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Kawano M, Arai T, Kabuki T. Skim Milk Culture of Lactobacillus johnsonii SBT0309 Increases Intestinal Alkaline Phosphatase Activity and Inhibits Lipopolysaccharide-Induced Interleukin-8 Production in Intestinal Epithelial Cells. Cells 2025; 14:358. [PMID: 40072089 PMCID: PMC11898809 DOI: 10.3390/cells14050358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/26/2025] [Accepted: 02/27/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Intestinal alkaline phosphatase (IAP) is an enzyme expressed in the intestinal brush border, which may exert anti-inflammatory effects by detoxifying lipopolysaccharides (LPSs), thereby preventing metabolic disorders. Various food components have been reported to influence IAP activity. However, few studies have evaluated the effects of fermented milk on IAP activity. In this study, we aimed to investigate fermented milk with high IAP-activating capacity and investigate its effect. METHODS We screened a skim milk culture (SC), a fermented milk model, using differentiated Caco-2 cells. We investigated the effect of SC on IAP activity and gene expression in the Drosophila midgut. Quantitative PCR and immunoblot assays were conducted to examine gene and protein levels. RESULTS Among the SC samples from different lactic acid bacteria or bifidobacteria, the SC of Lactobacillus johnsonii SBT0309 (LJ0309 SC) demonstrated a particularly strong capacity to activate IAP in Caco-2 cells, demonstrated by significantly increased IAP gene expression and protein levels in Caco-2 cells. Additionally, LJ0309 SC inhibited increased secretion of IL-8 in LPS-stimulated Caco-2 cells. Finally, in Drosophila melanogaster fed LJ0309 SC, we observed an increase in both IAP activity and gene expression in the midgut. CONCLUSIONS LJ0309 SC increased IAP activity and gene expression in both Caco-2 cells and the Drosophila midgut, and inhibited the inflammatory response in LPS-stimulated Caco-2 cells. Although further in vivo studies are required, LJ0309 SC might help to ameliorate LPS-induced inflammation and disease via IAP activation.
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Affiliation(s)
- Michio Kawano
- Milk Science Research Institute, MEGMILK SNOW BRAND Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi, Saitama 350-1165, Japan
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Abramov VM, Kosarev IV, Machulin AV, Deryusheva EI, Priputnevich TV, Panin AN, Chikileva IO, Abashina TN, Manoyan AM, Ivanova OE, Papazyan TT, Nikonov IN, Suzina NE, Melnikov VG, Khlebnikov VS, Sakulin VK, Samoilenko VA, Gordeev AB, Sukhikh GT, Uversky VN, Karlyshev AV. Consortium of Lactobacillus crispatus 2029 and Ligilactobacillus salivarius 7247 Strains Shows In Vitro Bactericidal Effect on Campylobacter jejuni and, in Combination with Prebiotic, Protects Against Intestinal Barrier Dysfunction. Antibiotics (Basel) 2024; 13:1143. [PMID: 39766533 PMCID: PMC11672454 DOI: 10.3390/antibiotics13121143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/23/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives:Campylobacter jejuni (CJ) is the etiological agent of the world's most common intestinal infectious food-borne disease, ranging from mild symptoms to fatal outcomes. The development of innovative synbiotics that inhibit the adhesion and reproduction of multidrug-resistant (MDR) CJ in animals and humans, thereby preserving intestinal homeostasis, is relevant. We have created a synbiotic based on the consortium of Lactobacillus crispatus 2029 (LC2029), Ligilactobacillus salivarius 7247 (LS7247), and a mannan-rich prebiotic (Actigen®). The purpose of this work was to study the in vitro anti-adhesive and antagonistic activities of the created synbiotic against MDR CJ strains, along with its role in preventing intestinal barrier dysfunction, which disrupts intestinal homeostasis. Methods: A complex of microbiological, immunological, and molecular biological methods was used. The ability of the LC2029 and LS7247 consortium to promote intestinal homeostasis in vitro was assessed by the effectiveness of controlling CJ-induced TLR4 activation, secretion of pro-inflammatory cytokines, development of intestinal barrier dysfunction, and production of intestinal alkaline phosphatase (IAP). Results: All MDR CJ strains showed marked adhesion to human Caco-2, pig IPEC-J2, chicken CPCE, and bovine BPCE enterocytes. For the first time, we found that the prebiotic and cell-free culture supernatant (CFS) from the consortium of LC2029 and LS7247 strains exhibit an additive effect in inhibiting the adhesion of MDR strains of CJ to human and animal enterocytes. CFS from the LC2029 and LS7247 consortium increased the permeability of the outer and inner membranes of CJ cells, which led to extracellular leakage of ATP and provided access to the peptidoglycan of the pathogen for the peptidoglycan-degrading bacteriocins nisin and enterolysin A produced by LS7247. The LC2029 and LS7247 consortium showed a bactericidal effect on CJ strains. Co-cultivation of the consortium with CJ strains resulted in a decrease in the viability of the pathogen by 6 log. CFS from the LC2029 and LS7247 consortium prevented the growth of CJ-induced TLR4 mRNA expression in enterocytes. The LC2029 and LS7247 consortium inhibited a CJ-induced increase in IL-8 and TNF-α production in enterocytes, prevented CJ-induced intestinal barrier dysfunction, maintained the transepithelial electrical resistance of the enterocyte monolayers, and prevented an increase in intestinal paracellular permeability and zonulin secretion. CFS from the consortium stimulated IAP mRNA expression in enterocytes. The LC2029 and LS7247 consortium and the prebiotic Actigen represent a new synergistic synbiotic with anti-CJ properties that prevents intestinal barrier dysfunction and preserves intestinal homeostasis. Conclusions: These data highlight the potential of using a synergistic synbiotic as a preventive strategy for creating feed additives and functional nutrition products based on it to combat the prevalence of campylobacteriosis caused by MDR strains in animals and humans.
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Affiliation(s)
- Vyacheslav M. Abramov
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Igor V. Kosarev
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Andrey V. Machulin
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia
| | - Evgenia I. Deryusheva
- Institute for Biological Instrumentation, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia
| | - Tatiana V. Priputnevich
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Alexander N. Panin
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
| | - Irina O. Chikileva
- Blokhin National Research Center of Oncology, Ministry of Health, 115478 Moscow, Russia;
| | - Tatiana N. Abashina
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia
| | - Ashot M. Manoyan
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
| | - Olga E. Ivanova
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
| | | | - Ilia N. Nikonov
- Federal State Budgetary Educational Institution of Higher Education, St. Petersburg State University of Veterinary Medicine, 196084 Saint Petersburg, Russia
| | - Nataliya E. Suzina
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia
| | - Vyacheslav G. Melnikov
- Gabrichevsky Research Institute for Epidemiology and Microbiology, 125212 Moscow, Russia
| | | | - Vadim K. Sakulin
- Institute of Immunological Engineering, 142380 Lyubuchany, Russia
| | - Vladimir A. Samoilenko
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia
| | - Alexey B. Gordeev
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Gennady T. Sukhikh
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Vladimir N. Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
| | - Andrey V. Karlyshev
- Department of Biomolecular Sciences, School of Life Sciences, Chemistry and Pharmacy, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston upon Thames KT1 2EE, UK;
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Machulin AV, Abramov VM, Kosarev IV, Deryusheva EI, Priputnevich TV, Panin AN, Manoyan AM, Chikileva IO, Abashina TN, Blumenkrants DA, Ivanova OE, Papazyan TT, Nikonov IN, Suzina NE, Melnikov VG, Khlebnikov VS, Sakulin VK, Samoilenko VA, Gordeev AB, Sukhikh GT, Uversky VN, Karlyshev AV. A Novel Bifidobacterium longum Subsp. longum T1 Strain from Cow's Milk: Homeostatic and Antibacterial Activity against ESBL-Producing Escherichia coli. Antibiotics (Basel) 2024; 13:924. [PMID: 39452191 PMCID: PMC11505560 DOI: 10.3390/antibiotics13100924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 09/20/2024] [Accepted: 09/25/2024] [Indexed: 10/26/2024] Open
Abstract
Background/Objectives: The global emergence of antibiotic-resistant zooanthroponotic Escherichia coli strains, producing extended-spectrum beta-lactamases (ESBL-E) and persisting in the intestines of farm animals, has now led to the development of a pandemic of extra-intestinal infectious diseases in humans. The search for innovative probiotic microorganisms that eliminate ESBL-E from the intestines of humans and animals is relevant. Previously, we received three isolates of bifidobacteria: from milk of a calved cow (BLLT1), feces of a newborn calf (BLLT2) and feces of a three-year-old child who received fresh milk from this calved cow (BLLT3). Our goal was to evaluate the genetic identity of BLLT1, BLLT2, BLLT3 isolates using genomic DNA fingerprinting (GDF), to study the tolerance, adhesion, homeostatic and antibacterial activity of BLLT1 against ESBL-E. Methods: We used a complex of microbiological, molecular biological, and immunological methods, including next generation sequencing (NGS). Results: GDF showed that DNA fragments of BLLT2 and BLLT3 isolates were identical in number and size to DNA fragments of BLLT1. These data show for the first time the possibility of natural horizontal transmission of BLLT1 through with the milk of a calved cow into the intestines of a calf and the intestines of a child. BLLT1 was resistant to gastric and intestinal stresses and exhibited high adhesive activity to calf, pig, chicken, and human enterocytes. This indicates the unique ability of BLLT1 to inhabit the intestines of animals and humans. We are the first to show that BLLT1 has antibacterial activity against ESBL-E strains that persist in humans and animals. BLLT1 produced 145 ± 8 mM of acetic acid, which reduced the pH of the nutrient medium from 6.8 to 5.2. This had an antibacterial effect on ESBL-E. The genome of BLLT1 contains ABC-type carbohydrate transporter gene clusters responsible for the synthesis of acetic acid with its antibacterial activity against ESBL-E. BLLT1 inhibited TLR4 mRNA expression induced by ESBL-E in HT-29 enterocytes, and protected the enterocyte monolayers used in this study as a bio-model of the intestinal barrier. BLLT1 increased intestinal alkaline phosphatase (IAP) as one of the main molecular factors providing intestinal homeostasis. Conclusions: BLLT1 shows promise for the creation of innovative functional nutritional products for humans and feed additives for farm animals that will reduce the spread of ESBL-E strains in the food chain.
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Affiliation(s)
- Andrey V. Machulin
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia (N.E.S.)
| | - Vyacheslav M. Abramov
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Igor V. Kosarev
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Evgenia I. Deryusheva
- Institute for Biological Instrumentation, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia
| | - Tatiana V. Priputnevich
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Alexander N. Panin
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
| | - Ashot M. Manoyan
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
| | - Irina O. Chikileva
- Blokhin National Research Center of Oncology, Ministry of Health, 115478 Moscow, Russia
| | - Tatiana N. Abashina
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia (N.E.S.)
| | - Dmitriy A. Blumenkrants
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
| | - Olga E. Ivanova
- Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Federal State Budgetary Institution “The Russian State Center for Animal Feed and Drug Standardization and Quality” (FGBU VGNKI), 123022 Moscow, Russia
| | | | - Ilia N. Nikonov
- Federal State Budgetary Educational Institution of Higher Education, St. Petersburg State University of Veterinary Medicine, 196084 Saint Petersburg, Russia
| | - Nataliya E. Suzina
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia (N.E.S.)
| | - Vyacheslav G. Melnikov
- Gabrichevsky Research Institute for Epidemiology and Microbiology, 125212 Moscow, Russia
| | | | - Vadim K. Sakulin
- Institute of Immunological Engineering, 142380 Lyubuchany, Russia
| | - Vladimir A. Samoilenko
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of Russian Academy of Science”, Russian Academy of Science, 142290 Pushchino, Russia (N.E.S.)
| | - Alexey B. Gordeev
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Gennady T. Sukhikh
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health, 117997 Moscow, Russia; (T.V.P.); (A.B.G.)
| | - Vladimir N. Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
| | - Andrey V. Karlyshev
- Department of Biomolecular Sciences, School of Life Sciences, Chemistry and Pharmacy, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston upon Thames KT1 2EE, UK;
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Mustafa MN, Channar PA, Sarfraz M, Saeed A, Ejaz SA, Aziz M, Alasmary FA, Alsoqair HY, Raza H, Kim SJ, Hamad A. Synthesis, kinetic studies and in-silico investigations of novel quinolinyl-iminothiazolines as alkaline phosphatase inhibitors. J Enzyme Inhib Med Chem 2023; 38:2163394. [PMID: 36629454 PMCID: PMC9848371 DOI: 10.1080/14756366.2022.2163394] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Deposition of hydroxyapatite (HA) or alkaline phosphate crystals on soft tissues causes the pathological calcification diseases comprising of end-stage osteoarthritis (OA), ankylosing spondylitis (AS), medial artery calcification and tumour calcification. The pathological calcification is symbolised by increased concentration of tissue non-specific alkaline phosphatase (TNAP). An efficient therapeutic strategy to eradicate these diseases is required, and for this the alkaline phosphatase inhibitors can play a potential role. In this context a series of novel quinolinyl iminothiazolines was synthesised and evaluated for alkaline phosphatase inhibition potential. All the compounds were subjected to DFT studies where N-benzamide quinolinyl iminothiazoline (6g), N-dichlorobenzamide quinolinyl iminothiazoline (6i) and N-nitrobenzamide quinolinyl iminothiazoline (6j) were found as the most reactive compounds. Then during the in-vitro testing, the compound N-benzamide quinolinyl iminothiazoline (6g) exhibited the maximum alkaline phosphatase inhibitory effect (IC50 = 0.337 ± 0.015 µM) as compared to other analogues and standard KH2PO4 (IC50 = 5.245 ± 0.477 µM). The results were supported by the molecular docking studies, molecular dynamics simulations and kinetic analysis which also revealed the inhibitory potential of compound N-benzamide quinolinyl iminothiazoline (6g) against alkaline phosphatase. This compound can be act as lead molecule for the synthesis of more effective inhibitors and can be suggested to test at the molecular level.
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Affiliation(s)
| | - Pervaiz Ali Channar
- Department of Basic sciences and Humanities, Dawood University of Engineering and Technology, Karachi, Pakistan
| | - Muhammad Sarfraz
- College of Pharmacy, Al Ain Campus, Al Ain University, Al Ain, United Arab Emirates
| | - Aamer Saeed
- Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan,Aamer Saeed Department of Chemistry, Quaid-i-Azam University-45320, Islamabad, Pakistan
| | - Syeda Abida Ejaz
- Department of Pharmaceutical Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan,CONTACT Syeda Abida Ejaz Department of Pharmaceutical Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Mubashir Aziz
- Department of Pharmaceutical Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Fatmah Ali Alasmary
- Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Hanadi Yaqob Alsoqair
- Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Hussain Raza
- Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea
| | - Song Ja Kim
- Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea
| | - Asad Hamad
- Faculty of Pharmacy, Grand Asian University Sialkot, Sialkot, Pakistan
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Dissanayake WMN, Chandanee MR, Lee SM, Heo JM, Yi YJ. Change in intestinal alkaline phosphatase activity is a hallmark of antibiotic-induced intestinal dysbiosis. Anim Biosci 2023; 36:1403-1413. [PMID: 37170509 PMCID: PMC10472154 DOI: 10.5713/ab.23.0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/08/2023] [Accepted: 04/07/2023] [Indexed: 05/13/2023] Open
Abstract
OBJECTIVE Intestinal alkaline phosphatase (IAP) maintains intestinal homeostasis by detoxifying bacterial endotoxins and regulating gut microbiota, and lipid absorption. Antibiotics administered to animals can cause gut dysbiosis and barrier disruption affecting animal health. Therefore, the present study sought to investigate the role of IAP in the intestinal environment in dysbiosis. METHODS Young male mice aged 9 weeks were administered a high dose of antibiotics to induce dysbiosis. They were then sacrificed after 4 weeks to collect the serum and intestinal organs. The IAP activity in the ileum and the level of cytokines in the serum samples were measured. Quantitative real-time polymerase chain reaction analysis of RNA from the intestinal samples was performed using primers for tight junction proteins (TJPs) and proinflammatory cytokines. The relative intensity of IAP and toll-like receptor 4 (TLR4) in intestinal samples was evaluated by western blotting. RESULTS The IAP activity was significantly lower in the ileum samples of the dysbiosisinduced group compared to the control. The interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha concentrations were significantly higher in the ileum samples of the dysbiosis-induced group. The RNA expression levels of TJP2, claudin-3, and claudin-11 showed significantly lower values in the intestinal samples from the dysbiosis-induced mice. Results from western blotting revealed that the intensity of IAP expression was significantly lower in the ileum samples of the dysbiosis-induced group, while the intensity of TLR4 expression was significantly higher compared to that of the control group without dysbiosis. CONCLUSION The IAP activity and relative mRNA expression of the TJPs decreased, while the levels of proinflammatory cytokines increased, which can affect intestinal integrity and the function of the intestinal epithelial cells. This suggests that IAP is involved in mediating the intestinal environment in dysbiosis induced by antibiotics and is an enzyme that can potentially be used to maintain the intestinal environment in animal health care.
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Affiliation(s)
| | - Malavige Romesha Chandanee
- Department of Agricultural Education, College of Education, Sunchon National University, Suncheon 57922,
Korea
| | - Sang-Myeong Lee
- Laboratory of Veterinary Virology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644,
Korea
| | - Jung Min Heo
- College of Agriculture and Life Sciences, Department of Animal Science and Biotechnology, Chungnam National University, Daejeon 34134,
Korea
| | - Young-Joo Yi
- Department of Agricultural Education, College of Education, Sunchon National University, Suncheon 57922,
Korea
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Araújo JR, Serafim T, Ismael S, Calhau C, Faria A, Teixeira D. Intestinal Alkaline Phosphatase Activity and Efficiency Are Altered in Severe COVID-19 Patients. GASTRO HEP ADVANCES 2023; 2:911-917. [PMID: 39130768 PMCID: PMC11307804 DOI: 10.1016/j.gastha.2023.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 07/11/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Although gut inflammation and dysbiosis have been implicated in the pathophysiology of severe cases of coronavirus disease 2019 (COVID-19), the role of intestinal anti-inflammatory enzymes, such as alkaline phosphatase, is still underexplored. Therefore, the aim of this study was to compare intestinal alkaline phosphatase (iALP) activity and its proinflammatory substrate - bacterial lipopolysaccharide (LPS) - concentration between mild-to-moderate and severe COVID-19 patients. Methods Stool samples collected from 53 mild-to-moderate and 57 severe adult COVID-19 patients, previously enrolled in a national multicentre cross-sectional study (NCT04355741), were analysed for iALP activity and LPS concentration. Results iALP activity decreased by 40% in severe compared to mild-to-moderate COVID-19 patients (median [interquartile range] of 120.6 [25.2-593.1] nmol pNP/min/g of protein vs 202.8 [102.1-676.1] nmol pNP/min/g of protein; P = .04) after adjustment for clinical and gut microbiota parameters. Regarding fecal LPS, its concentration was found to be decreased in severe patients (mean ± standard error of mean of 18,118 ± 1225 EU/g of feces vs 22,508 ± 1203 EU/g of feces; P = .01), although this parameter did not correlate with plasma levels of C-reactive protein (P = .08), a sensitive biomarker of systemic inflammation. In contrast, fecal ALP activity / LPS concentration ratio, an indicator of iALP efficiency, was found to be increased in severe compared to mild-to-moderate COVID-19 patients (P = .04). Conclusion Changes in iALP kinetic parameters found in severe COVID-19 patients may represent a potential mechanism to counterbalance alterations in gut homeostasis (eg inflammation and dysbiosis) associated with COVID-19 severity.
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Affiliation(s)
- João R. Araújo
- Nutrition & Metabolism Department, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
- Nutrition & Metabolism, CINTESIS@RISE, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Thainá Serafim
- Nutrition & Metabolism Department, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Shámila Ismael
- Nutrition & Metabolism Department, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
- Nutrition & Metabolism, CINTESIS@RISE, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
- CHRC, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Conceição Calhau
- Nutrition & Metabolism Department, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
- Nutrition & Metabolism, CINTESIS@RISE, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Ana Faria
- Nutrition & Metabolism Department, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
- Nutrition & Metabolism, CINTESIS@RISE, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
- CHRC, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Diana Teixeira
- Nutrition & Metabolism Department, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
- Nutrition & Metabolism, CINTESIS@RISE, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
- CHRC, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
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Jassas RS, Naeem N, Sadiq A, Mehmood R, Alenazi NA, Al-Rooqi MM, Mughal EU, Alsantali RI, Ahmed SA. Current status of N-, O-, S-heterocycles as potential alkaline phosphatase inhibitors: a medicinal chemistry overview. RSC Adv 2023; 13:16413-16452. [PMID: 37274413 PMCID: PMC10233329 DOI: 10.1039/d3ra01888a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/24/2023] [Indexed: 06/06/2023] Open
Abstract
Heterocycles are a class of compounds that have been found to be potent inhibitors of alkaline phosphatase (AP), an enzyme that plays a critical role in various physiological processes such as bone metabolism, cell growth and differentiation, and has been linked to several diseases such as cancer and osteoporosis. AP is a widely distributed enzyme, and its inhibition has been considered as a therapeutic strategy for the treatment of these diseases. Heterocyclic compounds have been found to inhibit AP by binding to the active site of the enzyme, thereby inhibiting its activity. Heterocyclic compounds such as imidazoles, pyrazoles, and pyridines have been found to be potent AP inhibitors and have been studied as potential therapeutics for the treatment of cancer, osteoporosis, and other diseases. However, the development of more potent and selective inhibitors that can be used as therapeutics for the treatment of various diseases is an ongoing area of research. Additionally, the study of the mechanism of action of heterocyclic AP inhibitors is an ongoing area of research, which could lead to the identification of new targets and new therapeutic strategies. The enzyme known as AP has various physiological functions and is present in multiple tissues and organs throughout the body. This article presents an overview of the different types of AP isoforms, their distribution, and physiological roles. It also discusses the structure and mechanism of AP, including the hydrolysis of phosphate groups. Furthermore, the importance of AP as a clinical marker for liver disease, bone disorders, and cancer is emphasized, as well as its use in the diagnosis of rare inherited disorders such as hypophosphatasia. The potential therapeutic applications of AP inhibitors for different diseases are also explored. The objective of this literature review is to examine the function of alkaline phosphatase in various physiological conditions and diseases, as well as analyze the structure-activity relationships of recently reported inhibitors. The present review summarizes the structure-activity relationship (SAR) of various heterocyclic compounds as AP inhibitors. The SAR studies of these compounds have revealed that the presence of a heterocyclic ring, particularly a pyridine, pyrimidine, or pyrazole ring, in the molecule is essential for inhibitory activity. Additionally, the substitution pattern and stereochemistry of the heterocyclic ring also play a crucial role in determining the potency of the inhibitor.
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Affiliation(s)
- Rabab S Jassas
- Department of Chemistry, Jamoum University College, Umm Al-Qura University Makkah 21955 Saudi Arabia
| | - Nafeesa Naeem
- Department of Chemistry, University of Gujrat Gujrat 50700 Pakistan
| | - Amina Sadiq
- Department of Chemistry, Govt. College Women University Sialkot 51300 Pakistan
| | - Rabia Mehmood
- Department of Chemistry, Govt. College Women University Sialkot 51300 Pakistan
| | - Noof A Alenazi
- Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University Al-kharj 11942 Saudi Arabia
| | - Munirah M Al-Rooqi
- Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University 21955 Makkah Saudi Arabia
| | | | - Reem I Alsantali
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University P.O. Box 11099 Taif 21944 Saudi Arabia
| | - Saleh A Ahmed
- Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University 21955 Makkah Saudi Arabia
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8
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Matzaras R, Nikopoulou A, Protonotariou E, Christaki E. Gut Microbiota Modulation and Prevention of Dysbiosis as an Alternative Approach to Antimicrobial Resistance: A Narrative Review. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2022; 95:479-494. [PMID: 36568836 PMCID: PMC9765331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Background: The importance of gut microbiota in human health is being increasingly studied. Imbalances in gut microbiota have been associated with infection, inflammation, and obesity. Antibiotic use is the most common and significant cause of major alterations in the composition and function of the gut microbiota and can result in colonization with multidrug-resistant bacteria. Methods: The purpose of this review is to present existing evidence on how microbiota modulation and prevention of gut dysbiosis can serve as tools to combat antimicrobial resistance. Results: While the spread of antibiotic-resistant pathogens requires antibiotics with novel mechanisms of action, the number of newly discovered antimicrobial classes remains very low. For this reason, the application of alternative modalities to combat antimicrobial resistance is necessary. Diet, probiotics/prebiotics, selective oropharyngeal or digestive decontamination, and especially fecal microbiota transplantation (FMT) are under investigation with FMT being the most studied. But, as prevention is better than cure, the implementation of antimicrobial stewardship programs and strict infection control measures along with newly developed chelating agents could also play a crucial role in decreasing colonization with multidrug resistant organisms. Conclusion: New alternative tools to fight antimicrobial resistance via gut microbiota modulation, seem to be effective and should remain the focus of further research and development.
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Affiliation(s)
- Rafail Matzaras
- Infectious Diseases Unit, Department of Medicine,
University General Hospital of Ioannina, University of Ioannina, Ioannina,
Greece
| | - Anna Nikopoulou
- Department of Internal Medicine, G. Papanikolaou
General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Efthimia Protonotariou
- Department of Microbiology, AHEPA University Hospital,
Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eirini Christaki
- Infectious Diseases Unit, Department of Medicine,
University General Hospital of Ioannina, University of Ioannina, Ioannina,
Greece,To whom all correspondence should be addressed:
Eirini Christaki, University General Hospital of Ioannina, St. Niarchou,
Ioannina, Greece; ; ORCID:
https://www.orcid.org/0000-0002-8152-6367
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9
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Wu H, Wang Y, Li H, Meng L, Zheng N, Wang J. Protective Effect of Alkaline Phosphatase Supplementation on Infant Health. Foods 2022; 11:foods11091212. [PMID: 35563935 PMCID: PMC9101100 DOI: 10.3390/foods11091212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/13/2022] [Accepted: 04/13/2022] [Indexed: 12/03/2022] Open
Abstract
Alkaline phosphatase (ALP) is abundant in raw milk. Because of its high heat resistance, ALP negative is used as an indicator of successful sterilization. However, pasteurized milk loses its immune protection against allergy. Clinically, ALP is also used as an indicator of organ diseases. When the activity of ALP in blood increases, it is considered that diseases occur in viscera and organs. Oral administration or injecting ALP will not cause harm to the body and has a variety of probiotic effects. For infants with low immunity, ALP intake is a good prebiotic for protecting the infant’s intestine from potential pathogenic bacteria. In addition, ALP has a variety of probiotic effects for any age group, including prevention and treatment intestinal diseases, allergies, hepatitis, acute kidney injury (AKI), diabetes, and even the prevention of aging. The prebiotic effects of alkaline phosphatase on the health of infants and consumers and the content of ALP in different mammalian raw milk are summarized. The review calls on consumers and manufacturers to pay more attention to ALP, especially for infants with incomplete immune development. ALP supplementation is conducive to the healthy growth of infants.
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Affiliation(s)
- Haoming Wu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (J.W.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Yang Wang
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China;
| | - Huiying Li
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (J.W.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Lu Meng
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (J.W.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Nan Zheng
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (J.W.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Correspondence: ; Tel.: +86-10-62816069
| | - Jiaqi Wang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.W.); (H.L.); (L.M.); (J.W.)
- Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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10
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Huang S, Rong X, Liu M, Liang Z, Geng Y, Wang X, Zhang J, Ji C, Zhao L, Ma Q. Intestinal Mucosal Immunity-Mediated Modulation of the Gut Microbiome by Oral Delivery of Enterococcus faecium Against Salmonella Enteritidis Pathogenesis in a Laying Hen Model. Front Immunol 2022; 13:853954. [PMID: 35371085 PMCID: PMC8967290 DOI: 10.3389/fimmu.2022.853954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/15/2022] [Indexed: 12/22/2022] Open
Abstract
Enterococcus faecium (E. faecium) is a protective role that has crucial beneficial functions on intestinal homeostasis. This study aimed to investigate the effects of E. faecium on the laying performance, egg quality, host metabolism, intestinal mucosal immunity, and gut microbiota of laying hens under the Salmonella Enteritidis (S. Enteritidis) challenge. A total of 400 45-week-old laying hens were randomly divided into four treatments (CON, EF, SCON, and SEF groups) with five replicates for each group and 20 hens per replicate and fed with a basal diet or a basal diet supplemented with E. faecium (2.5 × 108 cfu/g feed). The experiment comprised two phases, consisting of the pre-salmonella challenged phase (from day 14 to day 21) and the post-salmonella challenged phase (from day 21 to day 42). At day 21 and day 22, the hens in SCON and SEF groups were orally challenged with 1.0 ml suspension of 109 cfu/ml S. Enteritidis (CVCC3377) daily, whereas the hens in CON and EF groups received the same volume of sterile PBS. Herein, our results showed that E. faecium administration significantly improved egg production and shell thickness during salmonella infection. Also, E. faecium affected host lipid metabolism parameters via downregulating the concentration of serum triglycerides, inhibited oxidative stress, and enhanced immune functions by downregulating the level of serum malondialdehyde and upregulating the level of serum immunoglobulin G. Of note, E. faecium supplementation dramatically alleviated intestinal villi structure injury and crypt atrophy, and improved intestinal mucosal barrier injuries caused by S. Enteritidis challenge. Moreover, our data revealed that E. faecium supplementation ameliorated S. Enteritidis infection-induced gut microbial dysbiosis by altering the gut microbial composition (reducing Bacteroides, Desulfovibrio, Synergistes, and Sutterella, and increasing Barnesiella, Butyricimonas, Bilophila, and Candidatus_Soleaferrea), and modulating the gut microbial function, such as cysteine and methionine metabolism, pyruvate metabolism, fatty acid metabolism, tryptophan metabolism, salmonella infection, and the PI3K-Akt signaling pathway. Taken together, E. faecium has a strong capacity to inhibit the S. Enteritidis colonization of hens. The results highlight the potential of E. faecium supplementation as a dietary supplement to combat S. Enteritidis infection in animal production and to promote food safety.
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Affiliation(s)
- Shimeng Huang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Xiaoping Rong
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Meiling Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Zhongjun Liang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yanqiang Geng
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China.,Poultry Mineral Nutrition Laboratory, College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Xinyue Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Jianyun Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Cheng Ji
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Lihong Zhao
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Qiugang Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
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11
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Intestinal Alkaline Phosphatase: A Review of This Enzyme Role in the Intestinal Barrier Function. Microorganisms 2022; 10:microorganisms10040746. [PMID: 35456797 PMCID: PMC9026380 DOI: 10.3390/microorganisms10040746] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023] Open
Abstract
Intestinal alkaline phosphatase (IALP) has recently assumed a special relevance, being the subject of study in the prevention and treatment of certain diseases related to leaky gut. This brush border enzyme (ecto-enzyme) plays an important role in the maintenance of intestinal microbial homeostasis and intestinal barrier function through its ability to dephosphorylate lipopolysaccharide (LPS). This review addresses how IALP and intestinal barrier dysfunction may be implicated in the pathophysiology of specific diseases such as inflammatory bowel disease, necrotizing enterocolitis, and metabolic syndrome. The use of IALP as a possible biomarker to assess intestinal barrier function and strategies to modulate IALP activity are also discussed.
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12
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Li C, Wang G, Zhang Q, Huang Y, Li F, Wang W. Developmental changes of nutrient digestion in young lambs are influenced by weaning and associated with intestinal microbiota. Anim Biotechnol 2022:1-15. [PMID: 35085474 DOI: 10.1080/10495398.2022.2025817] [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] [Indexed: 12/13/2022]
Abstract
Understanding the effects of weaning on the changes of digestive function could help to design efficient intervention strategies for promoting the development of the lamb during the early stages of life. In this study, 24 lambs were divided into two groups (control group, lambs were not weaned; and weaning group, lambs were weaned at 21 days of age). The growth, nutrient digestion, gastrointestinal enzyme activity, plasma biochemical indicators, and intestinal microbiota at 7-49 days were determined, as well as the impact of early weaning. The nutrient digestion changed rapidly with age, especially at 14-28 days (p < 0.05). Weaning reduced the dry matter (DM), crude protein (CP), and ether extract (EE) intake and digestion, but increased the starch, neutral detergent fiber (NDF), and acid detergent fiber (ADF) intake and digestion (p < 0.05). Weaning did not affect the overall jejunal microbiota (p > 0.05), but affected the relative abundance of certain bacteria taxa (p < 0.05). Lactic acid-producing bacteria, such as Olsenella, Bacillus, Sharpea, and Bifidobacterium are closely related to CP or EE digestion and growth performance (p < 0.05). In summary, we delineated the pattern of nutrient digestion and intestinal microbiota development in young lambs, and the impact of early weaning.
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Affiliation(s)
- Chong Li
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China.,State Key Laboratory of Grassland Agro-Ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China
| | - Guoxiu Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Qian Zhang
- Institute of Grassland Research of CAAS, Chinese Academy of Agricultural Sciences, Hohhot, China
| | - Yongliang Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Fadi Li
- State Key Laboratory of Grassland Agro-Ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China
| | - Weimin Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
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13
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Giacomodonato MN, Sarnacki SH, Aya Castañeda MDR, Garófalo AN, Betancourt DM, Cerquetti MC, Noto Llana M. Salmonella enterica serovar Enteritidis biofilm lifestyle induces lower pathogenicity and reduces inflammatory response in a murine model compared to planktonic bacteria. Rev Argent Microbiol 2021; 54:166-174. [PMID: 34961640 DOI: 10.1016/j.ram.2021.10.003] [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: 04/02/2021] [Revised: 06/28/2021] [Accepted: 10/04/2021] [Indexed: 12/23/2022] Open
Abstract
Salmonellaenterica serovar Enteritidis (S. Enteritidis) is the most frequent serovar involved in human salmonellosis. It has been demonstrated that about 80% of infections are related to biofilm formation. There is scant information about the pathogenicity of S. Enteritidis and its relationship to biofilm production. In this regard, this study aimed to investigate the differential host response induced by S. Enteritidis biofilm and planktonic lifestyle. To this purpose, biofilm and planktonic bacteria were inoculated to BALB/c mice and epithelial cell culture. Survival studies revealed that biofilm is less virulent than planktonic cells. Reduced signs of intestinal inflammation and lower bacterial translocation were observed in animals inoculated with Salmonella biofilm compared to the planktonic group. Results showed that Salmonella biofilm was impaired for invasion of non-phagocytic cells and induces a lower inflammatory response in vivo and in vitro compared to that of planktonic bacteria. Taken together, the outcome of Salmonella-host interaction varies depending on the bacterial lifestyle.
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Affiliation(s)
- Mónica N Giacomodonato
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM-UBA-CONICET), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Sebastián H Sarnacki
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM-UBA-CONICET), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Del Rosario Aya Castañeda
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM-UBA-CONICET), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ailín N Garófalo
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM-UBA-CONICET), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diana M Betancourt
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM-UBA-CONICET), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María C Cerquetti
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM-UBA-CONICET), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mariángeles Noto Llana
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM-UBA-CONICET), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
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14
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Singh SB, Lin HC. Role of Intestinal Alkaline Phosphatase in Innate Immunity. Biomolecules 2021; 11:biom11121784. [PMID: 34944428 PMCID: PMC8698947 DOI: 10.3390/biom11121784] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/23/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022] Open
Abstract
Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel disease IBD, necrotizing enterocolitis, and metabolic syndrome and that exogenous IAP supplementation improves the outcomes associated with these disorders. Additionally, studies using transgenic IAP-knock out (IAP-KO) mouse models further support the importance of the defensive role of IAP in the intestine. Supplementation of exogenous IAP and cellular overexpression of IAP have also been used in vitro to dissect out the downstream mechanisms of this protein in mammalian cell lines. Some of the innate immune functions of IAP include lipopolysaccharide (LPS) detoxification, protection of gut barrier integrity, regulation of gut microbial communities and its anti-inflammatory roles. A novel function of IAP recently identified is the induction of autophagy. Due to its critical role in the gut physiology and its excellent safety profile, IAP has been used in phase 2a clinical trials for treating conditions such as sepsis-associated acute kidney injury. Many excellent reviews discuss the role of IAP in physiology and pathophysiology and here we extend these to include recent updates on this important host defense protein and discuss its role in innate immunity via its effects on bacteria as well as on host cells. We will also discuss the relationship between IAP and autophagy and how these two pathways may act in concert to protect the gut.
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Affiliation(s)
- Sudha B. Singh
- Biomedical Research Institute of New Mexico, Albuquerque, NM 87108, USA;
| | - Henry C. Lin
- Medicine Service, New Mexico VA Health Care System, Albuquerque, NM 87108, USA
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
- Correspondence:
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15
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Kühn F, Duan R, Ilmer M, Wirth U, Adiliaghdam F, Schiergens TS, Andrassy J, Bazhin AV, Werner J. Targeting the Intestinal Barrier to Prevent Gut-Derived Inflammation and Disease: A Role for Intestinal Alkaline Phosphatase. Visc Med 2021; 37:383-393. [PMID: 34722721 DOI: 10.1159/000515910] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/16/2021] [Indexed: 02/02/2023] Open
Abstract
Background Intestinal alkaline phosphatase (IAP) as a tissue-specific isozyme of alkaline phosphatases is predominantly produced by enterocytes in the proximal small intestine. In recent years, an increasing number of pathologies have been identified to be associated with an IAP deficiency, making it very worthwhile to review the various roles, biological functions, and potential therapeutic aspects of IAP. Summary IAP primarily originates and acts in the intestinal tract but affects other organs through specific biological axes related to its fundamental roles such as promoting gut barrier function, dephosphorylation/detoxification of lipopolysaccharides (LPS), and regulation of gut microbiota. Key Messages Numerous studies reporting on the different roles and the potential therapeutic value of IAP across species have been published during the last decade. While IAP deficiency is linked to varying degrees of physiological dysfunctions across multiple organ systems, the supplementation of IAP has been proven to be beneficial in several translational and clinical studies. The increasing evidence of the salutary functions of IAP underlines the significance of the naturally occurring brush border enzyme.
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Affiliation(s)
- Florian Kühn
- Department of General, Visceral and Transplant Surgery, University Hospital of LMU Munich, Munich, Germany
| | - Ruifeng Duan
- Department of General, Visceral and Transplant Surgery, University Hospital of LMU Munich, Munich, Germany
| | - Matthias Ilmer
- Department of General, Visceral and Transplant Surgery, University Hospital of LMU Munich, Munich, Germany
| | - Ulrich Wirth
- Department of General, Visceral and Transplant Surgery, University Hospital of LMU Munich, Munich, Germany
| | - Fatemeh Adiliaghdam
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tobias S Schiergens
- Department of General, Visceral and Transplant Surgery, University Hospital of LMU Munich, Munich, Germany
| | - Joachim Andrassy
- Department of General, Visceral and Transplant Surgery, University Hospital of LMU Munich, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral and Transplant Surgery, University Hospital of LMU Munich, Munich, Germany
| | - Jens Werner
- Department of General, Visceral and Transplant Surgery, University Hospital of LMU Munich, Munich, Germany
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16
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Wu H, Wang Y, Yao Q, Fan L, Meng L, Zheng N, Li H, Wang J. Alkaline phosphatase attenuates LPS-induced liver injury by regulating the miR-146a-related inflammatory pathway. Int Immunopharmacol 2021; 101:108149. [PMID: 34634739 DOI: 10.1016/j.intimp.2021.108149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/09/2021] [Accepted: 09/07/2021] [Indexed: 11/27/2022]
Abstract
Lipopolysaccharide (LPS) can remain in dairy products after the sterilization of milk powder and may pose a threat to the health of infants and young children. There is a large amount of alkaline phosphatase (ALP) in raw milk, which can remove the phosphate bond of LPS, thus, detoxifying it. ALP is regarded as an indicator of the success of milk sterilization due to its strong heat resistance. ALP can alleviate the toxicity of LPS in enteritis and nephritis models, but the mechanism by which oral-intake of ALP protects liver tissue from LPS stimulation is unclear. In this study, an in vivo acute mouse liver injury model was induced by C. sakazakii LPS (200 μg/kg) and used to verify the protective mechanism of ALP (200 U/kg) on mice livers. The related pathways were also verified by in vitro cell culture. Enzyme linked immunosorbent assays (ELISAs), quantitative reverse transcription PCR (RT-qPCR) and western blotting were used to detect the levels of inflammatory factors at the protein level and RNA level, and to confirm the inflammation of liver tissue caused by LPS. ALP was found to alleviate acute liver injury in vitro by activating miR-146a. We found that ALP could up-regulate the level of miR146a and subsequently alleviates the expression of TLR4, TNF-α, matured IL-1β, and NF-κB in mouse liver tissue and hepatocytes; thus, reducing liver inflammation. Herein, we demonstrated for the first time that oral-intake of ALP protected liver tissue by up-regulating the expression of miR-146a and alleviating inflammatory reactions; thus, providing a research basis for the proper processing of milk. This study also suggests that producers should improve the awareness of the protective effects of bioactive proteins in raw milk.
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Affiliation(s)
- Haoming Wu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Yang Wang
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Qianqian Yao
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Linlin Fan
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Lu Meng
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Nan Zheng
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Huiying Li
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Jiaqi Wang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
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Lannoy V, Côté-Biron A, Asselin C, Rivard N. Phosphatases in toll-like receptors signaling: the unfairly-forgotten. Cell Commun Signal 2021; 19:10. [PMID: 33494775 PMCID: PMC7829650 DOI: 10.1186/s12964-020-00693-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023] Open
Abstract
Over the past 2 decades, pattern recognition receptors (PRRs) have been shown to be on the front line of many illnesses such as autoimmune, inflammatory, and neurodegenerative diseases as well as allergies and cancer. Among PRRs, toll-like receptors (TLRs) are the most studied family. Dissecting TLRs signaling turned out to be advantageous to elaborate efficient treatments to cure autoimmune and chronic inflammatory disorders. However, a broad understanding of TLR effectors is required to propose a better range of cures. In addition to kinases and E3 ubiquitin ligases, phosphatases emerge as important regulators of TLRs signaling mediated by NF-κB, type I interferons (IFN I) and Mitogen-Activated Protein Kinases signaling pathways. Here, we review recent knowledge on TLRs signaling modulation by different classes and subclasses of phosphatases. Thus, it becomes more and more evident that phosphatases could represent novel therapeutic targets to control pathogenic TLRs signaling. Video Abstract.
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Affiliation(s)
- Valérie Lannoy
- Department of Immunology and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, rue Jean Mignault, Sherbrooke, QC, J1E4K8, Canada
| | - Anthony Côté-Biron
- Department of Immunology and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, rue Jean Mignault, Sherbrooke, QC, J1E4K8, Canada
| | - Claude Asselin
- Department of Immunology and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, rue Jean Mignault, Sherbrooke, QC, J1E4K8, Canada
| | - Nathalie Rivard
- Department of Immunology and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, rue Jean Mignault, Sherbrooke, QC, J1E4K8, Canada.
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18
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Alvarenga L, Cardozo LFMF, Lindholm B, Stenvinkel P, Mafra D. Intestinal alkaline phosphatase modulation by food components: predictive, preventive, and personalized strategies for novel treatment options in chronic kidney disease. EPMA J 2020; 11:565-579. [PMID: 33240450 PMCID: PMC7680467 DOI: 10.1007/s13167-020-00228-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022]
Abstract
Alkaline phosphatase (AP) is a ubiquitous membrane-bound glycoprotein that catalyzes phosphate monoesters' hydrolysis from organic compounds, an essential process in cell signaling. Four AP isozymes have been described in humans, placental AP, germ cell AP, tissue nonspecific AP, and intestinal AP (IAP). IAP plays a crucial role in gut microbial homeostasis, nutrient uptake, and local and systemic inflammation, and its dysfunction is associated with persistent inflammatory disorders. AP is a strong predictor of mortality in the general population and patients with cardiovascular and chronic kidney disease (CKD). However, little is known about IAP modulation and its possible consequences in CKD, a disease characterized by gut microbiota imbalance and persistent low-grade inflammation. Mitigating inflammation and dysbiosis can prevent cardiovascular complications in patients with CKD, and monitoring factors such as IAP can be useful for predicting those complications. Here, we review IAP's role and the results of nutritional interventions targeting IAP in experimental models to prevent alterations in the gut microbiota, which could be a possible target of predictive, preventive, personalized medicine (PPPM) to avoid CKD complications. Microbiota and some nutrients may activate IAP, which seems to have a beneficial impact on health; however, data on CKD remains scarce.
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Affiliation(s)
- L. Alvarenga
- Post Graduation Program in Medical Sciences, (UFF) Federal Fluminense University Niterói-Rio de Janeiro (RJ), Niterói, Brazil
| | - L. F. M. F. Cardozo
- Post Graduation Program in Cardiovascular Sciences, Federal Fluminense University (UFF), Niterói, Rio de Janeiro (RJ) Brazil
| | - B. Lindholm
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Technology and Intervention, Karolinska Institutet, Stockholm, Sweden
| | - P. Stenvinkel
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Technology and Intervention, Karolinska Institutet, Stockholm, Sweden
| | - D. Mafra
- Post Graduation Program in Medical Sciences, (UFF) Federal Fluminense University Niterói-Rio de Janeiro (RJ), Niterói, Brazil
- Post Graduation Program in Cardiovascular Sciences, Federal Fluminense University (UFF), Niterói, Rio de Janeiro (RJ) Brazil
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19
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Adiliaghdam F, Cavallaro P, Mohad V, Almpani M, Kühn F, Gharedaghi MH, Najibi M, Rahme LG, Hodin RA. Targeting the gut to prevent sepsis from a cutaneous burn. JCI Insight 2020; 5:137128. [PMID: 33004693 PMCID: PMC7566703 DOI: 10.1172/jci.insight.137128] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 08/26/2020] [Indexed: 12/13/2022] Open
Abstract
Severe burn injury induces gut barrier dysfunction and subsequently a profound systemic inflammatory response. In the present study, we examined the role of the small intestinal brush border enzyme, intestinal alkaline phosphatase (IAP), in preserving gut barrier function and preventing systemic inflammation after burn wound infection in mice. Mice were subjected to a 30% total body surface area dorsal burn with or without intradermal injection of Pseudomonas aeruginosa. Mice were gavaged with 2000 units of IAP or vehicle at 3 and 12 hours after the insult. We found that both endogenously produced and exogenously supplemented IAP significantly reduced gut barrier damage, decreased bacterial translocation to the systemic organs, attenuated systemic inflammation, and improved survival in this burn wound infection model. IAP attenuated liver inflammation and reduced the proinflammatory characteristics of portal serum. Furthermore, we found that intestinal luminal contents of burn wound-infected mice negatively impacted the intestinal epithelial integrity compared with luminal contents of control mice and that IAP supplementation preserved monolayer integrity. These results indicate that oral IAP therapy may represent an approach to preserving gut barrier function, blocking proinflammatory triggers from entering the portal system, preventing gut-induced systemic inflammation, and improving survival after severe burn injuries.
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Affiliation(s)
- Fatemeh Adiliaghdam
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paul Cavallaro
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Vidisha Mohad
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Marianna Almpani
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Shriners Hospital for Children, Boston, Massachusetts, USA
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Florian Kühn
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Department of General, Visceral and Transplant Surgery, Hospital of the University of Munich, Munich, Germany
| | - Mohammad Hadi Gharedaghi
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mehran Najibi
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Laurence G. Rahme
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Shriners Hospital for Children, Boston, Massachusetts, USA
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Richard A. Hodin
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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20
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Bilski J, Wojcik D, Danielak A, Mazur-Bialy A, Magierowski M, Tønnesen K, Brzozowski B, Surmiak M, Magierowska K, Pajdo R, Ptak-Belowska A, Brzozowski T. Alternative Therapy in the Prevention of Experimental and Clinical Inflammatory Bowel Disease. Impact of Regular Physical Activity, Intestinal Alkaline Phosphatase and Herbal Products. Curr Pharm Des 2020; 26:2936-2950. [DOI: 10.2174/1381612826666200427090127] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 04/18/2020] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are multifactorial, chronic, disabling, and progressive diseases characterised by cyclical nature, alternating between active and quiescent states. While the aetiology of IBD is not fully understood, this complex of diseases involve a combination of factors including the genetic predisposition and changes in microbiome as well as environmental risk factors such as high-fat and low-fibre diets, reduced physical activity, air pollution and exposure to various toxins and drugs such as antibiotics. The prevalence of both IBD and obesity is increasing in parallel, undoubtedly proving the existing interactions between these risk factors common to both disorders to unravel poorly recognized cell signaling and molecular alterations leading to human IBD. Therefore, there is still a significant and unmet need for supportive and adjunctive therapy for IBD patients directed against the negative consequences of visceral obesity and bacterial dysbiosis. Among the alternative therapies, a moderate-intensity exercise can benefit the health and well-being of IBD patients and improve both the healing of human IBD and experimental animal colitis. Intestinal alkaline phosphatase (IAP) plays an essential role in the maintenance of intestinal homeostasis intestinal and the mechanism of mucosal defence. The administration of exogenous IAP could be recommended as a therapeutic strategy for the cure of diseases resulting from the intestinal barrier dysfunction such as IBD. Curcumin, a natural anti-inflammatory agent, which is capable of stimulating the synthesis of endogenous IAP, represents another alternative approach in the treatment of IBD. This review was designed to discuss potential “nonpharmacological” alternative and supplementary therapeutic approaches taking into account epidemiological and pathophysiological links between obesity and IBD, including changes in the functional parameters of the intestinal mucosa and alterations in the intestinal microbiome.
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Affiliation(s)
- Jan Bilski
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland
| | - Dagmara Wojcik
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Aleksandra Danielak
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Agnieszka Mazur-Bialy
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Katherine Tønnesen
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Bartosz Brzozowski
- Gastroenterology and Hepatology Clinic, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Surmiak
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Robert Pajdo
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Agata Ptak-Belowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
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The Effects of a Glucocorticoid Receptor Agonist (GRA) on the Immune Function, Nutrient Digestibility, and Wean-to-Finish Growth Performance of Early-Weaned Pigs. Animals (Basel) 2020; 10:ani10060953. [PMID: 32486260 PMCID: PMC7341203 DOI: 10.3390/ani10060953] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 12/28/2022] Open
Abstract
Simple Summary Early weaning is a common practice in modern swine production. Despite advantages, it exposes piglets to numerous stressors at an age when their digestive system is not fully developed. This exposure results in the hyper-activation of the immune system, which in turn reduces growth performance immediately following weaning. One common practice in the pig industry has been to use in-feed antibiotics to mitigate some of the negative effects of early weaning on the immune system and growth. However, recent concerns over antibiotic resistance have created a need for an alternative strategy. We previously have shown that a glucocorticoid-like compound can effectively improve growth performance of newly weaned pigs by regulating their immune response. In the present study, we evaluated the viability of this treatment as an alternative to in-feed antibiotics by directly comparing the effects of the two treatments on measures of immune function, nutrient digestibility, short-term growth and long-term growth. We found that treatment with glucocorticoid-like compounds reduces inflammation, improves nutrient digestibility and enhances short term growth. These effects in turn lead to long-term body weight superiority that is comparable to antibiotic treatment. In conclusion, treating early weaned pigs with glucocorticoid-like compounds is a suitable alternative to the use of in-feed antibiotics. Abstract This study assessed the viability of glucocorticoid receptor agonist (GRA) treatment as an alternative to in-feed antibiotics (ANT) in wean-to-finish pigs. A total of 209 piglets were assigned to eight treatments based on a factorial arrangement, with GRA (+ vs. −; dexamethasone, 0.2 mg/kg body weight, BW), ANT (+ vs. −; 110 mg/kg in-feed Tylosin) and sex (gilt vs. barrow) as the main factors. The serial slaughter technique and serial blood collection were performed on 115 pigs during the first week post-weaning to collect blood, tissue and ileal digesta samples. Fecal samples were collected to determine energy digestibility. In comparison to ANT, GRA more effectively improved the measures of systemic inflammation, protein utilization and recovery-associated biomarkers (p ≤ 0.05). Relative to the control group, GRA treatment improved (p ≤ 0.03) dietary nutrient digestibility relative to control pigs, which was comparable to ANT effects. Relative to the control group, all groups had a higher ADG and BW during the starter phase (p < 0.01). Similar to the ANT group, GRA improved the gain-to-feed ratio relative to the control group during the starter phase. Relative to control pigs, overall BW was higher in GRA and ANT pigs during the grow-to-finish phase (p < 0.01). Collectively, these results suggest that GRA injection improves the growth performance of newly weaned pigs by reducing weaning-induced inflammation and improving nutrient digestibility. GRA can be used as an alternative to in-feed ANT to mitigate the effects of weaning stress on pigs.
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22
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Lallès JP. Recent advances in intestinal alkaline phosphatase, inflammation, and nutrition. Nutr Rev 2020; 77:710-724. [PMID: 31086953 DOI: 10.1093/nutrit/nuz015] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In recent years, much new data on intestinal alkaline phosphatase (IAP) have been published, and major breakthroughs have been disclosed. The aim of the present review is to critically analyze the publications released over the last 5 years. These breakthroughs include, for example, the direct implication of IAP in intestinal tight junction integrity and barrier function maintenance; chronic intestinal challenge with low concentrations of Salmonella generating long-lasting depletion of IAP and increased susceptibility to inflammation; the suggestion that genetic mutations in the IAP gene in humans contribute to some forms of chronic inflammatory diseases and loss of functional IAP along the gut and in stools; stool IAP as an early biomarker of incipient diabetes in humans; and omega-3 fatty acids as direct inducers of IAP in intestinal tissue. Many recent papers have also explored the prophylactic and therapeutic potential of IAP and other alkaline phosphatase (AP) isoforms in various experimental settings and diseases. Remarkably, nearly all data confirm the potent anti-inflammatory properties of (I)AP and the negative consequences of its inhibition on health. A simplified model of the body AP system integrating the IAP compartment is provided. Finally, the list of nutrients and food components stimulating IAP has continued to grow, thus emphasizing nutrition as a potent lever for limiting inflammation.
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Affiliation(s)
- Jean-Paul Lallès
- Institut National de la Recherche Agronomique (INRA), Human Nutrition Division, Clermont-Ferrand, France, and the Centre de Recherche en Nutrition Humaine Ouest, Nantes, France
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23
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Zaher DM, El‐Gamal MI, Omar HA, Aljareh SN, Al‐Shamma SA, Ali AJ, Zaib S, Iqbal J. Recent advances with alkaline phosphatase isoenzymes and their inhibitors. Arch Pharm (Weinheim) 2020; 353:e2000011. [DOI: 10.1002/ardp.202000011] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 02/09/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Dana M. Zaher
- Sharjah Institute for Medical ResearchSharjah United Arab Emirates
| | - Mohammed I. El‐Gamal
- Sharjah Institute for Medical ResearchSharjah United Arab Emirates
- College of PharmacySharjah United Arab Emirates
- Department of Medicinal ChemistryFaculty of PharmacyMansoura Egypt
| | - Hany A. Omar
- Sharjah Institute for Medical ResearchSharjah United Arab Emirates
- College of PharmacySharjah United Arab Emirates
- Department of PharmacologyFaculty of PharmacyBeni‐Suef Egypt
| | | | | | - Aya J. Ali
- College of PharmacySharjah United Arab Emirates
| | - Sumera Zaib
- Centre for Advanced Drug ResearchCOMSATS University Islamabad Abbottabad Campus Abbottabad Pakistan
| | - Jamshed Iqbal
- Centre for Advanced Drug ResearchCOMSATS University Islamabad Abbottabad Campus Abbottabad Pakistan
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24
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Singh SB, Carroll-Portillo A, Coffman C, Ritz NL, Lin HC. Intestinal Alkaline Phosphatase Exerts Anti-Inflammatory Effects Against Lipopolysaccharide by Inducing Autophagy. Sci Rep 2020; 10:3107. [PMID: 32080230 PMCID: PMC7033233 DOI: 10.1038/s41598-020-59474-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 01/23/2020] [Indexed: 12/21/2022] Open
Abstract
Intestinal alkaline phosphatase (IAP) regulates bicarbonate secretion, detoxifies lipopolysaccharide (LPS), regulates gut microbes, and dephosphorylates proinflammatory nucleotides. IAP also exhibits anti-inflammatory effects in a Toll-like Receptor-4 (TLR-4) dependent manner. However, it is not known whether IAP induces autophagy. We tested the hypothesis that IAP may induce autophagy which may mediate the anti-inflammatory effects of IAP. We found that exogenous IAP induced autophagy in intestinal epithelial cells and in macrophages. TLR4INC34 (C34), a TLR4 signaling inhibitor, suppressed IAP-induced autophagy. IAP also inhibited LPS-induced IL-1β mRNA expression and activation of NF-κB. When autophagy was blocked by 3-methyladenine (3MA) or by Atg5 siRNA, IAP failed to block LPS-mediated effects. IAP also upregulated autophagy-related gene expression in small intestine in mice. We administered either vehicle or IAP (100 U/ml) in drinking water for 14 days in C57BL/6 mice. Mice were sacrificed and ileal tissues collected. Increased expression of Atg5, Atg16, Irgm1, Tlr4, and Lyz genes was observed in the IAP treated group compared to the vehicle treated group. Increase in Atg16 protein expression and fluorescence intensity of LC3 was also observed in IAP-treated tissues compared to the vehicle-treated tissues. Thus, our study lays the framework for investigating how IAP and autophagy may act together to control inflammatory conditions.
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Affiliation(s)
- Sudha B Singh
- Biomedical Research Institute of New Mexico, VA Health Care System, Albuquerque, New Mexico, USA, 87108
| | - Amanda Carroll-Portillo
- Biomedical Research Institute of New Mexico, VA Health Care System, Albuquerque, New Mexico, USA, 87108
| | - Cristina Coffman
- Biomedical Research Institute of New Mexico, VA Health Care System, Albuquerque, New Mexico, USA, 87108
| | - Nathaniel L Ritz
- Biomedical Research Institute of New Mexico, VA Health Care System, Albuquerque, New Mexico, USA, 87108.,Department of Anatomy & Neuroscience, University College Cork; APC Microbiome institute, University College Cork, Cork, Ireland
| | - Henry C Lin
- Section of Gastroenterology, Medicine Service, New Mexico VA Health Care System, Albuquerque, New Mexico, USA, 87108. .,Division of Gastroenterology and Hepatology, Department of Medicine, the University of New M5052651711exico, Albuquerque, New Mexico, 87131, USA.
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25
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Intestinal Alkaline Phosphatase Deficiency Is Associated with Ischemic Heart Disease. DISEASE MARKERS 2019; 2019:8473565. [PMID: 31915470 PMCID: PMC6930721 DOI: 10.1155/2019/8473565] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 11/20/2019] [Accepted: 11/30/2019] [Indexed: 12/15/2022]
Abstract
Background We have previously shown that the deficiency of the gut enzyme intestinal alkaline phosphatase (IAP) is associated with type 2 diabetes mellitus (T2DM) in humans, and mice deficient in IAP develop the metabolic syndrome, a precipitant of T2DM and ischemic heart disease (IHD). We hypothesized that IAP deficiency might also be associated with IHD in humans. We aimed to determine the correlation between the IAP level and IHD in humans. Methods and Results The IHD patients were recruited from the National Institute of Cardiovascular Diseases (NICVD), Dhaka, Bangladesh, and the control healthy participants were recruited from a suburban community of Dhaka. We determined the IAP level in the stools of 292 IHD patients (187 males, 105 females) and 331 healthy control people (84 males, 247 females). We found that compared to controls, IHD patients have approx. 30% less IAP (mean ± SEM: 63.7 ± 3.5 vs. 44.9 ± 2.1 U/g stool, respectively; p < 0.000001), which indicates that IAP deficiency is associated with IHD, and a high level of IAP is probably protective against IHD in humans. The adjusted generalized linear model (GLM) of regression analysis predicted a strong association of IAP with IHD (p = 0.0035). Multiple logistic regression analysis showed an independent inverse relationship between the IAP level and the IHD status (odds ratio, OR = 0.993 with 95% CI 0.987-0.998; p < 0.01). Conclusions IAP deficiency is associated with IHD, and a high level of IAP might be protective against IHD.
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Abid MB, Shah NN, Maatman TC, Hari PN. Gut microbiome and CAR-T therapy. Exp Hematol Oncol 2019; 8:31. [PMID: 31827982 PMCID: PMC6862813 DOI: 10.1186/s40164-019-0155-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022] Open
Abstract
Considerable progress has been made in cancer therapeutics recently with targeted strategies that are efficacious and less toxic. Immunotherapy and chimeric antigen receptor (CAR) T-cells are increasingly being evaluated in a variety of tumors in the relapsed/refractory as well as frontline disease settings, predominantly in hematologic malignancies (HM). Despite impressive outcomes in select patients, there remains significant heterogeneity in clinical response to CAR T-cells. The gut microbiome has emerged as one of the key host factors that could potentially be modulated to enhance responses to immunotherapy. Several recent human studies receiving immunotherapy showed a significantly superior response and survival in patients with the more diverse gut microbiome. Currently, it is unknown if gut microbiota modulates anti-tumor responses to CAR T-cells. Based on molecular and immunological understanding, we hypothesize that strategically manipulating gut microbiota may enhance responses to CAR T-cells. In this review, we further discuss resistance mechanisms to CAR T-cells in HM, potential approaches to overcome resistance by harnessing gut microbiota and other related novel strategies.
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Affiliation(s)
- Muhammad Bilal Abid
- 1Division of Infectious Diseases, Medical College of Wisconsin (MCW), Hub for Collaborative Medicine, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA.,2Division of Hematology/Oncology, Medical College of Wisconsin (MCW), Milwaukee, WI USA
| | - Nirav N Shah
- 2Division of Hematology/Oncology, Medical College of Wisconsin (MCW), Milwaukee, WI USA
| | - Theresa C Maatman
- 3Division of Internal Medicine, Medical College of Wisconsin (MCW), Milwaukee, WI USA
| | - Parameswaran N Hari
- 2Division of Hematology/Oncology, Medical College of Wisconsin (MCW), Milwaukee, WI USA
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Brichacek AL, Brown CM. Alkaline phosphatase: a potential biomarker for stroke and implications for treatment. Metab Brain Dis 2019; 34:3-19. [PMID: 30284677 PMCID: PMC6351214 DOI: 10.1007/s11011-018-0322-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 09/24/2018] [Indexed: 12/14/2022]
Abstract
Stroke is the fifth leading cause of death in the U.S., with more than 100,000 deaths annually. There are a multitude of risks associated with stroke, including aging, cardiovascular disease, hypertension, Alzheimer's disease (AD), and immune suppression. One of the many challenges, which has so far proven to be unsuccessful, is the identification of a cost-effective diagnostic or prognostic biomarker for stroke. Alkaline phosphatase (AP), an enzyme first discovered in the 1920s, has been evaluated as a potential biomarker in many disorders, including many of the co-morbidities associated with stroke. This review will examine the basic biology of AP, and its most common isoenzyme, tissue nonspecific alkaline phosphatase (TNAP), with a specific focus on the central nervous system. It examines the preclinical and clinical evidence which supports a potential role for AP in stroke and suggests potential mechanism(s) of action for AP isoenzymes in stroke. Lastly, the review speculates on the clinical utility of AP isoenzymes as potential blood biomarkers for stroke or as AP-targeted treatments for stroke patients.
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Affiliation(s)
- Allison L Brichacek
- Department of Microbiology, Immunology, and Cell Biology, Center for Basic and Translational Stroke Research, WVU Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Box 9177, Morgantown, WV, 26506, USA
- Department of Neuroscience, Emergency Medicine, and Microbiology, Immunology and Cell Biology, Center for Basic and Translational Stroke Research, WVU Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Box 9303, Morgantown, WV, 26506, USA
| | - Candice M Brown
- Department of Microbiology, Immunology, and Cell Biology, Center for Basic and Translational Stroke Research, WVU Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Box 9177, Morgantown, WV, 26506, USA.
- Department of Neuroscience, Emergency Medicine, and Microbiology, Immunology and Cell Biology, Center for Basic and Translational Stroke Research, WVU Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Box 9303, Morgantown, WV, 26506, USA.
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Cutrignelli MI, Messina M, Tulli F, Randazzo B, Olivotto I, Gasco L, Loponte R, Bovera F. Evaluation of an insect meal of the Black Soldier Fly (Hermetia illucens) as soybean substitute: Intestinal morphometry, enzymatic and microbial activity in laying hens. Res Vet Sci 2018; 117:209-215. [PMID: 29304440 DOI: 10.1016/j.rvsc.2017.12.020] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 12/20/2017] [Accepted: 12/26/2017] [Indexed: 11/18/2022]
Abstract
This research investigated the ileum morphometry and enzymatic activity, the caecal volatile fatty acid production and the apparent nutrient digestibility in laying hens fed a Hermetia illucens larvae meal (HILM) as a complete replacement of diet soybean meal (SBM). The hens fed HILM exhibited a lower live weight (P<0.05) and a higher incidence of the full digestive tract (P<0.05) than the SBM group. In the duodenum, the maltase exhibited a higher (P<0.05) activity in the HILM group while the intestinal alkaline phosphatase (IAP) had a higher (P<0.05) activity in the SBM group. In the ileum, the maltase and saccarase had a higher activity in the HILM hens (P≤0.01) while the IAP and ɤ glutamil transferase had a higher activity in the SBM group (P<0.05 and P<0.01, respectively). The HILM group showed a higher (P<0.05) villi height in the duodenum, while the opposite happened in the jejunum and the ileum. Only in the ileum the crypt depth resulted higher (P<0.05) in the HIML group than in the SBM. The higher production of acetate (P<0.05) and butyrate (P<0.01) affected the total production of volatile fatty acids of the HILM group. The coefficient of apparent digestibility of dry and organic matter as well as of crude protein was higher (P<0.05) in SBM group. The total replacement of SBM with HILM in laying hens diet from 24 to 45weeks of age resulted in a higher caecal production of butyric acid while the enzymatic activities of brush border membrane were partially reduced.
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Affiliation(s)
- Monica Isabella Cutrignelli
- University of Napoli Federico II, Department of Veterinary Medicine and Animal Production, via F. Delpino, 1, 80137 Napoli, Italy
| | - Maria Messina
- University of Udine, Departmentof AgriFood, Environment and Animal Science, via Sondrio, 2, 33100 Udine, Italy
| | - Francesca Tulli
- University of Udine, Departmentof AgriFood, Environment and Animal Science, via Sondrio, 2, 33100 Udine, Italy
| | - Basilio Randazzo
- University Politecnica delle Marche, Department of Life and Environmental Sciences, via Brecce Bianche, 60131 Ancona, Italy
| | - Ike Olivotto
- University Politecnica delle Marche, Department of Life and Environmental Sciences, via Brecce Bianche, 60131 Ancona, Italy
| | - Laura Gasco
- Department of Agricultural, Forest, and Food Sciences, University of Torino, largo Braccini 2, 10095 Grugliasco, Italy
| | - Rosa Loponte
- University of Napoli Federico II, Department of Veterinary Medicine and Animal Production, via F. Delpino, 1, 80137 Napoli, Italy
| | - Fulvia Bovera
- University of Napoli Federico II, Department of Veterinary Medicine and Animal Production, via F. Delpino, 1, 80137 Napoli, Italy.
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Yang WH, Heithoff DM, Aziz PV, Sperandio M, Nizet V, Mahan MJ, Marth JD. Recurrent infection progressively disables host protection against intestinal inflammation. Science 2018; 358:358/6370/eaao5610. [PMID: 29269445 DOI: 10.1126/science.aao5610] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 11/13/2017] [Indexed: 12/15/2022]
Abstract
Intestinal inflammation is the central pathological feature of colitis and the inflammatory bowel diseases. These syndromes arise from unidentified environmental factors. We found that recurrent nonlethal gastric infections of Gram-negative Salmonella enterica Typhimurium (ST), a major source of human food poisoning, caused inflammation of murine intestinal tissue, predominantly the colon, which persisted after pathogen clearance and irreversibly escalated in severity with repeated infections. ST progressively disabled a host mechanism of protection by inducing endogenous neuraminidase activity, which accelerated the molecular aging and clearance of intestinal alkaline phosphatase (IAP). Disease was linked to a Toll-like receptor 4 (TLR4)-dependent mechanism of IAP desialylation with accumulation of the IAP substrate and TLR4 ligand, lipopolysaccharide-phosphate. The administration of IAP or the antiviral neuraminidase inhibitor zanamivir was therapeutic by maintaining IAP abundance and function.
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Affiliation(s)
- Won Ho Yang
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Sanford Burnham Prebys Medical Discovery Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Douglas M Heithoff
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Peter V Aziz
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Sanford Burnham Prebys Medical Discovery Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Markus Sperandio
- Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Victor Nizet
- Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Michael J Mahan
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Jamey D Marth
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA. .,Sanford Burnham Prebys Medical Discovery Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
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Jiang P, Liu Q, Ni Z, Wei Q, Li X, Xing S, Kong D, Li M. Primary study on the toxic mechanism of vanadyl trehalose in Kunming mice. Regul Toxicol Pharmacol 2018; 94:1-7. [PMID: 29305949 DOI: 10.1016/j.yrtph.2017.12.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Revised: 12/27/2017] [Accepted: 12/31/2017] [Indexed: 12/12/2022]
Abstract
It has been shown that vanadyl trehalose could lower blood glucose but show mild toxicity to the stomach and intestine in diabetic Kunming mice. We analysed antioxidant levels, pro-inflammatory cytokine expression, apoptosis factors and intestinal microflora alteration to explore the mechanism of vanadyl trehalose toxicity in Kunming mice. The results revealed that oral administration of vanadyl trehalose at tested dose caused significant changes in oxidative stress factor (MDA levels elevated but SOD and T-AOC decreased), expression of inflammatory factor (IL-1β, COX-2, TNF-α and iNOS increased), and apoptosis factor (Bcl-2/Bax decreased and caspase-3 increased), and intestinal microflora dysbiosis (the number of Enterobacteriaceae and Enterococcus increased and Lactobacillus and Bifidobacterium decreased) relative to the control of Kunming mice. These results suggest that the toxic mechanisms of vanadyl trehalose on the stomach and intestine likely involve activation of the oxidative stress system, increased inflammatory response, promotion of apoptosis and the disruption of the normal intestinal microflora.
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Affiliation(s)
- Pingzhe Jiang
- Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, 300071, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071, Tianjin, China
| | - Qiqi Liu
- Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, 300071, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071, Tianjin, China
| | - Zaizhong Ni
- Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, 300071, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071, Tianjin, China
| | - Qian Wei
- Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, 300071, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071, Tianjin, China
| | - Xiaodan Li
- Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, 300071, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071, Tianjin, China
| | - Shuguang Xing
- Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, 300071, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071, Tianjin, China
| | - Deling Kong
- Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, 300071, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071, Tianjin, China
| | - Minggang Li
- Key Laboratory for Bioactive Materials of the Ministry of Education, Institute of Molecular Biology, College of Life Science, Nankai University, 300071, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300071, Tianjin, China.
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Lehto M, Groop PH. The Gut-Kidney Axis: Putative Interconnections Between Gastrointestinal and Renal Disorders. Front Endocrinol (Lausanne) 2018; 9:553. [PMID: 30283404 PMCID: PMC6157406 DOI: 10.3389/fendo.2018.00553] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 08/30/2018] [Indexed: 12/15/2022] Open
Abstract
Diabetic kidney disease (DKD) is a devastating condition associated with increased morbidity and premature mortality. The etiology of DKD is still largely unknown. However, the risk of DKD development and progression is most likely modulated by a combination of genetic and environmental factors. Patients with autoimmune diseases, like type 1 diabetes, inflammatory bowel disease, and celiac disease, share some genetic background. Furthermore, gastrointestinal disorders are associated with an increased risk of kidney disease, although the true mechanisms have still to be elucidated. Therefore, the principal aim of this review is to evaluate the impact of disturbances in the gastrointestinal tract on the development of renal disorders.
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Affiliation(s)
- Markku Lehto
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
- *Correspondence: Markku Lehto
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
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Rader BA. Alkaline Phosphatase, an Unconventional Immune Protein. Front Immunol 2017; 8:897. [PMID: 28824625 PMCID: PMC5540973 DOI: 10.3389/fimmu.2017.00897] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 07/13/2017] [Indexed: 12/16/2022] Open
Abstract
Recent years have seen an increase in the number of studies focusing on alkaline phosphatases (APs), revealing an expanding complexity of function of these enzymes. Of the four human AP (hAP) proteins, most is known about tissue non-specific AP (TNAP) and intestinal AP (IAP). This review highlights current understanding of TNAP and IAP in relation to human health and disease. TNAP plays a role in multiple processes, including bone mineralization, vitamin B6 metabolism, and neurogenesis, is the genetic cause of hypophosphatasia, influences inflammation through regulation of purinergic signaling, and has been implicated in Alzheimer's disease. IAP regulates fatty acid absorption and has been implicated in the regulation of diet-induced obesity and metabolic syndrome. IAP and TNAP can dephosphorylate bacterial-derived lipopolysaccharide, and IAP has been identified as a potential regulator of the composition of the intestinal microbiome, an evolutionarily conserved function. Endogenous and recombinant bovine APs and recombinant hAPs are currently being explored for their potential as pharmacological agents to treat AP-associated diseases and mitigate multiple sources of inflammation. Continued research on these versatile proteins will undoubtedly provide insight into human pathophysiology, biochemistry, and the human holobiont.
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Affiliation(s)
- Bethany A Rader
- Department of Microbiology, Southern Illinois University, Carbondale, IL, United States
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Amelioration of Clostridium difficile Infection in Mice by Dietary Supplementation With Indole-3-carbinol. Ann Surg 2017; 265:1183-1191. [PMID: 27280500 DOI: 10.1097/sla.0000000000001830] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To determine the therapeutic effects of dietary supplementation on Clostridium difficile infection (CDI). BACKGROUND With limited treatment options, the rise of C. difficile-associated disease has spurred on the search for novel therapies. Recent data define a role for the aryl hydrocarbon receptor (AHR) and diet-derived AHR ligands in mucosal immunity. We investigated the efficacy of indole-3-carbinol (I3C), a dietary supplement, and AHR precursor ligand in a murine model of CDI. METHODS C57BL/6 (B6), AHR, and AHR mice were placed on either grain-based or semipurified diets with or without I3C before and during CDI. Mice were followed clinically for a minimum of 6 days or euthanized between days 0 and 4 of inoculation for analysis of the inflammatory response and microbiota. RESULTS B6 mice fed an AHR ligand-deficient, semipurified diet have significantly increased disease severity (P<0.001) and mortality (P < 0.001) compared with mice fed on diet containing I3C. The addition of I3C to the diet of AHR null mice had less of an impact than in AHR heterozygous littermates, although some protection was seen. Mice on semipurified I3C-diet had increased cecal Tregs, ILC3s, and γδ T cells and an increased neutrophilic response without increased inflammation or bacterial translocation compared with controls. CONCLUSIONS I3C is a powerful treatment to reduce impact of CDI in mice. The findings indicate I3C may be acting through both AHR-dependent and -independent mechanisms in this model. Dietary supplementation with I3C is a potential new therapy for prevention and amelioration of C. difficile disease.
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Abstract
Cardiovascular disease is the main cause of early death in the settings of chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and ageing. Cardiovascular events can be caused by an imbalance between promoters and inhibitors of mineralization, which leads to vascular calcification. This process is akin to skeletal mineralization, which is carefully regulated and in which isozymes of alkaline phosphatase (ALP) have a crucial role. Four genes encode ALP isozymes in humans. Intestinal, placental and germ cell ALPs are tissue-specific, whereas the tissue-nonspecific isozyme of ALP (TNALP) is present in several tissues, including bone, liver and kidney. TNALP has a pivotal role in bone calcification. Experimental overexpression of TNALP in the vasculature is sufficient to induce vascular calcification, cardiac hypertrophy and premature death, mimicking the cardiovascular phenotype often found in CKD and T2DM. Intestinal ALP contributes to the gut mucosal defence and intestinal and liver ALPs might contribute to the acute inflammatory response to endogenous or pathogenic stimuli. Here we review novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases. We also discuss new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.
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Intestinal alkaline phosphatase deficiency leads to dysbiosis and bacterial translocation in the newborn intestine. J Surg Res 2017; 218:35-42. [PMID: 28985873 DOI: 10.1016/j.jss.2017.03.049] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 03/24/2017] [Accepted: 03/29/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND Intestinal alkaline phosphatase (IAP) has been shown to help maintain intestinal homeostasis. Decreased expression of IAP has been linked with pediatric intestinal diseases associated with bacterial overgrowth and subsequent inflammation. We hypothesize that the absence of IAP leads to dysbiosis, with increased inflammation and permeability of the newborn intestine. METHODS Sprague-Dawley heterozygote IAP cross-matches were bred. Pups were dam fed ad lib and euthanized at weaning. The microbiotas of terminal ileum (TI) and colon was determined by quantitative real-time polymerase chain reaction (qRT-PCR) of subphylum-specific bacterial 16S ribosomal RNA. RT-PCR was performed on TI for inflammatory cytokines. Intestinal permeability was quantified by fluorescein isothiocyanate-dextran permeability and bacterial translocation by qRT-PCR for bacterial 16S ribosomal RNA in mesenteric lymph nodes. Statistical analysis was done by chi-square analysis. RESULTS All three genotypes had similar concentrations of bacteria in the TI and colon. However, IAP knockout (IAP-KO) had significantly decreased diversity of bacterial species in their colonic stool compared with heterozygous and wild-type (WT). IAP-KO pups had a nonstatistically significant 3.9-fold increased inducible nitric oxide synthase messenger RNA expression compared with WT (IAP-KO, 3.92 ± 1.36; WT, 1.0 ± 0.27; P = 0.03). IAP-KO also had significantly increased bacterial translocation to mesenteric lymph nodes occurred in IAP-KO (IAP-KO, 7625 RFU/g ± 3469; WT, 4957 RFU/g ± 1552; P = 0.04). Furthermore, IAP-KO had increased permeability (IAP-KO, 0.297 mg/mL ± 0.2; WT, 0.189 mg/mL ± 0.15 P = 0.07), but was not statistically significant. CONCLUSIONS Deficiency of IAP in the newborn intestine is associated with dysbiosis and increased inflammation, permeability, and bacterial translocation.
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The Role of Intestinal Alkaline Phosphatase in Inflammatory Disorders of Gastrointestinal Tract. Mediators Inflamm 2017; 2017:9074601. [PMID: 28316376 PMCID: PMC5339520 DOI: 10.1155/2017/9074601] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 01/26/2017] [Indexed: 02/06/2023] Open
Abstract
Over the past few years, the role of intestinal alkaline phosphatase (IAP) as a crucial mucosal defence factor essential for maintaining gut homeostasis has been established. IAP is an important apical brush border enzyme expressed throughout the gastrointestinal tract and secreted both into the intestinal lumen and into the bloodstream. IAP exerts its effects through dephosphorylation of proinflammatory molecules including lipopolysaccharide (LPS), flagellin, and adenosine triphosphate (ATP) released from cells during stressful events. Diminished activity of IAP could increase the risk of disease through changes in the microbiome, intestinal inflammation, and intestinal permeability. Exogenous IAP exerts a protective effect against intestinal and systemic inflammation in a variety of diseases and represents a potential therapeutic agent in diseases driven by gut barrier dysfunction such as IBD. The intestinal protective mechanisms are impaired in IBD patients due to lower synthesis and activity of endogenous IAP, but the pathomechanism of this enzyme deficiency remains unclear. IAP has been safely administered to humans and the human recombinant form of IAP has been developed. This review was designed to provide an update in recent research on the involvement of IAP in intestinal inflammatory processes with focus on IBD in experimental animal models and human patients.
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Chu FF, Esworthy RS, Doroshow JH, Shen B. NADPH oxidase-1 deficiency offers little protection in Salmonella typhimurium-induced typhlitis in mice. World J Gastroenterol 2016; 22:10158-10165. [PMID: 28028364 PMCID: PMC5155175 DOI: 10.3748/wjg.v22.i46.10158] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 10/09/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To test whether Nox1 plays a role in typhlitis induced by Salmonella enterica serovar Typhimurium (S. Tm) in a mouse model.
METHODS Eight-week-old male wild-type (WT) and Nox1 knockout (KO) C57BL6/J (B6) mice were administered metronidazole water for 4 d to make them susceptible to S. Tm infection by the oral route. The mice were given plain water and administered with 4 different doses of S. Tm by oral gavage. The mice were followed for another 4 d. From the time of the metronidazole application, the mice were observed twice daily and weighed daily. The ileum, cecum and colon were removed for sampling at the fourth day post-inoculation. Portions of all three tissues were fixed for histology and placed in RNAlater for mRNA/cDNA preparation and quantitative real-time PCR. The contents of the cecum were recovered for estimation of S. Tm CFU.
RESULTS We found Nox1-knockout (Nox1-KO) mice were not more sensitive to S. Tm colonization and infection than WT B6 mice. This conclusion is based on the following observations: (1) S. Tm-infection induced similar weight loss in Nox1-KO mice compared to WT mice; (2) the same S. Tm CFU was recovered from the cecal content of Nox1-KO and WT mice regardless of the inoculation dose, except the lowest inoculation dose (2 × 106 CFU) for which the Nox1-KO had one-log lower CFU than WT mice; (3) there is no difference in cecal pathology between WT and Nox1-KO groups; and (4) there are no S. Tm infection-induced changes in gene expression levels (IL-1b, TNF-α, and Duox2) between WT and Nox1-KO groups. The Alpi gene expression was more suppressed by S. Tm treatment in WT than the Nox1-KO cecum.
CONCLUSION Nox1 does not protect mice from S. Tm colonization. Nox1-KO provides a very minor protective effect against S. Tm infection. Using NOX1-specific inhibitors for colitis therapy should not increase risks in bacterial infection.
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Rentea RM, Lam V, Biesterveld B, Fredrich KM, Callison J, Fish BL, Baker JE, Komorowski R, Gourlay DM, Otterson MF. Radiation-induced changes in intestinal and tissue-nonspecific alkaline phosphatase: implications for recovery after radiation therapy. Am J Surg 2016; 212:602-608. [PMID: 27501776 DOI: 10.1016/j.amjsurg.2016.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 04/03/2016] [Accepted: 06/27/2016] [Indexed: 01/12/2023]
Abstract
BACKGROUND Exogenous replacement of depleted enterocyte intestinal alkaline phosphatase (IAP) decreases intestinal injury in models of colitis. We determined whether radiation-induced intestinal injury could be mitigated by oral IAP supplementation and the impact on tissue-nonspecific AP. METHODS WAG/RjjCmcr rats (n = 5 per group) received lower hemibody irradiation (13 Gy) followed by daily gavage with phosphate-buffered saline or IAP (40 U/kg/d) for 4 days. Real-time polymerase chain reaction, AP activity, and microbiota analysis were performed on intestine. Lipopolysaccharide and cytokine analysis was performed on serum. Data were expressed as a mean ± SEM with P greater than .05 considered significant. RESULTS Intestine of irradiated animals demonstrates lower hemibody irradiation and is associated with upregulation of tissue-nonspecific AP, downregulation of IAP, decreased AP activity, and altered composition of the intestinal microbiome. CONCLUSIONS Supplemental IAP after radiation may be beneficial in mitigating intestinal radiation syndrome as evidenced by improved histologic injury, decreased acute intestinal inflammation, and normalization of intestinal microbiome.
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Affiliation(s)
- Rebecca M Rentea
- Department of Surgery, Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108, USA.
| | - Vy Lam
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Ben Biesterveld
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | | | - Jennifer Callison
- Department of Surgery, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI, USA
| | - Brian L Fish
- Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - John E Baker
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Richard Komorowski
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - David M Gourlay
- Division of Pediatric Surgery, Medical College of Wisconsin, Children's Hospital of Wisconsin, Children's Research Institute, Milwaukee, WI, USA
| | - Mary F Otterson
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
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Fawley J, Gourlay DM. Intestinal alkaline phosphatase: a summary of its role in clinical disease. J Surg Res 2016; 202:225-34. [PMID: 27083970 PMCID: PMC4834149 DOI: 10.1016/j.jss.2015.12.008] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 11/07/2015] [Accepted: 12/08/2015] [Indexed: 12/19/2022]
Abstract
Over the past few years, there is increasing evidence implicating a novel role for Intestinal Alkaline Phosphatase (IAP) in mitigating inflammatory mediated disorders. IAP is an endogenous protein expressed by the intestinal epithelium that is believed to play a vital role in maintaining gut homeostasis. Loss of IAP expression or function is associated with increased intestinal inflammation, dysbiosis, bacterial translocation and subsequently systemic inflammation. As these events are a cornerstone of the pathophysiology of many diseases relevant to surgeons, we sought to review recent research in both animal and humans on IAP's physiologic function, mechanisms of action and current research in specific surgical diseases.
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Affiliation(s)
- Jason Fawley
- Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee; Department of Surgery, Division of Pediatric Surgery, Children's Hospital of Wisconsin, Milwaukee
| | - David M Gourlay
- Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee; Department of Surgery, Division of Pediatric Surgery, Children's Hospital of Wisconsin, Milwaukee.
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Melo ADB, Silveira H, Luciano FB, Andrade C, Costa LB, Rostagno MH. Intestinal Alkaline Phosphatase: Potential Roles in Promoting Gut Health in Weanling Piglets and Its Modulation by Feed Additives - A Review. ASIAN-AUSTRALASIAN JOURNAL OF ANIMAL SCIENCES 2016; 29:16-22. [PMID: 26732323 PMCID: PMC4698684 DOI: 10.5713/ajas.15.0120] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 04/17/2015] [Accepted: 05/11/2015] [Indexed: 01/09/2023]
Abstract
The intestinal environment plays a critical role in maintaining swine health. Many factors such as diet, microbiota, and host intestinal immune response influence the intestinal environment. Intestinal alkaline phosphatase (IAP) is an important apical brush border enzyme that is influenced by these factors. IAP dephosphorylates bacterial lipopolysaccharides (LPS), unmethylated cytosine-guanosine dinucleotides, and flagellin, reducing bacterial toxicity and consequently regulating toll-like receptors (TLRs) activation and inflammation. It also desphosphorylates extracellular nucleotides such as uridine diphosphate and adenosine triphosphate, consequently reducing inflammation, modulating, and preserving the homeostasis of the intestinal microbiota. The apical localization of IAP on the epithelial surface reveals its role on LPS (from luminal bacteria) detoxification. As the expression of IAP is reported to be downregulated in piglets at weaning, LPS from commensal and pathogenic gram-negative bacteria could increase inflammatory processes by TLR-4 activation, increasing diarrhea events during this phase. Although some studies had reported potential IAP roles to promote gut health, investigations about exogenous IAP effects or feed additives modulating IAP expression and activity yet are necessary. However, we discussed in this paper that the critical assessment reported can suggest that exogenous IAP or feed additives that could increase its expression could show beneficial effects to reduce diarrhea events during the post weaning phase. Therefore, the main goals of this review are to discuss IAP’s role in intestinal inflammatory processes and present feed additives used as growth promoters that may modulate IAP expression and activity to promote gut health in piglets.
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Affiliation(s)
- A D B Melo
- Department of Animal Sciences, Universidade Federal de Lavras, Lavras, MG 37200-000, Brazil
| | - H Silveira
- Department of Animal Sciences, Universidade Federal de Lavras, Lavras, MG 37200-000, Brazil
| | - F B Luciano
- Department of Animal Sciences, Universidade Federal de Lavras, Lavras, MG 37200-000, Brazil
| | - C Andrade
- Department of Animal Sciences, Universidade Federal de Lavras, Lavras, MG 37200-000, Brazil
| | - L B Costa
- Department of Animal Sciences, Universidade Federal de Lavras, Lavras, MG 37200-000, Brazil
| | - M H Rostagno
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
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Malo MS. A High Level of Intestinal Alkaline Phosphatase Is Protective Against Type 2 Diabetes Mellitus Irrespective of Obesity. EBioMedicine 2015; 2:2016-23. [PMID: 26844282 PMCID: PMC4703762 DOI: 10.1016/j.ebiom.2015.11.027] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 11/15/2015] [Accepted: 11/16/2015] [Indexed: 01/26/2023] Open
Abstract
Mice deficient in intestinal alkaline phosphatase (IAP) develop type 2 diabetes mellitus (T2DM). We hypothesized that a high level of IAP might be protective against T2DM in humans. We determined IAP levels in the stools of 202 diabetic patients and 445 healthy non-diabetic control people. We found that compared to controls, T2DM patients have approx. 50% less IAP (mean +/- SEM: 67.4 +/- 3.2 vs 35.3 +/- 2.5 U/g stool, respectively; p < 0.000001) indicating a protective role of IAP against T2DM. Multiple logistic regression analyses showed an independent association between the IAP level and diabetes status. With each 25 U/g decrease in stool IAP, there is a 35% increased risk of diabetes. The study revealed that obese people with high IAP (approx. 65 U/g stool) do not develop T2DM. Approx. 65% of the healthy population have < 65.0 U/g stool IAP, and predictably, these people might have 'the incipient metabolic syndrome', including 'incipient diabetes', and might develop T2DM and other metabolic disorders in the near future. In conclusion, high IAP levels appear to be protective against diabetes irrespective of obesity, and a 'temporal IAP profile' might be a valuable tool for predicting 'the incipient metabolic syndrome', including 'incipient diabetes'.
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Kaliannan K, Wang B, Li XY, Kim KJ, Kang JX. A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia. Sci Rep 2015; 5:11276. [PMID: 26062993 PMCID: PMC4650612 DOI: 10.1038/srep11276] [Citation(s) in RCA: 251] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 05/05/2015] [Indexed: 12/16/2022] Open
Abstract
Metabolic endotoxemia, commonly derived from gut dysbiosis, is a primary cause of chronic low grade inflammation that underlies many chronic diseases. Here we show that mice fed a diet high in omega-6 fatty acids exhibit higher levels of metabolic endotoxemia and systemic low-grade inflammation, while transgenic conversion of tissue omega-6 to omega-3 fatty acids dramatically reduces endotoxemic and inflammatory status. These opposing effects of tissue omega-6 and omega-3 fatty acids can be eliminated by antibiotic treatment and animal co-housing, suggesting the involvement of the gut microbiota. Analysis of gut microbiota and fecal transfer revealed that elevated tissue omega-3 fatty acids enhance intestinal production and secretion of intestinal alkaline phosphatase (IAP), which induces changes in the gut bacteria composition resulting in decreased lipopolysaccharide production and gut permeability, and ultimately, reduced metabolic endotoxemia and inflammation. Our findings uncover an interaction between host tissue fatty acid composition and gut microbiota as a novel mechanism for the anti-inflammatory effect of omega-3 fatty acids. Given the excess of omega-6 and deficiency of omega-3 in the modern Western diet, the differential effects of tissue omega-6 and omega-3 fatty acids on gut microbiota and metabolic endotoxemia provide insight into the etiology and management of today's health epidemics.
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Affiliation(s)
- Kanakaraju Kaliannan
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Bin Wang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Xiang-Yong Li
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Kui-Jin Kim
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Jing X. Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
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Estaki M, DeCoffe D, Gibson DL. Interplay between intestinal alkaline phosphatase, diet, gut microbes and immunity. World J Gastroenterol 2014; 20:15650-15656. [PMID: 25400448 PMCID: PMC4229529 DOI: 10.3748/wjg.v20.i42.15650] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Revised: 04/29/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
Intestinal alkaline phosphatase (IAP) plays an essential role in intestinal homeostasis and health through interactions with the resident microbiota, diet and the gut. IAP’s role in the intestine is to dephosphorylate toxic microbial ligands such as lipopolysaccharides, unmethylated cytosine-guanosine dinucleotides and flagellin as well as extracellular nucleotides such as uridine diphosphate. IAP’s ability to detoxify these ligands is essential in protecting the host from sepsis during acute inflammation and chronic inflammatory conditions such as inflammatory bowel disease. Also important in these complications is IAP’s ability to regulate the microbial ecosystem by forming a complex relationship between microbiota, diet and the intestinal mucosal surface. Evidence reveals that diet alters IAP expression and activity and this in turn can influence the gut microbiota and homeostasis. IAP’s ability to maintain a healthy gastrointestinal tract has accelerated research on its potential use as a therapeutic agent against a multitude of diseases. Exogenous IAP has been shown to have beneficial effects when administered during ulcerative colitis, coronary bypass surgery and sepsis. There are currently a handful of human clinical trials underway investigating the effects of exogenous IAP during sepsis, rheumatoid arthritis and heart surgery. In light of these findings IAP has been marked as a novel agent to help treat a variety of other inflammatory and infectious diseases. The purpose of this review is to highlight the essential characteristics of IAP in protection and maintenance of intestinal homeostasis while addressing the intricate interplay between IAP, diet, microbiota and the intestinal epithelium.
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Intestinal alkaline phosphatase deficiency leads to lipopolysaccharide desensitization and faster weight gain. Infect Immun 2014; 83:247-58. [PMID: 25348635 DOI: 10.1128/iai.02520-14] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Animals develop in the presence of complex microbial communities, and early host responses to these microbes can influence key aspects of development, such as maturation of the immune system, in ways that impact adult physiology. We previously showed that the zebrafish intestinal alkaline phosphatase (ALPI) gene alpi.1 was induced by Gram-negative bacterium-derived lipopolysaccharide (LPS), a process dependent on myeloid differentiation primary response gene 88 (MYD88), and functioned to detoxify LPS and prevent excessive host inflammatory responses to commensal microbiota in the newly colonized intestine. In the present study, we examined whether the regulation and function of ALPI were conserved in mammals. We found that among the mouse ALPI genes, Akp3 was specifically upregulated by the microbiota, but through a mechanism independent of LPS or MYD88. We showed that disruption of Akp3 did not significantly affect intestinal inflammatory responses to commensal microbiota or animal susceptibility to Yersinia pseudotuberculosis infection. However, we found that Akp3(-/-) mice acquired LPS tolerance during postweaning development, suggesting that Akp3 plays an important role in immune education. Finally, we demonstrated that inhibiting LPS sensing with a mutation in CD14 abrogated the accelerated weight gain in Akp3(-/-) mice receiving a high-fat diet, suggesting that the weight gain is caused by excessive LPS in Akp3(-/-) mice.
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Malo MS, Moaven O, Muhammad N, Biswas B, Alam SN, Economopoulos KP, Gul SS, Hamarneh SR, Malo NS, Teshager A, Mohamed MMR, Tao Q, Narisawa S, Millán JL, Hohmann EL, Warren HS, Robson SC, Hodin RA. Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates. Am J Physiol Gastrointest Liver Physiol 2014; 306:G826-38. [PMID: 24722905 PMCID: PMC4024727 DOI: 10.1152/ajpgi.00357.2013] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.
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Affiliation(s)
- Madhu S. Malo
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Omeed Moaven
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Nur Muhammad
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Brishti Biswas
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Sayeda N. Alam
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | | | - Sarah Shireen Gul
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Sulaiman R. Hamarneh
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Nondita S. Malo
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Abeba Teshager
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Mussa M. Rafat Mohamed
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Qingsong Tao
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
| | - Sonoko Narisawa
- 2Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California;
| | - José Luis Millán
- 2Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California;
| | - Elizabeth L. Hohmann
- 3Infectious Disease Unit, Departments of Pediatrics and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and
| | - H. Shaw Warren
- 3Infectious Disease Unit, Departments of Pediatrics and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and
| | - Simon C. Robson
- 4Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Richard A. Hodin
- 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
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