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Martínez-Ruiz M, Robeson MS, Piccolo BD. Fueling the fire: colonocyte metabolism and its effect on the colonic epithelia. Crit Rev Food Sci Nutr 2025:1-20. [PMID: 40405692 DOI: 10.1080/10408398.2025.2507701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2025]
Abstract
Colonic permeability is a major consequence of dysbiosis and diseases affecting the colon, further contributing to inflammation and extraintestinal diseases. Recent advances have shed light on the association between colonocyte energy utilization and the mechanisms that support epithelial function and homeostasis. One unifying theme is the induction of colonocyte hypoxia, driven by the aerobic oxidation of microbial-derived butyrate, as a critical factor promoting multiple cellular processes that support intestinal barrier function, mucus secretion, and the maintenance of synergistic luminal microbes. Particular attention will be focused on experimental evidence supporting beta-oxidation via activation of peroxisome proliferators-activated receptor-γ (PPAR) and upregulation and activation of processes that promote barrier function by hypoxia-inducible factor (HIF) signaling. Growing evidence suggests that colonocyte energy utilization is tightly regulated and switches between beta-oxidation of butyrate and anaerobic glycolysis, the latter being associated with several disease states. As most of the primary literature associated with colonocyte energy utilization has focused on adult models, evidence supporting butyrate oxidation in the neonatal gut is lacking. Thus, this review details the current state of knowledge linking colonocyte substrate utilization to mechanisms supporting gut health, but also highlights the counterindications of colonic butyrate availability and utilization in developmental periods.
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Affiliation(s)
- Manuel Martínez-Ruiz
- USDA-ARS Arkansas Children's Nutrition Center, Little Rock, AR, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Michael S Robeson
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Brian D Piccolo
- USDA-ARS Arkansas Children's Nutrition Center, Little Rock, AR, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Han J, Meng X, Kong H, Li X, Chen P, Zhang XA. Links between short-chain fatty acids and osteoarthritis from pathology to clinic via gut-joint axis. Stem Cell Res Ther 2025; 16:251. [PMID: 40390010 PMCID: PMC12090658 DOI: 10.1186/s13287-025-04386-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 05/09/2025] [Indexed: 05/21/2025] Open
Abstract
Short-chain fatty acids (SCFAs), the primary metabolites produced by the microbial fermentation of dietary fibers in the gut, have a key role in protecting gut health. Increasing evidence indicates SCFAs can exert effects on distant tissues and organs beyond the gut via blood circulation. Osteoarthritis (OA) is a chronic inflammatory joint disease that severely diminishes the physical function and quality of life. However, effective clinical treatments for OA remain elusive. Recent studies have shown that SCFAs can exert beneficial effects on damaged joints in OA. SCFAs can mitigate OA progression by preserving intestinal barrier function and maintaining the integrity of cartilage and subchondral bone, suggesting that they have substantial potential to be the adjunctive treatment strategy for OA. This review described the SCFAs in the human body and their cellular signaling mechanism, and summarized the multiple effects of SCFAs (especially butyrate, propionate, and acetate) on the prevention and treatment of OA by regulating the gut-joint axis, providing novel insights into their promising clinical applications.
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Affiliation(s)
- Juanjuan Han
- College of Exercise and Health, Shenyang Sport University, Shenyang, 110100, China
| | - Xin Meng
- College of Exercise and Health, Shenyang Sport University, Shenyang, 110100, China
| | - Hui Kong
- College of Exercise and Health, Shenyang Sport University, Shenyang, 110100, China
| | - Xinran Li
- College of Exercise and Health, Shenyang Sport University, Shenyang, 110100, China
| | - Peijie Chen
- School of Exercise and Health, Shanghai University of Sport, Shanghai, 200438, China
| | - Xin-An Zhang
- College of Exercise and Health, Shenyang Sport University, Shenyang, 110100, China.
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Yao Y, Hong Q, Ding S, Cui J, Li W, Zhang J, Sun Y, Yu Y, Yu M, Zhang C, Chen L, Jiang J, Hu Y. An umbrella review of meta-analyses on the effects of microbial therapy in metabolic dysfunction-associated steatotic liver disease. Clin Nutr 2025; 47:1-13. [PMID: 39978229 DOI: 10.1016/j.clnu.2025.02.007] [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: 11/08/2024] [Revised: 12/09/2024] [Accepted: 02/04/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND Current pharmacological treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) are often accompanied by adverse side effects. Consequently, probiotics, prebiotics, and synbiotics, which are bioactive compounds from fermented foods and offer fewer side effects, have garnered significant attention as alternative therapeutic strategies. OBJECTIVE This study aims to assess the efficacy of microbial therapies-probiotics, prebiotics, and synbiotics-in managing MASLD and to identify the optimal treatment modality for various clinical indicators through a comprehensive umbrella review of meta-analyses. METHODS A thorough literature search was conducted across PubMed, Web of Science, EMBASE, Cochrane Library, and Scopus to identify 23 meta-analyses over 18,999 MASLD patients as of November 2024. RESULTS The findings indicate that microbial treatments positively influence levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), homeostasis model assessment of insulin resistance (HOMA-IR), insulin, tumour necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and body mass index (BMI) in MASLD patients. Notably, probiotics were most effective in reducing TC, ALT, AST, GGT, insulin, TNF-α, and BMI; prebiotics were most effective in reducing TG; and synbiotics were most effective in reducing LDL-C, HOMA-IR, and CRP. CONCLUSION Our study provides robust evidence for microbial treatments of MASLD, enabling targeted interventions for different indicators.
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Affiliation(s)
- Yuanyue Yao
- College of Biological and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Qing Hong
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd., Shanghai, 200436, China
| | - Siqi Ding
- College of Biological and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Jie Cui
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Wenhui Li
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Jian Zhang
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Ye Sun
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Yiyang Yu
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Mingzhou Yu
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Chengcheng Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, 214122, Wuxi, Jiangsu, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Lianmin Chen
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Nanjing Medical University, Nanjing, 21100, China
| | - Jinchi Jiang
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China.
| | - Yonghong Hu
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
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Cui Y, Liu Y, Yang J, Duan H, Wang P, Guo L, Guo Y, Li S, Zhao Y, Wang J, Qi G, Guan J. Microencapsulated Lactobacillus plantarum promotes intestinal development through gut colonization of layer chicks. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 18:1-16. [PMID: 38989011 PMCID: PMC11231655 DOI: 10.1016/j.aninu.2024.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 01/29/2024] [Accepted: 03/12/2024] [Indexed: 07/12/2024]
Abstract
The effects of Lactobacillus plantarum in microencapsulation (LPM) on intestinal development in layer chicks were investigated in this study, as well as the colonization of L. plantarum in the gut. A total of 480 healthy Hy-Line Brown layer chicks at 0 d old were randomly divided into 4 groups (8 replicates each treatment), and the diets of these birds were supplemented with nothing (control), L. plantarum (0.02 g/kg feed; 109 CFU/kg feed), LPM (1.0 g/kg feed; 109 CFU/kg feed) and wall material of LPM (WM; 0.98 g/kg feed), respectively. Compared to control, LPM improved growth performance and intestinal development of layer chicks, evidenced by significantly increased body weight, average daily gain, average daily feed intake, villus height, villus height/crypt depth, as well as weight and length of the duodenum, jejunum and ileum (P < 0.05). These results could be attributed to the increased colonization of L. plantarum in the gut, which was verified by significant increases in lactic acid content, viable counts in chyme and mucosa (P < 0.05), as well as a visible rise in number of strains labeled with fluorescein isothiocyanate. Meanwhile, the relative abundances of Lactobacillus and Bifidobacterium significantly increased in response to microencapsulated L. plantarum supplementation (P < 0.05), accompanied by the significant up-regulation of colonization related genes (P < 0.05), encoding solute carrier family, monocarboxylate transporter, activin A receptor, succinate receptor and secretogranin II. To sum up, microencapsulated L. plantarum supplementation promoted intestinal development, which could be attributed to the enhancement of L. plantarum colonization in the intestine through the mutual assistance of Bifidobacterium and interactions with colonization related transmembrane proteins.
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Affiliation(s)
- Yaoming Cui
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Yanxia Liu
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Jing Yang
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Haitao Duan
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan 450046, China
| | - Peng Wang
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Linna Guo
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Yanjiao Guo
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Suying Li
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Yating Zhao
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Jinrong Wang
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Guanghai Qi
- Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Junjun Guan
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
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Sawant H, Selvaraj R, Manogaran P, Borthakur A. Intestinal Epithelial Creatine Transporter SLC6A8 Dysregulation in Inflammation and in Response to Adherent Invasive E. coli Infection. Int J Mol Sci 2024; 25:6537. [PMID: 38928243 PMCID: PMC11204174 DOI: 10.3390/ijms25126537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Creatine transporter (CrT1) mediates cellular uptake of creatine (Cr), a nutrient pivotal in maintaining energy homeostasis in various tissues including intestinal epithelial cells (IECs). The impact of CrT1 deficiency on the pathogenesis of various psychiatric and neurological disorders has been extensively investigated. However, there are no studies on its regulation in IECs in health and disease. Current studies have determined differential expression of CrT1 along the length of the mammalian intestine and its dysregulation in inflammatory bowel disease (IBD)-associated inflammation and Adherent Invasive E. coli (AIEC) infection. CrT1 mRNA and protein levels in normal intestines and their alterations in inflammation and following AIEC infection were determined in vitro in model IECs (Caco-2/IEC-6) and in vivo in SAMP1/YitFc mice, a model of spontaneous ileitis resembling human IBD. CrT1 is differentially expressed in different regions of mammalian intestines with its highest expression in jejunum. In vitro, CrT1 function (Na+-dependent 14C-Cr uptake), expression and promoter activity significantly decreased following TNFα/IL1β treatments and AIEC infection. SAMP1 mice and ileal organoids generated from SAMP1 mice also showed decreased CrT1 mRNA and protein compared to AKR controls. Our studies suggest that Cr deficiency in IECs secondary to CrT1 dysregulation could be a key factor contributing to IBD pathogenesis.
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Affiliation(s)
| | | | | | - Alip Borthakur
- Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.S.); (R.S.); (P.M.)
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Farajipour H, Matin HR, Asemi Z, Sadr S, Tajabadi-Ebrahimi M, Sharifi N, Banikazemi Z, Taghizadeh M, Mirzaei H. The effects of probiotics supplements on metabolic indices and clinical signs in patients with diabetic retinopathy, a randomized double blind clinical trial. J Diabetes Metab Disord 2024; 23:1133-1140. [PMID: 38932908 PMCID: PMC11196520 DOI: 10.1007/s40200-024-01399-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 02/07/2024] [Indexed: 06/28/2024]
Abstract
Purpose This study was carried out to evaluate the effects of probiotics administration on clinical status and metabolic profiles in diabetic retinopathy (DR) patients. Methods This randomized, double-blind, placebo-controlled trial was conducted among 72 DR patients. Subjects received probiotics including Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium langum, Bifidobacterium lactis daily (2 × 109 CFU/each strain) (n = 36) or placebo (starch) (n = 36) and were instructed to take one capsule daily for 12 weeks. Finally, 55 participants [probiotic group (n = 30) and placebo group (n = 25)] completed the study. Fasting blood samples were obtained at baseline and after the 12-week intervention to determine metabolic profiles. To determine the effects of probiotic supplementation on clinical symptoms and biochemical variables, we used one-way repeated measures analysis of variance. Results After the 12-week intervention, compared with the placebo, probiotic supplementation significantly decreased means serum insulin concentrations (Probiotic group: -4.9 ± 6.5vs. Placebo group: 3.0 ± 7.7 µIU/mL, Ptime×group<0.001), homeostatic model assessment for insulin resistance (Probiotic group: -2.5 ± 3.8 vs. Placebo group: 1.1 ± 2.7, Ptime×group<0.001) and hemoglobin A1c (HbA1C) (Probiotic group: -0.4 ± 0.7 vs. Placebo group: -0.02 ± 0.2%, Ptime×group=0.01), and significantly increased the quantitative insulin sensitivity check index (QUICKI) (Probiotic group: 0.02 ± 0.03 vs. Placebo group: -0.03 ± 0.04, Ptime×group<0.001). There was no significant effect of probiotic administration on other metabolic profiles and clinical symptoms. Conclusions Overall, probiotic supplementation after 12 weeks in DR patients had beneficial effects on few metabolic profiles. This study was registered under the Iranian website for clinical trials as http://www.irct.ir: IRCT20130211012438N29.
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Affiliation(s)
- Hasan Farajipour
- Department of Ophthalmology, School of Medicine, Matini Hospital, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamid Reza Matin
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Zatollah Asemi
- Faculty member of Science Department, Science Faculty, Islamic Azad University, Tehran Central branch, Tehran, Iran
| | - Saeed Sadr
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Tajabadi-Ebrahimi
- Faculty member of Science Department, Science Faculty, Islamic Azad University, Tehran Central branch, Tehran, Iran
| | - Nasrin Sharifi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zarrin Banikazemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohsen Taghizadeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Tomkinson S, Triscott C, Schenk E, Foey A. The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19. Pathogens 2023; 12:928. [PMID: 37513775 PMCID: PMC10384479 DOI: 10.3390/pathogens12070928] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 07/30/2023] Open
Abstract
Probiotic bacteria are able to modulate general antiviral responsiveness, including barrier functionality and innate and adaptive immune responses. The COVID-19 pandemic, resulting from SARS-CoV-2 infection, has created a need to control and treat this viral infection and its ensuing immunopathology with a variety of approaches; one such approach may involve the administration of probiotic bacteria. As with most viral infections, its pathological responses are not fully driven by the virus, but are significantly contributed to by the host's immune response to viral infection. The potential adoption of probiotics in the treatment of COVID-19 will have to appreciate the fine line between inducing antiviral immunity without over-provoking immune inflammatory responses resulting in host-derived immunopathological tissue damage. Additionally, the effect exerted on the immune system by SARS-CoV-2 evasion strategies will also have to be considered when developing a robust response to this virus. This review will introduce the immunopathology of COVID-19 and the immunomodulatory effects of probiotic strains, and through their effects on a range of respiratory pathogens (IAV, SARS-CoV, RSV), as well as SARS-CoV-2, will culminate in a focus on how these bacteria can potentially manipulate both infectivity and immune responsiveness via barrier functionality and both innate and adaptive immunity. In conclusion, the harnessing of induction and augmentation of antiviral immunity via probiotics may not only act as an ingestible adjuvant, boosting immune responsiveness to SARS-CoV-2 infection at the level of barrier integrity and innate and adaptive immunity, but also act prophylactically to prevent infection and enhance protection afforded by current vaccine regimens.
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Affiliation(s)
- Sophie Tomkinson
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
| | - Cloe Triscott
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
| | - Emily Schenk
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
- Peninsula Medical School, Faculty of Health, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
| | - Andrew Foey
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK
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Mendoza-León MJ, Mangalam AK, Regaldiz A, González-Madrid E, Rangel-Ramírez MA, Álvarez-Mardonez O, Vallejos OP, Méndez C, Bueno SM, Melo-González F, Duarte Y, Opazo MC, Kalergis AM, Riedel CA. Gut microbiota short-chain fatty acids and their impact on the host thyroid function and diseases. Front Endocrinol (Lausanne) 2023; 14:1192216. [PMID: 37455925 PMCID: PMC10349397 DOI: 10.3389/fendo.2023.1192216] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 05/23/2023] [Indexed: 07/18/2023] Open
Abstract
Thyroid disorders are clinically characterized by alterations of L-3,5,3',5'-tetraiodothyronine (T4), L-3,5,3'-triiodothyronine (T3), and/or thyroid-stimulating hormone (TSH) levels in the blood. The most frequent thyroid disorders are hypothyroidism, hyperthyroidism, and hypothyroxinemia. These conditions affect cell differentiation, function, and metabolism. It has been reported that 40% of the world's population suffers from some type of thyroid disorder and that several factors increase susceptibility to these diseases. Among them are iodine intake, environmental contamination, smoking, certain drugs, and genetic factors. Recently, the intestinal microbiota, composed of more than trillions of microbes, has emerged as a critical player in human health, and dysbiosis has been linked to thyroid diseases. The intestinal microbiota can affect host physiology by producing metabolites derived from dietary fiber, such as short-chain fatty acids (SCFAs). SCFAs have local actions in the intestine and can affect the central nervous system and immune system. Modulation of SCFAs-producing bacteria has also been connected to metabolic diseases, such as obesity and diabetes. In this review, we discuss how alterations in the production of SCFAs due to dysbiosis in patients could be related to thyroid disorders. The studies reviewed here may be of significant interest to endocrinology researchers and medical practitioners.
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Affiliation(s)
- María José Mendoza-León
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | | | - Alejandro Regaldiz
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Medicina Veterinaria y Agronomía, Instituto de Ciencias Naturales, Universidad de las Américas, Santiago, Chile
| | - Enrique González-Madrid
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Ma. Andreina Rangel-Ramírez
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Oscar Álvarez-Mardonez
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Omar P. Vallejos
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Constanza Méndez
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M. Bueno
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Felipe Melo-González
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Yorley Duarte
- Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Ma. Cecilia Opazo
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Medicina Veterinaria y Agronomía, Instituto de Ciencias Naturales, Universidad de las Américas, Santiago, Chile
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia A. Riedel
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
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Li Q, Zheng T, Ding H, Chen J, Li B, Zhang Q, Yang S, Zhang S, Guan W. Exploring the Benefits of Probiotics in Gut Inflammation and Diarrhea-From an Antioxidant Perspective. Antioxidants (Basel) 2023; 12:1342. [PMID: 37507882 PMCID: PMC10376667 DOI: 10.3390/antiox12071342] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 07/30/2023] Open
Abstract
Inflammatory bowel disease (IBD), characterized by an abnormal immune response, includes two distinct types: Crohn's disease (CD) and ulcerative colitis (UC). Extensive research has revealed that the pathogeny of IBD encompasses genetic factors, environmental factors, immune dysfunction, dysbiosis, and lifestyle choices. Furthermore, patients with IBD exhibit both local and systemic oxidative damage caused by the excessive presence of reactive oxygen species. This oxidative damage exacerbates immune response imbalances, intestinal mucosal damage, and dysbiosis in IBD patients. Meanwhile, the weaning period represents a crucial phase for pigs, during which they experience pronounced intestinal immune and inflammatory responses, leading to severe diarrhea and increased mortality rates. Pigs are highly similar to humans in terms of physiology and anatomy, making them a potential choice for simulating human IBD. Although the exact mechanism behind IBD and post-weaning diarrhea remains unclear, the oxidative damage, in its progression and pathogenesis, is well acknowledged. Besides conventional anti-inflammatory drugs, certain probiotics, particularly Lactobacillus and Bifidobacteria strains, have been found to possess antioxidant properties. These include the scavenging of reactive oxygen species, chelating metal ions to inhibit the Fenton reaction, and the regulation of host antioxidant enzymes. Consequently, numerous studies in the last two decades have committed to exploring the role of probiotics in alleviating IBD. Here, we sequentially discuss the oxidative damage in IBD and post-weaning diarrhea pathogenesis, the negative consequences of oxidative stress on IBD, the effectiveness of probiotics in IBD treatment, the application of probiotics in weaned piglets, and the potential antioxidant mechanisms of probiotics.
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Affiliation(s)
- Qihui Li
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Tenghui Zheng
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Hanting Ding
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Jiaming Chen
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Baofeng Li
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Qianzi Zhang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Siwang Yang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Shihai Zhang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, China
| | - Wutai Guan
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, China
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10
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Couto MR, Andrade N, Magro F, Martel F. Bile salts and proinflammatory cytokines inhibit MCT1-mediated cellular uptake of butyrate and interfere with its antiproliferative properties. Exp Cell Res 2023; 429:113670. [PMID: 37290498 DOI: 10.1016/j.yexcr.2023.113670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 06/10/2023]
Abstract
Butyrate (BT) is important in the prevention and inhibition of colorectal cancer (CRC). Inflammatory bowel disease, a risk factor for CRC, is associated with higher levels of proinflammatory cytokines and bile acids. The aim of this work was to investigate the interaction of these compounds in inhibiting BT uptake by Caco-2 cells, as a mechanism contributing to the link between IBD and CRC. TNF-α, IFN-γ, chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) markedly reduce 14C-BT uptake. All these compounds appear to inhibit MCT1-mediated BT cellular uptake at a posttranscriptional level, and, because their effect is not additive, they are most probably inhibiting MCT1 by a similar mechanism. Correspondingly, the antiproliferative effect of BT (MCT1-dependent) and of the proinflammatory cytokines and CDCA were not additive. In contrast, the cytotoxic effect of BT (MCT1-independent) and of the proinflammatory cytokines and CDCA were additive. In conclusion, proinflammatory cytokines (TNF-α and IFN-γ) and bile acids (DCA and CDCA) inhibit MCT1-mediated BT cellular uptake. These proinflammatory cytokines and CDCA were found to interfere with the antiproliferative effect of BT, mediated by an inhibitory effect upon MCT1-mediated cellular uptake of BT.
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Affiliation(s)
- Mafalda R Couto
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Instituto de Investigação e Inovação Em Saúde (i3S), University of Porto, Porto, Portugal
| | - Nelson Andrade
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; REQUIMTE/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Portugal; Instituto de Investigação e Inovação Em Saúde (i3S), University of Porto, Porto, Portugal
| | - Fernando Magro
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Instituto de Investigação e Inovação Em Saúde (i3S), University of Porto, Porto, Portugal
| | - Fátima Martel
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Gastroenterology Unit, Department of Medicine, Centro Hospitalar S. João, Porto, Portugal; Instituto de Investigação e Inovação Em Saúde (i3S), University of Porto, Porto, Portugal.
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11
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Obi‐Azuike C, Ebiai R, Gibson T, Hernandez A, Khan A, Anugwom G, Urhi A, Prasad S, Souabni SA, Oladunjoye F. A systematic review on gut-brain axis aberrations in bipolar disorder and methods of balancing the gut microbiota. Brain Behav 2023; 13:e3037. [PMID: 37127945 PMCID: PMC10275531 DOI: 10.1002/brb3.3037] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 03/21/2023] [Accepted: 04/17/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND Bipolar disorder (BD) is a mood disorder that affects millions worldwide. Up to half of the diagnosed patients are reported to not receive adequate treatment. This study aims to assess the relationship between the gut-brain axis and BD and to discuss and compare the efficacy of varying methods of balancing gut microbiotas in BD. METHODS Using PubMed, Embase, and Google Scholar from November 2021 to February 2022, we found 5310 studies on gut microbiota and its relation to BD. Using our inclusion criteria, 5283 studies were excluded. A total of 27 full-text articles were assessed for eligibility. Also, 12 articles that met our criteria and eligibility criteria reported on 613 BD patients. RESULTS Most studies analyzed found an overall difference in gut microbiota composition in bipolar patients compared to healthy controls, though the alterations found were not consistent. Differences in Lactobacillus, Faecalibacterium, and Ruminococcus abundance in BD compared to controls were found to be the most consistent across a few of the studies, but their effects on the gut-brain axis conflicted. Probiotic supplementation was found to lower patient rehospitalizations and significantly improve depressive symptoms and cognitive impairments among patients with BD. CONCLUSIONS Multiple studies included in this review point toward a possible link between BD and the gut microbiota. Probiotic supplements and other gut-balancing therapies could serve as effective adjunctive methods for the treatment of BD. Notable limitations of the studies included for analysis were small sample sizes and majority observational study designs. Furthermore, the microbiota aberrations found in patients with BD were not consistent across multiple studies. Despite these limitations, our findings demonstrate the need for further research regarding the relationship between aberrant gut microbiota profiles and BD, as well as the effectiveness of gut balancing methods as adjunctive treatments.
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Affiliation(s)
- Crystal Obi‐Azuike
- Department of Psychiatry and Behavioral SciencesTulane University School of MedicineNew Orleans, Los AngelesUSA
| | - Ruona Ebiai
- Department of Internal MedicineOchsner Clinic FoundationNew OrleansLouisianaUSA
| | - Taneil Gibson
- Department of PsychiatryUniversity of Medicine and Health Sciences (UMHS)New YorkNew YorkUSA
| | - Ariana Hernandez
- Department of PsychiatryUniversity of Medicine and Health Sciences (UMHS)New YorkNew YorkUSA
| | - Asma Khan
- Department of PsychiatryLake Erie College of Osteopathic MedicineEriePennsylvaniaUSA
| | - Gibson Anugwom
- Menninger Department of Psychiatry & Behavioral SciencesBaylor College of MedicineHoustonTexasUSA
| | - Alexsandra Urhi
- Department of Mental HealthFederal Medical CenterAsaba, Delta StateNigeria
| | - Sakshi Prasad
- Department of PsychiatryNational Pirogov Memorial Medical UniversityVinnytsya, VinnytsyaUkraine
| | - Sara Ait Souabni
- Faculty of Medicine and Pharmacy of MarrakeshCadi Ayyad University‐Marrakech, MarrakechMorocco
| | - Funso Oladunjoye
- Menninger Department of Psychiatry & Behavioral SciencesBaylor College of MedicineHoustonTexasUSA
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12
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Kostelac D, Gerić M, Gajski G, Frece J. Probiotic bacteria isolated from fermented meat displays high antioxidant and anti-inflammatory potential. Mutagenesis 2023; 38:58-63. [PMID: 36318230 DOI: 10.1093/mutage/geac023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
One of the ways to impact emerging problems of unhealthy diet such as microbiota dysbiosis, inflammation, and oxidative stress is the application of probiotics and their incorporation into different food matrices. Discovery and selection of appropriate probiotic bacteria is challenging procedure especially for fermented meat products that have also been described as a potential source of resilient probiotic microorganisms. The aim of this study was to investigate probiotic bacteria Lactiplantibacillus plantarum 1K isolated from traditional fermented meat product for its potential beneficial properties. Furthermore, small probiotic metabolites were extracted, and their anti-inflammatory activity was tested in a lipopolysaccharide-stimulated inflammatory model on human peripheral blood mononuclear cells (PBMCs). Safety characteristics of metabolites including cytotoxicity and genotoxicity were also determined. Investigated probiotic strain exerted high antioxidant potential by viable cells but also by metabolite fraction. Viable cells retained the satisfactory antioxidant activity after gastrointestinal transit. Extracted probiotic metabolites significantly inhibited TNF-α production in LPS-stimulated PBMC thus exerting anti-inflammatory activity. Metabolites alone showed no cytotoxic or genotoxic activity toward isolated immune cells. Obtained results indicate the possibility to use fermented meat products as sources for specific probiotics that might provide antioxidant and anti-inflammatory benefits for the consumers.
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Affiliation(s)
- Deni Kostelac
- Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10000 Zagreb, Croatia
| | - Marko Gerić
- Institute for Medical Research and Occupational Health, Mutagenesis Unit, Ksaverska cesta 2, 10000 Zagreb, Croatia
| | - Goran Gajski
- Institute for Medical Research and Occupational Health, Mutagenesis Unit, Ksaverska cesta 2, 10000 Zagreb, Croatia
| | - Jadranka Frece
- Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10000 Zagreb, Croatia
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13
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Interaction between Butyrate and Tumor Necrosis Factor α in Primary Rat Colonocytes. Biomolecules 2023; 13:biom13020258. [PMID: 36830627 PMCID: PMC9953264 DOI: 10.3390/biom13020258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/15/2023] [Accepted: 01/24/2023] [Indexed: 02/01/2023] Open
Abstract
Butyrate, a short-chain fatty acid, is utilized by the gut epithelium as energy and it improves the gut epithelial barrier. More recently, it has been associated with beneficial effects on immune and cardiovascular homeostasis. Conversely, tumor necrosis factor alpha (TNFα) is a pro-inflammatory and pro-hypertensive cytokine. While butyrate and TNFα are both linked with hypertension, studies have not yet addressed their interaction in the colon. Here, we investigated the capacity of butyrate to modulate a host of effects of TNFα in primary rodent colonic cells in vitro. We measured ATP levels, cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitochondrial oxidative phosphorylation, and glycolytic activity in colonocytes following exposure to either butyrate or TNFα, or both. To address the potential mechanisms, transcripts related to oxidative stress, cell fate, and cell metabolism (Pdk1, Pdk2, Pdk4, Spr, Slc16a1, Slc16a3, Ppargc1a, Cs, Lgr5, Casp3, Tnfr2, Bax, Bcl2, Sod1, Sod2, and Cat) were measured, and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to profile the metabolic responses of colonocytes following exposure to butyrate and TNFα. We found that both butyrate and TNFα lowered cellular ATP levels towards a quiescent cell energy phenotype, characterized by decreased oxygen consumption and extracellular acidification. Co-treatment with butyrate ameliorated TNFα-induced cytotoxicity and the reduction in cell viability. Butyrate also opposed the TNFα-mediated decrease in MMP and mitochondrial-to-intracellular calcium ratios, suggesting that butyrate may protect colonocytes against TNFα-induced cytotoxicity by decreasing mitochondrial calcium flux. The relative expression levels of pyruvate dehydrogenase kinase 4 (Pdk4) were increased via co-treatment of butyrate and TNFα, suggesting the synergistic inhibition of glycolysis. TNFα alone reduced the expression of monocarboxylate transporters slc16a1 and slc16a3, suggesting effects of TNFα on butyrate uptake into colonocytes. Of the 185 metabolites that were detected with LC-MS, the TNFα-induced increase in biopterin produced the only significant change, suggesting an alteration in mitochondrial biogenesis in colonocytes. Considering the reports of elevated colonic TNFα and reduced butyrate metabolism in many conditions, including in hypertension, the present work sheds light on cellular interactions between TNFα and butyrate in colonocytes that may be important in understanding conditions of the colon.
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14
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Farajipour H, Sadr S, Matin HR, Aschner M, Asemi Z, Banikazemi Z, Mirzaei H, Taghizadeh M. Therapeutic effect of probiotics on metabolic indices and clinical signs in age-related macular degeneration. J Immunoassay Immunochem 2022; 44:229-241. [PMID: 36576143 DOI: 10.1080/15321819.2022.2159765] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Probiotics positively influence age-related macular degeneration (ARMD) given their propensity to attenuate oxidative and inflammatory stress. We addressed the impact of probiotics on metabolic profiles, clinical indices, inflammatory and oxidative stress parameters in ARMD patients. We performed a randomized, double-blind, placebo-controlled trial analyzing 57 subjects with ARMD aged between 50 and 85 years. Subjects were randomized into two groups, and received daily for 8 weeks either probiotic capsule or placebo. Fasting blood samples were obtained at baseline and after the 8-week intervention for the determination of metabolic profiles and oxidative stress biomarkers. After the 8-week intervention, compared with the placebo, probiotic supplementation significantly increased means HDL-cholesterol (Probiotic group: +3.86±4.42 vs. Placebo group: -0.55±4.93 mg/dL, P = .001), plasma total antioxidant capacity (TAC) (Probiotic group: +77.43±168.30 vs. Placebo group: -23.12±169.22 mmol/L, P = .02) and significantly decreased malondialdehyde (MDA) levels (Probiotic group: -0.18±0.46 vs. Placebo group: +0.18±0.25 µmol/L, P = .001). There was no significant effect of probiotic administration on other metabolic profiles and clinical symptoms. Overall, an eight-week probiotic administration among ARMD patients had beneficial effects on TAC, MDA and HDL-cholesterol levels; however, it did not affect clinical signs and other metabolic profiles.
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Affiliation(s)
- Hasan Farajipour
- Department of Ophthalmology, School of Medicine, Matini Hospital, Kashan University of Medical Sciences, Kashan, Iran
| | - Saeed Sadr
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamid Reza Matin
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 209, 1300 Morris Park Avenue, Bronx, New York 10461, USA
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zarrin Banikazemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.,Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohsen Taghizadeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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15
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van Deuren T, Blaak EE, Canfora EE. Butyrate to combat obesity and obesity-associated metabolic disorders: Current status and future implications for therapeutic use. Obes Rev 2022; 23:e13498. [PMID: 35856338 PMCID: PMC9541926 DOI: 10.1111/obr.13498] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/04/2022] [Accepted: 06/28/2022] [Indexed: 12/17/2022]
Abstract
Evidence is increasing that disturbances in the gut microbiome may play a significant role in the etiology of obesity and type 2 diabetes. The short chain fatty acid butyrate, a major end product of the bacterial fermentation of indigestible carbohydrates, is reputed to have anti-inflammatory properties and positive effects on body weight control and insulin sensitivity. However, whether butyrate has therapeutic potential for the treatment and prevention of obesity and obesity-related complications remains to be elucidated. Overall, animal studies strongly indicate that butyrate administered via various routes (e.g., orally) positively affects adipose tissue metabolism and functioning, energy and substrate metabolism, systemic and tissue-specific inflammation, and insulin sensitivity and body weight control. A limited number of human studies demonstrated interindividual differences in clinical effectiveness suggesting that outcomes may depend on the metabolic, microbial, and lifestyle-related characteristics of the target population. Hence, despite abundant evidence from animal data, support of human data is urgently required for the implementation of evidence-based oral and gut-derived butyrate interventions. To increase the efficacy of butyrate-focused interventions, future research should investigate which factors impact treatment outcomes including baseline gut microbial activity and functionality, thereby optimizing targeted-interventions and identifying individuals that merit most from such interventions.
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Affiliation(s)
- Thirza van Deuren
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Ellen E Blaak
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Emanuel E Canfora
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
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16
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Noviardi H, Iswantini D, Mulijani S, Wahyudi ST, Khusniati T. Anti-inflammatory and Immunostimulant Therapy with Lactobacillus fermentum and Lactobacillus plantarum in COVID-19: A Literature Review. BORNEO JOURNAL OF PHARMACY 2022. [DOI: 10.33084/bjop.v5i3.3367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Inflammatory diseases are diseases characterized by inflammatory symptoms. Acute inflammatory disease can cause dysregulation of the inflammatory immune response, thereby inhibiting the development of protective immunity against infection. Among the acute inflammatory disease is COVID-19. The initial viral infection causes the antigen-presenting cells to detect the virus through a phagocytosis mechanism in the form of macrophage and dendritic cells. Lactobacillus fermentum and L. plantarum are gram-positive bacteria potentially serving as immunomodulators caused by inflammation and immune system response. Short-chain fatty acids (SCFA) produced by Lactobacillus can induce immune response through tolerogenic dendritic cells. This probiotic bacterium can induce the production of different cytokines or chemokines. Following the results of in vitro and in vivo tests, L. fermentum and L. plantarum can induce IL-10 release to activate regulatory T-cell and inhibit tumor necrosis factor-α (TNF-α) binding activity of nuclear factor kappa B (NF-κB). Literature review showed that dysregulation of inflammatory immune response disorders due to inflammatory disease could be treated using probiotic bacteria L. fermentum and L. plantarum. Therefore, it is necessary to conduct further studies on the potential of indigenous Indonesian strains of these two bacteria as anti-inflammatory and immunostimulants.
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Affiliation(s)
| | | | | | | | - Tatik Khusniati
- National Research and Innovation Agency Republic of Indonesia
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17
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Ali I, Raza A, Ahmad MA, Li L. Nutrient sensing mechanism of short-chain fatty acids in mastitis control. Microb Pathog 2022; 170:105692. [DOI: 10.1016/j.micpath.2022.105692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/02/2022] [Accepted: 07/22/2022] [Indexed: 10/16/2022]
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18
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You H, Tan Y, Yu D, Qiu S, Bai Y, He J, Cao H, Che Q, Guo J, Su Z. The Therapeutic Effect of SCFA-Mediated Regulation of the Intestinal Environment on Obesity. Front Nutr 2022; 9:886902. [PMID: 35662937 PMCID: PMC9157426 DOI: 10.3389/fnut.2022.886902] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/20/2022] [Indexed: 12/12/2022] Open
Abstract
Intestinal environment disorder is a potential pathological mechanism of obesity. There is increasing evidence that disorders in the homeostasis of the intestinal environment can affect various metabolic organs, such as fat and liver, and lead to metabolic diseases. However, there are few therapeutic approaches for obesity targeting the intestinal environment. In this review, on the one hand, we discuss how intestinal microbial metabolites SCFA regulate intestinal function to improve obesity and the possible mechanisms and pathways related to obesity-related pathological processes (depending on SCFA-related receptors such as GPCRs, MCT and SMCT, and through epigenetic processes). On the other hand, we discuss dietary management strategies to enrich SCFA-producing bacteria and target specific SCFA-producing bacteria and whether fecal bacteria transplantation therapy to restore the composition of the gut microbiota to regulate SCFA can help prevent or improve obesity. Finally, we believe that it will be of great significance to establish a working model of gut– SCFA– metabolic disease development in the future for the improvement this human health concern.
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Affiliation(s)
- Huimin You
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of Glucolipid Metabolic Disorder, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yue Tan
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of Glucolipid Metabolic Disorder, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dawei Yu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of Glucolipid Metabolic Disorder, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shuting Qiu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of Glucolipid Metabolic Disorder, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jincan He
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd, Guangzhou, China
| | - Jiao Guo
- Key Laboratory of Glucolipid Metabolic Disorder, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of Glucolipid Metabolic Disorder, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
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19
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Lee SY, Byun HJ, Choi H, Won JI, Han J, Park S, Kim D, Sung JH. Development of a Pumpless Microfluidic System to Study the Interaction between Gut Microbes and Intestinal Epithelial Cells. BIOTECHNOL BIOPROC E 2022. [DOI: 10.1007/s12257-021-0268-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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20
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Lactiplantibacillus plantarum inhibits colon cancer cell proliferation as function of its butyrogenic capability. Biomed Pharmacother 2022; 149:112755. [PMID: 35276466 DOI: 10.1016/j.biopha.2022.112755] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 11/21/2022] Open
Abstract
Lactobacilli have been shown to inhibit or suppress cancer cell growth through the release of strain-specific bioactive metabolites and their inclusion in functional foods could exert a health promoting activity on human health. Herein, we examined the antiproliferative activity of the Lactiplantibacillus plantarum strains S2T10D and O2T60C, which have been previously shown to exert different butyrogenic activities. Human HT-29 cells were employed as an in vitro colon cancer model and both bacterial strains were found to inhibit their growth. However, the strain S2T10D showed a greater antiproliferative activity which, interestingly, was correlated to its butyrogenic capability. Noteworthy, for the non-butyrogenic strain O2T60C, the growth inhibitory capability was rather limited. Furthermore, both the butyrate-containing supernatant of S2T10D and glucose-deprived cell culture medium supplemented with the same concentration of butyrate found in S2T10D supernatant, induced a pH-independent cancer cell growth inhibition accompanied by downregulation of cyclin D1 at mRNA level. The downregulation of cyclin D1 gene expression was accompanied by cell cycle arrest in G2/M phase and decrease of cyclin B1 and D1 protein levels. This in vitro study underlines the impact of Lpb. plantarum in the growth inhibition of cancer cells, and proposes butyrate-mediated cell cycle regulation as a potential involved mechanism. Since the production of butyric acid in Lpb. plantarum has been proven strain-dependent and differentially boosted by specific prebiotic compounds, our results open future research paths to determine whether this metabolic activity could be modulated in vivo by enhancing this antiproliferative effects on cancer cells.
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21
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Gut-derived butyrate suppresses ocular surface inflammation. Sci Rep 2022; 12:4512. [PMID: 35296712 PMCID: PMC8927112 DOI: 10.1038/s41598-022-08442-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 02/23/2022] [Indexed: 12/16/2022] Open
Abstract
Dry eye is a common ocular inflammatory disorder characterized by tear film instability and reduced tear production. There is increasing evidence that homeostasis of the ocular surface is impacted by the intestinal microbiome. We are interested in investigating the potential role of microbially produced small molecules in mediating the interaction between the intestinal microbiota and the ocular surface. One such molecule is butyrate, a short-chain fatty acid (SCFA) produced by certain members of the gut microbiota through fermentation of dietary fiber. Here we show that SCFA transporter SLC5A8 is expressed in vivo in murine conjunctival and corneal epithelium. Pre-treatment of in vitro corneal epithelial cultures or bone marrow-derived dendritic cells (BMDCs) with phenylbutyrate (PBA) reduces lipopolysaccharide-induced pro-inflammatory Tnf expression. Corneal epithelial cultures and BMDCs isolated from Slc5a8 knockout mice are unable to respond to PBA pre-treatment, suggesting that SLC5A8 is required for the protective effect of PBA. The treatment of mice undergoing desiccating stress (DS) with oral tributyrin, a prodrug form of butyrate, reduces inflammation at the ocular surface in vivo, and this effect partially requires SLC5A8. Finally, expression analysis on conjunctival tissue isolated from mice subjected to DS with and without tributyrin treatment revealed that treatment downregulated genes involved in Type I interferon signaling. Together these data support our hypothesis that SCFAs produced in the gut participate in the maintenance of ocular surface homeostasis.
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22
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Ornelas A, Dowdell AS, Lee JS, Colgan SP. Microbial Metabolite Regulation of Epithelial Cell-Cell Interactions and Barrier Function. Cells 2022; 11:cells11060944. [PMID: 35326394 PMCID: PMC8946845 DOI: 10.3390/cells11060944] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/04/2022] [Accepted: 03/07/2022] [Indexed: 02/04/2023] Open
Abstract
Epithelial cells that line tissues such as the intestine serve as the primary barrier to the outside world. Epithelia provide selective permeability in the presence of a large constellation of microbes, termed the microbiota. Recent studies have revealed that the symbiotic relationship between the healthy host and the microbiota includes the regulation of cell–cell interactions at the level of epithelial tight junctions. The most recent findings have identified multiple microbial-derived metabolites that influence intracellular signaling pathways which elicit activities at the epithelial apical junction complex. Here, we review recent findings that place microbiota-derived metabolites as primary regulators of epithelial cell–cell interactions and ultimately mucosal permeability in health and disease.
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Affiliation(s)
- Alfredo Ornelas
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - Alexander S. Dowdell
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - J. Scott Lee
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - Sean P. Colgan
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
- Rocky Mountain Regional Veterans Affairs Medical Center, 1700 N. Wheeling St., Aurora, CO 80045, USA
- Correspondence:
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Souders CL, Zubcevic J, Martyniuk CJ. Tumor Necrosis Factor Alpha and the Gastrointestinal Epithelium: Implications for the Gut-Brain Axis and Hypertension. Cell Mol Neurobiol 2022; 42:419-437. [PMID: 33594519 PMCID: PMC8364923 DOI: 10.1007/s10571-021-01044-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/11/2021] [Indexed: 12/17/2022]
Abstract
The colonic epithelium is the site of production and transport of many vasoactive metabolites and neurotransmitters that can modulate the immune system, affect cellular metabolism, and subsequently regulate blood pressure. As an important interface between the microbiome and its host, the colon can contribute to the development of hypertension. In this critical review, we highlight the role of colonic inflammation and microbial metabolites on the gut brain axis in the pathology of hypertension, with special emphasis on the interaction between tumor necrosis factor α (TNFα) and short chain fatty acid (SCFA) metabolites. Here, we review the current literature and identify novel pathways in the colonic epithelium related to hypertension. A network analysis on transcriptome data previously generated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats reveals differences in several pathways associated with inflammation involving TNFα (NF-κB and STAT Expression Targets) as well as oxidative stress. We also identify down-regulation of networks associated with gastrointestinal function, cardiovascular function, enteric nervous system function, and cholinergic and adrenergic transmission. The analysis also uncovered transcriptome responses related to glycolysis, butyrate oxidation, and mitochondrial function, in addition to gut neuropeptides that serve as modulators of blood pressure and metabolic function. We present a model for the role of TNFα in regulating bacterial metabolite transport and neuropeptide signaling in the gastrointestinal system, highlighting the complexity of host-microbiota interactions in hypertension.
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Affiliation(s)
- Christopher L Souders
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Jasenka Zubcevic
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA.
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, PO BOX 100274, Gainesville, FL, 32611, USA.
| | - Christopher J Martyniuk
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA.
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, PO BOX 100274, Gainesville, FL, 32611, USA.
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Naghizadeh M, Dalgaard TS, Klaver L, Engberg RM. Effects of encapsulated butyrate and salinomycin on gut leakage and intestinal inflammation in broilers. Br Poult Sci 2022; 63:499-509. [PMID: 35170392 DOI: 10.1080/00071668.2022.2042483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
1. The objectives of this study were to i) compare the effects of a commercial product providing encapsulated butyrate (EB) in combination with salinomycin in diets of broilers with impaired intestinal integrity and ii) to identify easy-to-measure biomarkers to evaluate intestinal integrity and health.2. In total, 672, one-day-old male broilers (Ross 308) were randomly assigned to three experimental groups (eight replicates/group): no dietary supplement (control); EB (500 mg/kg, UltraGuard™-DUO, Devenish, Ireland); salinomycin (69 mg/kg feed, Sacox® 120). Impaired gut integrity was induced by a 10 times overdose of a commercial attenuated live vaccine against coccidiosis (Hipracox®, Hipra) on d 17 combined with a grower feed providing rye (50 g/kg diet).3. Improved intestinal integrity and functionality were reflected by reduced fluorescein isothiocyanate-dextran (FITC-D) plasma levels, reduced bacterial translocation to the liver (on d 21) and increased plasma coloration level on d 21 after dietary supplementation of salinomycin, compared to a non-supplemented control diet. Both EB and salinomycin reduced plasma levels of D-lactate (P<0.05).4. An anti-inflammatory effect of salinomycin was indicated as the transient increase in circulating monocytes observed in the EB and control group from 20 to 28 d of age was slightly, but not significantly reduced, in the salinomycin-fed group. Interestingly, greater expression of tumour necrosis factor α (TNF-α) and mucin 2 (MUC2) genes (P=0.039 and P = 0.067, respectively) were detected in the group receiving salinomycin.5. These effects may have collectively contributed to the significantly improved performance of broilers supplemented with salinomycin. The results indicated that EB at 500 mg/kg in feed, in contrast to salinomycin, neither supported gut health nor modulated intestinal integrity in broilers.
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Affiliation(s)
- Mohammad Naghizadeh
- Department of Animal Science, Aarhus University, Blichers Allé 20, P.O. Box 50, DK-8830 Tjele, Denmark
| | - Tina Sørensen Dalgaard
- Department of Animal Science, Aarhus University, Blichers Allé 20, P.O. Box 50, DK-8830 Tjele, Denmark
| | - Laura Klaver
- Department of Animal Science, Aarhus University, Blichers Allé 20, P.O. Box 50, DK-8830 Tjele, Denmark
| | - Ricarda Margarete Engberg
- Department of Animal Science, Aarhus University, Blichers Allé 20, P.O. Box 50, DK-8830 Tjele, Denmark
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Kim HJ, An J, Ha EM. Lactobacillus plantarum-derived metabolites sensitize the tumor-suppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells. J Microbiol 2021; 60:100-117. [PMID: 34964946 DOI: 10.1007/s12275-022-1533-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022]
Abstract
A critical obstacle to the successful treatment of colorectal cancer (CRC) is chemoresistance. Chemoresistant CRC cells contribute to treatment failure by providing a mechanism of drug lethargy and modifying chemoresistance-associated molecules. The gut microbiota provide prophylactic and therapeutic effects by targeting CRC through anticancer mechanisms. Among them, Lactobacillus plantarum contributes to the health of the host and is clinically effective in treating CRC. This study confirmed that 5-fluorouracil (5-FU)-resistant CRC HCT116 (HCT116/5FUR) cells acquired butyrate-insensitive properties. To date, the relationship between 5-FU-resistant CRC and butyrate resistance has not been elucidated. Here, we demonstrated that the acquisition of butyrate resistance in HCT116/5FUR cells was strongly correlated with the inhibition of the expression and function of SMCT1, a major transporter of butyrate in colonocytes. L. plantarum-cultured cell-free supernatant (LP) restored the functional expression of SMCT1 in HCT116/5FUR cells, leading to butyrate-induced antiproliferative effect and apoptosis. These results suggest that LP has a synergistic effect on the SMCT1/butyrate-mediated tumor suppressor function and is a potential chemosensitizer to overcome dual 5-FU and butyrate resistance in HCT116 cells.
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Affiliation(s)
- Hye-Ju Kim
- College of Pharmacy, Daegu Catholic University, Gyeongsan, 38430, Republic of Korea
| | - JaeJin An
- Medical Convergence Textile Center, Gyeongbuk Techno Park, Gyeongsan, 38408, Republic of Korea
| | - Eun-Mi Ha
- College of Pharmacy, Daegu Catholic University, Gyeongsan, 38430, Republic of Korea.
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Anbazhagan AN, Priyamvada S, Kumar A, Jayawardena D, Borthakur A, Saksena S, Gill RK, Alrefai WA, Dudeja PK. miR-29a, b, and c regulate SLC5A8 expression in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2021; 321:G223-G231. [PMID: 34231393 PMCID: PMC8410106 DOI: 10.1152/ajpgi.00148.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 01/31/2023]
Abstract
Short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fiber exert myriad of beneficial effects including the amelioration of inflammation. SCFAs exist as anions at luminal pH; their entry into the cells depends on the expression and function of monocarboxylate transporters. In this regard, sodium-coupled monocarboxylate transporter-1 (SMCT-1) is one of the major proteins involved in the absorption of SCFA in the mammalian colon. However, very little is known about the mechanisms of regulation of SMCT-1 expression in health and disease. MicroRNAs (miRs) are known to play a key role in modulating gene expression. In silico analysis showed miR-29a, b, and c with highest context score and its binding region was conserved among mammals. The 3'-untranslated region (UTR) of human SMCT-1 gene was cloned into pmirGLO vector upstream of luciferase reporter and transiently transfected with miR-29a, b, and c mimics into Caco-2 and/or T-84 cells. The presence of UTR of this gene significantly decreased luciferase activity compared with empty vector. Cotransfection with miR-29a, b, or c resulted in further decrease in 3'-UTR activity of SMCT-1 luciferase constructs. Mimic transfection significantly decreased SMCT-1 protein expression without altering mRNA expression. Furthermore, the expression of miR-29a and c were significantly lower in mouse colon compared with small intestine, consistent with higher levels of SMCT-1 protein in the colon. Our studies demonstrated a novel finding in which miR-29a, b, and c downregulate SMCT-1 expression in colonic epithelial cells and may partly explain the differential expression of these transporters along the length of the gastrointestinal (GI) tract.NEW & NOTEWORTHY Our study for the first time reports the posttranscriptional regulation of SMCT-1 by miR-29a, b, and c in colonic epithelial cells. We also demonstrate that the expression of these microRNAs is lower in the mouse proximal and distal colon which partially explains the higher expression level of SMCT-1 in the colon compared with small intestine.
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Affiliation(s)
- Arivarasu N Anbazhagan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Shubha Priyamvada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Anoop Kumar
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Dulari Jayawardena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Alip Borthakur
- Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia
| | - Seema Saksena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Waddah A Alrefai
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Pradeep K Dudeja
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
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Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease. Cells 2021; 10:cells10071775. [PMID: 34359944 PMCID: PMC8304699 DOI: 10.3390/cells10071775] [Citation(s) in RCA: 240] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 06/29/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant means of butyrate transport from the intestinal lumen to epithelial cytoplasm, where the molecule undergoes rapid β-oxidation to generate cellular fuel. However, not all epithelial cells metabolize butyrate equally. Undifferentiated colonocytes, including neoplastic cells and intestinal stem cells at the epithelial crypt base preferentially utilize glucose over butyrate for cellular fuel. This divergent metabolic conditioning is central to the phenomenon known as “butyrate paradox”, in which butyrate induces contradictory effects on epithelial proliferation in undifferentiated and differentiated colonocytes. There is evidence that accumulation of butyrate in epithelial cells results in histone modification and altered transcriptional activation that halts cell cycle progression. This manifests in the apparent protective effect of butyrate against colonic neoplasia. A corollary to this process is butyrate-induced inhibition of intestinal stem cells. Yet, emerging research has illustrated that the evolution of the crypt, along with butyrate-producing bacteria in the intestine, serve to protect crypt base stem cells from butyrate’s anti-proliferative effects. Butyrate also regulates epithelial inflammation and tolerance to antigens, through production of anti-inflammatory cytokines and induction of tolerogenic dendritic cells. The role of butyrate in the pathogenesis and treatment of intestinal neoplasia, inflammatory bowel disease and malabsorptive states is evolving, and holds promise for the potential translation of butyrate’s cellular function into clinical therapies.
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Su J, Zhang W, Ma C, Xie P, Blachier F, Kong X. Dietary Supplementation With Xylo-oligosaccharides Modifies the Intestinal Epithelial Morphology, Barrier Function and the Fecal Microbiota Composition and Activity in Weaned Piglets. Front Vet Sci 2021; 8:680208. [PMID: 34222403 PMCID: PMC8241929 DOI: 10.3389/fvets.2021.680208] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/20/2021] [Indexed: 11/13/2022] Open
Abstract
The present study determined the effects of dietary xylo-oligosaccharides (XOS) supplementation on the morphology of jejunum and ileum epithelium, fecal microbiota composition, metabolic activity, and expression of genes related to colon barrier function. A total of 150 piglets were randomly assigned to one of five groups: a blank control group (receiving a basal diet), three XOS groups (receiving the basal diet supplemented with 100, 250, and 500 g/t XOS, respectively), as well as a positive control group, used as a matter of comparison, that received the basal diet supplemented with 0.04 kg/t virginiamycin, 0.2 kg/t colistin, and 3,000 mg/kg ZnO. The trial was carried out for 56 days. The results showed that the lowest dose tested (100 g/t XOS) increased (P < 0.05) the ileal villus height, the relative amount of Lactobacillus and Bifidobacterium spp., and the concentration of acetic acid and short-chain fatty acid in feces when compared with the blank control group. In conclusion, dietary 100 g/t XOS supplementation modifies the intestinal ecosystem in weaned piglets in an apparently overall beneficial way.
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Affiliation(s)
- Jiayi Su
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Chinese Academy of Sciences Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Wanghong Zhang
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Chinese Academy of Sciences Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Cui Ma
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Chinese Academy of Sciences Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Peifeng Xie
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Chinese Academy of Sciences Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Francois Blachier
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Paris, France
| | - Xiangfeng Kong
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Chinese Academy of Sciences Key Laboratory of Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
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Liu X, Guo W, Cui S, Tang X, Zhao J, Zhang H, Mao B, Chen W. A Comprehensive Assessment of the Safety of Blautia producta DSM 2950. Microorganisms 2021; 9:microorganisms9050908. [PMID: 33922843 PMCID: PMC8146736 DOI: 10.3390/microorganisms9050908] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/17/2021] [Accepted: 04/18/2021] [Indexed: 12/19/2022] Open
Abstract
In recent years, Blautia has attracted attention for its role in ameliorating host diseases. In particular, Blautia producta DSM 2950 has been considered a potential probiotic due to its ability to mitigate inflammation in poly(I:C) induced HT-29 cells. Thus, to promote the development of indigenous intestinal microorganisms with potential probiotic function, we conducted a comprehensive experimental analysis of DSM 2950 to determine its safety. This comprised a study of its potential virulence genes, antibiotic resistance genes, genomic islands, antibiotic resistance, and hemolytic activity and a 14-day test of its acute oral toxicity in mice. The results indicated no toxin-related virulence genes in the DSM 2950 genome. Most of the genomic islands in DSM 2950 were related to metabolism, rather than virulence expression. DSM 2950 was sensitive to most of the tested antibiotics but was tolerant of treatment with kanamycin, neomycin, clindamycin, or ciprofloxacin, probably because it possessed the corresponding antibiotic resistance genes. Oral acute toxicity tests indicated that the consumption of DSM 2950 does not cause toxic side effects in mice. Overall, the safety profile of DSM 2950 confirmed that it could be a candidate probiotic for use in food and pharmaceutical preparations.
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Affiliation(s)
- Xuemei Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (X.L.); (W.G.); (X.T.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Weiling Guo
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (X.L.); (W.G.); (X.T.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Shumao Cui
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (X.L.); (W.G.); (X.T.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Correspondence: (S.C.); (B.M.); Tel.: +86-510-8591-2155 (B.M.)
| | - Xin Tang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (X.L.); (W.G.); (X.T.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (X.L.); (W.G.); (X.T.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (X.L.); (W.G.); (X.T.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Bingyong Mao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (X.L.); (W.G.); (X.T.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Correspondence: (S.C.); (B.M.); Tel.: +86-510-8591-2155 (B.M.)
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (X.L.); (W.G.); (X.T.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
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Screening of Lactobacillus strains that enhance SCFA uptake in intestinal epithelial cells. Eur Food Res Technol 2021. [DOI: 10.1007/s00217-021-03686-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Altered intestinal epithelial nutrient transport: an underappreciated factor in obesity modulated by diet and microbiota. Biochem J 2021; 478:975-995. [PMID: 33661278 DOI: 10.1042/bcj20200902] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/31/2022]
Abstract
Dietary nutrients absorbed in the proximal small intestine and assimilated in different tissues have a profound effect on overall energy homeostasis, determined by a balance between body's energy intake and expenditure. In obesity, altered intestinal absorption and consequently tissue assimilation of nutrients may disturb the energy balance leading to metabolic abnormalities at the cellular level. The absorption of nutrients such as sugars, amino acids and fatty acids released from food digestion require high-capacity transporter proteins expressed in the intestinal epithelial absorptive cells. Furthermore, nutrient sensing by specific transporters/receptors expressed in the epithelial enteroendocrine cells triggers release of gut hormones involved in regulating energy homeostasis via their effects on appetite and food intake. Therefore, the intestinal epithelial cells play a pivotal role in the pathophysiology of obesity and associated complications. Over the past decade, gut microbiota has emerged as a key factor contributing to obesity via its effects on digestion and absorption of nutrients in the small intestine, and energy harvest from dietary fiber, undigested component of food, in the large intestine. Various mechanisms of microbiota effects on obesity have been implicated. However, the impact of obesity-associated microbiota on the intestinal nutrient transporters needs extensive investigation. This review marshals the limited studies addressing the altered structure and function of the gut epithelium in obesity with special emphasis on nutrient transporters and role of diet and microbiota. The review also discusses the thoughts and controversies and research gaps in this field.
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Vrzáčková N, Ruml T, Zelenka J. Postbiotics, Metabolic Signaling, and Cancer. Molecules 2021; 26:molecules26061528. [PMID: 33799580 PMCID: PMC8000401 DOI: 10.3390/molecules26061528] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/05/2021] [Accepted: 03/09/2021] [Indexed: 12/19/2022] Open
Abstract
Postbiotics are health-promoting microbial metabolites delivered as a functional food or a food supplement. They either directly influence signaling pathways of the body or indirectly manipulate metabolism and the composition of intestinal microflora. Cancer is the second leading cause of death worldwide and even though the prognosis of patients is improving, it is still poor in the substantial part of the cases. The preventable nature of cancer and the importance of a complex multi-level approach in anticancer therapy motivate the search for novel avenues of establishing the anticancer environment in the human body. This review summarizes the principal findings demonstrating the usefulness of both natural and synthetic sources of postbotics in the prevention and therapy of cancer. Specifically, the effects of crude cell-free supernatants, the short-chain fatty acid butyrate, lactic acid, hydrogen sulfide, and β-glucans are described. Contradictory roles of postbiotics in healthy and tumor tissues are highlighted. In conclusion, the application of postbiotics is an efficient complementary strategy to combat cancer.
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Couto MR, Gonçalves P, Magro F, Martel F. Microbiota-derived butyrate regulates intestinal inflammation: Focus on inflammatory bowel disease. Pharmacol Res 2020; 159:104947. [DOI: 10.1016/j.phrs.2020.104947] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/04/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022]
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Deficiency of Dietary Fiber in Slc5a8-Null Mice Promotes Bacterial Dysbiosis and Alters Colonic Epithelial Transcriptome towards Proinflammatory Milieu. Can J Gastroenterol Hepatol 2019; 2019:2543082. [PMID: 31976310 PMCID: PMC6949682 DOI: 10.1155/2019/2543082] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 12/02/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the intestinal tract due to disruption of the symbiotic relationship between the host immune system and microbiota. Various factors alter the gut microbiota which lead to dysbiosis; in particular, diet and dietary fibers constitute important determinants. Dietary fiber protects against IBD; bacteria ferment these dietary fibers in colon and generate short-chain fatty acids (SCFAs), which mediate the anti-inflammatory actions of dietary fibers. SLC5A8 is a high-affinity transporter in the apical membrane of colonic epithelium which mediates the entry of SCFAs from the lumen into cells in Na+-coupled manner. Due to the unique transport kinetics, the function of the transporter becomes important only under conditions of low dietary fiber intake. Here, we have examined the impact of dietary fiber deficiency on luminal microbial composition and transcriptomic profile in colonic epithelium in wild-type (WT) and Slc5a8-null (KO) mice. We fed WT and KO mice with fiber-containing diet (FC-diet) or fiber-free diet (FF-diet) and analyzed the luminal bacterial composition by sequencing 16S rRNA gene in feces. Interestingly, results showed significant differences in the microbial community depending on dietary fiber content and on the presence or absence of Slc5a8. There were also marked differences in the transcriptomic profile of the colonic epithelium depending on the dietary fiber content and on the presence or absence of Slc5a8. We conclude that absence of fiber in diet in KO mice causes bacterial dysbiosis and alters gene expression in the colon that is conducive for inflammation.
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Wongsen S, Werawatganon D, Tumwasorn S. Lactobacillus plantarum B7 attenuates Salmonella typhimurium infection in mice: preclinical study in vitro and in vivo. ASIAN BIOMED 2019. [DOI: 10.1515/abm-2019-0022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Abstract
Background
Salmonella typhimurium is a cause of gastroenteritis including diarrhea. Lactobacillus plantarum is a probiotic widely used to prevent and treat diarrhea.
Objectives
To determine the protective effects of L. plantarum B7 on diarrhea in mice induced by S. typhimurium.
Methods
Inhibition of S. typhimurium growth by L. plantarum B7 was determined using an agar spot method. Mice were divided into 3 groups (n = 8 each): a control group, an S group administered 3 × 109 CFU/mL S. typhimurium, and an S + LP group administered 1 × 109 CFU/mL L. plantarum B7 and 3 × 109 CFU/mL S. typhimurium daily for 3 days. Counts of S. typhimurium and percentage of fecal moisture content (%FMC) were determined from stool samples. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and CXCL1 were determined.
Results
L. plantarum B7 produced a clear zone on S. typhimurium. There were significantly less S. typhimurium in the feces from mice in the S+LP group than in the S group. Serum levels of TNF-α, IL-6, and CXCL1 in mice from the S group were significantly higher than levels in the S+LP and control groups. Feces from mice in the S group were soft and loose, whereas in the S+LP group they were hard and rod shaped. The %FMC in the S+LP group was significantly less than in the S group.
Conclusions
L. plantarum B7 can inhibit growth of S. typhimurium, decrease levels of proinflammatory cytokines, and attenuate symptoms of diarrhea induced in mice by S. typhimurium.
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Affiliation(s)
- Siwaporn Wongsen
- Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University , Bangkok 10330 , Thailand
| | - Duangporn Werawatganon
- Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University , Bangkok 10330 , Thailand
| | - Somying Tumwasorn
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University , Bangkok 10330 , Thailand
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Rao MC. Physiology of Electrolyte Transport in the Gut: Implications for Disease. Compr Physiol 2019; 9:947-1023. [PMID: 31187895 DOI: 10.1002/cphy.c180011] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR-CAS technology, stem cell-derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na+ /K+ ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl- channels and the basolateral Na+ -K+ -2Cl- cotransporter, NKCC1 and K+ channels. Absorption chiefly involves apical membrane Na+ /H+ exchangers and Cl- /HCO3 - exchangers in the small intestine and proximal colon and Na+ channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947-1023, 2019.
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Affiliation(s)
- Mrinalini C Rao
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
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Kim JH, Lee M, Kim SH, Kim SR, Lee BW, Kang ES, Cha BS, Cho JW, Lee YH. Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk. Diabetes Obes Metab 2019; 21:801-811. [PMID: 30407726 DOI: 10.1111/dom.13577] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 10/18/2018] [Accepted: 10/31/2018] [Indexed: 12/21/2022]
Abstract
AIM To investigate sodium-glucose cotransporter 2 inhibitor (SGLT2i)-induced changes in ketogenic enzymes and transporters in normal and diabetic mice models. MATERIALS AND METHODS Normal mice were randomly assigned to receive either vehicle or SGLT2i (25 mg/kg/d by oral gavage) for 7 days. Diabetic mice were treated with vehicle, insulin (4.5 units/kg/d by subcutaneous injection) or SGLT2i (25 mg/kg/d by intra-peritoneal injection) for 5 weeks. Serum and tissues of ketogenic organs were analysed. RESULTS In both normal and diabetic mice, SGLT2i increased beta-hydroxybutyrate (BHB) content in liver, kidney and colon tissue, as well as in serum and urine. In these organs, SGLT2i upregulated mRNA expression of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Similar patterns were observed in the kidney, ileum and colon for mRNA and protein expression of sodium-dependent monocarboxylate transporters (SMCTs), which mediate the cellular uptake of BHB and butyrate, an important substrate for intestinal ketogenesis. In diabetic mice under euglycaemic conditions, SGLT2i increased major ketogenic enzymes and SMCTs, while insulin suppressed ketogenesis. CONCLUSIONS SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney and intestine, suggesting the integrated physiological consequences for ketone body metabolism of SGLT2i administration.
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Affiliation(s)
- Jin Hee Kim
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Hyun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - So Ra Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Won Cho
- Department of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul, Republic of Korea
| | - Yong-Ho Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
- Department of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul, Republic of Korea
- Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
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Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJM, Faber KN, Hermoso MA. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Front Immunol 2019; 10:277. [PMID: 30915065 PMCID: PMC6421268 DOI: 10.3389/fimmu.2019.00277] [Citation(s) in RCA: 2107] [Impact Index Per Article: 351.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 01/31/2019] [Indexed: 12/13/2022] Open
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as Inflammatory Bowel Diseases (IBD), are caused by a complex interplay between genetic, immunologic, microbial and environmental factors. Dysbiosis of the gut microbiome is increasingly considered to be causatively related to IBD and is strongly affected by components of a Western life style. Bacteria that ferment fibers and produce short chain fatty acids (SCFAs) are typically reduced in mucosa and feces of patients with IBD, as compared to healthy individuals. SCFAs, such as acetate, propionate and butyrate, are important metabolites in maintaining intestinal homeostasis. Several studies have indeed shown that fecal SCFAs levels are reduced in active IBD. SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function. Recent findings, however, show that SCFAs, and in particular butyrate, also have important immunomodulatory functions. Absorption of SCFAs is facilitated by substrate transporters like MCT1 and SMCT1 to promote cellular metabolism. Moreover, SCFAs may signal through cell surface G-protein coupled receptors (GPCRs), like GPR41, GPR43, and GPR109A, to activate signaling cascades that control immune functions. Transgenic mouse models support the key role of these GPCRs in controlling intestinal inflammation. Here, we present an overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for IBD. Moreover, we discuss the therapeutic potential of SCFAs for IBD, either applied directly or by stimulating SCFAs-producing bacteria through pre- or probiotic approaches.
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Affiliation(s)
- Daniela Parada Venegas
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Marjorie K De la Fuente
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Glauben Landskron
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - María Julieta González
- Program of Cell and Molecular Biology, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile
| | - Rodrigo Quera
- Inflammatory Bowel Diseases Program, Department of Gastroenterology, Clínica Las Condes, Santiago, Chile
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Hermie J M Harmsen
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.,Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Marcela A Hermoso
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
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Dickerson F, Adamos M, Katsafanas E, Khushalani S, Origoni A, Savage C, Schweinfurth L, Stallings C, Sweeney K, Goga J, Yolken RH. Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial. Bipolar Disord 2018; 20:614-621. [PMID: 29693757 DOI: 10.1111/bdi.12652] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Immunological abnormalities play a role in the pathophysiology of mania and have been associated with relapse. Probiotic organisms such as Lactobacilli and Bifidobacteria modulate inflammation in humans and animal models. The trial examined whether the administration of probiotic organisms prevents psychiatric rehospitalizations in patients recently discharged following hospitalization for mania. METHODS Patients hospitalized for mania (N = 66) were randomized after discharge to receive 24 weeks of adjunctive probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or adjunctive placebo in a parallel two-group design format. The effect of treatment group on the risk of rehospitalization was calculated using Cox regression models. The modulating effect of systemic inflammation was measured employing an inflammation score based on immunoglobulin levels directed at previously defined antigens. RESULTS During the 24-week observation period there were a total of 24 rehospitalizations in the 33 individuals who received placebo and eight rehospitalizations in the 33 individuals who received the probiotics (z = 2.63, P = .009). Hazard functions indicated that the administration of the probiotics was associated with a significant advantage in time to all psychiatric rehospitalizations (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.10, .69; P = .007). Probiotic treatment also resulted in fewer days rehospitalized (mean 8.3 vs 2.8 days for placebo and probiotic treatment, respectively; χ2 = 5.17, P = .017). The effect of the probiotic treatment on the prevention of rehospitalization was increased in individuals with elevated levels of systemic inflammation at baseline. CONCLUSION Probiotic supplementation is associated with a lower rate of rehospitalization in patients who have been recently discharged following hospitalization for mania.
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Affiliation(s)
- Faith Dickerson
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Maria Adamos
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Emily Katsafanas
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Sunil Khushalani
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Andrea Origoni
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Christina Savage
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Lucy Schweinfurth
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Cassie Stallings
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Kevin Sweeney
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Joshana Goga
- Stanley Research Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA
| | - Robert H Yolken
- Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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40
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Zhang J, Ma JY, Li QH, Su H, Sun X. Lactobacillus rhamnosus GG induced protective effect on allergic airway inflammation is associated with gut microbiota. Cell Immunol 2018; 332:77-84. [DOI: 10.1016/j.cellimm.2018.08.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/19/2018] [Accepted: 08/01/2018] [Indexed: 12/14/2022]
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41
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Anandam KY, Alwan OA, Subramanian VS, Srinivasan P, Kapadia R, Said HM. Effect of the proinflammatory cytokine TNF-α on intestinal riboflavin uptake: inhibition mediated via transcriptional mechanism(s). Am J Physiol Cell Physiol 2018; 315:C653-C663. [PMID: 30156861 DOI: 10.1152/ajpcell.00295.2018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Riboflavin (RF), is essential for normal cellular metabolism/function. Intestinal RF absorption occurs via a specific carrier-mediated process that involves the apical transporter RFVT-3 ( SLC52A3) and the basolateral RFVT-1 (SLC52A1). Previously, we characterized different cellular/molecular aspects of the intestinal RF uptake process, but nothing is known about the effect of proinflammatory cytokines on the uptake event. We addressed this issue using in vitro, ex vivo, and in vivo models. First, we determined the level of mRNA expression of the human (h)RFVT-3 and hRFVT-1 in intestinal tissue of patients with inflammatory bowel disease (IBD) and observed a markedly lower level compared with controls. In the in vitro model, exposing Caco-2 cells to tumor necrosis factor-α (TNF-α) led to a significant inhibition in RF uptake, an effect that was abrogated upon knocking down TNF receptor 1 (TNFR1). The inhibition in RF uptake was associated with a significant reduction in the expression of hRFVT-3 and -1 protein and mRNA levels, as well as in the activity of the SLC52A3 and SLC52A1 promoters. The latter effects appear to involve Sp1 and NF-κB sites in these promoters. Similarly, exposure of mouse small intestinal enteroids and wild-type mice to TNF-α led to a significant inhibition in physiological and molecular parameters of intestinal RF uptake. Collectively, these findings demonstrate that exposure of intestinal epithelial cells to TNF-α leads to inhibition in RF uptake and that this effect is mediated, at least in part, via transcriptional mechanism(s). These findings may explain the significantly low RF levels observed in patients with IBD.
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Affiliation(s)
- Kasin Yadunandam Anandam
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Omar A Alwan
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Veedamali S Subramanian
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Padmanabhan Srinivasan
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Rubina Kapadia
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Hamid M Said
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
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42
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Subramanian VS, Sabui S, Subramenium GA, Marchant JS, Said HM. Tumor necrosis factor alpha reduces intestinal vitamin C uptake: a role for NF-κB-mediated signaling. Am J Physiol Gastrointest Liver Physiol 2018; 315:G241-G248. [PMID: 29631379 PMCID: PMC6139644 DOI: 10.1152/ajpgi.00071.2018] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal vitamin C uptake. Intestinal inflammation and prolonged infection are associated with increased serum and intestinal mucosa levels of tumor necrosis factor-α (TNF-α), which also exerts profound effects on the intestinal absorption process. Elevated levels of TNF-α have been linked to the pathogenesis of inflammatory bowel disease (IBD) and malabsorption of nutrients, and patients with this condition have low levels of vitamin C. To date, little is known about the effect of TNF-α on intestinal absorption of vitamin C. We studied the impact of TNF-α on ascorbic acid (AA) transport using a variety of intestinal preparations. The expression level of human SVCT-1 mRNA is significantly lower in patients with IBD. TNF-α treated Caco-2 cells and mice showed a significant inhibition of intestinal 14C-AA uptake. This inhibition was associated with significant decreases in SVCT-1 protein, mRNA, and heterogeneous nuclear RNA levels in TNF-α treated Caco-2 cells, mouse jejunum, and enteroids. Also, TNF-α caused a significant inhibition in the SLC23A1 promoter activity. Furthermore, treatment of Caco-2 cells with celastrol (NF-κB inhibitor) blocked the inhibitory effect caused by TNF-α on AA uptake, SVCT-1 protein, and mRNA expression, as well as the activity of SLC23A1 promoter. Treatment of TNF-α also led to a significant decrease in the expression of hepatocyte nuclear factor-1-α, which drives the basal activity of SLC23A1 promoter, and this effect was reversed by celastrol. Together, these findings show that TNF-α inhibits intestinal AA uptake, and this effect is mediated, at least in part, at the level of transcription of the SLC23A1 gene via the NF-κB pathway. NEW & NOTEWORTHY Our findings show that tumor necrosis factor-α inhibits intestinal ascorbic acid uptake in both in vitro and in vivo systems, and this inhibitory effect is mediated, at least in part, at the level of transcription of the SLC23A1 (sodium-dependent vitamin C transporter-1) gene via the NF-κB pathway.
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Affiliation(s)
- Veedamali S. Subramanian
- 1Department of Medicine, University of California, Irvine, California,2Department of Physiology and Biophysics, University of California, Irvine, California,3Department of Veterans Affairs Medical Center, Long Beach, California
| | - Subrata Sabui
- 1Department of Medicine, University of California, Irvine, California,2Department of Physiology and Biophysics, University of California, Irvine, California,3Department of Veterans Affairs Medical Center, Long Beach, California
| | - Ganapathy A. Subramenium
- 1Department of Medicine, University of California, Irvine, California,2Department of Physiology and Biophysics, University of California, Irvine, California,3Department of Veterans Affairs Medical Center, Long Beach, California
| | - Jonathan S. Marchant
- 4Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Hamid M. Said
- 1Department of Medicine, University of California, Irvine, California,2Department of Physiology and Biophysics, University of California, Irvine, California,3Department of Veterans Affairs Medical Center, Long Beach, California
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Ghonimy A, Zhang DM, Farouk MH, Wang Q. The Impact of Carnitine on Dietary Fiber and Gut Bacteria Metabolism and Their Mutual Interaction in Monogastrics. Int J Mol Sci 2018; 19:1008. [PMID: 29597260 PMCID: PMC5979481 DOI: 10.3390/ijms19041008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/06/2018] [Accepted: 03/21/2018] [Indexed: 12/20/2022] Open
Abstract
Carnitine has vital roles in the endogenous metabolism of short chain fatty acids. It can protect and support gut microbial species, and some dietary fibers can reduce the available iron involved in the bioactivity of carnitine. There is also an antagonistic relationship between high microbial populations and carnitine bioavailability. This review shows the interactions between carnitine and gut microbial composition. It also elucidates the role of carnitine bacterial metabolism, mitochondrial function, fiber fermentability, and short chain fatty acids (SCFAs).
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Affiliation(s)
- Abdallah Ghonimy
- College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China.
| | - Dong Ming Zhang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China.
- Tonghua Normal University, Tonghua 134000, China.
| | - Mohammed Hamdy Farouk
- College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China.
- Department of Animal Production, Faculty of Agriculture, Al-Azhar University, Cairo 11884, Egypt.
| | - Qiuju Wang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China.
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44
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Le B, Yang SH. Efficacy of Lactobacillus plantarum in prevention of inflammatory bowel disease. Toxicol Rep 2018; 5:314-317. [PMID: 29854599 PMCID: PMC5977373 DOI: 10.1016/j.toxrep.2018.02.007] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 02/21/2018] [Accepted: 02/21/2018] [Indexed: 12/15/2022] Open
Abstract
L. plantarum have effects on inflammation for the prevention and management IBD. The mechanisms of action of L. plantarum on IBD are complex. Further clinical studies are needed to validate its potential use in IBD in humans. L. plantarum are considered safe overall for use as feed additives and humans. The incidence of inflammatory bowel disease (IBD) is increasing globally. Altered gut bacteria and bacterial metabolic pathways are two important factors in the initiation and progression of IBD. Lactobacillus plantarum is distributed in a variety of ecological niches, has a proven ability to survive gastric transit, and can colonize the intestinal tract of human and other mammals. Several studies have described the effects of L. plantarum consumption on human physiology. This review summarizes the safety and the effects of L. plantarum in vitro and in animal models for the prevention and management of IBD. L. plantarum modulates the ratio of Th1 and Th2 cells by stimulating the production of different inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, IL-12, and interferon-gamma. The blocking of cyclooxygenase-2 in Th1 also is an apoptotic inhibition mechanism. This overview of the molecular studies addresses the activity of L. plantarum in the human gut environment and its’ potential for remission of IBD.
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Affiliation(s)
- Bao Le
- Department of Biotechnology, Chonnam National University, Yeosu, 59626, Republic of Korea
| | - Seung Hwan Yang
- Department of Biotechnology, Chonnam National University, Yeosu, 59626, Republic of Korea
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45
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Gonçalves P, Araújo JR, Di Santo JP. A Cross-Talk Between Microbiota-Derived Short-Chain Fatty Acids and the Host Mucosal Immune System Regulates Intestinal Homeostasis and Inflammatory Bowel Disease. Inflamm Bowel Dis 2018; 24:558-572. [PMID: 29462379 DOI: 10.1093/ibd/izx029] [Citation(s) in RCA: 277] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Indexed: 12/22/2022]
Abstract
Gut microbiota has a fundamental role in the energy homeostasis of the host and is essential for proper "education" of the immune system. Intestinal microbial communities are able to ferment dietary fiber releasing short-chain fatty acids (SCFAs). The SCFAs, particularly butyrate (BT), regulate innate and adaptive immune cell generation, trafficing, and function. For example, BT has an anti-inflammatory effect by inhibiting the recruitment and proinflammatory activity of neutrophils, macrophages, dendritic cells, and effector T cells and by increasing the number and activity of regulatory T cells. Gut microbial dysbiosis, ie, a microbial community imbalance, has been suggested to play a role in the development of inflammatory bowel disease (IBD). The relationship between dysbiosis and IBD has been difficult to prove, especially in humans, and is probably complex and dynamic, rather than one of a simple cause and effect relationship. However, IBD patients have dysbiosis with reduced numbers of SCFAs-producing bacteria and reduced BT concentration that is linked to a marked increase in the number of proinflammatory immune cells in the gut mucosa of these patients. Thus, microbial dysbiosis and reduced BT concentration may be a factor in the emergence and severity of IBD. Understanding the relationship between microbial dysbiosis and reduced BT concentration to IBD may lead to novel therapeutic interventions.
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Affiliation(s)
- Pedro Gonçalves
- Innate Immunity Unit, Institut Pasteur, Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, Paris, France
| | - João Ricardo Araújo
- Molecular Microbial Pathogenesis Unit, Institut Pasteur, Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U1202, Paris, France
| | - James P Di Santo
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, Paris, France
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Sivaprakasam S, Bhutia YD, Yang S, Ganapathy V. Short-Chain Fatty Acid Transporters: Role in Colonic Homeostasis. Compr Physiol 2017; 8:299-314. [PMID: 29357130 PMCID: PMC6019286 DOI: 10.1002/cphy.c170014] [Citation(s) in RCA: 185] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Short-chain fatty acids (SCFA; acetate, propionate, and butyrate) are generated in colon by bacterial fermentation of dietary fiber. Though diffusion in protonated form is a significant route, carrier-mediated mechanisms constitute the major route for the entry of SCFA in their anionic form into colonic epithelium. Several transport systems operate in cellular uptake of SCFA. MCT1 (SLC16A1) and MCT4 (SLC16A3) are H+-coupled and mediate electroneutral transport of SCFA (H+: SCFA stoichiometry; 1:1). MCT1 is expressed both in the apical membrane and basolateral membrane of colonic epithelium whereas MCT4 specifically in the basolateral membrane. SMCT1 (SLC5A8) and SMCT2 (SLC5A12) are Na+-coupled; SMCT1-mediated transport is electrogenic (Na+: SCFA stoichiometry; 2:1) whereas SMCT2-mediated transport is electroneutral (Na+: SCFA stoichiometry; 1:1). SMCT1 and SMCT2 are expressed exclusively in the apical membrane. An anion-exchange mechanism also operates in the apical membrane in which SCFA entry in anionic form is coupled to bicarbonate efflux; the molecular identity of this exchanger however remains unknown. All these transporters are subject to regulation, notably by their substrates themselves; this process involves cell-surface receptors with SCFA as signaling molecules. There are significant alterations in the expression of these transporters in ulcerative colitis and colon cancer. The tumor-associated changes occur via transcriptional regulation by p53 and HIF1α and by promoter methylation. As SCFA are obligatory for optimal colonic health, the transporters responsible for the entry and transcellular transfer of these bacterial products in colonic epithelium are critical determinants of colonic function under physiological conditions and in disease states. © 2018 American Physiological Society. Compr Physiol 8:299-314, 2018.
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Affiliation(s)
- Sathish Sivaprakasam
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Yangzom D. Bhutia
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Shengping Yang
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
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Intaraphairot T, Chinpaisal C, Apirakaramwong A. Effect of Curcumin on SMCT-1 Expression and Dichloroacetate Toxicity in HCT116 Colon Cancer Cells. PHARMACEUTICAL SCIENCES 2017. [DOI: 10.15171/ps.2017.17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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Couto MR, Gonçalves P, Catarino TA, Martel F. The Effect of Inflammatory Status on Butyrate and Folate Uptake by Tumoral (Caco-2) and Non-Tumoral (IEC-6) Intestinal Epithelial Cells. CELL JOURNAL 2017; 19:96-105. [PMID: 28580313 PMCID: PMC5448317 DOI: 10.22074/cellj.2017.4859] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/13/2017] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Colorectal cancer (CRC) is the second leading cause of cancer death in occidental countries. Chronic inflammatory bowel disease (crohn's disease and ulcerative colitis) is associated with an increased risk for CRC development. The aim of this work was to investigate the relationship between inflammatory status and absorption of nutrients with a role in CRC pathogenesis. MATERIALS AND METHODS In this experimental study, we evaluated the in vitro effect of tumour necrosis factor-alpha (TNF-α), interferon-γ (IF-γ), and acetylsalicylic acid on 14C-butyrate (14C- BT), 3H-folic acid (3H-FA) uptake, and on proliferation, viability and differentiation of Caco-2 and IEC-6 cells in culture. RESULTS The proinflammatory cytokines TNF-α and INF-γ were found to decrease uptake of a low concentration of 14C-BT (10 µM) by Caco-2 (tumoral) and IEC-6 (normal) intestinal epithelial cell lines. However, the effect of TNF-α and INF-γ in IEC-6 cells is most probably related to a cytotoxic and antiproliferative impact. In contrast, INF-γ increases uptake of a high concentration (10 mM) of 14C-BT in Caco-2 cells. The anticarcinogenic effect of BT (10 mM) in these cells is not affected by the presence of this cytokine. On the other hand, acetylsalicylic acid stimulates 14C-BT uptake by Caco-2 cells and potentiates its antiproliferative effect. Finally, both TNF-α and INF-γ cause a significant decrease in 3H-FA uptake by Caco-2 cells. CONCLUSION The inflammatory status has an impact upon cellular uptake of BT and FA, two nutrients with a role in CRC pathogenesis. Moreover, the anti-inflammatory acetylsalicylic acid potentiates the anticarcinogenic effect of BT in Caco-2 cells by increasing its cellular uptake.
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Affiliation(s)
- Mafalda R. Couto
- Department of Biochemistry, Faculty of Medicine and Institute for Research and Innovation in Health Sciences,
University of Porto, Porto, Portugal
| | - Pedro Gonçalves
- Department of Biochemistry, Faculty of Medicine and Institute for Research and Innovation in Health Sciences,
University of Porto, Porto, Portugal
- Innate Immunity Unit, Institute Pasteur, French National Institute of Health and Medical Research (INSERM), U668,
Paris, France
| | - Telmo A. Catarino
- Department of Biochemistry, Faculty of Medicine and Institute for Research and Innovation in Health Sciences,
University of Porto, Porto, Portugal
| | - Fátima Martel
- Department of Biochemistry, Faculty of Medicine and Institute for Research and Innovation in Health Sciences,
University of Porto, Porto, Portugal
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Bluemel S, Williams B, Knight R, Schnabl B. Precision medicine in alcoholic and nonalcoholic fatty liver disease via modulating the gut microbiota. Am J Physiol Gastrointest Liver Physiol 2016; 311:G1018-G1036. [PMID: 27686615 PMCID: PMC5206291 DOI: 10.1152/ajpgi.00245.2016] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/25/2016] [Indexed: 02/08/2023]
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) represent a major health burden in industrialized countries. Although alcohol abuse and nutrition play a central role in disease pathogenesis, preclinical models support a contribution of the gut microbiota to ALD and NAFLD. This review describes changes in the intestinal microbiota compositions related to ALD and NAFLD. Findings from in vitro, animal, and human studies are used to explain how intestinal pathology contributes to disease progression. This review summarizes the effects of untargeted microbiome modifications using antibiotics and probiotics on liver disease in animals and humans. While both affect humoral inflammation, regression of advanced liver disease or mortality has not been demonstrated. This review further describes products secreted by Lactobacillus- and microbiota-derived metabolites, such as fatty acids and antioxidants, that could be used for precision medicine in the treatment of liver disease. A better understanding of host-microbial interactions is allowing discovery of novel therapeutic targets in the gut microbiota, enabling new treatment options that restore the intestinal ecosystem precisely and influence liver disease. The modulation options of the gut microbiota and precision medicine employing the gut microbiota presented in this review have excellent prospects to improve treatment of liver disease.
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Affiliation(s)
- Sena Bluemel
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Brandon Williams
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Rob Knight
- Departments of Pediatrics and Computer Science and Engineering, University of California San Diego, La Jolla, California; and
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California;
- Veterans Affairs San Diego Healthcare System, San Diego, California
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Mohammadi AA, Jazayeri S, Khosravi-Darani K, Solati Z, Mohammadpour N, Asemi Z, Adab Z, Djalali M, Tehrani-Doost M, Hosseini M, Eghtesadi S. The effects of probiotics on mental health and hypothalamic-pituitary-adrenal axis: A randomized, double-blind, placebo-controlled trial in petrochemical workers. Nutr Neurosci 2016; 19:387-395. [PMID: 25879690 DOI: 10.1179/1476830515y.0000000023] [Citation(s) in RCA: 160] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE The aim of this study was to determine effects of probiotic yogurt and multispecies probiotic capsule supplementation on mental health and hypothalamic-pituitary-adrenal axis in petrochemical workers. METHODS The present randomized double-blind, placebo-controlled trial was conducted on 70 petrochemical workers. Subjects were randomly divided into three groups to receive 100 g/day probiotic yogurt + one placebo capsule (n = 25) or one probiotic capsule daily + 100 g/day conventional yogurt (n = 25) or 100 g/day conventional yogurt + one placebo capsule (n = 20) for 6 weeks. Mental health parameters including general health questionnaire (GHQ) and depression anxiety and stress scale (DASS) scores were measured. Fasting blood samples were obtained at the beginning and 6 weeks after the intervention to quantify hypothalamic-pituitary-adrenal axis. RESULTS After 6 weeks of intervention, a significant improvement of GHQ was observed in the probiotic yogurt (18.0 ± 1.5 vs. 13.5 ± 1.9, P = 0.007) and in the probiotic capsule group (16.9 ± 1.8 vs. 9.8 ± 1.9, P = 0.001), as well as a significant improvement in DASS scores in the probiotic yogurt (23.3 ± 3.7 vs. 13.0 ± 3.7, P = 0.02) and the probiotic capsule group (18.9 ± 3.2 vs. 9.4 ± 4.0, P = 0.006). However, there was no significant improvement in the conventional yogurt group (P = 0.05 for GHQ and P = 0.08 for DASS). DISCUSSION The consumption of probiotic yogurt or a multispecies probiotic capsule had beneficial effects on mental health parameters in petrochemical workers.
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Affiliation(s)
- Ali Akbar Mohammadi
- a Department of Nutrition, School of Public Health , Iran University of Medical Sciences , Tehran , Iran
| | - Shima Jazayeri
- a Department of Nutrition, School of Public Health , Iran University of Medical Sciences , Tehran , Iran
| | - Kianoush Khosravi-Darani
- b Research Department of Food Technology Research , National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences , Tehran
| | - Zahra Solati
- c School of Nutritional Sciences and Dietetics , Tehran University of Medical Sciences , Iran
| | - Nakisa Mohammadpour
- c School of Nutritional Sciences and Dietetics , Tehran University of Medical Sciences , Iran
| | - Zatollah Asemi
- d Research Center for Biochemistry and Nutrition in Metabolic Diseases , Kashan University of Medical Sciences , Iran
| | - Zohre Adab
- c School of Nutritional Sciences and Dietetics , Tehran University of Medical Sciences , Iran
| | - Mahmoud Djalali
- c School of Nutritional Sciences and Dietetics , Tehran University of Medical Sciences , Iran
| | - Mehdi Tehrani-Doost
- e Department of Psychiatry, Roozbeh Hospital , Tehran University of Medical Sciences , Iran
| | - Mostafa Hosseini
- f Department of Epidemiology and Biostatistics, School of Public Health , Tehran University of Medical Sciences , Iran
| | - Shahryar Eghtesadi
- a Department of Nutrition, School of Public Health , Iran University of Medical Sciences , Tehran , Iran
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