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Bao X, Wu J. Natural anti-adhesive components against pathogenic bacterial adhesion and infection in gastrointestinal tract: case studies of Helicobacter pylori, Salmonella enterica, Clostridium difficile, and diarrheagenic Escherichia coli. Crit Rev Food Sci Nutr 2024:1-46. [PMID: 39666022 DOI: 10.1080/10408398.2024.2436139] [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: 12/13/2024]
Abstract
Antimicrobial resistance (AMR) poses a global public health concern. Recognizing the critical role of bacterial adhesion in pathogenesis of infection, anti-adhesive therapy emerges as a promising approach to impede initial bacterial attachment, thus preventing pathogenic colonization and infection. Natural anti-adhesive agents derived from food sources are generally safe and have the potential to inhibit the emergence of resistant bacteria. This comprehensive review explored diverse natural dietary components exhibiting anti-adhesive activities against several model enteric pathogens, including Helicobacter pylori, Salmonella enterica, Clostridium difficile, and three key diarrheagenic Escherichia coli (i.e., enterotoxigenic E. coli, enteropathogenic E. coli, and enterohemorrhagic E. coli). Investigating various anti-adhesive products will advance our understanding of current research of the field and inspire further development of these agents as potential nutraceuticals or adjuvants to improve the efficacy of conventional antibiotics.
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Affiliation(s)
- Xiaoyu Bao
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
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Gad El-Hak HN, Mohamed FH. Effect of lactoferrin supplement on cadmium chloride induced toxicity to male rats: Toxicopathological, ultrastructural and immunological studies. Int Immunopharmacol 2023; 125:111182. [PMID: 37944217 DOI: 10.1016/j.intimp.2023.111182] [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: 07/22/2023] [Revised: 10/21/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023]
Abstract
This study sought to determine whether lactoferrin supplementation could counteract the harm that cadmium (Cd) induced to the rats. The effect of Cd and lactoferrin were investigated in hematological, biochemical, histological, immunohistochemical expression and ultrastructural studies. After 30 days of treatment, rats exposed to Cd had significantly higher levels of Cd in their blood, more oxidized lipids, and less antioxidant capacity overall. Supplemental lactoferrin also significantly undoes that effect. Hematological and biochemical parameters changed along with the increase in blood Cd levels. The histological integrity of the liver, kidney, spleen, and (axillary, cervical, mesenteric and popliteal) lymph nodes that had been damaged by Cd exposure was also restored by lactoferrin supplementation. Moreover, the liver and spleen ultrastructure showed the same improvement. In addition, the spleen of Lf/Cd group showed less immunohistochemical expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in comparison to the Cd group. In conclusion, the current study showed that supplementing with lactoferrin improved immune response and restored biochemical and oxidative stability induced by Cd.
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Imoto I, Yasuma T, D’Alessandro-Gabazza CN, Oka S, Misaki M, Horiki N, Gabazza EC. Antimicrobial Effects of Lactoferrin against Helicobacter pylori Infection. Pathogens 2023; 12:599. [PMID: 37111484 PMCID: PMC10144760 DOI: 10.3390/pathogens12040599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Helicobacter (H.) pylori is the primary causative agent of various gastroduodenal diseases. H. pylori is an adapted microorganism that has evolved to survive in the acidic conditions of the human stomach, possessing a natural strategy for colonizing harsh environments. Despite the implementation of various eradication regimens worldwide, the eradication rate of H. pylori has decreased to less than 80% in recent years due to the emergence of antibiotic-resistant strains. This has posed a significant challenge in treating H. pylori infection, as antibiotic resistance and side effects have become increasingly problematic. Lactoferrin, a member of the transferrin family, is an iron-binding protein with antioxidant, antibacterial, antiviral, and anti-inflammatory properties that promote human health. The concentrations of lactoferrin in the gastric juice and mucosa significantly increase during H. pylori infection and are strongly correlated with the severity of gastric mucosal inflammation. Numerous researchers have studied the antimicrobial properties of lactoferrin both in vitro and in vivo. In addition, recent studies have investigated the addition of oral lactoferrin supplementation to H. pylori eradication therapy, even though monotherapy with lactoferrin does not eradicate the microorganism. In this article, we reviewed the survival strategy of H. pylori to evade the antimicrobial activity of human lactoferrin and explore the potential of lactoferrin in H. pylori eradication therapy.
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Affiliation(s)
- Ichiro Imoto
- Digestive Endoscopy Center, Doshinkai Tohyama Hospital, Minami-shinmachi 17-22, Tsu, Mie 514-0043, Japan;
| | - Taro Yasuma
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan; (T.Y.)
| | - Corina N. D’Alessandro-Gabazza
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan; (T.Y.)
| | - Satoko Oka
- Department of Internal Medicine, Doshinkai Tohyama Hospital, Minami-shinmachi 17-22, Tsu, Mie 514-0043, Japan
| | - Moriharu Misaki
- Department of Internal Medicine, Doshinkai Tohyama Hospital, Minami-shinmachi 17-22, Tsu, Mie 514-0043, Japan
| | - Noriyuki Horiki
- Digestive Center, Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507, Japan
| | - Esteban C. Gabazza
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan; (T.Y.)
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Einerhand AWC, van Loo-Bouwman CA, Weiss GA, Wang C, Ba G, Fan Q, He B, Smit G. Can Lactoferrin, a Natural Mammalian Milk Protein, Assist in the Battle against COVID-19? Nutrients 2022; 14:nu14245274. [PMID: 36558432 PMCID: PMC9782828 DOI: 10.3390/nu14245274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 11/30/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Notwithstanding mass vaccination against specific SARS-CoV-2 variants, there is still a demand for complementary nutritional intervention strategies to fight COVID-19. The bovine milk protein lactoferrin (LF) has attracted interest of nutraceutical, food and dairy industries for its numerous properties-ranging from anti-viral and anti-microbial to immunological-making it a potential functional ingredient in a wide variety of food applications to maintain health. Importantly, bovine LF was found to exert anti-viral activities against several types of viruses, including certain SARS-CoV-2 variants. LF's potential effect on COVID-19 patients has seen a rapid increase of in vitro and in vivo studies published, resulting in a model on how LF might play a role during different phases of SARS-CoV-2 infection. Aim of this narrative review is two-fold: (1) to highlight the most relevant findings concerning LF's anti-viral, anti-microbial, iron-binding, immunomodulatory, microbiota-modulatory and intestinal barrier properties that support health of the two most affected organs in COVID-19 patients (lungs and gut), and (2) to explore the possible underlying mechanisms governing its mode of action. Thanks to its potential effects on health, bovine LF can be considered a good candidate for nutritional interventions counteracting SARS-CoV-2 infection and related COVID-19 pathogenesis.
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Affiliation(s)
| | | | | | - Caiyun Wang
- Inner Mongolia Dairy Technology Research Institute Co., Ltd., Hohhot 010110, China
| | - Genna Ba
- Inner Mongolia Yili Industrial Group Co., Ltd., Hohhot 010110, China
| | - Qicheng Fan
- Inner Mongolia Yili Industrial Group Co., Ltd., Hohhot 010110, China
| | - Baoping He
- Inner Mongolia Yili Industrial Group Co., Ltd., Hohhot 010110, China
| | - Gerrit Smit
- Yili Innovation Center Europe, 6708 WH Wageningen, The Netherlands
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Avalos-Gómez C, Ramírez-Rico G, Ruiz-Mazón L, Sicairos NL, Serrano-Luna J, de la Garza M. Lactoferrin: An Effective Weapon in the Battle Against Bacterial Infections. Curr Pharm Des 2022; 28:3243-3260. [PMID: 36284379 DOI: 10.2174/1381612829666221025153216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/27/2022] [Indexed: 01/28/2023]
Abstract
The emergence of multidrug-resistant bacterial strains with respect to commercially available antimicrobial drugs has marked a watershed in treatment therapies to fight pathogens and has stimulated research on alternative remedies. Proteins of the innate immune system of mammals have been highlighted as potentially yielding possible treatment options for infections. Lactoferrin (Lf) is one of these proteins; interestingly, no resistance to it has been found. Lf is a conserved cationic nonheme glycoprotein that is abundant in milk and is also present in low quantities in mucosal secretions. Moreover, Lf is produced and secreted by the secondary granules of neutrophils at infection sites. Lf is a molecule of approximately 80 kDa that displays multiple functions, such as antimicrobial, anti-viral, anti-inflammatory, and anticancer actions. Lf can synergize with antibiotics, increasing its potency against bacteria. Lactoferricins (Lfcins) are peptides resulting from the N-terminal end of Lf by proteolytic cleavage with pepsin. They exhibit several anti-bacterial effects similar to those of the parental glycoprotein. Synthetic analog peptides exhibiting potent antimicrobial properties have been designed. The aim of this review is to update understanding of the structure and effects of Lf and Lfcins as anti-bacterial compounds, focusing on the mechanisms of action in bacteria and the use of Lf in treatment of infections in patients, including those studies where no significant differences were found. Lf could be an excellent option for prevention and treatment of bacterial diseases, mainly in combined therapies with antibiotics or other antimicrobials.
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Affiliation(s)
- Christian Avalos-Gómez
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de Mexico, Mexico
| | - Gerardo Ramírez-Rico
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de Mexico, Mexico.,Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México (UNAM), Km 2.5 Carretera Cuautitlán- Teoloyucan, Cuautitlán Izcalli, 54714, Mexico
| | - Lucero Ruiz-Mazón
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de Mexico, Mexico
| | - Nidia León Sicairos
- Departamento de Investigación, Hospital Pediátrico de Sinaloa, Unidad de Investigación, Facultad de Medicina, Universidad Autónoma de Sinaloa, Mexico
| | - Jesús Serrano-Luna
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de Mexico, Mexico
| | - Mireya de la Garza
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de Mexico, Mexico
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Miyakawa M, Oda H, Tanaka M. Clinical research review: usefulness of bovine lactoferrin in child health. Biometals 2022; 36:473-489. [PMID: 35941293 PMCID: PMC10182119 DOI: 10.1007/s10534-022-00430-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 07/29/2022] [Indexed: 11/28/2022]
Abstract
Lactoferrin (LF) is abundant in human milk and plays an important role in the health of children. Bovine LF (bLF) has high homology with human LF and has been reported to have multiple biological functions. Several clinical studies have been conducted considering these properties, which reported the usefulness of bLF. This review was aimed to provide an overview of the clinical evidence in children. We searched clinical reports investigating the effects of bLF in children and identified 36 studies on the role of bLF in infections, iron metabolism, body growth, cerebral development, and fecal microbiome. Considering the accumulated evidence, bLF may contribute to the child health, particularly by suppressing or alleviating gastrointestinal and respiratory symptoms, and improving the iron status of children with anemia or those at high risk of anemia. The dose of bLF varies depending on the expected effect and target age, but may not necessarily have to be as high as human LF in human milk. Some of the beneficial effects of bLF have not been fully validated due to limited clinical evidence or being observed in the secondary analysis of some studies. Further clinical evidence would add significant value to the use of bLF in child health.
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Affiliation(s)
- Momoko Miyakawa
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry, Co., Ltd., Zama, Kanagawa, Japan
| | - Hirotsugu Oda
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry, Co., Ltd., Zama, Kanagawa, Japan.
| | - Miyuki Tanaka
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry, Co., Ltd., Zama, Kanagawa, Japan
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Impact of food-derived bioactive peptides on gut function and health. Food Res Int 2021; 147:110485. [PMID: 34399481 DOI: 10.1016/j.foodres.2021.110485] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/10/2021] [Accepted: 05/23/2021] [Indexed: 12/14/2022]
Abstract
The gastrointestinal tract (GIT) is the largest interface between our body and the environment. It is an organ system extending from the mouth to the anus and functions for food intake, digestion, transport and absorption of nutrients, meanwhile providing protection from environmental factors, like toxins, antigens, and pathogens. Diet is one of the leading factors modulating the function of the GIT. Bioactive peptides presenting naturally in food or derived from food proteins during digestion or processing have been revealed multifunctional in diverse biological processes, including maintaining gut health and function. This review summarizes the available evidence regarding the effects of food-derived bioactive peptides on gut function and health. Findings and insights from studies based on in vitro and animal models are discussed. The gastrointestinal mucosa maintains a delicate balance between immune tolerance to nutrients and harmful components, which is crucial for the digestive system's normal functions. Dietary bioactive peptides positively impact gastrointestinal homeostasis by modulating the barrier function, immune responses, and gut microbiota. However, there is limited clinical evidence on the safety and efficacy of bioactive peptides, much less on the applications of dietary peptides for the treatment or prevention of diseases related to the GIT. Further study is warranted to establish the applications of bioactive peptides in regulating gut health and function.
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Mizuki M, Tsukahara T, Oda H, Tanaka M, Yamauchi K, Abe F, Nomiyama T. Effects of Lactoferrin on Prevention of Acute Gastrointestinal Symptoms in Winter: A Randomized, Double-Blinded, Placebo-Controlled Trial for Staff of Kindergartens and Nursery Schools in Japan. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17249582. [PMID: 33371454 PMCID: PMC7767418 DOI: 10.3390/ijerph17249582] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 12/24/2022]
Abstract
This study investigated the preventive effects of lactoferrin (LF) on subjective acute gastrointestinal symptoms during the winter in a randomized, double-blinded, placebo-controlled parallel-group comparative trial. The eligible subjects were healthy adults working at kindergartens and nursery schools. We randomized the subjects to the Placebo group (0 mg/day), the Low LF group (200 mg/day), and the High LF group (600 mg/day) for 12 weeks. The prevalence of acute gastrointestinal symptoms was significantly lower in the High LF (13/112 vs. 26/116; p = 0.030) and the Low LF (13/107 vs. 26/116; p = 0.040) groups than in the Placebo group. The adjusted odds ratio for the prevalence of acute gastrointestinal symptoms was 2.78 (95% CI: 1.19–6.47) in the Placebo group compared with the High LF group. LF is useful to prevent acute gastrointestinal symptoms among childcare workers, who mainly consist of women.
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Affiliation(s)
- Masaru Mizuki
- Department of Occupational Medicine, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; (M.M.); (T.N.)
- Department of Preventive Medicine and Public Health, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Teruomi Tsukahara
- Department of Occupational Medicine, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; (M.M.); (T.N.)
- Department of Preventive Medicine and Public Health, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
- Correspondence: ; Tel.: +81-263-37-2622; Fax: +81-263-37-3449
| | - Hirotsugu Oda
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., Zama, Kanagawa 252-8583, Japan; (H.O.); (M.T.); (K.Y.); (F.A.)
| | - Miyuki Tanaka
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., Zama, Kanagawa 252-8583, Japan; (H.O.); (M.T.); (K.Y.); (F.A.)
| | - Koji Yamauchi
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., Zama, Kanagawa 252-8583, Japan; (H.O.); (M.T.); (K.Y.); (F.A.)
| | - Fumiaki Abe
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., Zama, Kanagawa 252-8583, Japan; (H.O.); (M.T.); (K.Y.); (F.A.)
| | - Tetsuo Nomiyama
- Department of Occupational Medicine, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; (M.M.); (T.N.)
- Department of Preventive Medicine and Public Health, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
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Cutone A, Ianiro G, Lepanto MS, Rosa L, Valenti P, Bonaccorsi di Patti MC, Musci G. Lactoferrin in the Prevention and Treatment of Intestinal Inflammatory Pathologies Associated with Colorectal Cancer Development. Cancers (Basel) 2020; 12:3806. [PMID: 33348646 PMCID: PMC7766217 DOI: 10.3390/cancers12123806] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 12/20/2022] Open
Abstract
The connection between inflammation and cancer is well-established and supported by genetic, pharmacological and epidemiological data. The inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, have been described as important promoters for colorectal cancer development. Risk factors include environmental and food-borne mutagens, dysbalance of intestinal microbiome composition and chronic intestinal inflammation, with loss of intestinal epithelial barrier and enhanced cell proliferation rate. Therapies aimed at shutting down mucosal inflammatory response represent the foundation for IBDs treatment. However, when applied for long periods, they can alter the immune system and promote microbiome dysbiosis and carcinogenesis. Therefore, it is imperative to find new safe substances acting as both potent anti-inflammatory and anti-pathogen agents. Lactoferrin (Lf), an iron-binding glycoprotein essential in innate immunity, is generally recognized as safe and used as food supplement due to its multifunctionality. Lf possesses a wide range of immunomodulatory and anti-inflammatory properties against different aseptic and septic inflammatory pathologies, including IBDs. Moreover, Lf exerts anti-adhesive, anti-invasive and anti-survival activities against several microbial pathogens that colonize intestinal mucosa of IBDs patients. This review focuses on those activities of Lf potentially useful for the prevention/treatment of intestinal inflammatory pathologies associated with colorectal cancer development.
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Affiliation(s)
- Antimo Cutone
- Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy; (A.C.); (G.I.)
| | - Giusi Ianiro
- Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy; (A.C.); (G.I.)
| | - Maria Stefania Lepanto
- Department of Public Health and Infectious Diseases, University of Rome La Sapienza, 00185 Rome, Italy; (M.S.L.); (L.R.); (P.V.)
| | - Luigi Rosa
- Department of Public Health and Infectious Diseases, University of Rome La Sapienza, 00185 Rome, Italy; (M.S.L.); (L.R.); (P.V.)
| | - Piera Valenti
- Department of Public Health and Infectious Diseases, University of Rome La Sapienza, 00185 Rome, Italy; (M.S.L.); (L.R.); (P.V.)
| | | | - Giovanni Musci
- Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy; (A.C.); (G.I.)
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Superti F. Lactoferrin from Bovine Milk: A Protective Companion for Life. Nutrients 2020; 12:nu12092562. [PMID: 32847014 PMCID: PMC7551115 DOI: 10.3390/nu12092562] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/19/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
Lactoferrin (Lf), an iron-binding multifunctional glycoprotein belonging to the transferrin family, is present in most biological secretions and reaches particularly high concentrations in colostrum and breast milk. A key function of lactoferrin is non-immune defence and it is considered to be a mediator linking innate and adaptive immune responses. Lf from bovine milk (bLf), the main Lf used in human medicine because of its easy availability, has been designated by the United States Food and Drug Administration as a food additive that is generally recognized as safe (GRAS). Among the numerous protective activities exercised by this nutraceutical protein, the most important ones demonstrated after its oral administration are: Antianemic, anti-inflammatory, antimicrobial, immunomodulatory, antioxidant and anticancer activities. All these activities underline the significance in host defence of bLf, which represents an ideal nutraceutical product both for its economic production and for its tolerance after ingestion. The purpose of this review is to summarize the most important beneficial activities demonstrated following the oral administration of bLf, trying to identify potential perspectives on its prophylactic and therapeutic applications in the future.
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Affiliation(s)
- Fabiana Superti
- National Centre for Innovative Technologies in Public Health, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy
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Cuomo P, Papaianni M, Fulgione A, Guerra F, Capparelli R, Medaglia C. An Innovative Approach to Control H. pylori-Induced Persistent Inflammation and Colonization. Microorganisms 2020; 8:microorganisms8081214. [PMID: 32785064 PMCID: PMC7463796 DOI: 10.3390/microorganisms8081214] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/06/2020] [Accepted: 08/08/2020] [Indexed: 12/23/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative bacterium which colonizes the human stomach. The ability of H. pylori to evade the host defense system and the emergence of antibiotic resistant strains result in bacteria persistence and chronic inflammation, which leads to both severe gastric and extra-gastric diseases. Consequently, innovative approaches able to overcome H. pylori clinical outcomes are needed. In this work, we develop a novel non-toxic therapy based on the synergistic action of H. pylori phage and lactoferrin adsorbed on hydroxyapatite nanoparticles, which effectively impairs bacteria colonization and minimizes the damage of the host pro-inflammatory response.
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Affiliation(s)
- Paola Cuomo
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Naples, Italy; (P.C.); (M.P.)
| | - Marina Papaianni
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Naples, Italy; (P.C.); (M.P.)
| | - Andrea Fulgione
- Istituto Zooprofilattico Sperimentale del Mezzogiorno (IZSM), 80055 Portici, Naples, Italy;
| | - Fabrizia Guerra
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy;
| | - Rosanna Capparelli
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Naples, Italy; (P.C.); (M.P.)
- Correspondence:
| | - Chiara Medaglia
- Department of Microbiology and Molecular Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland;
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Ciccaglione AF, Di Giulio M, Di Lodovico S, Di Campli E, Cellini L, Marzio L. Bovine lactoferrin enhances the efficacy of levofloxacin-based triple therapy as first-line treatment of Helicobacter pylori infection: an in vitro and in vivo study. J Antimicrob Chemother 2020; 74:1069-1077. [PMID: 30668729 PMCID: PMC6419617 DOI: 10.1093/jac/dky510] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/24/2018] [Accepted: 11/12/2018] [Indexed: 12/11/2022] Open
Abstract
Objectives To evaluate the in vitro antimicrobial/antivirulence action of bovine lactoferrin and its ability to synergize with levofloxacin against resistant Helicobacter pylori strains and to analyse the effect of levofloxacin, amoxicillin and esomeprazole with and without bovine lactoferrin as the first-line treatment for H. pylori infection. Methods The bovine lactoferrin antimicrobial/antivirulence effect was analysed in vitro by MIC/MBC determination and twitching motility against six clinical H. pylori strains and a reference strain. The synergism was evaluated using the chequerboard assay. The prospective therapeutic trial was carried out on two separate patient groups, one treated with esomeprazole/amoxicillin/levofloxacin and the other with esomeprazole/amoxicillin/levofloxacin/bovine lactoferrin. Treatment outcome was determined with the [13C]urea breath test. Results In vitro, bovine lactoferrin inhibited the growth of 50% of strains at 10 mg/mL and expressed 50% bactericidal effect at 40 mg/mL. The combination of levofloxacin and bovine lactoferrin displayed a synergistic effect for all strains, with the best MIC reduction of 16- and 32-fold for levofloxacin and bovine lactoferrin, respectively. Bovine lactoferrin at one-fourth MIC reduced microbial motility significantly for all strains studied. In the in vivo study, 6 of 24 patients recruited had treatment failure recorded with esomeprazole/amoxicillin/levofloxacin (75% success, 95% CI 57.68%–92.32%), and in the group with esomeprazole/amoxicillin/levofloxacin/bovine lactoferrin, 2 out of 53 patients recruited had failure recorded (96.07% success, 95% CI 90.62%–101.38%). Conclusions Bovine lactoferrin can be considered a novel potentiator for restoring susceptibility in resistant H. pylori strains. Bovine lactoferrin added to a triple therapy in first-line treatment potentiates the therapeutic effect.
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Affiliation(s)
| | - Mara Di Giulio
- Department of Pharmacy, 'G. d'Annunzio' University, Via dei Vestini, Chieti, Italy
| | - Silvia Di Lodovico
- Department of Pharmacy, 'G. d'Annunzio' University, Via dei Vestini, Chieti, Italy
| | - Emanuela Di Campli
- Department of Pharmacy, 'G. d'Annunzio' University, Via dei Vestini, Chieti, Italy
| | - Luigina Cellini
- Department of Pharmacy, 'G. d'Annunzio' University, Via dei Vestini, Chieti, Italy
| | - Leonardo Marzio
- Digestive Sciences Unit, 'G. d'Annunzio' University, Pescara Civic Hospital, Via Fonte Romana 8, Pescara, Italy
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Sanwlani R, Fonseka P, Chitti SV, Mathivanan S. Milk-Derived Extracellular Vesicles in Inter-Organism, Cross-Species Communication and Drug Delivery. Proteomes 2020; 8:11. [PMID: 32414045 PMCID: PMC7356197 DOI: 10.3390/proteomes8020011] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/07/2020] [Accepted: 05/11/2020] [Indexed: 12/13/2022] Open
Abstract
Milk is considered as more than a source of nutrition for infants and is a vector involved in the transfer of bioactive compounds and cells. Milk contains abundant quantities of extracellular vesicles (EVs) that may originate from multiple cellular sources. These nanosized vesicles have been well characterized and are known to carry a diverse cargo of proteins, nucleic acids, lipids and other biomolecules. Milk-derived EVs have been demonstrated to survive harsh and degrading conditions in gut, taken up by various cell types, cross biological barriers and reach peripheral tissues. The cargo carried by these dietary EVs has been suggested to have a role in cell growth, development, immune modulation and regulation. Hence, there is considerable interest in understanding the role of milk-derived EVs in mediating inter-organismal and cross-species communication. Furthermore, various attributes such as it being a natural source, as well as its abundance, scalability, economic viability and lack of unwarranted immunologic reactions, has generated significant interest in deploying milk-derived EVs for clinical applications such as drug delivery and disease therapy. In this review, the role of milk-derived EVs in inter-organismal, cross-species communication and in drug delivery is discussed.
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Affiliation(s)
| | | | | | - Suresh Mathivanan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3083, Australia; (R.S.); (P.F.); (S.V.C.)
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14
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Wang LS, Echeveste CE, Yu J, Huang YW, Lechner J, Mei L, Sanvanson P, Yearsley M, Wang CK, Stoner G. Can Natural Products Suppress Resistant Helicobacter pylori to Fight Against Gastric Diseases in Humans? EFOOD 2020; 1:53-60. [PMID: 34308385 PMCID: PMC8301227 DOI: 10.2991/efood.k.200211.001] [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] [Indexed: 01/06/2023] Open
Abstract
More than 50% of the world's population is infected with Helicobacter pylori. H. pylori is the major causative agent of gastric ulcers and gastric cancer. H. pylori eradication using antibiotics either alone or together with a proton pump inhibitor is the primary strategy to decrease the incidence of gastric cancer. Although eradication therapy is effective, there are significant adverse effects and more importantly, resistance to antibiotics occurs, which represents a major therapeutic challenge. Multiple natural products have been shown to suppress H. pylori both in vitro and in animal model systems. However, only a handful of natural products have been evaluated in human clinical trials. The focus of this review is to summarize the results of published human clinical trials to assess the ability of natural products to reduce or eliminate H. pylori infections. Current evidence suggests that these products appear to have great potential to be developed as pharmaceutical candidates for eradication of H. pylori, hopefully both antibiotic-sensitive and antibiotic-resistant strains. Frequent consumption of locally produced foodstuff for controlling H. pylori infection in different countries around the world may well be a feasible long-term solution to fight against this worldwide prevalent pathogen.
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Affiliation(s)
- Li-Shu Wang
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Carla Elena Echeveste
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Yi-Wen Huang
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - John Lechner
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Ling Mei
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Patrick Sanvanson
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Martha Yearsley
- Department of Pathology, Ohio State University, Columbus, OH, USA
| | - Chin-Kun Wang
- School of Nutrition, Chung Shan Medical University, Taichung City, Taiwan
| | - Gary Stoner
- Department of Microbiology and Immunology, Montana State University, Bozeman, MT, USA
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Obaidat MM, Roess AA. First nationwide seroepidemiology and risk factors report of Helicobater pylori in Jordan. Helicobacter 2019; 24:e12572. [PMID: 30868689 DOI: 10.1111/hel.12572] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 01/16/2019] [Accepted: 01/24/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Helicobacter pylori inhabits the gastric mucosa of humans and causes 89% of all gastric cancers. This is the first study of the seroprevalence, spatial distribution, and risk factors for H pylori in Jordan. MATERIALS AND METHODS This is a cross-sectional study of 460 healthy participants (aged between 15 and 81 years) proportionately sampled across each region of Jordan. Sera samples were tested for H pylori using Enzygnost® anti-H pylori immunoglobulin G enzyme-linked immunosorbent assay. Participants completed a validated questionnaire about potential risk factors including food consumption habits and environmental and animal exposure. Multivariate generalized linear models identified risk factors for infection. RESULTS The results showed a high seroprevalence (88.6%; 95% confidence interval [CI]: 85.3-91.2) of H pylori in the study population. After adjusting for possible confounders, age, consumption of raw milk, and location of residence were significantly associated with seropositivity. Older participants aged 30-49 years had an 11% greater risk of seropositivity compared to participants aged 15-29 years. Participants who consume raw milk and dairy products have a 9% decreased risk in seropositivity (prevalence ratio = 0.92; 95% CI: 0.84-0.99) compared to those who do not consume these products. CONCLUSION This study reports a negative association between consumption of raw milk and seropositivity, and this is in line with several studies that report consumption of raw milk may be protective against H pylori. However, because of the risk of other serious pathogens associated with the consumption of raw dairy products, this study recommends pasteurization of raw milk. Future studies on the effect of fermented dairy products on H pylori colorization in gastric mucosa are recommended.
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Affiliation(s)
- Mohammad M Obaidat
- Department of Veterinary Pathology and Public Health, Faculty of Veterinary Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Amira A Roess
- Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington, District of Columbia
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Xia Y, Meng G, Zhang Q, Liu L, Wu H, Shi H, Bao X, Su Q, Gu Y, Fang L, Yu F, Yang H, Yu B, Sun S, Wang X, Zhou M, Jia Q, Zhao H, Song K, Niu K. Dietary Patterns are Associated with Helicobacter Pylori Infection in Chinese Adults: A Cross-Sectional Study. Sci Rep 2016; 6:32334. [PMID: 27573193 PMCID: PMC5004161 DOI: 10.1038/srep32334] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 08/03/2016] [Indexed: 12/14/2022] Open
Abstract
Previous studies indicated that food consumption was associated with Helicobacter pylori infection, but no study has yet investigated the association between Helicobacter pylori infection and dietary patterns. The aim of this study was to evaluate the associations between Helicobacter pylori infection and dietary patterns in Tianjin, China. The final cross-sectional study population comprised 10407 participants. Dietary consumption of participants was assessed via food frequency questionnaire. Factor analysis was used to identify dietary patterns, and Helicobacter pylori infection status was diagnosis by H. pylori urease Immunogold Testing kit. Participants in the highest quartile of the high-carbohydrate/sweet pattern showed a multivariable-adjusted OR (95% CI) of 1.65 (1.27–2.17) for the prevalence of H. pylori infection compared with those in the lowest quartile. The multiple adjusted OR for scores of the extreme quartile of high-protein/cholesterol pattern was 0.75 (95% CI, 0.57–0.98). This study demonstrated that a diet rich in carbohydrates and sweets was positively associated with the prevalence of H. pylori infection; interestingly, a diet characterized by high intake of animal offal, animal blood, fish, seafood, and poultry was associated with a reduction of prevalence of H. pylori infection.
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Affiliation(s)
- Yang Xia
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Ge Meng
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Qing Zhang
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Li Liu
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongmei Wu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Hongbin Shi
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Xue Bao
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Qian Su
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Yeqing Gu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Liyun Fang
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Fei Yu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Huijun Yang
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Bin Yu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Shaomei Sun
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Xing Wang
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Ming Zhou
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Qiyu Jia
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Honglin Zhao
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Kun Song
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Kaijun Niu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China.,Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China.,Collaborative Innovation Center of Non-communicable Disease, Tianjin Medical University, Tianjin, China
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Mudd AT, Alexander LS, Berding K, Waworuntu RV, Berg BM, Donovan SM, Dilger RN. Dietary Prebiotics, Milk Fat Globule Membrane, and Lactoferrin Affects Structural Neurodevelopment in the Young Piglet. Front Pediatr 2016; 4:4. [PMID: 26870719 PMCID: PMC4740374 DOI: 10.3389/fped.2016.00004] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 01/20/2016] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Milk fat globule membrane (MFGM) and lactoferrin have been identified as two components that have potential to affect neurodevelopment. While concentrations of some MFGM constituents in infant formulas are within human milk range, they may not be present at optimal or clinically effective levels. However, lactoferrin levels of infant formulas are consistently reported to be lower than human milk. This study sought to provide a novel combination of prebiotics, bovine-derived MFGM, and lactoferrin and assess their influence on neurodevelopment. METHODS Twenty-four male piglets were provided either TEST (n = 12) or CONT (n = 12) diet from 2 to 31 days of age. Piglets underwent spatial T-maze assessment starting at 17 days of age, were subjected to magnetic resonance imaging at 30 days of age, and were euthanized for tissue collection at 31 days of age. RESULTS Diffusion tensor imaging revealed differences in radial (P = 0.032) and mean (P = 0.028) diffusivities in the internal capsule, where CONT piglets had higher rates of diffusion compared with TEST piglets. Voxel-based morphometry indicated larger (P < 0.05) differences in cortical gray and white matter concentrations, with CONT piglets having larger tissue clusters in these regions compared with TEST piglets. In the spatial T-maze assessment, CONT piglets exhibited shorter latency to choice compared with TEST piglets on day 2 of acquisition and days 3 and 4 of reversal. CONCLUSION Observed differences in microstructure maturation of the internal capsule and cortical tissue concentrations suggest that piglets provided TEST diet were more advanced developmentally than piglets provided CONT diet. Therefore, supplementation of infant formula with prebiotics, MFGM, and lactoferrin may support neurodevelopment in human infants.
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Affiliation(s)
- Austin T Mudd
- Piglet Nutrition and Cognition Laboratory, Department of Animal Sciences, University of Illinois, Urbana, IL, USA; Neuroscience Program, University of Illinois, Urbana, IL, USA
| | - Lindsey S Alexander
- Piglet Nutrition and Cognition Laboratory, Department of Animal Sciences, University of Illinois , Urbana, IL , USA
| | - Kirsten Berding
- Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, USA
| | | | - Brian M Berg
- Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Mead Johnson Pediatric Nutrition Institute, Evansville, IN, USA
| | - Sharon M Donovan
- Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, USA
| | - Ryan N Dilger
- Piglet Nutrition and Cognition Laboratory, Department of Animal Sciences, University of Illinois, Urbana, IL, USA; Neuroscience Program, University of Illinois, Urbana, IL, USA; Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA
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18
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Liu XF, Cheng GX, Yuan YP, Zhang AM, Luo J, Liu SG, Chen JQ, Dong XQ, Zhang L, Ma LQ. Effect of recombinant human lactoferrin treatment on mRNA expression of vacuolating cytotoxin A and content of tumor necrosis factor-α in gastric tissue of mice with Helicobacter pylori-associated gastritis. Shijie Huaren Xiaohua Zazhi 2015; 23:2860-2867. [DOI: 10.11569/wcjd.v23.i18.2860] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore whether recombinant human lactoferrin (rhLF) plus triple therapy can increase the rate of Helicobacter pylori(H. pylori) eradication, reduce gastric mucosal inflammation, and inhibit vacuolating cytotoxin (VacA) mRNA expression.
METHODS: One hundred and ninety-two H. pylori ATCC43504 infected Babl/c mice with gastritis were randomly divided into four groups: A (rhLF+standard triple therapy), B (rhLF alone), C (standard triple therapy alone), and D (saline). H. pyloricolonization of the gastric mucosa was assessed by silver staining. Gastric mucosal inflammation was assessed by HE staining. Tumor necrosis factor (TNF)-α content was determined by ELISA. VacA mRNA expression was detected by RT-PCR.
RESULTS: Compared with group D, the rate of H. pylori colonization and gastric mucosal inflammation score decreased significantly in groups A, B, and C (P < 0.05). Compared with groups B and C, the rate of H. pylori colonization and gastric mucosal inflammation score decreased significantly in group A (P < 0.05). rhLF plus standard triple therapy significantly decreased gastric TNF-α content (28.64 pg/mL ± 12.07 pg/mL vs 300.16 pg/mL ± 59.1 pg/mL, 54.96 pg/mL ± 15.02 pg/mL, 503.25 pg/mL ± 1.35 pg/mL, P < 0.01) and VacA mRNA expression (P < 0.01) compared with groups B, C and D.
CONCLUSION: rhLF combined with triple therapy can improve H. pylori eradication rate, reduce gastric mucosal inflammation possibly by inhibiting proinflammatory factor release, and effectively inhibit VacA mRNA expression.
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Fahey JW, Stephenson KK, Wallace AJ. Dietary amelioration of Helicobacter infection. Nutr Res 2015; 35:461-73. [PMID: 25799054 PMCID: PMC4465045 DOI: 10.1016/j.nutres.2015.03.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/01/2015] [Accepted: 03/02/2015] [Indexed: 12/18/2022]
Abstract
We review herein the basis for using dietary components to treat and/or prevent Helicobacter pylori infection, with emphasis on (a) work reported in the last decade, (b) dietary components for which there is mechanism-based plausibility, and (c) components for which clinical results on H pylori amelioration are available. There is evidence that a diet-based treatment may reduce the levels and/or the virulence of H pylori colonization without completely eradicating the organism in treated individuals. This concept was endorsed a decade ago by the participants in a small international consensus conference held in Honolulu, Hawaii, USA, and interest in such a diet-based approach has increased dramatically since then. This approach is attractive in terms of cost, treatment, tolerability, and cultural acceptability. This review, therefore, highlights specific foods, food components, and food products, grouped as follows: bee products (eg, honey and propolis); probiotics; dairy products; vegetables; fruits; oils; essential oils; and herbs, spices, and other plants. A discussion of the small number of clinical studies that are available is supplemented by supportive in vitro and animal studies. This very large body of in vitro and preclinical evidence must now be followed up with rationally designed, unambiguous human trials.
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Affiliation(s)
- Jed W Fahey
- Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology & Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Center for Human Nutrition, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
| | - Katherine K Stephenson
- Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology & Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Alison J Wallace
- New Zealand Institute for Plant and Food Research Limited, Lincoln, New Zealand
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20
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Nanda R, Das P, Tripathy PK. Breast milk: immunosurveillance in infancy. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2014. [DOI: 10.1016/s2222-1808(14)60665-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Takeuchi H, Trang VT, Morimoto N, Nishida Y, Matsumura Y, Sugiura T. Natural products and food components with anti- Helicobacter pylori activities. World J Gastroenterol 2014; 20:8971-8978. [PMID: 25083070 PMCID: PMC4112882 DOI: 10.3748/wjg.v20.i27.8971] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 01/20/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
The bacterial pathogen Helicobacter pylori (H. pylori) colonizes in over half of the world’s population. H. pylori that establishes life-long infection in the stomach is definitely associated with gastro-duodenal diseases and a wide variety of non-gastrointestinal tract conditions such as immune thrombocytopenia. Triple therapy which consists of a proton pump inhibitor and combinations of two antibiotics (amoxicillin, clarithromycin or amoxicillin, metronidazol) is commonly used for H. pylori eradication. Recently, the occurrence of drug-resistant H. pylori and the adverse effect of antibiotics have severely weakened eradication therapy. Generally antibiotics induce the disturbance of human gastrointestinal microflora. Furthermore, there are inappropriate cases of triple therapy such as allergy to antibiotics, severe complications (liver and/or kidney dysfunction), the aged and people who reject the triple therapy. These prompt us to seek alterative agents instead of antibiotics and to develop more effective and safe therapy with these agents. The combination of these agents actually may result in lower a dose of antibiotics. There are many reports world-wide that non-antibiotic substances from natural products potentially have an anti-H. pylori agent. We briefly review the constituents derived from nature that fight against H. pylori in the literature with our studies.
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Rai D, Adelman AS, Zhuang W, Rai GP, Boettcher J, Lönnerdal B. Longitudinal Changes in Lactoferrin Concentrations in Human Milk: A Global Systematic Review,. Crit Rev Food Sci Nutr 2014; 54:1539-47. [DOI: 10.1080/10408398.2011.642422] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Sachdeva A, Rawat S, Nagpal J. Efficacy of fermented milk and whey proteins in Helicobacter pylori eradication: A review. World J Gastroenterol 2014; 20:724-737. [PMID: 24574746 PMCID: PMC3921482 DOI: 10.3748/wjg.v20.i3.724] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 10/12/2013] [Accepted: 12/06/2013] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) eradication is considered a necessary step in the management of peptic ulcer disease, chronic gastritis, gastric adenocarcinoma and mucosa associated lymphoid tissue lymphoma. Standard triple therapy eradication regimens are inconvenient and achieve unpredictable and often poor results. Eradication rates are decreasing over time with increase in antibiotic resistance. Fermented milk and several of its component whey proteins have emerged as candidates for complementary therapy. In this context the current review seeks to summarize the current evidence available on their role in H. pylori eradication. Pertinent narrative/systematic reviews, clinical trials and laboratory studies on individual components including fermented milk, yogurt, whey proteins, lactoferrin, α-lactalbumin (α-LA), glycomacropeptide and immunoglobulin were comprehensively searched and retrieved from Medline, Embase, Scopus, Cochrane Controlled Trials Register and abstracts/proceedings of conferences up to May 2013. A preponderance of the evidence available on fermented milk-based probiotic preparations and bovine lactoferrin suggests a beneficial effect in Helicobacter eradication. Evidence for α-LA and immunoglobulins is promising while that for glycomacropeptide is preliminary and requires substantiation. The magnitude of the potential benefit documented so far is small and the precise clinical settings are ill defined. This restricts the potential use of this group as a complementary therapy in a nutraceutical setting hinging on better patient acceptability/compliance. Further work is necessary to identify the optimal substrate, fermentation process, dose and the ideal clinical setting (prevention/treatment, first line therapy/recurrence, symptomatic/asymptomatic, gastritis/ulcer diseases etc.). The potential of this group in high antibiotic resistance or treatment failure settings presents interesting possibilities and deserves further exploration.
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Abstract
In a nutshellLactoferrin is found in milk - human and animal. It has therapeutic potential as an iron supplement, against infection, inflammation and cancer.The evidence is so far mainly laboratory and animal data, with a small number of human trials beginning to be published, to this point with mixed results. An example is its use as treatment for Helicobacter pylori infection.
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Healthy Multifunctional Spectra of Milk Glycoproteins and Their Fragments – a Review Article. POL J FOOD NUTR SCI 2012. [DOI: 10.2478/v10222-012-0053-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Suganuma M, Watanabe T, Yamaguchi K, Takahashi A, Fujiki H. Human gastric cancer development with TNF-α-inducing protein secreted from Helicobacter pylori. Cancer Lett 2012; 322:133-8. [PMID: 22459353 DOI: 10.1016/j.canlet.2012.03.027] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 03/13/2012] [Accepted: 03/21/2012] [Indexed: 12/12/2022]
Abstract
TNF-α-inducing protein (Tipα) is a unique carcinogenic factor of Helicobacter pylori, which is secreted into culture broth. The biological activities of Tipα and deletion mutant were studied. Tipα protein specifically binds to cell-surface nucleolin and then enters the gastric cancer cells, where TNF-α and chemokine gene expressions are induced by NF-κB activation. Nucleolin localizes on the surface of gastric cancer cells, and interaction between Tipα and cell-surface nucleolin causes a cancer-oriented microenvironment that increases the risk of gastric cancer. This paper discusses a new mechanism of gastric cancer development with H. pylori and provides a new preventive strategy.
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Affiliation(s)
- Masami Suganuma
- Research Institute for Clinical Oncology, Saitama Cancer Center, Japan.
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Horemans T, Kerstens M, Clais S, Struijs K, van den Abbeele P, Van Assche T, Maes L, Cos P. Evaluation of the anti-adhesive effect of milk fat globule membrane glycoproteins on Helicobacter pylori in the human NCI-N87 cell line and C57BL/6 mouse model. Helicobacter 2012; 17:312-8. [PMID: 22759332 DOI: 10.1111/j.1523-5378.2012.00948.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND The interest in non-antibiotic therapies for Helicobacter pylori infections in man has considerably grown because increasing numbers of antibiotic-resistant strains are being reported. Intervention at the stage of bacterial attachment to the gastric mucosa could be an approach to improve the control/eradication rate of this infection. MATERIALS AND METHODS Fractions of purified milk fat globule membrane glycoproteins were tested in vitro for their cytotoxic and direct antibacterial effect. The anti-adhesive effect on H. pylori was determined first in a cell model using the mucus-producing gastric epithelial cell line NCI-N87 and next in the C57BL/6 mouse model after dosing at 400 mg/kg protein once or twice daily from day -2 to day 4 post-infection. Bacterial loads were determined by using quantitative real-time PCR and the standard plate count method. RESULTS The milk fat globule membrane fractions did not show in vitro cytotoxicity, and a marginal antibacterial effect was demonstrated for defatted milk fat globule membrane at 256 μg/mL. In the anti-adhesion assay, the results varied from 56.0 ± 5.3% inhibition for 0.3% crude milk fat globule membrane to 79.3 ± 3.5% for defatted milk fat globule membrane. Quite surprisingly, in vivo administration of the same milk fat globule membrane fractions did not confirm the anti-adhesive effects and even caused an increase in bacterial load in the stomach. CONCLUSIONS The promising anti-adhesion in vitro results could not be confirmed in the mouse model, even after the highest attainable exposure. It is concluded that raw or defatted milk fat globule membrane fractions do not have any prophylactic or therapeutic potential against Helicobacter infection.
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Affiliation(s)
- Tessa Horemans
- Laboratory of Microbiology, Parasitology, and Hygiene-LMPH, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Abstract
INTRODUCTION Recently, pharmacotherapy has advanced extensively, but there are still many refractory diseases which cannot be solved fully by existing therapeutic agents. Therefore, alternative medicine and health foods are now attracting much attention, for example, lactoferrin (LF): a multifunctional glycoprotein. As LF is non-toxic and low-cost, its application in healthcare and therapeutics is expected to be widespread. AREAS COVERED In this review, LF's general basic features are described. The interaction of LF with its receptors activates the immune system, including cytokine production and balance. In particular, the immune activation of orally administered LF is considered as a new strategy for the treatment of refractory diseases, such as inflammatory bowel disease, virus infection and tumor metastasis. Also mentioned are the problems associated with the use of LF. As LF is degraded rapidly in the body due to enzymatic hydrolysis, high amounts or frequent dosing is required; an appropriate delivery system may improve these problems and increase its efficiency. EXPERT OPINION Chemical modifications, such as PEGylation, can enhance the stability of LF in the body, resulting in increased efficacy. Also, liposomes and enteric or microparticulate formulations can promote the function of LF in oral administration due to target site delivery and protection of LF from enzymatic hydrolysis. These delivery systems are expected to improve the utility of LF.
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Affiliation(s)
- Hiraku Onishi
- Hoshi University, Department of Drug Delivery Research, Ebara, Shinagawa-ku, Tokyo, Japan.
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Bovine antibody-based oral immunotherapy for reduction of intragastric Helicobacter pylori colonization: a randomized clinical trial. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2011; 25:207-13. [PMID: 21523262 DOI: 10.1155/2011/672093] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Antibiotic-based regimens are frequently used for the treatment of Helicobacter pylori infection. These regimens fail to eradicate H pylori in 15% to 40% of patients, primarily due to antimicrobial resistance and insufficient patient compliance. Effective prevention and eradication of H pylori by passive immunization with orally administered bovine antibodies has been demonstrated in animal studies, and may serve as an alternative therapy in humans. OBJECTIVE To study the efficacy and safety of orally administered bovine anti-H pylori antibodies for the reduction of intragastric bacterial load and eradication of H pylori in humans. METHODS Dairy cows were immunized against H pylori. After confirmation of the presence of anti-H pylori antibodies in the milk, the milk was subsequently processed into a whey protein concentrate (WPC). In a prospective, double-blind, placebo-controlled randomized clinical trial, H pylori-infected subjects were randomly assigned to treatment with the WPC preparation or placebo. Study medication was continued for 28 days; subjects were followed-up for 56 days. RESULTS Of the 30 subjects included, 27 completed the protocol. Of these 27 evaluable subjects, 14 were treated with WPC and 13 with placebo. There was no significant difference in urea breath test decrease between the WPC- and placebo-treated group (P=0.75). H pylori-associated gastritis and density were not significantly reduced in either group after treatment (P>0.05 for all). CONCLUSION Bovine antibody-based oral immunotherapy appears to be safe, but does not significantly reduce intragastric density in humans. Further studies are needed to determine whether WPC treatment has additional value to conventional antibiotic treatment for H pylori.
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El-Loly MM, Mahfouz MB. Lactoferrin in Relation to Biological Functions and Applications: A Review. ACTA ACUST UNITED AC 2011. [DOI: 10.3923/ijds.2011.79.111] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Watanabe T, Tsuge H, Imagawa T, Kise D, Hirano K, Beppu M, Takahashi A, Yamaguchi K, Fujiki H, Suganuma M. Nucleolin as cell surface receptor for tumor necrosis factor-alpha inducing protein: a carcinogenic factor of Helicobacter pylori. J Cancer Res Clin Oncol 2010; 136:911-21. [PMID: 20049476 DOI: 10.1007/s00432-009-0733-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Accepted: 11/13/2009] [Indexed: 12/16/2022]
Abstract
PURPOSE Tumor necrosis factor-alpha inducing protein (Tipalpha) is a unique carcinogenic factor released from Helicobacter pylori (H. pylori). Tipalpha specifically binds to cells and is incorporated into cytosol and nucleus, where it strongly induces expression of TNF-alpha and chemokine genes mediated through NF-kappaB activation, resulting in tumor development. To elucidate mechanism of action of Tipalpha, we studied a binding protein of Tipalpha in gastric epithelial cells. METHODS Tipalpha binding protein was found in cell lysates of mouse gastric cancer cell line MGT-40 by FLAG-pull down assay and identified to be cell surface nucleolin by flow cytometry using anti-nucleolin antibody. Incorporation of Tipalpha into the cells was determined by Western blotting and expression of TNF-alpha gene was quantified by RT-PCR. RESULTS Nucleolin was co-precipitated with Tipalpha-FLAG, but not with del-Tipalpha-FLAG (an inactive mutant). After treatment with Tipalpha-FLAG, incorporated Tipalpha was co-immunoprecipitated with endogenous nucleolin using anti-nucleolin antibody. The direct binding of Tipalpha to recombinant His-tagged nucleolin fragment (284-710) was also confirmed. Although nucleolin is an abundant non-ribosomal protein of the nucleolus, we found that nucleolin is present on the cell surface of MGT-40 cells. Pretreatment with anti-nucleolin antibody enhanced Tipalpha-incorporation into the cells through nucleolin internalization. In addition, pretreatment with tunicamycin, an inhibitor of N-glycosylation, decreased the amounts of cell surface nucleolin and inhibited both internalization of Tipalpha and expression of TNF-alpha gene. CONCLUSIONS All the results indicate that nucleolin acts as a receptor for Tipalpha and shuttles Tipalpha from cell surface to cytosol and nuclei. These findings provide a new mechanistic insight into gastric cancer development with Tipalpha.
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Affiliation(s)
- Tatsuro Watanabe
- Saitama Cancer Center, Research Institute for Clinical Oncology, Kitaadachi-gun, Saitama 362-0806, Japan
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Sachdeva A, Nagpal J. Meta-analysis: efficacy of bovine lactoferrin in Helicobacter pylori eradication. Aliment Pharmacol Ther 2009; 29:720-30. [PMID: 19183156 DOI: 10.1111/j.1365-2036.2009.03934.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Several randomized-controlled trials (RCTs) have sought to determine the efficacy of bovine lactoferrin in Helicobacter pylori eradication with equivocal results. AIM To evaluate the effect of bovine lactoferrin supplementation in H. pylori eradication. METHODS Electronic databases, reviews, bibliographies, abstracts and conference proceedings were searched. Included trials had to be randomized or quasi-randomized and controlled, using bovine lactoferrin in the intervention group, treating Helicobacter-infected subjects and evaluating eradication of H. pylori as an outcome. RESULTS The search identified five eligible RCTs (of 169). Data were available for 682 subjects (bovine lactoferrin group-n = 316; control group-n = 366). The pooled odds ratio (five studies) for eradication by intention-to-treat analysis was 2.22 (95% CI 1.44-3.44; P = 0.0003) using the fixed effects model (FEM) and 2.24 (95% CI 1.15-4.35; P = 0.0003) using the random effects model (REM) (Cochran's Q = 6.83; P = 0.145). The pooled risk difference was 0.11 (95% CI 0.05-0.16; P = 0.0001) by FEM (Cochran's Q = 6.67; P = 0.154) and 0.10 (95% CI 0.04-0.17; P = 0.0023) by REM. There was no significant difference in incidence of adverse effects. CONCLUSION Bovine lactoferrin potentially improves H. pylori eradication rates without any impact on adverse effects, but available evidence is limited and further research is necessary to confirm the findings.
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Affiliation(s)
- A Sachdeva
- Department of Clinical Epidemiology, Sitaram Bhartia Institute of Science and Research, New Delhi, India
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Jodlowski TZ, Lam S, Ashby CR. Emerging therapies for the treatment of Helicobacter pylori infections. Ann Pharmacother 2008; 42:1621-39. [PMID: 18845620 DOI: 10.1345/aph.1l234] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To describe emerging therapies, such as levofloxacin, moxifloxacin, rifabutin, rifaximin, tinidazole, doxycycline, minocycline, lactoferrin, and plaunotol for the eradication of Helicobacter pylori infection. DATA SOURCES Relevant information was identified through a search of MEDLINE (1966-July 2008), PubMed (1955-July 2008), American Search Premier (1975-July 2008), International Pharmaceutical Abstracts (1960-2008), Science Citation Index Expanded (1996-2008), Cochrane Databases (publications archived until July 2008), and various tertiary sources using the terms Helicobacter pylori, fluoroquinolones, levofloxacin, moxifloxacin, rifabutin, rifaximin, lactoferrin, plaunotol, tinidazole, doxycycline, minocycline, faropenem, new treatments, refractory, and salvage alone or in combination. STUDY SELECTION AND DATA EXTRACTION Relevant information was identified and selected based on clinical relevance and value of information. In vitro and in vivo data were included if available. DATA SYNTHESIS Data exist supporting the use of levofloxacin or rifabutin as salvage therapies for H. pylori infection. Levofloxacin triple therapy has been recommended in the current treatment guideline, but more data are needed, especially from studies conducted in the US. A rifabutin-based regimen is better tolerated than conventional quadruple therapy, but its use is limited due to cost, hematologic adverse effects, drug interactions, and predicted development of resistance. Tinidazole appears to be an option, particularly as sequential therapy when combined with other agents; however, its use is limited by the high prevalence of nitroimidazole-resistant H. pylori strains in the US. Moxifloxacin data are limited. Data supporting the use of rifaximin, doxycycline, and minocycline are lacking or do not show benefit of these drugs over standard treatments. CONCLUSIONS H. pylori infection remains one of the most significant infections worldwide, and treatment failure rate with the current standard therapy continues to rise. Other treatment options should be explored to meet the emerging challenge.
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Affiliation(s)
- Tomasz Z Jodlowski
- College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
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Abstract
In clinical practice the recommended treatment regimens achieve only an 80%Helicobacter pylori eradication rate and this rate is lower in patients who have failed first-line treatment. The increasing indications for H. pylori treatment (idiopathic thrombocytopenia and iron deficiency anemia) and an increasing trend of antibiotic resistance (especially in southern Europe) emphasize the need for more effective H. pylori eradication. Smoking and a short duration of treatment, especially in patients with functional dyspepsia, are predictors of eradication failure. In first line, the best option remains the clarithromycin-based regimens but an extended treatment duration is now indicated. Following first-line treatment failure, 14-day proton pump inhibitor triple therapy employing alternative antibiotics or quadruple therapy could be used. Levofloxacin-based 10-day triple therapy seems to be an encouraging strategy following one or more eradication failures.
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Affiliation(s)
- Lucas G Cavallaro
- Department of Clinical Sciences, Section of Gastroenterology, University of Parma, Parma, Italy
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