinology and Gastroenterology, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PL, UK;
| | - Umer Z. Ijaz
- School of Engineering, University of Glasgow, Glasgow G12 8QQ, UK;
| | - Christopher A. Lamb
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK;
| | - John C. Mansfield
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK;
| | - Stephen Lewis
- Department of Gastroenterology, Derriford Hospital, Plymouth PL6 8DH, UK;
| | - D. Mark Pritchard
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK; (A.F.); (D.M.P.); (C.S.P.)
| | - Chris S. Probert
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK; (A.F.); (D.M.P.); (C.S.P.)
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Koleini N, Shapiro JS, Geier J, Ardehali H. Ironing out mechanisms of iron homeostasis and disorders of iron deficiency. J Clin Invest 2021; 131:e148671. [PMID: 34060484 DOI: 10.1172/jci148671] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients' symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.
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40
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Ribeiro M, Fonseca L, Anjos JS, Capo-Chichi JCC, Borges NA, Burrowes J, Mafra D. Oral iron supplementation in patients with chronic kidney disease: Can it be harmful to the gut microbiota? Nutr Clin Pract 2021; 37:81-93. [PMID: 33979013 DOI: 10.1002/ncp.10662] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Patients with chronic kidney disease (CKD) have several pathophysiological alterations, including anemia, one of the first changes in CKD patients. More recently, researchers have observed that the intestinal microbiota alterations are also another complication in these patients. The most common treatment for anemia is oral (mainly ferrous sulfate) or intravenous iron supplementation. Despite being a necessary treatment, recent studies have reported that supplementation with oral iron may increase its availability in the intestine, leading to disturbance in the gut microbiota and also to oxidative stress in the enterocytes, which may change the permeability and the microbiota profile. Although it is a therapy routinely used in patients with CKD, supplementation with oral iron on the gut microbiota has been rarely studied in these patients. Thus, this review will discuss the relationship between iron and the gut microbiota and the possible effects of oral iron supplementation on gut microbiota in patients with CKD.
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Affiliation(s)
- Marcia Ribeiro
- Graduate Program in Nutrition Sciences, Fluminense Federal University (UFF), Niterói, Rio de Janeiro, Brazil.,Unidade de Pesquisa Clinica (UPC)-University Hospital Antonio Pedro, Niterói, Rio de Janeiro, Brazil
| | - Larissa Fonseca
- Unidade de Pesquisa Clinica (UPC)-University Hospital Antonio Pedro, Niterói, Rio de Janeiro, Brazil.,Graduate Program in Medical Sciences, Fluminense Federal University (UFF), Niterói, Rio de Janeiro, Brazil
| | - Juliana S Anjos
- Unidade de Pesquisa Clinica (UPC)-University Hospital Antonio Pedro, Niterói, Rio de Janeiro, Brazil.,Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói, Rio de Janeiro, Brazil
| | - Jean C C Capo-Chichi
- Graduate Program in Medical Sciences, Fluminense Federal University (UFF), Niterói, Rio de Janeiro, Brazil
| | - Natália A Borges
- Institute of Nutrition, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil
| | | | - Denise Mafra
- Graduate Program in Nutrition Sciences, Fluminense Federal University (UFF), Niterói, Rio de Janeiro, Brazil.,Unidade de Pesquisa Clinica (UPC)-University Hospital Antonio Pedro, Niterói, Rio de Janeiro, Brazil.,Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói, Rio de Janeiro, Brazil.,Graduate Program in Medical Sciences, Fluminense Federal University (UFF), Niterói, Rio de Janeiro, Brazil
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Detlie TE, Lindstrøm JC, Jahnsen ME, Finnes E, Zoller H, Moum B, Jahnsen J. Hypophosphatemia after high-dose intravenous iron treatment in patients with inflammatory bowel disease: Mechanisms and possible clinical impact. World J Gastroenterol 2021; 27:2039-2053. [PMID: 34007138 PMCID: PMC8108035 DOI: 10.3748/wjg.v27.i17.2039] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/19/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND High-dose intravenous iron is an effective treatment option for iron deficiency (ID) or ID anaemia (IDA) in inflammatory bowel disease (IBD). However, treatment with ferric carboxymaltose (FCM) has been associated with the development of hypophosphatemia.
AIM To investigate mechanisms behind the development of hypophosphatemia after intravenous iron treatment, and disclose symptoms and clinical manifestations related to hypophosphatemia short-term.
METHODS A prospective observational study of adult IBD patients with ID or IDA was conducted between February 1, 2017 and July 1, 2018 at two separate university hospitals in the southeast region of Norway. Patients received one dose of 1000 mg of either FCM or ferric derisomaltose (FDI) and were followed for an observation period of at least 7 wk. Blood and urine samples were collected for relevant analyses at baseline, week 2 and at week 6. Clinical symptoms were assessed at the same timepoints using a respiratory function test, a visual analogue scale, and a health-related quality of life questionnaire.
RESULTS A total of 106 patients was available for analysis in this study. The FCM treatment group consisted of 52 patients and hypophosphatemia was present in 72.5% of the patients at week 2, and in 21.6% at week 6. In comparison, the FDI treatment group consisted of 54 patients and 11.3% of the patients had hypophosphatemia at week 2, and 3.7% at week 6. The difference in incidence was highly significant at both week 2 and 6 (P < 0.001 and P < 0.013, respectively). We observed a significantly higher mean concentration of intact fibroblast growth factor 23 (P < 0.001), a significant rise in mean urine fractional excretion of phosphate (P = 0.004), a significant decrease of 1,25-dihydroxyvitamin D (P < 0.001) and of ionised calcium levels (P < 0.012) in the FCM-treated patients compared with patients who received FDI. No clinical symptoms could with certainty be related to hypophosphatemia, since neither the respiratory function test, SF-36 (36-item short form health survey) or the visual analogue scale scores resulted in significant differences between patients who developed hypophosphatemia or not.
CONCLUSION Fibroblast growth factor 23 has a key role in FCM induced hypophosphatemia, probably by inducing loss of phosphate in the urine. Short-term clinical impact of hypophosphatemia was not demonstrated.
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Affiliation(s)
- Trond Espen Detlie
- Department of Gastroenterology, Akershus University Hospital, Lørenskog 1478, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
| | - Jonas Christoffer Lindstrøm
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
- Health Services Research Unit, Akershus University Hospital, Lørenskog 1478, Norway
| | - Marte Eide Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog 1478, Norway
| | - Elisabeth Finnes
- Division of Medicine, Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo 0424, Norway
| | - Heinz Zoller
- Department of Medicine II, Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck A-6020, Austria
| | - Bjørn Moum
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
- Division of Medicine, Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo 0424, Norway
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog 1478, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
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Mahalhal A, Burkitt MD, Duckworth CA, Hold GL, Campbell BJ, Pritchard DM, Probert CS. Long-Term Iron Deficiency and Dietary Iron Excess Exacerbate Acute Dextran Sodium Sulphate-Induced Colitis and Are Associated with Significant Dysbiosis. Int J Mol Sci 2021; 22:3646. [PMID: 33807459 PMCID: PMC8037348 DOI: 10.3390/ijms22073646] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Oral iron supplementation causes gastrointestinal side effects. Short-term alterations in dietary iron exacerbate inflammation and alter the gut microbiota, in murine models of colitis. Patients typically take supplements for months. We investigated the impact of long-term changes in dietary iron on colitis and the microbiome in mice. METHODS We fed mice chow containing differing levels of iron, reflecting deficient (100 ppm), normal (200 ppm), and supplemented (400 ppm) intake for up to 9 weeks, both in absence and presence of dextran sodium sulphate (DSS)-induced chronic colitis. We also induced acute colitis in mice taking these diets for 8 weeks. Impact was assessed (i) clinically and histologically, and (ii) by sequencing the V4 region of 16S rRNA. RESULTS In mice with long-term changes, the iron-deficient diet was associated with greater weight loss and histological inflammation in the acute colitis model. Chronic colitis was not influenced by altering dietary iron however there was a change in the microbiome in DSS-treated mice consuming 100 ppm and 400 ppm iron diets, and control mice consuming the 400 ppm iron diet. Proteobacteria levels increased significantly, and Bacteroidetes levels decreased, in the 400 ppm iron DSS group at day-63 compared to baseline. CONCLUSIONS Long-term dietary iron alterations affect gut microbiota signatures but do not exacerbate chronic colitis, however acute colitis is exacerbated by such dietary changes. More work is needed to understand the impact of iron supplementation on IBD. The change in the microbiome, in patients with colitis, may arise from the increased luminal iron and not simply from colitis.
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Affiliation(s)
- Awad Mahalhal
- Department of Molecular and Cellular Cancer Medicine, Institute of Systems, Molecular and Integrated Biology, University of Liverpool, Liverpool L69 3GE, UK; (A.M.); (D.M.P.)
- Department of Anatomy and Histology, Faculty of Medicine, Benghazi University, Benghazi, Libya
| | - Michael D. Burkitt
- Division of Diabetes Endocrinology and Gastroenterology, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PL, UK;
| | - Carrie A. Duckworth
- Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK;
| | - Georgina L. Hold
- Microbiome Research Centre, St George & Sutherland Clinical School, Clinical Sciences (Pitney) Building, University of New South Wales Sydney, Kogarah, NSW 2217, Australia;
| | - Barry J. Campbell
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 3GE, UK;
| | - David Mark Pritchard
- Department of Molecular and Cellular Cancer Medicine, Institute of Systems, Molecular and Integrated Biology, University of Liverpool, Liverpool L69 3GE, UK; (A.M.); (D.M.P.)
| | - Chris S. Probert
- Department of Molecular and Cellular Cancer Medicine, Institute of Systems, Molecular and Integrated Biology, University of Liverpool, Liverpool L69 3GE, UK; (A.M.); (D.M.P.)
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Management of anaemia in patients with inflammatory bowel disease - results of a questionnaire among Polish healthcare professionals. GASTROENTEROLOGY REVIEW 2021; 16:89-94. [PMID: 33986893 PMCID: PMC8112275 DOI: 10.5114/pg.2021.104738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 07/08/2020] [Indexed: 11/17/2022]
Abstract
Introduction Anaemia is the most common systemic and extraintestinal complication of inflammatory bowel disease (IBD). Its impact on quality of life is significant; hence, it is important for healthcare professionals to manage it correctly. Aim To assess the knowledge among doctors about the diagnostics and treatment of anaemia in IBD patients. Material and methods The questionnaire survey was conducted among 169 doctors of different specialties. Eighty-seven (51.5%) of the respondents were gastroenterologists. Results 97.7% (84) of gastroenterologists and 92.6% (75) of all responders replied that all IBD patients should be monitored for anaemia (p = 0.266); however, only one-third of gastroenterologists knew the exact haemoglobin cut-off level in men with Crohn's disease. The necessity of monitoring vitamin B12 was indicated by 53.7% (36) of gastroenterologists and by 24.1 % (13) of other specialists (p = 0.002). Nine percent (6) of gastrologists and 3.7% (2) of other specialists screened for folic acid (p = 0.0431). 13.1% (11) of gastroenterologists and 35% (28) of other specialists frequently used iv iron (p = 0.003). 44.1% (26) of gastroenterologists and 52% (26) of other specialists administered between 1000 mg and 1500 mg of iv iron during hospitalization. Only 11.9 % (7) of GI-specialists and 2% (1) of non-GI-specialists administered total doses over 1500 mg (p = 0.155). 71% (62) of gastroenterologists and 73% (60) of all physicians did not observe any adverse events of iv iron. Conclusions Although the diagnostic approach to anaemia in IBD patients varies among respondents, knowledge of guidelines was slightly better among GI-professionals then among other doctors.
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Oral and Intravenous Iron Therapy Differentially Alter the On- and Off-Tumor Microbiota in Anemic Colorectal Cancer Patients. Cancers (Basel) 2021; 13:cancers13061341. [PMID: 33809624 PMCID: PMC8002270 DOI: 10.3390/cancers13061341] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/03/2021] [Accepted: 03/12/2021] [Indexed: 12/25/2022] Open
Abstract
Iron deficiency anemia is a common complication of colorectal cancer and may require iron therapy. Oral iron can increase the iron available to gut bacteria and may alter the colonic microbiota. We performed an intervention study to compare oral and intravenous iron therapy on the colonic tumor-associated (on-tumor) and paired non-tumor-associated adjacent (off-tumor) microbiota. Anemic patients with colorectal adenocarcinoma received either oral ferrous sulphate (n = 16) or intravenous ferric carboxymaltose (n = 24). On- and off-tumor biopsies were obtained post-surgery and microbial profiling was performed using 16S ribosomal RNA analysis. Off-tumor α- and β-diversity were significantly different between iron treatment groups. No differences in on-tumor diversity were observed. Off-tumor microbiota of oral iron-treated patients showed higher abundances of the orders Clostridiales, Cytophagales, and Anaeroplasmatales compared to intravenous iron-treated patients. The on-tumor microbiota was enriched with the orders Lactobacillales and Alteromonadales in the oral and intravenous iron groups, respectively. The on- and off-tumor microbiota associated with intravenous iron-treated patients infers increased abundances of enzymes involved in iron sequestration and anti-inflammatory/oncogenic metabolite production, compared to oral iron-treated patients. Collectively, this suggests that intravenous iron may be a more appropriate therapy to limit adverse microbial outcomes compared to oral iron.
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Sienkiewicz M, Jaśkiewicz A, Tarasiuk A, Fichna J. Lactoferrin: an overview of its main functions, immunomodulatory and antimicrobial role, and clinical significance. Crit Rev Food Sci Nutr 2021; 62:6016-6033. [PMID: 33685299 DOI: 10.1080/10408398.2021.1895063] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Lactoferrin (LF), a glycoprotein found in mucosal secretions, is characterized by a wide range of functions, including immunomodulatory and anti-inflammatory activities. Moreover, several investigations confirmed that LF displays high effectiveness against multiple bacteria and viruses and may be regarded as a potential inhibitor of enveloped viruses, such as presently prevailing SARS-CoV-2. In our review, we discuss available studies about LF functions and bioavailability of different LF forms in in vitro and in vivo models. Moreover, we characterize the potential benefits and side effects of LF use; we also briefly summarize the latest clinical trials examining LF application. Finally, we point potential role of LF in inflammatory bowel disease and indicate its use as a marker for disease severity.
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Affiliation(s)
- Michał Sienkiewicz
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Andrzej Jaśkiewicz
- Institute of Food Technology and Analysis, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Lodz, Poland
| | - Aleksandra Tarasiuk
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Li CY, Li XY, Shen L, Ji HF. Regulatory effects of transition metals supplementation/deficiency on the gut microbiota. Appl Microbiol Biotechnol 2021; 105:1007-1015. [PMID: 33449129 DOI: 10.1007/s00253-021-11096-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/22/2020] [Accepted: 01/03/2021] [Indexed: 12/13/2022]
Abstract
Transition metal ions are essential micronutrients for all living organisms and exert a wide range of effects on human health. The uptake of transition metal ions occurs primarily in the gastrointestinal tract, which is colonized by trillions of bacterial cells. In recent years, increasing studies have indicated that transition metals have regulatory effects on the gut microbiota. In view of the significant effect of the gut microbiota on human health and involvement in the pathogenesis of a wide range of diseases, in this paper, we provide a comprehensive discussion on the regulatory effects of four kinds of transition metal ions on the gut microbiota. A total of 20 animal model and human studies concerning the regulatory effects of four types of transition metal ions (i.e., iron, copper, zinc, and manganese) on gut microbiota were summarized. Both the deficiency and supplementation of these transition metal ions on the gut microbiota were considered. Furthermore, the potential mechanisms governing the regulatory effects of transition metal ions on the gut microbiota were also discussed. KEY POINTS : • Regulatory effects of iron, copper, zinc, and manganese on gut microbiota were reviewed. • Both deficiency and supplementation of metal ions on gut microbiota were considered. • Mechanisms governing effects of metal ions on gut microbiota were discussed.
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Affiliation(s)
- Cheng-Yu Li
- Institute of Biomedical Research, Shandong University of Technology, Zibo, Shandong, People's Republic of China.,Shandong Provincial Research Center for Bioinformatic Engineering and Technique, School of Life Sciences, Shandong University of Technology, Zibo, Shandong, People's Republic of China
| | - Xin-Yu Li
- Institute of Biomedical Research, Shandong University of Technology, Zibo, Shandong, People's Republic of China.,Shandong Provincial Research Center for Bioinformatic Engineering and Technique, School of Life Sciences, Shandong University of Technology, Zibo, Shandong, People's Republic of China
| | - Liang Shen
- Institute of Biomedical Research, Shandong University of Technology, Zibo, Shandong, People's Republic of China. .,Shandong Provincial Research Center for Bioinformatic Engineering and Technique, School of Life Sciences, Shandong University of Technology, Zibo, Shandong, People's Republic of China.
| | - Hong-Fang Ji
- Institute of Biomedical Research, Shandong University of Technology, Zibo, Shandong, People's Republic of China. .,Shandong Provincial Research Center for Bioinformatic Engineering and Technique, School of Life Sciences, Shandong University of Technology, Zibo, Shandong, People's Republic of China.
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Sorensen RJ, Drouillard JS, Douthit TL, Ran Q, Marthaler DG, Kang Q, Vahl CI, Lattimer JM. Effect of hay type on cecal and fecal microbiome and fermentation parameters in horses. J Anim Sci 2021; 99:skaa407. [PMID: 33515482 PMCID: PMC7846146 DOI: 10.1093/jas/skaa407] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/23/2020] [Indexed: 11/12/2022] Open
Abstract
The effect of hay type on the microbiome of the equine gastrointestinal tract is relatively unexplored. Our objective was to characterize the cecal and fecal microbiome of mature horses consuming alfalfa or Smooth Bromegrass (brome) hay. Six cecally cannulated horses were used in a split-plot design run as a crossover in two periods. The whole plot treatment was ad libitum access to brome or alfalfa hay fed over two 21-d acclimation periods with subplots of sampling location (cecum and rectum) and sampling hour. Each acclimation period was followed by a 24-h collection period where cecal and fecal samples were collected every 3 h for analysis of pH and volatile fatty acids (VFA). Fecal and cecal samples were pooled and sent to a commercial lab (MR DNA, Shallowater, TX) for the amplification of the V4 region of the 16S rRNA gene and sequenced using Illumina HiSeq. The main effects of hay on VFA, pH, and taxonomic abundances were analyzed using the MIXED procedure of SAS 9.4 with fixed effects of hay, hour, location, period, and all possible interactions and random effect of horse. Alpha and beta diversities were analyzed using the R Dame package. Horses fed alfalfa had greater fecal than cecal pH (P ≤ 0.05), whereas horses fed brome had greater cecal than fecal pH (P ≤ 0.05). Regardless of hay type, total VFA concentrations were greater (P ≤ 0.05) in the cecum than in feces, and alfalfa resulted in greater (P ≤ 0.05) VFA concentrations than brome in both sampling locations. Alpha diversity was greater (P ≤ 0.05) in fecal compared with cecal samples. Microbial community structure within each sampling location and hay type differed from one another (P ≤ 0.05). Bacteroidetes were greater (P ≤ 0.05) in the cecum compared with the rectum, regardless of hay type. Firmicutes and Firmicutes:Bacteroidetes were greater (P ≤ 0.05) in the feces compared with cecal samples of alfalfa-fed horses. In all, fermentation parameters and bacterial abundances were impacted by hay type and sampling location in the hindgut.
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Affiliation(s)
- Rachel J Sorensen
- Department of Animal Sciences and Industry, College of Agriculture, Kansas State University, Manhattan, KS
| | - James S Drouillard
- Department of Animal Sciences and Industry, College of Agriculture, Kansas State University, Manhattan, KS
| | - Teresa L Douthit
- Department of Animal Sciences and Industry, College of Agriculture, Kansas State University, Manhattan, KS
| | - Qinghong Ran
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS
| | - Douglas G Marthaler
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS
| | - Qing Kang
- Department of Statistics, College of Arts and Sciences, Kansas State University, Manhattan, KS
| | - Christopher I Vahl
- Department of Statistics, College of Arts and Sciences, Kansas State University, Manhattan, KS
| | - James M Lattimer
- Department of Animal Sciences and Industry, College of Agriculture, Kansas State University, Manhattan, KS
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Li Y, Chen F, Xie Y, Yang Q, Luo H, Jia P, Shi Z, Wang S, Zheng X. Feiyangchangweiyan capsule protects against ulcerative colitis in mice by modulating the OSM/OSMR pathway and improving gut microbiota. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 80:153372. [PMID: 33113505 DOI: 10.1016/j.phymed.2020.153372] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 09/15/2020] [Accepted: 10/01/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Feiyangchangweiyan capsule (FYC) is a traditional Chinese medicine formulation used in the clinical treatment of acute and chronic gastroenteritis and bacterial dysentery. However, the effect of FYC on ulcerative colitis (UC) and the mechanism thereof remains unknown. PURPOSE To investigate the protective effect of FYC on UC mice induced by dextran sulfate sodium and illustrate the potential mechanism of this effect. METHODS Here, we established a model of UC mice by dextran sulfate sodium and administered with FYC. The disease activity index (DAI), colon length, myeloperoxidase (MPO) content in serum, pathological structure and ultrastructural changes, and inflammatory cell infiltration of colon tissue were evaluated. Transcriptome and 16S rDNA sequencing were employed to illuminate the mechanism of FYC in the protection of UC mice. RESULTS FYC significantly alleviates the pathological damage and the infiltration of inflammatory cells in colon tissue of dextran sulfate sodium induced UC mice, rescues shortened colon length, reduces DAI score, MPO content in serum, and pro-inflammatory factors including IL-1β, IL-6, CCL11, MCP-1 and MIP-2, and increases anti-inflammatory factors such as IL-10. Transcriptomics revealed that Oncostatin M (OSM) and its receptor (OSMR) are the critical pathway for UC treatment by FYC. OSM and OSMR increased in UC mice compared to control mice, and decreased with FYC, which was verified via measurement of OSM and OSMR mRNA and protein levels. Furthermore, we observed that FYC modulates intestinal microbiome composition (e.g., the proportion of Barnesiella/Proteobacteria) by affecting the inflammatory factors. CONCLUSION FYC exerts an effect on UC by inhibiting the OSM/OSMR pathway and regulating inflammatory factors to improve the intestinal flora.
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Affiliation(s)
- Yao Li
- Northwest University, Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Xi'an 710069, Shaanxi, China
| | - Fei Chen
- Department of Emergency Surgery, Wuhan No.1 Hospital, No.215 Zhongshan Road, Wuhan 430022, China
| | - Yanhua Xie
- Northwest University, Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Xi'an 710069, Shaanxi, China
| | - Qian Yang
- Department of Chinese Materia Medica and Natural Medicines, Air Force Medical University, Changle West Road No.169, Xi'an 710032 Shaanxi, P.R. China
| | - Huanhuan Luo
- Northwest University, Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Xi'an 710069, Shaanxi, China
| | - Pu Jia
- Northwest University, Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Xi'an 710069, Shaanxi, China
| | - Zhihui Shi
- Shaanxi Junbisha Pharmaceutical Limited Company, Xianyang 712015, Shaanxi, China
| | - Siwang Wang
- Northwest University, Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Xi'an 710069, Shaanxi, China; Department of Chinese Materia Medica and Natural Medicines, Air Force Medical University, Changle West Road No.169, Xi'an 710032 Shaanxi, P.R. China.
| | - Xiaohui Zheng
- Northwest University, Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Xi'an 710069, Shaanxi, China.
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Aksan A, Schoepfer A, Juillerat P, Vavricka S, Bettencourt M, Ramirez de Arellano A, Gavata S, Morin N, Valentine WJ, Hunt B. Iron Formulations for the Treatment of Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease: A Cost-Effectiveness Analysis in Switzerland. Adv Ther 2021; 38:660-677. [PMID: 33216324 PMCID: PMC7854431 DOI: 10.1007/s12325-020-01553-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 10/24/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD) and can result in reduced quality of life and increased healthcare costs. IDA is treated with iron supplementation, either with oral iron therapy (OI) or intravenous iron formulations, including ferric carboxymaltose (FCM), iron isomaltoside 1000 (IIM), and iron sucrose (IS). This analysis compared the cost-effectiveness of FCM versus IIM, IS, and OI in terms of additional cost per additional responder in Switzerland. METHODS A health economic model was developed to assess the additional cost per additional responder, defined as normalization or an increase of at least 2 g/dL in hemoglobin levels, for FCM versus IIM, IS, and OI. To date, no single head-to-head trial comparing all therapies is available, and therefore relative efficacy data were taken from a published network meta-analysis. Costs of treatment were calculated in 2020 Swiss francs (CHF) using a microcosting approach, and included the costs of iron, healthcare professional time, and consumables. Costs are also presented in euros (EUR) based on an exchange rate of CHF 1 = EUR 0.94. RESULTS Response rates with FCM, IIM, IS, and OI were 81%, 74%, 75%, and 69%, respectively, with FCM projected to be the most effective treatment. FCM was associated with cost savings of CHF 24 (EUR 23) versus IIM and of CHF 147 (EUR 138) versus IS, and increased costs by CHF 345 (EUR 324) versus OI. Therefore FCM was considered dominant versus both IIM and IS, improving clinical outcomes with cost savings. FCM was associated with an incremental cost-effectiveness ratio of CHF 2970 (EUR 2792) per additional responder versus OI. CONCLUSIONS FCM was projected to be the most cost-effective intravenous iron therapy in Switzerland, increasing the number of responders and leading to cost savings for healthcare payers.
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The Impact of Low-Level Iron Supplements on the Faecal Microbiota of Irritable Bowel Syndrome and Healthy Donors Using In Vitro Batch Cultures. Nutrients 2020; 12:nu12123819. [PMID: 33327501 PMCID: PMC7764926 DOI: 10.3390/nu12123819] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 11/30/2020] [Accepted: 12/08/2020] [Indexed: 12/14/2022] Open
Abstract
Ferrous iron supplementation has been reported to adversely alter the gut microbiota in infants. To date, the impact of iron on the adult microbiota is limited, particularly at low supplementary concentrations. The aim of this research was to explore the impact of low-level iron supplementation on the gut microbiota of healthy and Irritable Bowel Syndrome (IBS) volunteers. Anaerobic, pH-controlled in vitro batch cultures were inoculated with faeces from healthy or IBS donors along with iron (ferrous sulphate, nanoparticulate iron and pea ferritin (50 μmol−1 iron)). The microbiota were explored by fluorescence in situ hybridisation coupled with flow cytometry. Furthermore, metabolite production was assessed by gas chromatography. IBS volunteers had different starting microbial profiles to healthy controls. The sources of iron did not negatively impact the microbial population, with results of pea ferritin supplementation being similar to nanoparticulate iron, whilst ferrous sulphate led to enhanced Bacteroides spp. The metabolite data suggested no shift to potentially negative proteolysis. The results indicate that low doses of iron from the three sources were not detrimental to the gut microbiota. This is the first time that pea ferritin fermentation has been tested and indicates that low dose supplementation of iron is unlikely to be detrimental to the gut microbiota.
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