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Ghaffari MH, Sauerwein H, Sadri H, Schuchardt S, Martín-Tereso J, Doelman JH, Daniel JB. Longitudinal characterization of the metabolome of dairy cows transitioning from one lactation to the next: Investigations in fecal samples. J Dairy Sci 2025; 108:5405-5419. [PMID: 40043758 DOI: 10.3168/jds.2025-26273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 01/31/2025] [Indexed: 05/03/2025]
Abstract
The fecal metabolome comprises metabolites that are excreted or not absorbed by the animal. This study examined the changes in the fecal metabolome of dairy cows from the end of one lactation period, through the dry period, and into the subsequent lactation. Twelve Holstein cows (BW = 745 ± 71 kg, BCS = 3.43 ± 0.66) were housed in a tiestall barn from 7 wk before to 15 wk after parturition, with dry-off occurring approximately 6 wk before the expected calving date (mean dry-off time = 42 d). Fecal samples were taken at wk -7, -5, -1, +1, +5, +10, and +15 relative to calving. Targeted metabolomics identified a total of 93 metabolites, including AA, biogenic amines, bile acids (BA), acylcarnitines (AcylCN), and some phospholipids. Principal component analysis (PCA) revealed clear metabolic shifts that showed a clear separation between the samples from the dry period and the samples from the end, early, and middle of lactation, indicating significant changes in the metabolic profiles in the feces. The transition from the dry period (wk -5, -1 relative to calving) to lactation (wk +1, +5, +10, +15, and -7 relative to calving) is characterized by an increase in fecal AA and metabolites, such as Glu, Met, β-alanine, and methionine sulfoxide, reflecting a shift in nitrogen metabolism to support increased protein metabolism for milk production. Higher concentrations of polyamines, such as spermidine and putrescine, were observed postpartum, indicating increased cell growth and improved tissue regeneration. Elevated gamma-aminobutyric acid levels during lactation indicate increased microbial activity driven by a nutrient-rich diet. Results showed significant adjustments in BA profiles as cows transitioned into lactation. Deoxycholic acid remained the predominant BA in feces, reflecting ongoing microbial transformation, whereas glycine- and taurine-conjugated BA increased postpartum, suggesting improved enterohepatic circulation and lipid absorption. Fecal AcylCN showed dynamic shifts with elevated levels during late gestation, a decrease in the dry period, and an increase postpartum, indicating increased fatty acid oxidation to meet energy demands. Results showed that phosphatidylcholines decreased prepartum but increased after calving. This indicates shifts in lipid metabolism reflecting energy requirements in lactation and suggests that fecal lipid composition is an indicator of metabolic adaptations in dairy cows. In particular, PCA revealed considerable overlap in the fecal metabolite profiles of multiparous and primiparous cows, indicating similar metabolic profiles. This was also confirmed by volcano plots, which showed no significant differences in fecal metabolism between the 2 groups across different weeks relative to calving (wk -7, -5, -1, +1, +5, +10, and +15). Overall, these results emphasize the complex interactions between dietary factors, liver and gastrointestinal function, and the gut microbiome in shaping the fecal metabolite profile of dairy cows. These results underscore the value of this data set in advancing the application of fecal metabolome profiling to investigate metabolic changes during critical transitions in the lactation cycle of dairy cows.
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Affiliation(s)
- M H Ghaffari
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
| | - H Sauerwein
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - H Sadri
- Department of Clinical Science, Faculty of Veterinary Medicine, University of Tabriz, 5166616471 Tabriz, Iran
| | - S Schuchardt
- Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | | | - J H Doelman
- Trouw Nutrition R&D, 3800 AG, Amersfoort, the Netherlands
| | - J B Daniel
- Trouw Nutrition R&D, 3800 AG, Amersfoort, the Netherlands.
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Feng G, Wang G, Li T, Han C, Han K, Guo J, Wan Z, Yang X. Phosphatidylcholine Surface Hydration-Dependent Adsorption to Mucin Enhances Intestinal Mucus Barrier Function. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2024; 40:18977-18987. [PMID: 39169607 DOI: 10.1021/acs.langmuir.4c01666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
The crucial role of zwitterionic phosphatidylcholines (PC) within mucus gel is essential for maintaining intestinal homeostasis, while the underlying mechanism remains incompletely understood. Herein, we compared the dynamic interfacial adsorption behavior of saturated dipalmitoylphosphatidylcholine (DPPC) and unsaturated dioleoylphosphatidylcholine (DOPC) to intestinal mucin and their impact on the intestinal mucus barrier function. Results of quartz crystal microbalance with dissipation showed that the highly surface-hydrated DPPC vesicles exhibited significantly faster and more extensive adsorption to purified intestinal mucin than the slightly surface-hydrated DOPC vesicles. Utilizing an intestinal Caco-2/HT29-MTX coculture model, we observed that DPPC vesicles adsorbed much more to the mucus gel compared to DOPC vesicles. Additionally, DPPC vesicle adsorption displayed increased wetting, and converse for DOPC vesicles. Interestingly, both of them exhibited nearly the same protective effects against cell injury induced by peptic-tryptic digests of gliadin (PTG). The partial mechanism involved the binding of PTG to DPPC and DOPC within the mucus gel, thereby restricting PTG contact with the underlying epithelial cells. These findings shed light on the intricate interfacial dynamics of PC adsorption to mucin and their implications for maintaining the integrity of the intestinal mucus barrier.
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Affiliation(s)
- Guangxin Feng
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, 1299 Sansha Road, Huangdao District, Qingdao 266003, Shandong Province, China
| | - Gaoshang Wang
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China
| | - Tanghao Li
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China
| | - Chuanwu Han
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China
| | - Kaining Han
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China
| | - Jian Guo
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China
| | - Zhili Wan
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China
| | - Xiaoquan Yang
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China
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Drenckpohl DC, Christifano DN, Carlson SE. Is choline deficiency an unrecognized factor in necrotizing enterocolitis of preterm infants? Pediatr Res 2024; 96:875-883. [PMID: 38658665 DOI: 10.1038/s41390-024-03212-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/23/2024] [Accepted: 03/15/2024] [Indexed: 04/26/2024]
Abstract
We undertook this review to determine if it is plausible that choline or phosphatidylcholine (PC) deficiency is a factor in necrotizing enterocolitis (NEC) after two clinical trials found a dramatic and unexpected reduction in NEC in an experimental group provided higher PC compared to a control group. Sources and amounts of choline/PC for preterm infants are compared to the choline status of preterm infants at birth and following conventional nutritional management. The roles of choline/PC in intestinal structure, mucus, mesenteric blood flow, and the cholinergic anti-inflammatory system are summarized. Low choline/PC status is linked to prematurity/immaturity, parenteral and enteral feeding, microbial dysbiosis and hypoxia/ischemia, factors long associated with the risk of developing NEC. We conclude that low choline status exists in preterm infants provided conventional parenteral and enteral nutritional management, and that it is plausible low choline/PC status adversely affects intestinal function to set up the vicious cycle of inflammation, loss of intestinal barrier function and worsening tissue hypoxia that occurs with NEC. In conclusion, this review supports the need for randomized clinical trials to test the hypothesis that additional choline or PC provided parenterally or enterally can reduce the incidence of NEC in preterm infants. IMPACT STATEMENT: Low choline status in preterm infants who are managed by conventional nutrition is plausibly linked to the risk of developing necrotizing enterocolitis.
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Affiliation(s)
- Douglas C Drenckpohl
- Department of Food & Nutrition, OSF Healthcare Saint Francis Medical Center, Peoria, IL, 61637, USA
- Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, KS, 66106, USA
| | - Danielle N Christifano
- Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, KS, 66106, USA
| | - Susan E Carlson
- Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, KS, 66106, USA.
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Eissa EM, El Sisi AM, Bekhet MA, El-Ela FIA, Kharshoum RM, Ali AA, Alrobaian M, Ali AMA. pH-Sensitive In Situ Gel of Mirtazapine Invasomes for Rectal Drug Delivery: Protruded Bioavailability and Anti-Depressant Efficacy. Pharmaceuticals (Basel) 2024; 17:978. [PMID: 39204084 PMCID: PMC11357403 DOI: 10.3390/ph17080978] [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: 06/18/2024] [Revised: 07/04/2024] [Accepted: 07/17/2024] [Indexed: 09/03/2024] Open
Abstract
The present research emphasizes fabrication alongside the assessment of an innovative nano-vesicular membranous system known as invasomes (NVMs) laden with Mirtazapine for rectal administration. This system could circumvent the confines of orally administered counterparts regarding dose schedules and bioavailability. Mirtazapine invasomes were tailored by amalgamating phospholipid, cineole, and ethanol through a thin-film hydration approach rooted in the Box-Behnken layout. Optimization of composition parameters used to fabricate desired NVMs' physicochemical attributes was undertaken using the Design-Expert® program. The optimal MRZ-NVMs were subsequently transformed to a pH-triggered in situ rectal gel followed by animal pharmacodynamic and pharmacokinetic investigations relative to rectal plain gel and oral suspension. The optimized NVMs revealed a diameter size of 201.3 nm, a z potential of -28.8 mV, an entrapment efficiency of 81.45%, a cumulative release within 12 h of 67.29%, and a cumulative daily permeated quantity of 468.68 µg/cm2. Compared to the oral suspension, pharmacokinetic studies revealed a 2.85- and 4.45-fold increase in calculated rectal bioavailability in circulation and brain, respectively. Pharmacodynamic and immunohistopathology evaluations exposed superior MRZ-NVMs attributed to the orally administered drug. Consequently, rectal MRZ-NVMs can potentially be regarded as a prospective nanoplatform with valuable pharmacokinetics and tolerability assets.
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Affiliation(s)
- Essam M. Eissa
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; (E.M.E.); (A.M.E.S.); (M.A.B.); (R.M.K.); (A.A.A.)
| | - Amani M. El Sisi
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; (E.M.E.); (A.M.E.S.); (M.A.B.); (R.M.K.); (A.A.A.)
| | - Marina A. Bekhet
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; (E.M.E.); (A.M.E.S.); (M.A.B.); (R.M.K.); (A.A.A.)
| | - Fatma I. Abo El-Ela
- Department of Pharmacology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt;
| | - Rasha M. Kharshoum
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; (E.M.E.); (A.M.E.S.); (M.A.B.); (R.M.K.); (A.A.A.)
| | - Adel A. Ali
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; (E.M.E.); (A.M.E.S.); (M.A.B.); (R.M.K.); (A.A.A.)
| | - Majed Alrobaian
- Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia;
| | - Ahmed M. Abdelhaleem Ali
- Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia;
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Dignass A, Stremmel W, Horyński M, Poyda O, Armerding P, Fellermann K, Langhorst J, Kuehbacher T, Uebel P, Stein J, Novacek G, Avalueva E, Oliinyk O, Hasselblatt P, Dorofeyev A, Heinemann H, Mueller R, Greinwald R, Reinisch W. Modified-Release Phosphatidylcholine (LT-02) for Ulcerative Colitis: Two Double-Blind, Randomized, Placebo-Controlled Trials. Clin Gastroenterol Hepatol 2024; 22:810-820.e7. [PMID: 37806372 DOI: 10.1016/j.cgh.2023.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 09/06/2023] [Accepted: 09/26/2023] [Indexed: 10/10/2023]
Abstract
BACKGROUND & AIMS The aim of this study was to evaluate the efficacy of LT-02, a novel modified-release phosphatidylcholine (PC) formulation, for induction and maintenance of remission in patients with mild to moderate ulcerative colitis (UC) and inadequate response to mesalamine. METHODS LT-02 was evaluated in a multicenter double-blind, randomized, placebo-controlled study comprising a 12-week induction trial (PCG-2), followed by a 48-week maintenance trial (PCG-4). In PCG-2, patients were randomized 1:1:1 to treatment with 0.8 g LT-02 4 times daily (QID), 1.6 g LT-02 twice daily (BID), or placebo, respectively. All patients continued to take a standard dose of oral mesalamine (≥2.4 g/day). The primary end point in PCG-2 was deep remission. Patients achieving remission at week 12 were randomly assigned 2:1:1 to 1.6 g LT-02 BID, placebo, or 500 mg mesalamine (3 times daily), respectively, in PCG-4; the primary end point was remission at 48 weeks. RESULTS PCG-2 was terminated early for futility after a prespecified interim analysis; 466 patients (of 762 planned) were randomized. There was no statistically significant difference in deep remission at week 12 (placebo, 13.5%; LT-02 BID, 14.2%; LT-02 QID, 9.7%). In PCG-4, 150 patients (of approximately 400 planned) were randomized. There was no statistically significant difference in remission rates at week 48 (LT-02 BID, 49.3%; mesalamine, 50.0%; placebo, 43.2%). LT-02 was safe. CONCLUSIONS Despite prior evidence of beneficial effects of PC in phase 2 trials, our induction study with LT-02 in patients with mild to moderate UC was terminated prematurely for futility. Signals of efficacy in maintenance therapy require confirmation in an adequately powered maintenance trial. LT-02 was safe and well-tolerated. CLINICALTRIALS gov: NCT02280629, NCT02142725.
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Affiliation(s)
- Axel Dignass
- Department of Medicine I, Agaplesion Markus Krankenhaus, Frankfurt am Main, Germany.
| | - Wolfgang Stremmel
- Department of Gastroenterology, University Hospital of Heidelberg, Heidelberg, Germany
| | | | - Oleksandr Poyda
- Department of Proctology, O.O. Bogomolets National Medical University, Kyiv, Ukraine
| | | | - Klaus Fellermann
- Division of Gastroenterology, Medical Department I, Campus Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany
| | - Jost Langhorst
- Department of Internal and Integrative Medicine, Kliniken Essen-Mitte, Essen, Germany
| | - Tanja Kuehbacher
- Internal Medicine/Gastroenterology, Asklepios Westklinikum Hamburg, Hamburg, Germany
| | - Peter Uebel
- Study Center for Internal Medicine, Haus der Gesundheit, Ludwigshafen, Germany
| | - Juergen Stein
- Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt am Main, Germany
| | - Gottfried Novacek
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Elena Avalueva
- North-Western State Medical University named after I. I. Mechnikov of the Ministry of Health of the Russian Federation, St Petersburg, Russia
| | | | - Peter Hasselblatt
- Department of Medicine II and Medical Faculty, Medical Center University of Freiburg, Freiburg, Germany
| | - Andrey Dorofeyev
- Ukrainian-German Anti-ulcer Gastroenterology Centre, Kyiv, Ukraine
| | - Heidrun Heinemann
- Department of Clinical Research, Dr. Falk Pharma GmbH, Freiburg, Germany
| | - Ralph Mueller
- Department of Clinical Research, Dr. Falk Pharma GmbH, Freiburg, Germany
| | - Roland Greinwald
- Department of Clinical Research, Dr. Falk Pharma GmbH, Freiburg, Germany
| | - Walter Reinisch
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Liu W, Wang Q, Bai Y, Xiao H, Li Z, Wang Y, Wang Q, Yang J, Sun H. Potential Application of Intestinal Organoids in Intestinal Diseases. Stem Cell Rev Rep 2024; 20:124-137. [PMID: 37938407 DOI: 10.1007/s12015-023-10651-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2023] [Indexed: 11/09/2023]
Abstract
To accurately reveal the scenario and mecahnism of gastrointestinal diseases, the establishment of in vitro models of intestinal diseases and drug screening platforms have become the focus of attention. Over the past few decades, animal models and immortalized cell lines have provided valuable but limited insights into gastrointestinal research. In recent years, the development of intestinal organoid culture system has revolutionized in vitro studies of intestinal diseases. Intestinal organoids are derived from self-renewal and self-organization intestinal stem cells (ISCs), which can replicate the genetic characteristics, functions, and structures of the original tissues. Consequently, they provide new stragety for studying various intestinal diseases in vitro. In the review, we will discuss the culture techniques of intestinal organoids and describe the use of intestinal organoids as research tools for intestinal diseases. The role of intestinal epithelial cells (IECs) played in the pathogenesis of inflammatory bowel diseases (IBD) and the treatment of intestinal epithelial dysfunction will be highlighted. Besides, we review the current knowledge on using intestinal organoids as models to study the pathogenesis of IBD caused by epithelial dysfunction and to develop new therapeutic approaches. Finally, we shed light on the current challenges of using intestinal organoids as in vitro models.
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Affiliation(s)
- Wenxiu Liu
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
- Lanzhou Huazhitiancheng Biotechnologies Co., Ltd, Lanzhou, 730000, Gansu, China
| | - Qian Wang
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Yanrui Bai
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Han Xiao
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Zhunduo Li
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Yan Wang
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Qi Wang
- Lanzhou Huazhitiancheng Biotechnologies Co., Ltd, Lanzhou, 730000, Gansu, China.
| | - Jing Yang
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China.
| | - Hui Sun
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China.
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Wen Y, Tan L, Chen S, Wu N, Yao Y, Xu L, Xu M, Zhao Y, Tu Y. Egg yolk phosphatidylcholine alleviates DSS-induced colitis in BALB/c mice. Food Funct 2023; 14:9309-9323. [PMID: 37781872 DOI: 10.1039/d3fo02885b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Ulcerative colitis (UC) is a common inflammatory bowel disease, whose incidence is on the rise worldwide. The drugs commonly used for UC are often associated with a number of side effects. Therefore, the development of effective, food-borne substances for UC is in line with the current needs. Egg yolk phosphatidylcholine (EYPC) is one of the abundant lipids in egg yolk and possesses various biological activities. However, its protective effect against UC has not been clarified. In this study, the anti-UC activity of EYPC was investigated using a dextran sodium sulfate (DSS)-induced colitis model of BALB/c mice. The results showed that EYPC supplementation inhibited DSS-induced colon shortening, the spleen index and disease activity index increase and intestinal structural damage. EYPC could down-regulate the levels of TNF-α, IL-1β, IL-6 and MPO in the colon and restore the number of goblet cells and the level of tight junction (TJ) proteins. Besides, EYPC modulated the composition of the gut microbiota, lowered the relative abundance of the pathogenic bacterium Parabacteroides and upregulated the abundance of the beneficial bacteria Alistipes and Lachnospiraceae_NK4A136_group. These results evidenced that EYPC could attenuate DSS-induced colitis in mice and had the potential to prevent and treat UC.
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Affiliation(s)
- Yunpeng Wen
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Lixin Tan
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Shuping Chen
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Na Wu
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Yao Yao
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Lilan Xu
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Mingsheng Xu
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Yan Zhao
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Yonggang Tu
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China
- Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nanchang 330045, China
- Nanchang Key Laboratory of Egg Safety Production and Processing Engineering, Jiangxi Agricultural University, Nanchang 330045, China
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8
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Stremmel W, Vural H, Evliyaoglu O, Weiskirchen R. [Efficacy of enteric lecithin (phosphatidylcholine) in the treatment of ulcerative colitis: a meta-analysis]. MMW Fortschr Med 2022; 164:3-11. [PMID: 35831742 DOI: 10.1007/s15006-022-0832-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
BACKGROUND Phosphatidylcholine is an essential component of the intestinal mucus and serves as a protective shield against the ingress of bacteria from the stool. In the intestinal mucus of patients with ulcerative colitis, phosphatidylcholine is reduced by 70%, which makes the intestine susceptible to bacterial inflammation. Local application by administering enteric phosphatidylcholine could compensate for this deficiency. METHOD A summary analysis of three clinical studies published until now with 160 included patients with ulcerative colitis was performed. RESULTS AND CONCLUSION The meta-analysis showed that lecithin enriched with phosphatidylcholine and microencapsulated with Eudragit S-100 significantly improved the remission rate as well as the clinical and endoscopic picture. There was also an improvement in histology and quality of life. All parameters were significantly superior to placebo. The remission achieved was maintained significantly longer with enteric lecithin than with placebo. The side effect profile was identical to the placebo group, which is particularly important for the patients. In complementary medicine, phosphatidylcholine can be seen as protection for the intestines.
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Affiliation(s)
- Wolfgang Stremmel
- Medical Center Baden-Baden, Beethovenstraße 2, 76530, Baden-Baden, Deutschland.
| | - Hüseyin Vural
- Institut für Molekulare Pathobio-chemie, Experimentelle Gentherapie und Klinische Chemie, RWTH Universitätsklinikum Aachen, Aachen, Deutschland
| | - Osman Evliyaoglu
- Institut für Molekulare Pathobio-chemie, Experimentelle Gentherapie und Klinische Chemie, RWTH Universitätsklinikum Aachen, Aachen, Deutschland
| | - Ralf Weiskirchen
- Institut für Molekulare Pathobio-chemie, Experimentelle Gentherapie und Klinische Chemie, RWTH Universitätsklinikum Aachen, Aachen, Deutschland
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Fritsch DA, Jackson MI, Wernimont SM, Feld GK, MacLeay JM, Brejda JJ, Cochrane CY, Gross KL. Microbiome function underpins the efficacy of a fiber-supplemented dietary intervention in dogs with chronic large bowel diarrhea. BMC Vet Res 2022; 18:245. [PMID: 35751094 PMCID: PMC9233311 DOI: 10.1186/s12917-022-03315-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 05/16/2022] [Indexed: 11/10/2022] Open
Abstract
Background Chronic large bowel diarrhea is a common occurrence in pet dogs. While nutritional intervention is considered the primary therapy, the metabolic and gut microfloral effects of fiber and polyphenol-enriched therapeutic foods are poorly understood. Methods This prospective clinical study enrolled 31 adult dogs from private veterinary practices with chronic, active large bowel diarrhea. Enrolled dogs received a complete and balanced dry therapeutic food containing a proprietary fiber bundle for 56 days. Metagenomic and metabolomic profiling were performed on fecal samples at Days 1, 2, 3, 14, 28, and 56; metabolomic analysis was conducted on serum samples taken at Days 1, 2, 3, 28, and 56. Results The dietary intervention improved clinical signs and had a clear effect on the gut microfloral metabolic output of canines with chronic diarrhea, shifting gut metabolism from a predominantly proteolytic to saccharolytic fermentative state. Microbial metabolism of tryptophan to beneficial indole postbiotics and the conversion of plant-derived phenolics into bioavailable postbiotics were observed. The intervention altered the endocannabinoid, polyunsaturated fatty acid, and sphingolipid profiles, suggesting a modulation in gastrointestinal inflammation. Changes in membrane phospholipid and collagen signatures were indicative of improved gut function and possible alleviation of the pathophysiology related to chronic diarrhea. Conclusions In dogs with chronic diarrhea, feeding specific dietary fibers increased gut saccharolysis and bioavailable phenolic and indole-related compounds, while suppressing putrefaction. These changes were associated with improved markers of gut inflammation and stool quality. Supplementary Information The online version contains supplementary material available at 10.1186/s12917-022-03315-3.
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Affiliation(s)
- Dale A Fritsch
- Global Clinical Nutrition and Claims, Hill's Pet Nutrition, Inc., P.O. Box 1658, 1035 43rd St., Topeka, KS, 66601-1658, USA.
| | - Matthew I Jackson
- Global Clinical Nutrition and Claims, Hill's Pet Nutrition, Inc., P.O. Box 1658, 1035 43rd St., Topeka, KS, 66601-1658, USA.,Hill's Pet Nutrition, Inc., 1035 NE 43rd St., Topeka, KS, USA
| | - Susan M Wernimont
- Global Clinical Nutrition and Claims, Hill's Pet Nutrition, Inc., P.O. Box 1658, 1035 43rd St., Topeka, KS, 66601-1658, USA.,Hill's Pet Nutrition, Inc., 1035 NE 43rd St., Topeka, KS, USA
| | - Geoffrey K Feld
- Metabolon, Inc., 617 Davis Dr, Morrisville, NC, USA.,Geocyte, Dublin, OH, USA
| | | | | | - Chun-Yen Cochrane
- Global Clinical Nutrition and Claims, Hill's Pet Nutrition, Inc., P.O. Box 1658, 1035 43rd St., Topeka, KS, 66601-1658, USA.,Hill's Pet Nutrition, Inc., 1035 NE 43rd St., Topeka, KS, USA
| | - Kathy L Gross
- Global Clinical Nutrition and Claims, Hill's Pet Nutrition, Inc., P.O. Box 1658, 1035 43rd St., Topeka, KS, 66601-1658, USA.,Hill's Pet Nutrition, Inc., 1035 NE 43rd St., Topeka, KS, USA
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10
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Yamamoto-Furusho JK, Parra-Holguín NN. Emerging therapeutic options in inflammatory bowel disease. World J Gastroenterol 2021; 27:8242-8261. [PMID: 35068868 PMCID: PMC8717021 DOI: 10.3748/wjg.v27.i48.8242] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/04/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease that requires chronic treatment throughout the evolution of the disease, with a complex physiopathology that entails great challenges for the development of new and specific treatments for ulcerative colitis and Crohn´s disease. The anti-tumor necrosis factor alpha therapy has impacted the clinical course of IBD in those patients who do not respond to conventional treatment, so there is a need to develop new therapies and markers of treatment response. Various pathways involved in the development of the disease are known and the new therapies have focused on blocking the inflammatory process at the gastrointestinal level by oral, intravenous, subcutaneous, and topical route. All these new therapies can lead to more personalized treatments with higher success rates and fewer relapses. These treatments have not only focused on clinical remission, but also on achieving macroscopic changes at the endoscopic level and microscopic changes by achieving mucosal healing. These treatments are mainly based on modifying signaling pathways, by blocking receptors or ligands, reducing cell migration and maintaining the integrity of the epithelial barrier. Therefore, this review presents the efficacy and safety of the new treatments that are currently under study and the advances that have been made in this area in recent years.
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Affiliation(s)
- Jesus K Yamamoto-Furusho
- Gastroenterology Unit, Inflammatory Bowel Disease Clinic, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City 14080, Mexico
| | - Norma N Parra-Holguín
- Gastroenterology Unit, Inflammatory Bowel Disease Clinic, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City 14080, Mexico
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11
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Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms222111682. [PMID: 34769112 PMCID: PMC8584226 DOI: 10.3390/ijms222111682] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/20/2021] [Accepted: 10/27/2021] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic inflammation within the gastrointestinal (GI) tract. Despite the significant progress in understanding the etiology and development of treatment strategies, IBD remain incurable for thousands of patients. Metabolic deregulation is indicative of IBD, including substantial shifts in lipid metabolism. Recent data showed that changes in some phospholipids are very common in IBD patients. For instance, phosphatidylcholine (PC)/phosphatidylethanolamine (PE) and lysophosphatidylcholine (LPC)/PC ratios are associated with the severity of the inflammatory process. Composition of phospholipids also changes upon IBD towards an increase in arachidonic acid and a decrease in linoleic and a-linolenic acid levels. Moreover, an increase in certain phospholipid metabolites, such as lysophosphatidylcholine, sphingosine-1-phosphate and ceramide, can result in enhanced intestinal inflammation, malignancy, apoptosis or necroptosis. Because some phospholipids are associated with pathogenesis of IBD, they may provide a basis for new strategies to treat IBD. Current attempts are aimed at controlling phospholipid and fatty acid levels through the diet or via pharmacological manipulation of lipid metabolism.
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12
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Plant-Derived Nano and Microvesicles for Human Health and Therapeutic Potential in Nanomedicine. Pharmaceutics 2021; 13:pharmaceutics13040498. [PMID: 33917448 PMCID: PMC8067521 DOI: 10.3390/pharmaceutics13040498] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/28/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
Plants produce different types of nano and micro-sized vesicles. Observed for the first time in the 60s, plant nano and microvesicles (PDVs) and their biological role have been inexplicably under investigated for a long time. Proteomic and metabolomic approaches revealed that PDVs carry numerous proteins with antifungal and antimicrobial activity, as well as bioactive metabolites with high pharmaceutical interest. PDVs have also been shown to be also involved in the intercellular transfer of small non-coding RNAs such as microRNAs, suggesting fascinating mechanisms of long-distance gene regulation and horizontal transfer of regulatory RNAs and inter-kingdom communications. High loading capacity, intrinsic biological activities, biocompatibility, and easy permeabilization in cell compartments make plant-derived vesicles excellent natural or bioengineered nanotools for biomedical applications. Growing evidence indicates that PDVs may exert anti-inflammatory, anti-oxidant, and anticancer activities in different in vitro and in vivo models. In addition, clinical trials are currently in progress to test the effectiveness of plant EVs in reducing insulin resistance and in preventing side effects of chemotherapy treatments. In this review, we concisely introduce PDVs, discuss shortly their most important biological and physiological roles in plants and provide clues on the use and the bioengineering of plant nano and microvesicles to develop innovative therapeutic tools in nanomedicine, able to encompass the current drawbacks in the delivery systems in nutraceutical and pharmaceutical technology. Finally, we predict that the advent of intense research efforts on PDVs may disclose new frontiers in plant biotechnology applied to nanomedicine.
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13
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Stremmel W, Lukasova M, Weiskirchen R. The neglected biliary mucus and its phosphatidylcholine content: a putative player in pathogenesis of primary cholangitis-a narrative review article. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:738. [PMID: 33987436 PMCID: PMC8106090 DOI: 10.21037/atm-20-3591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare progressive cholangitis resulting in cirrhosis and cholangiocellular carcinoma. The pathogenesis is unclear and an effective medical therapy is not available. It is highly associated to ulcerative colitis for which recently a disturbance of the tight junction (TJ) barrier has been claimed as etiologic feature. Genetic mouse models with intestinal TJ disruption showed a defective transport of phosphatidylcholine (PC) to intestinal mucus. Consequently, an ulcerative colitis phenotype developed. In the present study we evaluate whether there is also a paracellular transport of PC through TJ to the apical side of cholangiocytes. As in ulcerative colitis, a TJ defect could lead to deficient PC in biliary mucus. It would impair the protective barrier against aggressive bile acids in bile. Indeed with polarized biliary tumor cells a vectorial transport of PC from basal to luminal side was demonstrated using a transwell culture system. PC was not taken up by the cells but moved paracellularly via TJ to the apical side driven by luminal HCO3- generated by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and the anion exchange protein 2 (AE2). If such a TJ-mediated PC translocation to the apical surface of cholangiocytes could be disrupted in a genetic mouse model, a PSC phenotype would be expected. With such an experimental model functional operative therapies can be evaluated. We propose that disruption of TJ mediated paracellular transport of PC to the apical side of cholangiocytes could lead to biliary mucus PC depletion. This may be a pathogenetic factor for development of PSC.
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Affiliation(s)
| | - Martina Lukasova
- Pharmacy of University Clinics of Heidelberg, Heidelberg, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
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14
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Stremmel W, Vural H, Evliyaoglu O, Weiskirchen R. Delayed-Release Phosphatidylcholine Is Effective for Treatment of Ulcerative Colitis: A Meta-Analysis. Dig Dis 2021; 39:508-515. [PMID: 33440385 DOI: 10.1159/000514355] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/22/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Phosphatidylcholine (PC) is intrinsically missing in intestinal mucus of patients with ulcerative colitis. Topical supplementation with delayed intestinal release PC formulations is assumed to compensate this lack. Three monocenter randomized controlled trials (RCTs) with a 30% PC-containing lecithin were successful, whereas 1 trial with >94% PC-containing lecithin failed. OBJECTIVES Evaluation of 30% PC-containing lecithin provided in a delayed intestinal release formulation for treatment efficacy of ulcerative colitis was evaluated by meta-analysis of 3 RCTs. METHODS Meta-analysis of 3 studies was performed using RevMan 5.3 software. Odds ratio (OR) and 95% Cl were calculated for remission, clinical and endoscopic improvement, histology, and life quality. p values <0.05 were accepted as significant. RESULTS The meta-analysis of 3 RTCs with 160 included patients with ulcerative colitis verified that PC improved the rate of remission (OR = 9.68), as well as clinical (OR = 30.58) and endoscopic outcomes (OR = 36.73). Within the available patient population, also histology and quality of life became better. All effects were significant over placebo. Achieved remission was maintained in a higher percentage of patients under intestinal-release PC formulation than placebo. The profile of adverse events was identical to the placebo population. CONCLUSIONS A 30% PC-containing lecithin in delayed intestinal release formulation improves clinical and endoscopic outcomes, histologic activity, and quality of life in patients with ulcerative colitis. For the patients, lack of adverse events is an important consideration.
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Affiliation(s)
| | - Hüseyin Vural
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
| | - Osman Evliyaoglu
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
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15
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Miclotte L, De Paepe K, Rymenans L, Callewaert C, Raes J, Rajkovic A, Van Camp J, Van de Wiele T. Dietary Emulsifiers Alter Composition and Activity of the Human Gut Microbiota in vitro, Irrespective of Chemical or Natural Emulsifier Origin. Front Microbiol 2020; 11:577474. [PMID: 33250870 PMCID: PMC7676226 DOI: 10.3389/fmicb.2020.577474] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022] Open
Abstract
The use of additives in food products has become an important public health concern. In recent reports, dietary emulsifiers have been shown to affect the gut microbiota, contributing to a pro-inflammatory phenotype and metabolic syndrome. So far, it is not yet known whether similar microbiome shifts are observable for a more diverse set of emulsifier types and to what extent these effects vary with the unique features of an individual's microbiome. To bridge this gap, we investigated the effect of five dietary emulsifiers on the fecal microbiota from 10 human individuals upon a 48 h exposure. Community structure was assessed with quantitative microbial profiling, functionality was evaluated by measuring fermentation metabolites, and pro-inflammatory properties were assessed with the phylogenetic prediction algorithm PICRUSt, together with a TLR5 reporter cell assay for flagellin. A comparison was made between two mainstream chemical emulsifiers (carboxymethylcellulose and P80), a natural extract (soy lecithin), and biotechnological emulsifiers (sophorolipids and rhamnolipids). While fecal microbiota responded in a donor-dependent manner to the different emulsifiers, profound differences between emulsifiers were observed. Rhamnolipids, sophorolipids, and soy lecithin eliminated 91 ± 0, 89 ± 1, and 87 ± 1% of the viable bacterial population after 48 h, yet they all selectively increased the proportional abundance of putative pathogens. Moreover, profound shifts in butyrate (-96 ± 6, -73 ± 24, and -34 ± 25%) and propionate (+13 ± 24, +88 ± 50, and +29 ± 16%) production were observed for these emulsifiers. Phylogenetic prediction indicated higher motility, which was, however, not confirmed by increased flagellin levels using the TLR5 reporter cell assay. We conclude that dietary emulsifiers can severely impact the gut microbiota, and this seems to be proportional to their emulsifying strength, rather than emulsifier type or origin. As biotechnological emulsifiers were especially more impactful than chemical emulsifiers, caution is warranted when considering them as more natural alternatives for clean label strategies.
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Affiliation(s)
- Lisa Miclotte
- Center for Microbial Ecology and Technology (CMET), Ghent University, Ghent, Belgium
| | - Kim De Paepe
- Center for Microbial Ecology and Technology (CMET), Ghent University, Ghent, Belgium
| | - Leen Rymenans
- Vlaams Instituut voor Biotechnologie (VIB) Nucleomics Core, Lab of Molecular Bacteriology – Rega, KULeuven, Ghent, Belgium
| | - Chris Callewaert
- Center for Microbial Ecology and Technology (CMET), Ghent University, Ghent, Belgium
| | - Jeroen Raes
- Vlaams Instituut voor Biotechnologie (VIB) Nucleomics Core, Lab of Molecular Bacteriology – Rega, KULeuven, Ghent, Belgium
| | - Andreja Rajkovic
- Department of Food Technology, Food Safety and Health, Ghent University, Ghent, Belgium
| | - John Van Camp
- Department of Food Technology, Food Safety and Health, Ghent University, Ghent, Belgium
| | - Tom Van de Wiele
- Center for Microbial Ecology and Technology (CMET), Ghent University, Ghent, Belgium
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16
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Effinger A, M O'Driscoll C, McAllister M, Fotaki N. Gastrointestinal diseases and their impact on drug solubility: Ulcerative Colitis. Eur J Pharm Sci 2020; 152:105458. [PMID: 32645424 DOI: 10.1016/j.ejps.2020.105458] [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: 03/27/2020] [Revised: 06/12/2020] [Accepted: 07/05/2020] [Indexed: 12/11/2022]
Abstract
For poorly soluble compounds, drug product performance in patients with Ulcerative Colitis (UC) compared to healthy subjects can be affected due to differences in drug solubility in GI fluids. A risk assessment tool was developed to identify compounds with a high risk of altered solubility in the GI fluids of UC patients. Pathophysiological changes impacting on the composition of GI fluids in UC patients were considered and UC biorelevant media representative of the stomach, intestine and colon were developed based on biorelevant media based on healthy subjects and literature data using a Design of Experiment approach. The UC media were characterised and revealed differences in surface tension, osmolality and buffer capacity compared to media based on healthy subjects. The solubility of six drugs was investigated in UC biorelevant media and results were related to media- and drug-dependent factors. A lower drug solubility in UC intestinal media was observed for compounds with a high lipophilicity. In UC simulated colonic fluids, drug solubility was altered for ionisable compounds. Additionally, a higher solubility of neutral lipophilic drugs was observed in UC fasted state colonic media with increased concentrations of soluble proteins. The developed UC biorelevant media offer the possibility to identify the risk of altered drug solubilisation in UC patients without conducting expensive clinical trials. A high risk was related to drug ionization properties and lipophilicity in the current study with all investigated drugs showing differences in solubility in biorelevant media based on UC patients compared to healthy subjects.
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Affiliation(s)
- Angela Effinger
- Department of Pharmacy and Pharmacology, University of Bath, Bath, UK
| | | | | | - Nikoletta Fotaki
- Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
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17
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Zhang G, Zwierzchowski G, Mandal R, Wishart DS, Ametaj BN. Serum metabolomics identifies metabolite panels that differentiate lame dairy cows from healthy ones. Metabolomics 2020; 16:73. [PMID: 32535675 DOI: 10.1007/s11306-020-01693-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 06/04/2020] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Although much is known about lameness application of metabolomics technologies to better understanding its etiology and pathogenesis is of utmost interest. OBJECTIVES The objective of this study was to investigate serum metabolite alterations in pre-lame, lame and post-lame dairy cows in order to identify potential screening serum metabolite biomarkers for lameness and better understand its pathobiology. METHODS A combination of direct injection and tandem mass spectrometry (DI-MS/MS) with a reverse-phase liquid chromatography and tandem mass spectrometry (LC-MS/MS) analysis was performed in the serum of six cases of lameness and 20 healthy control cows (CON) at - 8 and - 4 weeks prepartum, at lameness diagnosis week, and at + 4 and + 8 weeks postpartum. RESULTS Data indicated that pre-lame, lame, and post-lame cows experienced altered concentrations of multiple metabolites. It is interesting to note that throughout the 16-weeks of the study, 7 serum metabolites [e.g., diacyl-phosphatidylcholine (PC aa) C30:0, phosphatidylcholine acyl-alkyl (PC ae) C40:2, sphingomyelin (SM) (OH) C14:1, SM C18:0, isoleucine (Ile), leucine (Leu), and lysine (Lys)] differentiated CON cows from the lame ones. Furthermore, 4 metabolic pathways (i.e., Lys degradation, biotin metabolism, tryptophan (Trp) metabolism, and valine [(Val)-Leu-Ile degradation) were altered in cows with lameness during the onset and progression of the disease. CONCLUSION Multiple metabolite and pathway alterations were identified in the serum of pre-lame, lame, and post-lame cows that through light into the pathobiology of the disease and that can be used as potential biomarker sets that can predict the risk of lameness in dairy cows.
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Affiliation(s)
- Guanshi Zhang
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2P5, Canada
- Center for Renal Precision Medicine, Department of Medicine, University of Texas Health, San Antonio, TX, 78229, USA
| | - Grzegorz Zwierzchowski
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2P5, Canada
- Faculty of Biology and Biotechnology, University of Warmia and Mazury, 1a Oczapowskiego Str., 10-719, Olsztyn, Poland
| | - Rupasri Mandal
- Departments of Biological Sciences and Computing Science, University of Alberta, Edmonton, AB, T6G 2E9, Canada
| | - David S Wishart
- Departments of Biological Sciences and Computing Science, University of Alberta, Edmonton, AB, T6G 2E9, Canada
| | - Burim N Ametaj
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2P5, Canada.
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18
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Mödinger Y, Schön C, Wilhelm M, Hals PA. Plasma Kinetics of Choline and Choline Metabolites After A Single Dose of Superba BoostTM Krill Oil or Choline Bitartrate in Healthy Volunteers. Nutrients 2019; 11:nu11102548. [PMID: 31652561 PMCID: PMC6835836 DOI: 10.3390/nu11102548] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/16/2019] [Accepted: 10/18/2019] [Indexed: 12/23/2022] Open
Abstract
As an essential nutrient, the organic water-soluble compound choline is important for human health. Choline is required for numerous biological processes, including the synthesis of neurotransmitters, and it is an important prerequisite for structural integrity and the functioning of cells. A choline-rich diet provides crucial choline sources, yet additional choline dietary supplements might be needed to fully meet the body’s requirements. Dependent on the structure of choline in different sources, absorption and metabolism may differ and strongly impact the bioavailability of circulating choline. This study in healthy volunteers aimed to compare the pharmacokinetics of free choline and of selected choline metabolites between the single dose intake of phosphatidylcholine, present in SuperbaBoostTM krill oil, and choline bitartrate salt. Results demonstrate that albeit free choline levels in plasma were comparable between both choline sources, peak choline concentration was reached significantly later upon intake of SuperbaBoostTM. Moreover, the occurrence of choline metabolites differed between the study products. Levels of the biologically important metabolites betaine and dimethylglycine (DMG) were higher, while levels of trimethylamine N-oxide (TMAO) were substantially lower upon intake of SuperbaBoostTM compared to choline bitartrate.
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Affiliation(s)
- Yvonne Mödinger
- BioTeSys GmbH, Schelztorstraße 54-56, 73728 Esslingen, Germany.
| | | | - Manfred Wilhelm
- Department of Mathematics, Natural and Economic Sciences, Ulm University of Applied Sciences, Albert-Einstein-Allee 55, 89081 Ulm, Germany.
| | - Petter-Arnt Hals
- Aker BioMarine Antarctic AS, Oksenøyveien 10, 1327 Lysaker, Norway.
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Yoo JH, Donowitz M. Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases. World J Gastroenterol 2019; 25:4125-4147. [PMID: 31435168 PMCID: PMC6700704 DOI: 10.3748/wjg.v25.i30.4125] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/14/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
The introduction of biologics such as anti-tumor necrosis factor (TNF) monoclonal antibodies followed by anti-integrins has dramatically changed the therapeutic paradigm of inflammatory bowel diseases (IBD). Furthermore, a newly developed anti-p40 subunit of interleukin (IL)-12 and IL-23 (ustekinumab) has been recently approved in the United States for patients with moderate to severe Crohn’s disease who have failed treatment with anti-TNFs. However, these immunosuppressive therapeutics which focus on anti-inflammatory mechanisms or immune cells still fail to achieve long-term remission in a significant percentage of patients. This strongly underlines the need to identify novel treatment targets beyond immune suppression to treat IBD. Recent studies have revealed the critical role of intestinal epithelial cells (IECs) in the pathogenesis of IBD. Physical, biochemical and immunologic driven barrier dysfunctions of epithelial cells contribute to the development of IBD. In addition, the recent establishment of adult stem cell-derived intestinal enteroid/organoid culture technology has allowed an exciting opportunity to study human IECs comprising all normal epithelial cells. This long-term epithelial culture model can be generated from endoscopic biopsies or surgical resections and recapitulates the tissue of origin, representing a promising platform for novel drug discovery in IBD. This review describes the advantages of intestinal enteroids/organoids as a research tool for intestinal diseases, introduces studies with these models in IBD, and gives a description of the current status of therapeutic approaches in IBD. Finally, we provide an overview of the current endeavors to identify a novel drug target for IBD therapy based on studies with human enteroids/organoids and describe the challenges in using enteroids/organoids as an IBD model.
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Affiliation(s)
- Jun-Hwan Yoo
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
| | - Mark Donowitz
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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Abstract
Various therapeutic advances have led to a paradigm shift in the clinical management of patients with IBD. The introduction of immunosuppressive (such as azathioprine) and biologic agents (such as TNF blockers) has markedly reduced the need to use corticosteroids for therapy. Furthermore, the α4β7 integrin blocker vedolizumab has been introduced for clinical IBD therapy. Moreover, various new inhibitors of cytokines (for example, IL-6-IL-6R and IL-12-IL-23 blockers or apremilast), modulators of cytokine signalling events (for example, JAK inhibitors or SMAD7 blocker), inhibitors of transcription factors (for example, GATA3 or RORγt) and new anti-adhesion and anti-T-cell-activation and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors and MAdCAM1 inhibitors, regulatory T-cell therapy and stem cells) are currently being evaluated in controlled clinical trials. This Review aims to provide a comprehensive overview about current and future therapeutic approaches for IBD therapy. Furthermore, potential mechanisms of action of these therapeutic approaches and their implications for clinical therapy in IBD are discussed.
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Affiliation(s)
- Markus F Neurath
- Department of Medicine 1, Kussmaul Campus for Medical Research, Ludwig Demling Endoscopy Center of Excellence, Ulmenweg 18, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
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21
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The Immunosuppressant Mycophenolic Acid Alters Nucleotide and Lipid Metabolism in an Intestinal Cell Model. Sci Rep 2017; 7:45088. [PMID: 28327659 PMCID: PMC5361167 DOI: 10.1038/srep45088] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 02/16/2017] [Indexed: 01/14/2023] Open
Abstract
The study objective was to elucidate the molecular mechanisms underlying the negative effects of mycophenolic acid (MPA) on human intestinal cells. Effects of MPA exposure and guanosine supplementation on nucleotide concentrations in LS180 cells were assessed using liquid chromatography-mass spectrometry. Proteomics analysis was carried out using stable isotope labeling by amino acids in cell culture combined with gel-based liquid chromatography-mass spectrometry and lipidome analysis using 1H nuclear magnetic resonance spectroscopy. Despite supplementation, depletion of guanosine nucleotides (p < 0.001 at 24 and 72 h; 5, 100, and 250 μM MPA) and upregulation of uridine and cytidine nucleotides (p < 0.001 at 24 h; 5 μM MPA) occurred after exposure to MPA. MPA significantly altered 35 proteins mainly related to nucleotide-dependent processes and lipid metabolism. Cross-reference with previous studies of MPA-associated protein changes widely corroborated these results, but showed differences that may be model- and/or method-dependent. MPA exposure increased intracellular concentrations of fatty acids, cholesterol, and phosphatidylcholine (p < 0.01 at 72 h; 100 μM MPA) which corresponded to the changes in lipid-metabolizing proteins. MPA affected intracellular nucleotide levels, nucleotide-dependent processes, expression of structural proteins, fatty acid and lipid metabolism in LS180 cells. These changes may compromise intestinal membrane integrity and contribute to gastrointestinal toxicity.
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Wu Q, Zou M, Yang M, Zhou S, Yan X, Sun B, Wang Y, Chang S, Tang Y, Liang F, Yu S. Revealing Potential Biomarkers of Functional Dyspepsia by Combining 1H NMR Metabonomics Techniques and an Integrative Multi-objective Optimization Method. Sci Rep 2016; 6:18852. [PMID: 26743458 PMCID: PMC4705523 DOI: 10.1038/srep18852] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 11/27/2015] [Indexed: 12/31/2022] Open
Abstract
Metabonomics methods have gradually become important auxiliary tools for screening disease biomarkers. However, recognition of metabolites or potential biomarkers closely related to either particular clinical symptoms or prognosis has been difficult. The current study aims to identify potential biomarkers of functional dyspepsia (FD) by a new strategy that combined hydrogen nuclear magnetic resonance ((1)H NMR)-based metabonomics techniques and an integrative multi-objective optimization (LPIMO) method. First, clinical symptoms of FD were evaluated using the Nepean Dyspepsia Index (NDI), and plasma metabolic profiles were measured by (1)H NMR. Correlations between the key metabolites and the NDI scores were calculated. Then, LPIMO was developed to identify a multi-biomarker panel by maximizing diagnostic ability and correlation with the NDI score. Finally, a KEGG database search elicited the metabolic pathways in which the potential biomarkers are involved. The results showed that glutamine, alanine, proline, HDL, β-glucose, α-glucose and LDL/VLDL levels were significantly altered in FD patients. Among them, phosphatidycholine (PtdCho) and leucine/isoleucine (Leu/Ile) were positively and negatively correlated with the NDI Symptom Index (NDSI) respectively. Our procedure not only significantly improved the credibility of the biomarkers, but also demonstrated the potential of further explorations and applications to diagnosis and treatment of complex disease.
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Affiliation(s)
- Qiaofeng Wu
- Acupuncture and Tuina College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
| | - Meng Zou
- National Center for Mathematics and Interdisciplinary Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100080, China
| | - Mingxiao Yang
- Acupuncture and Tuina College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
| | - Siyuan Zhou
- Acupuncture and Tuina College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
| | - Xianzhong Yan
- National Center of Biomedical Analysis, Beijing, 100850, China
| | - Bo Sun
- National Center of Biomedical Analysis, Beijing, 100850, China
| | - Yong Wang
- National Center for Mathematics and Interdisciplinary Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100080, China
| | - Shyang Chang
- Department of Electrical Engineering, National Tsing Hua University, Hsinchu, 300, Taiwan
| | - Yong Tang
- Acupuncture and Tuina College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
| | - Fanrong Liang
- Acupuncture and Tuina College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
| | - Shuguang Yu
- Acupuncture and Tuina College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
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Castro-Gómez P, Garcia-Serrano A, Visioli F, Fontecha J. Relevance of dietary glycerophospholipids and sphingolipids to human health. Prostaglandins Leukot Essent Fatty Acids 2015; 101:41-51. [PMID: 26242691 DOI: 10.1016/j.plefa.2015.07.004] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 07/15/2015] [Accepted: 07/16/2015] [Indexed: 01/07/2023]
Abstract
Glycerophospholipids and sphingolipids participate in a variety of indispensable metabolic, neurological, and intracellular signaling processes. In this didactic paper we review the biological roles of phospholipids and try to unravel the precise nature of their putative healthful activities. We conclude that the biological actions of phospholipids activities potentially be nutraceutically exploited in the adjunct therapy of widely diffused pathologies such as neurodegeneration or the metabolic syndrome. As phospholipids can be recovered from inexpensive sources such as food processing by-products, ad-hoc investigation is warranted.
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Affiliation(s)
- P Castro-Gómez
- Department of Bioactivity and Food Analysis, Group of Lipids, Instituto de Investigación en Ciencias de la Alimentación (CIAL CSIC-UAM), Universidad Autónoma de Madrid, Nicolás Cabrera, 9, Madrid 28049, Spain
| | - A Garcia-Serrano
- Department of Bioactivity and Food Analysis, Group of Lipids, Instituto de Investigación en Ciencias de la Alimentación (CIAL CSIC-UAM), Universidad Autónoma de Madrid, Nicolás Cabrera, 9, Madrid 28049, Spain
| | - F Visioli
- Department of Molecular Medicine, University of Padova, Padova, Italy; IMDEA-Food, CEI UAM+CSIC, Madrid, Spain
| | - J Fontecha
- Department of Bioactivity and Food Analysis, Group of Lipids, Instituto de Investigación en Ciencias de la Alimentación (CIAL CSIC-UAM), Universidad Autónoma de Madrid, Nicolás Cabrera, 9, Madrid 28049, Spain.
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Zhu J, Wu Y, Guo Y, Tang Q, Lu T, Cai W, Huang H. Choline Alleviates Parenteral Nutrition-Associated Duodenal Motility Disorder in Infant Rats. JPEN J Parenter Enteral Nutr 2015; 40:995-1005. [PMID: 25904588 DOI: 10.1177/0148607115583674] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 03/08/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Parenteral nutrition (PN) has been found to influence duodenal motility in animals. Choline is an essential nutrient, and its deficiency is related to PN-associated organ diseases. Therefore, this study was aimed to investigate the role of choline supplementation in an infant rat model of PN-associated duodenal motility disorder. MATERIALS AND METHODS Three-week-old Sprague-Dawley male rats were fed chow and water (controls), PN solution (PN), or PN plus intravenous choline (600 mg/kg) (PN + choline). Rats underwent jugular vein cannulation for infusion of PN solution or 0.9% saline (controls) for 7 days. Duodenal oxidative stress status, concentrations of plasma choline, phosphocholine, and betaine and serum tumor necrosis factor (TNF)-α were assayed. The messenger RNA (mRNA) and protein expression of c-Kit proto-oncogene protein (c-Kit) and membrane-bound stem cell factor (mSCF) together with the electrophysiological features of slow waves in the duodenum were also evaluated. RESULTS Rats on PN showed increased reactive oxygen species; decreased total antioxidant capacity in the duodenum; reduced plasma choline, phosphocholine, and betaine; and enhanced serum TNF-α concentrations, which were reversed by choline intervention. In addition, PN reduced mRNA and protein expression of mSCF and c-Kit, which were inversed under choline administration. Moreover, choline attenuated depolarized resting membrane potential and declined the frequency and amplitude of slow waves in duodenal smooth muscles of infant rats induced by PN, respectively. CONCLUSION The addition of choline to PN may alleviate the progression of duodenal motor disorder through protecting smooth muscle cells from injury, promoting mSCF/c-Kit signaling, and attenuating impairment of interstitial cells of Cajal in the duodenum during PN feeding.
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Affiliation(s)
- Jie Zhu
- Department of Clinical Nutrition, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Wu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yonggao Guo
- Department of Gastroenterology, Xuzhou Central Hospital, Xuzhou, China
| | - Qingya Tang
- Department of Clinical Nutrition, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Lu
- Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Cai
- Department of Clinical Nutrition, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haiyan Huang
- Department of Gastroenterology, Xuzhou Central Hospital, Xuzhou, China
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Ben-Ami Shor D, Bashi T, Lachnish J, Fridkin M, Bizzaro G, Barshak I, Blank M, Shoenfeld Y. Phosphorylcholine-tuftsin compound prevents development of dextransulfate-sodium-salt induced murine colitis: implications for the treatment of human inflammatory bowel disease. J Autoimmun 2014; 56:111-7. [PMID: 25479760 DOI: 10.1016/j.jaut.2014.11.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 11/12/2014] [Accepted: 11/12/2014] [Indexed: 12/25/2022]
Abstract
Improved clinical findings of inflammatory bowel disease (IBD) upon treatment with helminthes and their ova were proven in animal models of IBD and in human clinical studies. The immunomodulatory properties of several helminthes were attributed to the phosphorylcholine (PC) molecule. We assessed the therapeutic potential of tuftsin-PC conjugate (TPC) to attenuate murine colitis. Colitis was induced by Dextransulfate-Sodium-Salt (DSS) in drinking water. TPC was given by daily oral ingestion (50 μg/0.1 ml/mouse or PBS) starting at day -2. Disease activity index (DAI) score was followed daily and histology of the colon was performed by H&E staining. Analysis of the cytokines profile in distal colon lysates was performed by immunoblot. Treatment of DSS induced colitis with TPC prevented the severity of colitis, including a reduction in the DAI score, less shortening of the colon and less inflammatory activity in histology. The immunoblot showed that the colitis preventive activity of TPC was associated with downregulation of colon pro-inflammatory IL-1β, TNFα and IL-17 cytokines expression, and enhancement of anti-inflammatory IL-10 cytokine expression. In the current study, we demonstrated that TPC treatment can prevent significantly experimental colitis induction in naïve mice. We propose the TPC as a novel potential small synthetic molecule to treat colitis.
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Affiliation(s)
- Dana Ben-Ami Shor
- Department of Gastroenterology, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Tomer Bashi
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Jordan Lachnish
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Mati Fridkin
- Department of Organic Chemistry, The Weizmann Institute of Sciences, Rehovot, Israel
| | - Giorgia Bizzaro
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Iris Barshak
- Institute of Pathology, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Miri Blank
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel; Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel.
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Le TT, Van Camp J, Dewettinck K. Milk Fat Globule Membrane Material. STUDIES IN NATURAL PRODUCTS CHEMISTRY 2014. [DOI: 10.1016/b978-0-444-63294-4.00012-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
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New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol 2014; 7:6-19. [PMID: 24084775 DOI: 10.1038/mi.2013.73] [Citation(s) in RCA: 251] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 08/16/2013] [Indexed: 02/06/2023]
Abstract
Healing of the inflamed mucosa (mucosal healing) is an emerging new goal for therapy and predicts clinical remission and resection-free survival in inflammatory bowel diseases (IBDs). The era of antitumor necrosis factor (TNF) antibody therapy was a remarkable progress in IBD therapy and anti-TNF agents led to mucosal healing in a subgroup of IBD patients; however, many patients do not respond to anti-TNF treatment highlighting the relevance of finding new targets for therapy of IBD. In particular, current studies are addressing the role of other anticytokine agents including antibodies against interleukin (IL)-6R, IL-13, and IL-12/IL-23 as well as new anti-inflammatory concepts (regulatory T cell therapy, Smad7 antisense, Jak inhibition, Toll-like receptor 9 stimulation, worm eggs). In addition, blockade of T-cell homing via the integrins α4β7 and the addressin mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) emerges as a promising new approach for IBD therapy. Here, new approaches for achieving mucosal healing are discussed as well as their implications for future therapy of IBD.
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Abstract
The pathogenesis of inflammatory bowel disease (IBD) is very complex, including a variety of genetic and environmental contributing factors. In this context, over the past few years, a picture of IBD as a primary defect of the innate immune system rather than the adaptive immune system has evolved. The intestinal antimicrobial barrier morphologically consists of a single layer of epithelial cells and the mucus and constitutes the first defense mechanism against the microbial burden of the gut. From a more mechanistic point of view, this barrier additionally depends on a crucial interplay between the mucus and antimicrobial peptides like for instance defensins. Disturbances in this system are in the pathophysiological center stage of IBD genesis and progression. In this article we will give a short overview about some of the key mechanisms in this context with special attention on defensins and the mucus layer.
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Affiliation(s)
- Thomas Klag
- Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany
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Richman E, Rhodes JM. Review article: evidence-based dietary advice for patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013; 38:1156-71. [PMID: 24102340 DOI: 10.1111/apt.12500] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 08/02/2013] [Accepted: 08/30/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND The therapeutic effect of enteral nutrition in Crohn's disease (CD) and the epidemiological associations between diet and inflammatory bowel disease (IBD) implicate diet in IBD causation. There is little evidence, however, to support specific dietary changes and patients often receive contradictory advice. AIM To review the literature on the impacts of diet on IBD causation and activity to produce guidance based on 'best available evidence'. METHOD Review of Medline, Embase and Cochrane databases from 1975 to 2012 using MeSH headings 'crohn's disease' 'ulcerative colitis' 'enteral' 'diet' 'nutrition' 'fatty acid' and 'food additives'. RESULTS Enteral nutrition with a formula-defined feed is effective treatment for CD, but approximately 50% of patients relapse within 6 months of return to normal diet. There is no direct evidence of benefit from any other specific dietary modification in CD, but indirect evidence supports recommendation of a low intake of animal fat, insoluble fibre and processed fatty foods containing emulsifiers. Foods tolerated in sustained remission may not be tolerated following relapse. Some evidence supports vitamin D supplementation. In ulcerative colitis (UC), evidence is weaker, but high intakes of meat and margarine correlate with increased UC incidence and high meat intake also correlates with increased likelihood of relapse. CONCLUSIONS There is little evidence from interventional studies to support specific dietary recommendations. Nevertheless, people with IBD deserve advice based on 'best available evidence' rather than no advice at all, although dietary intake should not be inappropriately restrictive. Further interventional studies of dietary manipulation are urgently required.
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Affiliation(s)
- E Richman
- Department of Dietetics, Royal Liverpool University Hospital, Liverpool, UK
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Sahoo S, Thiele I. Predicting the impact of diet and enzymopathies on human small intestinal epithelial cells. Hum Mol Genet 2013; 22:2705-22. [PMID: 23492669 PMCID: PMC3674809 DOI: 10.1093/hmg/ddt119] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Small intestinal epithelial cells (sIECs) have a significant share in whole body metabolism as they perform enzymatic digestion and absorption of nutrients. Furthermore, the diet plays a key role in a number of complex diseases including obesity and diabetes. The impact of diet and altered genetic backgrounds on human metabolism may be studied by using computational modeling. A metabolic reconstruction of human sIECs was manually assembled using the literature. The resulting sIEC model was subjected to two different diets to obtain condition-specific metabolic models. Fifty defined metabolic tasks evaluated the functionalities of these models, along with the respective secretion profiles, which distinguished between impacts of different dietary regimes. Under the average American diet, the sIEC model resulted in higher secretion flux for metabolites implicated in metabolic syndrome. In addition, enzymopathies were analyzed in the context of the sIEC metabolism. Computed results were compared with reported gastrointestinal (GI) pathologies and biochemical defects as well as with biomarker patterns used in their diagnosis. Based on our simulations, we propose that (i) sIEC metabolism is perturbed by numerous enzymopathies, which can be used to study cellular adaptive mechanisms specific for such disorders, and in the identification of novel co-morbidities, (ii) porphyrias are associated with both heme synthesis and degradation and (iii) disturbed intestinal gamma-aminobutyric acid synthesis may be linked to neurological manifestations of various enzymopathies. Taken together, the sIEC model represents a comprehensive, biochemically accurate platform for studying the function of sIEC and their role in whole body metabolism.
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Affiliation(s)
- Swagatika Sahoo
- Center for Systems Biology and Faculty of Industrial Engineering, Mechanical Engineering & Computer Science, University of Iceland, 101 Reykjavik, Iceland
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Sánchez-Fidalgo S, Cárdeno A, Sánchez-Hidalgo M, Aparicio-Soto M, Villegas I, Rosillo M, de la Lastra CA. Dietary unsaponifiable fraction from extra virgin olive oil supplementation attenuates acute ulcerative colitis in mice. Eur J Pharm Sci 2013; 48:572-81. [DOI: 10.1016/j.ejps.2012.12.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2012] [Revised: 12/01/2012] [Accepted: 12/03/2012] [Indexed: 02/07/2023]
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Cetinkaya M, Cansev M, Cekmez F, Tayman C, Canpolat FE, Kafa IM, Uysal S, Tunc T, Sarici SU. CDP-choline reduces severity of intestinal injury in a neonatal rat model of necrotizing enterocolitis. J Surg Res 2012; 183:119-28. [PMID: 23228325 DOI: 10.1016/j.jss.2012.11.032] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Revised: 10/03/2012] [Accepted: 11/16/2012] [Indexed: 01/19/2023]
Abstract
BACKGROUND Cytidine 5'-diphosphocholine (CDP-choline) is an endogenous intermediate in the biosynthesis of phosphatidylcholine, a contributor to the mucosal defense of the intestine. The aim of this study was to evaluate the possible cytoprotective effect of CDP-choline treatment on intestinal cell damage, membrane phospholipid content, inflammation, and apoptosis in a neonatal rat model of necrotizing enterocolitis (NEC). METHODS We divided a total of 30 newborn pups into three groups: control, NEC, and NEC + CDP-choline. We induced NEC by enteral formula feeding, exposure to hypoxia-hyperoxia, and cold stress. We administered CDP-choline intraperitoneally at 300 mg/kg/d for 3 d starting from the first day of life. We evaluated apoptosis macroscopically and histopathologically in combination with proinflammatory cytokines in the gut samples. Moreover, we determined membrane phospholipid levels as well as activities of xanthine oxidase, superoxide dismutase, glutathione peroxidase, and myeloperoxidase enzymes and the malondialdehyde content of intestinal tissue. RESULTS Mean clinical sickness score, macroscopic gut assessment score, and intestinal injury score were significantly improved, whereas mean apoptosis score and caspase-3 levels were significantly reduced in pups in the NEC + CDP-choline group compared with the NEC group. Tissue proinflammatory cytokine (interleukin-1β, interleukin-6, and tumor necrosis factor-α) levels as well as tissue malondialdehyde content and myeloperoxidase activities were reduced, whereas glutathione peroxidase and superoxide dismutase activities were preserved in the NEC + CDP-choline group. In addition, NEC damage reduced intestinal tissue membrane phospholipids, whereas CDP-choline significantly enhanced total phospholipid and phosphatidylcholine levels. Long-term follow-up in additional experiments revealed increased body weight, decreased clinical sickness scores, and enhanced survival in CDP-choline-receiving versus saline-receiving pups with NEC lesions. CONCLUSIONS Our study reports, for the first time, beneficial effects of CDP-choline treatment on intestinal injury in a neonatal rat model of NEC. Our data suggest that CDP-choline may be used as an effective therapeutic agent to prevent NEC.
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Affiliation(s)
- Merih Cetinkaya
- Division of Neonatology, Department of Pediatrics, Gulhane Military Medical Academy, Ankara, Turkey.
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Abstract
The pathogenetic mechanisms that cause the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are still under investigation. Nevertheless, there is broad agreement that luminal microbes are of particular relevance in the development of these conditions. In recent years, increasing evidence has shown that defects in the innate immunity are at the centre of both types of IBD. The innate intestinal barrier is provided by the epithelium which secretes antimicrobial peptides (so-called defensins) that are retained in the mucus layer. In ileal CD, the alpha-defensins are lacking owing to several Paneth cell defects. In colonic CD, the expression of beta-defensins is inadequate. This may be related to downregulation of the transcription factor peroxisome proliferator-activated receptor-gamma and in some cohorts is associated with a reduced HBD2 gene copy number. In UC, the mucus layer, which protects the host from the enormous amounts of luminal microbes, is defective. This is accompanied by an insufficient differentiation from intestinal stem cells towards goblet cells. All these disturbances in the gut barrier shift the balance from epithelial defence towards bacterial offence. The current treatment for CD and UC is based on suppression of this secondary inflammatory process. In future, patients may benefit from new therapeutic approaches stimulating the protective innate immune system.
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Affiliation(s)
- M Gersemann
- Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart
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Wolff MJ, Broadhurst MJ, Loke P. Helminthic therapy: improving mucosal barrier function. Trends Parasitol 2012; 28:187-94. [PMID: 22464690 DOI: 10.1016/j.pt.2012.02.008] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Revised: 02/29/2012] [Accepted: 02/29/2012] [Indexed: 12/21/2022]
Abstract
The epidemiology of autoimmune diseases and helminth infections led to suggestions that helminths could improve inflammatory conditions, which was then tested using animal models. This has translated to clinical investigations aimed at the safe and controlled reintroduction of helminthic exposure to patients suffering from autoimmune diseases (so-called 'helminthic therapy') in an effort to mitigate the inflammatory response. In this review, we summarize the results of recent clinical trials of helminthic therapy, with particular attention to mechanisms of action. Whereas previous reviews have emphasized immune regulatory mechanisms activated by helminths, we propose that enhancement of mucosal barrier function may have an equally important role in improving conditions of inflammatory bowel diseases.
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Affiliation(s)
- Martin J Wolff
- Division of Gastroenterology, Department of Medicine, New York University School of Medicine, New York, NY 10010, USA
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Küllenberg D, Taylor LA, Schneider M, Massing U. Health effects of dietary phospholipids. Lipids Health Dis 2012; 11:3. [PMID: 22221489 PMCID: PMC3316137 DOI: 10.1186/1476-511x-11-3] [Citation(s) in RCA: 332] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2011] [Accepted: 01/05/2012] [Indexed: 12/31/2022] Open
Abstract
Beneficial effects of dietary phospholipids (PLs) have been mentioned since the early 1900's in relation to different illnesses and symptoms, e.g. coronary heart disease, inflammation or cancer. This article gives a summary of the most common therapeutic uses of dietary PLs to provide an overview of their approved and proposed benefits; and to identify further investigational needs.From the majority of the studies it became evident that dietary PLs have a positive impact in several diseases, apparently without severe side effects. Furthermore, they were shown to reduce side effects of some drugs. Both effects can partially be explained by the fact that PL are highly effective in delivering their fatty acid (FA) residues for incorporation into the membranes of cells involved in different diseases, e.g. immune or cancer cells. The altered membrane composition is assumed to have effects on the activity of membrane proteins (e.g. receptors) by affecting the microstructure of membranes and, therefore, the characteristics of the cellular membrane, e.g. of lipid rafts, or by influencing the biosynthesis of FA derived lipid second messengers. However, since the FAs originally bound to the applied PLs are increased in the cellular membrane after their consumption or supplementation, the FA composition of the PL and thus the type of PL is crucial for its effect. Here, we have reviewed the effects of PL from soy, egg yolk, milk and marine sources. Most studies have been performed in vitro or in animals and only limited evidence is available for the benefit of PL supplementation in humans. More research is needed to understand the impact of PL supplementation and confirm its health benefits.
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Affiliation(s)
- Daniela Küllenberg
- Tumor Biology Center, Dept, of Clinical Research, D-79106 Freiburg, Germany
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