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1
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Barozier C, Wilms J, Echeverry-Munera J, Seymour D, Leal L. The administration route of indigestible gut permeability markers modulates urinary marker recovery in calves. JDS COMMUNICATIONS 2025; 6:60-64. [PMID: 39877179 PMCID: PMC11770294 DOI: 10.3168/jdsc.2024-0616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/15/2024] [Indexed: 01/31/2025]
Abstract
Indigestible gut permeability markers are used to assess gut integrity and can be administered to calves via a milk meal (MM) or orally pulsed (OP). This study investigated how marker administration route (ADM_R) affects the estimation of gut permeability in relation to milk replacer (MR) fat inclusion. Thirty-two newborn Holstein calves were blocked based on their arrival sequence at the facility. Within each block of 4 calves, calves were randomly assigned to one of 2 treatments (n = 16/treatment): a MR high in lactose (HL) and a MR high in fat (HF). During the first 5 d, calves were fed 6.0 L/d followed by 7.0 L/d offered in 2 meals per day at 15% solids. To evaluate gut permeability, indigestible markers (lactulose, d-mannitol, and chromium [Cr]-EDTA) were administered in 2 periods, on Tuesday and Thursday in the third week after arrival. Within each block, calves with different MR treatments were randomly assigned to a different marker ADM_R order: MM in the first period and OP in the second (n = 16) or the opposite order (n = 16). Thus, one block of 4 calves included all combinations of MR and ADM_R. Following marker administration, urine was collected over 2 sampling periods: the first from 0 to 6 h and the second from 6 to 24 h. Measurements included weekly BW and daily MR intake and fecal scoring. Intake, growth, and fecal consistency were not affected by dietary treatments or by ADM_R. The urinary recovery of lactulose was greater in calves fed HF during the 6- to 24-h and the overall 24-h collection period. Consistently, d-mannitol recovery tended to be greater in calves fed HF during the 24-h collection. With OP administration, the urinary recovery of all markers was greater between 0 and 6 h, whereas in the 6- to 24-h period, the recovery of lactose and d-mannitol were lower. Over 24 h of collection, Cr-EDTA recovery was greater with OP. No interaction between ADM_R and MR composition was detected. This suggests that both ADM_R were equivalent in assessing the effects of dietary interventions on gut permeability. However, different ADM_R likely affected the trajectory and time spent by the markers in each segment of the gut.
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Affiliation(s)
- C. Barozier
- Trouw Nutrition Research and Development, 3800 AG, Amersfoort, the Netherlands
- AgroParisTech, Université Paris-Saclay, 91120 Palaiseau, France
| | - J.N. Wilms
- Trouw Nutrition Research and Development, 3800 AG, Amersfoort, the Netherlands
| | - J. Echeverry-Munera
- Trouw Nutrition Research and Development, 3800 AG, Amersfoort, the Netherlands
| | - D.J. Seymour
- Trouw Nutrition Research and Development, 3800 AG, Amersfoort, the Netherlands
| | - L.N. Leal
- Trouw Nutrition Research and Development, 3800 AG, Amersfoort, the Netherlands
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2
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Park JE, Park HY, Kim YS, Park M. The Role of Diet, Additives, and Antibiotics in Metabolic Endotoxemia and Chronic Diseases. Metabolites 2024; 14:704. [PMID: 39728485 DOI: 10.3390/metabo14120704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Background/Objectives: Dietary patterns, including high-fat and high-carbohydrate diets (HFDs and HCDs), as well as non-dietary factors such as food additives and antibiotics, are strongly linked to metabolic endotoxemia, a critical driver of low-grade chronic inflammation. This review explores the mechanisms through which these factors impair intestinal permeability, disrupt gut microbial balance, and facilitate lipopolysaccharide (LPS) translocation into the bloodstream, contributing to metabolic disorders such as obesity, type 2 diabetes mellitus, and inflammatory bowel disease. Methods: The analysis integrates findings from recent studies on the effects of dietary components and gut microbiota interactions on intestinal barrier function and systemic inflammation. Focus is given to experimental designs assessing gut permeability using biochemical and histological methods, alongside microbiota profiling in both human and animal models. Results: HFDs and HCDs were shown to increase intestinal permeability and systemic LPS levels, inducing gut dysbiosis and compromising barrier integrity. The resulting endotoxemia promoted a state of chronic inflammation, disrupting metabolic regulation and contributing to the pathogenesis of various metabolic diseases. Food additives and antibiotics further exacerbated these effects by altering microbial composition and increasing gut permeability. Conclusions: Diet-induced alterations in gut microbiota and barrier dysfunction emerge as key mediators of metabolic endotoxemia and related disorders. Addressing dietary patterns and their impact on gut health is crucial for developing targeted interventions. Further research is warranted to standardize methodologies and elucidate mechanisms for translating these findings into clinical applications.
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Affiliation(s)
- Ji-Eun Park
- Food Functionality Research Division, Korea Food Research Institute, Jeonju 55365, Republic of Korea
- Department of Food Science and Technology, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Ho-Young Park
- Food Functionality Research Division, Korea Food Research Institute, Jeonju 55365, Republic of Korea
- Department of Food Biotechnology, Korea National University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Young-Soo Kim
- Department of Food Science and Technology, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Miri Park
- Food Functionality Research Division, Korea Food Research Institute, Jeonju 55365, Republic of Korea
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3
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Acharya B, Tofthagen M, Maciej-Hulme ML, Suissa MR, Karlsson NG. Limited support for a direct connection between prebiotics and intestinal permeability - a systematic review. Glycoconj J 2024; 41:323-342. [PMID: 39287885 PMCID: PMC11522178 DOI: 10.1007/s10719-024-10165-8] [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: 02/07/2024] [Revised: 08/20/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024]
Abstract
The intestinal barrier is a selective interface between the body´s external and the internal environment. Its layer of epithelial cells is joined together by tight junction proteins. In intestinal permeability (IP), the barrier is compromised, leading to increased translocation of luminal contents such as large molecules, toxins and even microorganisms. Numerous diseases including Inflammatory Bowel Disease (IBD), Coeliac disease (CD), autoimmune disorders, and diabetes are believed to be associated with IP. Dietary interventions, such as prebiotics, may improve the intestinal barrier. Prebiotics are non-digestible food compounds, that promote the growth and activity of beneficial bacteria in the gut. This systematic review assesses the connection between prebiotic usage and IP. PubMed and Trip were used to identify relevant studies conducted between 2010-2023. Only six studies were found, which all varied in the characteristics of the population, study design, and types of prebiotics interventions. Only one study showed a statistically significant effect of prebiotics on IP. Alteration of intestinal barrier function was measured by lactulose/mannitol, chromium-labelled Ethylenediaminetetraacetic acid (51Cr-EDTA), lactulose/rhamnose, and sucralose/erythritol excretion as well as zonulin and glucagon-like peptide 2 levels. Three studies also conducted gut microbiota assessment, and one of them showed statistically significant improvement of the gut microbiome. This study also reported a decrease in zonulin level. The main conclusion from this review is that there is a lack of human studies in this important field. Futhermore, large population studies and using standardized protocols, would be required to properly assess the impact of prebiotic intervention and improvement on IP.
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Affiliation(s)
- Binayak Acharya
- Department of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, St. Olavs Plass, P.O. Box 4, N-0130, Oslo, Norway
| | - Marthe Tofthagen
- Department of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, St. Olavs Plass, P.O. Box 4, N-0130, Oslo, Norway
| | - Marissa L Maciej-Hulme
- Department of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, St. Olavs Plass, P.O. Box 4, N-0130, Oslo, Norway
| | - Michal Rachel Suissa
- Department of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, St. Olavs Plass, P.O. Box 4, N-0130, Oslo, Norway
| | - Niclas G Karlsson
- Department of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, St. Olavs Plass, P.O. Box 4, N-0130, Oslo, Norway.
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4
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Tlais AZA, Polo A, Granehäll L, Filannino P, Vincentini O, De Battistis F, Di Cagno R, Gobbetti M. Sugar lowering in fermented apple-pear juice orchestrates a promising metabolic answer in the gut microbiome and intestinal integrity. Curr Res Food Sci 2024; 9:100833. [PMID: 39290653 PMCID: PMC11406026 DOI: 10.1016/j.crfs.2024.100833] [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: 05/17/2024] [Revised: 07/29/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024] Open
Abstract
Excessive sugar consumption in young people, who are the major consumers of sugary drinks, combined with limited physical activity, is an important determinant of obesity. Despite their natural appeal, fruit juices have a similar sugar content to that of sugary drinks and once metabolized, they may induce the same biological response. This study aimed to verify whether fermentation processes can make juice consumption healthier and whether reduced-sugar juices have a specific impact on intestinal function. We designed a tailored fermentation of apple-pear juices with lactic acid bacteria and yeasts, which resulted in a reduction of sugar content (27-66%) and caloric intake, and an increase in mannitol content. The impact of newly developed apple-pear juices on gut microbiome composition and functionality was evaluated in vitro using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). Promising changes were found in the gut microbiota and its metabolic responses and functionality, targeting pathways related to obesity and weight loss (lipopolysaccharide and secondary metabolite biosynthesis, polycyclic aromatic hydrocarbon degradation, and amino sugar and nucleotide sugar metabolism). Additionally, the fermented apple-pear juices positively modulated the intestinal epithelial features. While the simulation of the study simplifies the complex in vivo conditions, it suggests that low-sugar fermented apple-pear juices can elicit targeted responses in the gut ecosystem, contributing to healthier alternatives to traditional fruit juices.
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Affiliation(s)
- Ali Zein Alabiden Tlais
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
| | - Andrea Polo
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
| | - Lena Granehäll
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
| | - Pasquale Filannino
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70121, Bari, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
| | - Olimpia Vincentini
- U.O Alimentazione, Nutrizione e Salute, Dipartimento Sicurezza Alimentare, Nutrizione e Sanità Pubblica Veterinaria, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Francesca De Battistis
- U.O Alimentazione, Nutrizione e Salute, Dipartimento Sicurezza Alimentare, Nutrizione e Sanità Pubblica Veterinaria, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Raffaella Di Cagno
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
| | - Marco Gobbetti
- Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano-Bozen, 39100, Bolzano, Italy
- International Center on Food Fermentation, 39100, Bolzano, Italy
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Snelson M, Vanuytsel T, Marques FZ. Breaking the Barrier: The Role of Gut Epithelial Permeability in the Pathogenesis of Hypertension. Curr Hypertens Rep 2024; 26:369-380. [PMID: 38662328 PMCID: PMC11324679 DOI: 10.1007/s11906-024-01307-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2024] [Indexed: 04/26/2024]
Abstract
PURPOSE OF THE REVIEW To review what intestinal permeability is and how it is measured, and to summarise the current evidence linking altered intestinal permeability with the development of hypertension. RECENT FINDINGS Increased gastrointestinal permeability, directly measured in vivo, has been demonstrated in experimental and genetic animal models of hypertension. This is consistent with the passage of microbial substances to the systemic circulation and the activation of inflammatory pathways. Evidence for increased gut permeability in human hypertension has been reliant of a handful of blood biomarkers, with no studies directly measuring gut permeability in hypertensive cohorts. There is emerging literature that some of these putative biomarkers may not accurately reflect permeability of the gastrointestinal tract. Data from animal models of hypertension support they have increased gut permeability; however, there is a dearth of conclusive evidence in humans. Future studies are needed that directly measure intestinal permeability in people with hypertension.
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Affiliation(s)
- Matthew Snelson
- Hypertension Research Laboratory, School of Biological Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Francine Z Marques
- Hypertension Research Laboratory, School of Biological Sciences, Monash University, Melbourne, Australia.
- Victorian Heart Institute, Monash University, Melbourne, Australia.
- Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia.
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6
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O'Brien JW, Merali N, Pring C, Rockall T, Robertson D, Bartlett D, Frampton A. Gastrointestinal Permeability After Bariatric Surgery: A Systematic Review. Cureus 2024; 16:e60480. [PMID: 38883053 PMCID: PMC11180380 DOI: 10.7759/cureus.60480] [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] [Accepted: 05/17/2024] [Indexed: 06/18/2024] Open
Abstract
Gastrointestinal permeability refers to the movement of substances across the gut wall. This is mediated by endotoxemia (bacterial products entering the systemic circulation), and is associated with metabolic disease. The effect of bariatric surgery on permeability remains uncertain; the associated dietary, metabolic and weight changes are suggested to influence, or trigger, altered permeability. The primary aim of this study is to synthesize evidence and analyze the effect of bariatric surgery on permeability. A systematic review was performed, searching MEDLINE, EMBASE, and Scopus until February 2023, using MESH terms "intestinal permeability", "bariatric", for studies reporting in vivo assessment of permeability. Three cohort studies and two case series were identified (n=96). Data was heterogeneous; methodology and controls preclude meta-analysis. Gastroduodenal permeability reduced post-sleeve gastrectomy (SG). Two studies showed an increase in small intestinal permeability after biliopancreatic diversion. Two studies revealed a decrease in post-Roux-en-Y gastric bypass. One study identified increased colonic permeability six months post-SG. Evidence regarding permeability change after bariatric surgery is conflicting, notably for the small intestine. Impaired colonic permeability post-SG raises concerns regarding colonic protein fermentation and harmful dietary sequelae. There are multiple interacting variables confounding gastrointestinal permeability change; procedure type, altered microbiota and metabolic response to surgery. Further understanding of this important aspect of obesity is required, both before and after bariatric surgery.
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Affiliation(s)
- James W O'Brien
- Department of Surgery, School of Biosciences and Medicine, University of Surrey, Guildford, GBR
- Department of Minimal Access Therapy Training Unit, Royal Surrey NHS Foundation Trust, Guildford, GBR
| | - Nabeel Merali
- Department of Surgery, School of Biosciences and Medicine, University of Surrey, Guildford, GBR
- Department of Minimal Access Therapy Training Unit, Royal Surrey NHS Foundation Trust, Guildford, GBR
| | - Chris Pring
- Department of Bariatric Surgery, University Hospitals Sussex NHS Foundation Trust, Chichester, GBR
| | - Tim Rockall
- Department of Minimal Access Therapy Training Unit, Royal Surrey NHS Foundation Trust, Guildford, GBR
| | - Denise Robertson
- Department of Nutrition, School of Biosciences and Medicine, University of Surrey, Guildford, GBR
| | - David Bartlett
- Department of Nutrition, School of Biosciences and Medicine, University of Surrey, Guildford, GBR
| | - Adam Frampton
- Department of Surgery, School of Biosciences and Medicine, University of Surrey, Guildford, GBR
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7
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Baptista Pereira P, Torrejón E, Ferreira I, Carvalho AS, Teshima A, Sousa-Lima I, Beck HC, Costa-Silva B, Matthiesen R, Macedo MP, de Oliveira RM. Proteomic Profiling of Plasma- and Gut-Derived Extracellular Vesicles in Obesity. Nutrients 2024; 16:736. [PMID: 38474865 DOI: 10.3390/nu16050736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Obesity entails metabolic alterations across multiple organs, highlighting the role of inter-organ communication in its pathogenesis. Extracellular vesicles (EVs) are communication agents in physiological and pathological conditions, and although they have been associated with obesity comorbidities, their protein cargo in this context remains largely unknown. To decipher the messages encapsulated in EVs, we isolated plasma-derived EVs from a diet-induced obese murine model. Obese plasma EVs exhibited a decline in protein diversity while control EVs revealed significant enrichment in protein-folding functions, highlighting the importance of proper folding in maintaining metabolic homeostasis. Previously, we revealed that gut-derived EVs' proteome holds particular significance in obesity. Here, we compared plasma and gut EVs and identified four proteins exclusively present in the control state of both EVs, revealing the potential for a non-invasive assessment of gut health by analyzing blood-derived EVs. Given the relevance of post-translational modifications (PTMs), we observed a shift in chromatin-related proteins from glycation to acetylation in obese gut EVs, suggesting a regulatory mechanism targeting DNA transcription during obesity. This study provides valuable insights into novel roles of EVs and protein PTMs in the intricate mechanisms underlying obesity, shedding light on potential biomarkers and pathways for future research.
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Affiliation(s)
- Pedro Baptista Pereira
- Metabolic Diseases Research Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
| | - Estefania Torrejón
- Metabolic Diseases Research Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
| | - Inês Ferreira
- Metabolic Diseases Research Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
| | - Ana Sofia Carvalho
- Computational and Experimental Biology Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
| | - Akiko Teshima
- Metabolic Diseases Research Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
| | - Inês Sousa-Lima
- Metabolic Diseases Research Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
| | - Hans Christian Beck
- Centre for Clinical Proteomics, Department of Clinical Biochemistry, Odense University Hospital, DK-5000 Odense, Denmark
| | - Bruno Costa-Silva
- Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, 1400-038 Lisboa, Portugal
| | - Rune Matthiesen
- Computational and Experimental Biology Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
| | - Maria Paula Macedo
- Metabolic Diseases Research Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
| | - Rita Machado de Oliveira
- Metabolic Diseases Research Group, iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
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Li SX, Guo Y. Gut microbiome: New perspectives for type 2 diabetes prevention and treatment. World J Clin Cases 2023; 11:7508-7520. [DOI: 10.12998/wjcc.v11.i31.7508] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/19/2023] [Accepted: 10/23/2023] [Indexed: 11/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM), which is distinguished by increased glucose levels in the bloodstream, is a metabolic disease with a rapidly increasing incidence worldwide. Nevertheless, the etiology and characteristics of the mechanism of T2DM remain unclear. Recently, abundant evidence has indicated that the intestinal microbiota is crucially involved in the initiation and progression of T2DM. The gut microbiome, the largest microecosystem, engages in material and energy metabolism in the human body. In this review, we concentrated on the correlation between the gut flora and T2DM. Meanwhile, we summarized the pathogenesis involving the intestinal flora in T2DM, as well as therapeutic approaches aimed at modulating the gut microbiota for the management of T2DM. Through the analysis presented here, we draw attention to further exploration of these research directions.
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Affiliation(s)
- Shu-Xiao Li
- School of Clinical Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130000, Jilin Province, China
| | - Yan Guo
- School of Clinical Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130000, Jilin Province, China
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9
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Harasawa A, Ishiyama S, Mochizuki K. Fructo-oligosaccharide-mediated alteration in claudin expression in small intestinal absorptive Caco-2 cells is positively associated with the induction of inflammatory genes and the glucan receptor gene CLEC7A. Nutrition 2023; 115:112140. [PMID: 37481839 DOI: 10.1016/j.nut.2023.112140] [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: 03/24/2023] [Revised: 06/02/2023] [Accepted: 06/18/2023] [Indexed: 07/25/2023]
Abstract
OBJECTIVES Indigestible carbohydrates may strengthen tight junctions (TJs) independently of intestinal bacteria. This study investigated whether indigestible carbohydrates (i.e., fructo-oligosaccharides [FOS]) promote TJs directly to intestinal absorptive Caco-2 cells and examined the association between the expression of genes constructing TJs and other genes using mRNA microarray analysis. METHODS Caco-2 cells at 1.0 × 105/mL were seeded in a type I collagen plate and cultured in high-glucose Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal calf serum (FCS); the cells reached confluence at 7 d after seeding. Ten days after the cells reached confluency, they were cultured for 24 h in 10% FCS-containing DMEM medium supplemented with 0%, 5%, or 10% FOS. We performed mRNA microarray to identify the genes whose expression was altered by FOS. Subsequently, quantitative reverse transcription polymerase chain reaction was performed for these altered genes, including CLEC7A encoding the glucan receptor, and for the claudin (CLDN) family genes. The expression of CLDN2, CLDN4, and CLEC7A proteins was assessed using western blot analysis. RESULTS FOS decreased the mRNA and protein expression of CLDN2, which weakens TJs, and increased those of CLDN4, which strengthens TJs, in Caco-2 cells. FOS treatment (10%) reduced the mRNA expression of antioxidative genes and induced the expression of immune response-related genes, including CLEC7A, CCL2, and ITGA2. Furthermore, the expression of CLEC7A protein was enhanced by FOS. CONCLUSIONS Induction of TJ-strengthening CLDN4 and reduction of TJ-weakening CLDN2 by FOS treatment in small intestinal absorptive Caco-2 cells is positively associated with the induction of inflammatory genes, including CLEC7A.
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Affiliation(s)
- Aya Harasawa
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, Kofu, Japan
| | - Shiori Ishiyama
- Laboratory of Food and Nutritional Sciences, Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Japan
| | - Kazuki Mochizuki
- Laboratory of Food and Nutritional Sciences, Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Japan.
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10
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Rella S, Onyiah J, Baker C, Singh V, Her A, Rasouli N. Design and rationale for the SIB trial: a randomized parallel comparison of semaglutide versus placebo on intestinal barrier function in type 2 diabetes mellitus. Ther Adv Endocrinol Metab 2023; 14:20420188231207348. [PMID: 37916028 PMCID: PMC10617296 DOI: 10.1177/20420188231207348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 09/26/2023] [Indexed: 11/03/2023] Open
Abstract
Objective To describe the rationale and design of the SIB trial, an interventional clinical trial testing the hypothesis that subcutaneous (s.c.) once-weekly semaglutide can improve intestinal permeability and reduce systemic inflammation in participants with type 2 diabetes (T2D) and obesity. Methods SIB (NCT04979130) is an investigator-initiated, single-center randomized, double-blinded, placebo-controlled clinical study being conducted at the University of Colorado Anschutz Medical Campus. The primary objective of this novel trial is to test the hypothesis that subcutaneous (s.c.) once-weekly semaglutide could improve intestinal permeability and reduce systemic inflammation in participants with T2D and obesity. Eligible participants had a diagnosis of type 2 diabetes, elevated body mass index, and evidence of systemic inflammation. Participants were randomized 1:1 to s.c. semaglutide or placebo. Participants were assessed for intestinal permeability and markers of inflammation at baseline, mid-study, and at the end of the study. Efficacy assessments were based on the analysis of the following: lactulose:mannitol ratio test, serum lipopolysaccharide-binding protein (LBP), fecal calprotectin, inflammatory biomarkers (IL-6, TNF, IL-1, IL-8, hs-CRP), and HbA1c. All participants who enrolled in the trial provided written informed consent after having received written and oral information on the trial. The risks of semaglutide use were minimized by administration according to FDA-labeled use and close monitoring for adverse events. Discussion SIB is the first study to examine the effects of GLP-1 receptor agonists on intestinal permeability in humans and will provide important data on their impact on systemic inflammation and intestinal permeability in the setting of T2D and obesity.
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Affiliation(s)
- Steven Rella
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Mail Stop 8106, 12631 East 17th Avenue, Aurora, CO 80045-2559, USA
| | - Joseph Onyiah
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Chelsea Baker
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Vatsala Singh
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew Her
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Neda Rasouli
- University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
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11
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Pat Y, Ogulur I, Yazici D, Mitamura Y, Cevhertas L, Küçükkase OC, Mesisser SS, Akdis M, Nadeau K, Akdis CA. Effect of altered human exposome on the skin and mucosal epithelial barrier integrity. Tissue Barriers 2023; 11:2133877. [PMID: 36262078 PMCID: PMC10606824 DOI: 10.1080/21688370.2022.2133877] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/23/2022] [Accepted: 08/27/2022] [Indexed: 10/24/2022] Open
Abstract
Pollution in the world and exposure of humans and nature to toxic substances is continuously worsening at a rapid pace. In the last 60 years, human and domestic animal health has been challenged by continuous exposure to toxic substances and pollutants because of uncontrolled growth, modernization, and industrialization. More than 350,000 new chemicals have been introduced to our lives, mostly without any reasonable control of their health effects and toxicity. A plethora of studies show exposure to these harmful substances during this period with their implications on the skin and mucosal epithelial barrier and increasing prevalence of allergic and autoimmune diseases in the context of the "epithelial barrier hypothesis". Exposure to these substances causes an epithelial injury with peri-epithelial inflammation, microbial dysbiosis and bacterial translocation to sub-epithelial areas, and immune response to dysbiotic bacteria. Here, we provide scientific evidence on the altered human exposome and its impact on epithelial barriers.
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Affiliation(s)
- Yagiz Pat
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- Department of Medical Microbiology, Faculty of Medicine, Aydin Menderes University, Turkey
| | - Ismail Ogulur
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Duygu Yazici
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Yasutaka Mitamura
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Lacin Cevhertas
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- Department of Medical Immunology, Institute of Health Sciences, Bursa Uludag University, Turkey
| | - Ozan C Küçükkase
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Sanne S Mesisser
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Kari Nadeau
- Sean N. Parker Center for Allergy and Asthma Research, Stanford University and Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, CA, USA
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
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12
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Liu Y, Zhong W, Li X, Shen F, Ma X, Yang Q, Hong S, Sun Y. Diets, Gut Microbiota and Metabolites. PHENOMICS (CHAM, SWITZERLAND) 2023; 3:268-284. [PMID: 37325710 PMCID: PMC10260722 DOI: 10.1007/s43657-023-00095-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 06/17/2023]
Abstract
The gut microbiota refers to the gross collection of microorganisms, estimated trillions of them, which reside within the gut and play crucial roles in the absorption and digestion of dietary nutrients. In the past decades, the new generation 'omics' (metagenomics, transcriptomics, proteomics, and metabolomics) technologies made it possible to precisely identify microbiota and metabolites and describe their variability between individuals, populations and even different time points within the same subjects. With massive efforts made, it is now generally accepted that the gut microbiota is a dynamically changing population, whose composition is influenced by the hosts' health conditions and lifestyles. Diet is one of the major contributors to shaping the gut microbiota. The components in the diets vary in different countries, religions, and populations. Some special diets have been adopted by people for hundreds of years aiming for better health, while the underlying mechanisms remain largely unknown. Recent studies based on volunteers or diet-treated animals demonstrated that diets can greatly and rapidly change the gut microbiota. The unique pattern of the nutrients from the diets and their metabolites produced by the gut microbiota has been linked with the occurrence of diseases, including obesity, diabetes, nonalcoholic fatty liver disease, cardiovascular disease, neural diseases, and more. This review will summarize the recent progress and current understanding of the effects of different dietary patterns on the composition of gut microbiota, bacterial metabolites, and their effects on the host's metabolism.
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Affiliation(s)
- Yilian Liu
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Human Phenome Institute, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai, 200433 China
| | - Wanglei Zhong
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Human Phenome Institute, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai, 200433 China
| | - Xiao Li
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Human Phenome Institute, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai, 200433 China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442001 Hubei China
| | - Xiaonan Ma
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Human Phenome Institute, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai, 200433 China
| | - Qi Yang
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Human Phenome Institute, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai, 200433 China
| | - Shangyu Hong
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Human Phenome Institute, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai, 200433 China
| | - Yan Sun
- Masonic Medical Research Institute, 2150 Bleecker St, Utica, NY 13501 USA
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13
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Wang HW, Tang J, Sun L, Li Z, Deng M, Dai Z. Mechanism of immune attack in the progression of obesity-related type 2 diabetes. World J Diabetes 2023; 14:494-511. [PMID: 37273249 PMCID: PMC10236992 DOI: 10.4239/wjd.v14.i5.494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/06/2023] [Accepted: 03/30/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.
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Affiliation(s)
- Hua-Wei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jun Tang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li Sun
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ming Deng
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhe Dai
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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14
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Horowitz A, Chanez-Paredes SD, Haest X, Turner JR. Paracellular permeability and tight junction regulation in gut health and disease. Nat Rev Gastroenterol Hepatol 2023:10.1038/s41575-023-00766-3. [PMID: 37186118 PMCID: PMC10127193 DOI: 10.1038/s41575-023-00766-3] [Citation(s) in RCA: 255] [Impact Index Per Article: 127.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2023] [Indexed: 05/17/2023]
Abstract
Epithelial tight junctions define the paracellular permeability of the intestinal barrier. Molecules can cross the tight junctions via two distinct size-selective and charge-selective paracellular pathways: the pore pathway and the leak pathway. These can be distinguished by their selectivities and differential regulation by immune cells. However, permeability increases measured in most studies are secondary to epithelial damage, which allows non-selective flux via the unrestricted pathway. Restoration of increased unrestricted pathway permeability requires mucosal healing. By contrast, tight junction barrier loss can be reversed by targeted interventions. Specific approaches are needed to restore pore pathway or leak pathway permeability increases. Recent studies have used preclinical disease models to demonstrate the potential of pore pathway or leak pathway barrier restoration in disease. In this Review, we focus on the two paracellular flux pathways that are dependent on the tight junction. We discuss the latest evidence that highlights tight junction components, structures and regulatory mechanisms, their impact on gut health and disease, and opportunities for therapeutic intervention.
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Affiliation(s)
- Arie Horowitz
- UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Normandie University, Rouen, France
| | - Sandra D Chanez-Paredes
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xenia Haest
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jerrold R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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Stillhart C, Asteriadis A, Bocharova E, Eksteen G, Harder F, Kusch J, Tzakri T, Augustijns P, Matthys C, Vertzoni M, Weitschies W, Reppas C. The impact of advanced age on gastrointestinal characteristics that are relevant to oral drug absorption: An AGePOP review. Eur J Pharm Sci 2023; 187:106452. [PMID: 37098371 DOI: 10.1016/j.ejps.2023.106452] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/12/2023] [Accepted: 04/21/2023] [Indexed: 04/27/2023]
Abstract
The purpose of this review is to summarize the current knowledge on three physiological determinants of oral drug absorption, i.e., gastric emptying, volumes and composition of luminal fluids, and intestinal permeability, in the advanced age population, so that potential knowledge gaps and directions for further research efforts are identified. Published data on gastric emptying rates in older people are conflicting. Also, there are significant knowledge gaps, especially on gastric motility and emptying rates of drugs and of non-caloric fluids. Compared with younger adults, volumes of luminal contents seem to be slightly smaller in older people. Our understanding on the impact of advanced age on luminal physicochemical characteristics is, at best, very limited, whereas the impact of (co)morbidities and geriatric syndromes in the advanced age population has not been addressed to date. The available literature on the effect of advanced age on intestinal permeability is limited, and should be approached with caution, primarily due to the limitations of the experimental methodologies used.
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Affiliation(s)
| | - Adam Asteriadis
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Ekaterina Bocharova
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Gabriel Eksteen
- Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Fritz Harder
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium
| | - Jonas Kusch
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Theodora Tzakri
- Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, University of Greifswald, Germany
| | - Patrick Augustijns
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium
| | - Christophe Matthys
- Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium; Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium
| | - Maria Vertzoni
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Werner Weitschies
- Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, University of Greifswald, Germany
| | - Christos Reppas
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece.
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16
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Guo XJ, Dai SX, Lou JD, Ma XX, Hu XJ, Tu LP, Cui J, Lu H, Jiang T, Xu JT. Distribution characteristics of oral microbiota and its relationship with intestinal microbiota in patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2023; 14:1119201. [PMID: 37025407 PMCID: PMC10072265 DOI: 10.3389/fendo.2023.1119201] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/23/2023] [Indexed: 03/18/2023] Open
Abstract
Introduction Type 2 diabetes mellitus (T2DM) has a high incidence rate globally, increasing the burden of death, disability, and the economy worldwide. Previous studies have found that the compositions of oral and intestinal microbiota changed respectively in T2DM; whether the changes were associated or interacted between the two sites and whether there were some associations between T2DM and the ectopic colonization of oral microbiota in the gut still need to be identified. Research design and methods We performed a cross-sectional observational study; 183 diabetes and 74 controls were enrolled. We used high-throughput sequencing technology to detect the V3-V4 region of 16S rRNA in oral and stool samples. The Source Tracker method was used to identify the proportion of the intestinal microbiota that ectopic colonized from the oral cavity. Results The oral marker bacteria of T2DM were found, such as Actinobacteria, Streptococcus, Rothia, and the intestinal marker bacteria were Bifidobacterium, Streptococcus, and Blautia at the genus level. Among them, Actinobacteria and Blautia played a vital role in different symbiotic relationships of oral and intestinal microbiota. The commonly distributed bacteria, such as Firmicutes, Bacteroidetes, and Actinobacteria, were found in both oral and intestine. Moreover, the relative abundance and composition of bacteria were different between the two sites. The glycine betaine degradation I pathway was the significantly up-regulated pathway in the oral and intestinal flora of T2DM. The main serum indexes related to oral and intestinal flora were inflammatory. The relative abundance of Proteobacteria in the intestine and the Spirochete in oral was positively correlated, and the correlation coefficient was the highest, was 0.240 (P<0.01). The proportion of ectopic colonization of oral flora in the gut of T2DM was 2.36%. Conclusion The dysbacteriosis exited in the oral and intestine simultaneously, and there were differences and connections in the flora composition at the two sites in T2DM. Ectopic colonization of oral flora in the intestine might relate to T2DM. Further, clarifying the oral-gut-transmitting bacteria can provide an essential reference for diagnosing and treating T2DM in the future.
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Affiliation(s)
- Xiao-jing Guo
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Anesthesiology, Naval Medical University, Shanghai, China
| | - Shi-xuan Dai
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jin-di Lou
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xu-xiang Ma
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-juan Hu
- Shanghai Collaborative Innovation Center of Health Service in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li-ping Tu
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ji Cui
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hao Lu
- Department of Endocrinology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Jiang
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jia-tuo Xu
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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17
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Tahapary DL, Fatya AI, Kurniawan F, Marcella C, Rinaldi I, Tarigan TJE, Harbuwono DS, Yunir E, Soewondo P, Purnamasari D. Increased intestinal-fatty acid binding protein in obesity-associated type 2 diabetes mellitus. PLoS One 2023; 18:e0279915. [PMID: 36701395 PMCID: PMC9879407 DOI: 10.1371/journal.pone.0279915] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 12/18/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Obesity is a traditional risk factor for type 2 diabetes mellitus (T2DM). However, recent studies reported that metabolically unhealthy obesity (MUO) exerts a higher risk of developing T2DM than metabolically healthy obesity (MHO) because of its higher state of insulin resistance. This may happen due to metabolic endotoxemia through gut dysbiosis and increased intestinal permeability. Our study aimed to know the association of intestinal permeability using intestinal fatty acid-binding protein (I-FABP) with obesity-related T2DM patients in Indonesia. METHODS This was a cross-sectional study that recruited 63 participants with obesity defined using body mass index (BMI) classification for the Asia-Pacific population (BMI ≥25 kg/m2). All participants were then grouped into T2DM and non-T2DM based on American Diabetes Association (ADA) diagnostic criteria. The I-FABP levels were measured using the enzyme-linked immunosorbent assay method. RESULTS The I-FABP level of T2DM group was higher compared to non-T2DM group, namely 2.82 (1.23) ng/mL vs. 1.78 (0.81) ng/mL (p<0.001; mean difference 1.033 with 95% CI 0.51-1.55). This difference was not attenuated even after adjustment for age. The fitted regression model using linear regression was: i-FABP = 1.787+1.034*(DM) (R2 = 18.20%, standardized ß = 0.442, p<0.001). CONCLUSIONS This study underscores the association of intestinal permeability with T2DM in people with obesity and supports the evidence of the potential role of intestinal permeability in the pathogenesis of obesity-related T2DM.
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Affiliation(s)
- Dicky L. Tahapary
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- * E-mail: (DLT); (PS)
| | - Atikah I. Fatya
- Department of Internal Medicine, Fa culty of Medicine Universitas Indonesia, Jakarta, Indonesia
- Division of Hematology and Medical Oncology, Depa rtment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Farid Kurniawan
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Cicilia Marcella
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Ikhwan Rinaldi
- Department of Internal Medicine, Fa culty of Medicine Universitas Indonesia, Jakarta, Indonesia
- Division of Hematology and Medical Oncology, Depa rtment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
- Clinical Epidemiology and Evidence-based Medicine Unit, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Tri J. E. Tarigan
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Dante S. Harbuwono
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Em Yunir
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Pradana Soewondo
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- * E-mail: (DLT); (PS)
| | - Dyah Purnamasari
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
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Yi ZY, Chen L, Wang Y, He D, Zhao D, Zhang SH, Yu R, Huang JH. The potential mechanism of Liu-Wei-Di-Huang Pills in treatment of type 2 diabetic mellitus: from gut microbiota to short-chain fatty acids metabolism. Acta Diabetol 2022; 59:1295-1308. [PMID: 35857109 DOI: 10.1007/s00592-022-01922-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/11/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) has already become a global pandemic. Recently, reports showed its pathogenesis was closely related to a disorder of gut microbiota. In China, the Liu-Wei-Di-Huang Pills (LWDH) have treated T2DM for thousands of years. However, its therapeutic mechanism associated with gut microbiota is worthy of further study. AIMS This study aims to investigate the effects of LWDH on T2DM by regulating gut microbiota and short-chain fatty acids (SCFAs) in Goto-Kakizaki (GK) rats. METHODS T2DM models were successfully established based on GK rats and administrated with LWDH. The changes in fasting blood glucose (FBG), oral glucose tolerance test (OGTT), and serum insulin (INS) were determined, and the immunohistochemical (IHC) method was used to test INS expression in pancreas. The 16S-ribosomal DNA (16S rDNA) sequencing analysis assessed gut microbiota structural changes; a gas chromatography-mass spectrometer (GC-MS)-based metabolomics method was adopted to detect SCFA levels. The pathological morphology of jejunum was detected by hematoxylin-eosin (H&E) staining, and the expression of GPR43, GPR41, GLP-1, and GLP-1R was evaluated by qRT-PCR and ELISA, respectively. RESULTS We observed that GK rats treated with LWDH: (a) has altered the microbial structure and promoted the abundance of bacteria in Firmicutes, including Lactobacillus, Allobaculum, and Ruminococcus_2, (b) increased SCFAs levels involving acetic acid, propionic acid, and butyric acid and (c) alleviated T2DM and jejunum injuries potentially based on SCFAs-GPR43/41-GLP-1 pathway. CONCLUSION LWDH could improve T2DM by regulating gut microbiota and SCFAs, and the therapeutic mechanism might be related to the SCFAs-GPR43/41-GLP-1 pathway.
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Affiliation(s)
- Zi-Yang Yi
- Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410013, Hunan, People's Republic of China
| | - Lin Chen
- Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410013, Hunan, People's Republic of China
| | - Yan Wang
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Dan He
- Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410013, Hunan, People's Republic of China
| | - Di Zhao
- Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410013, Hunan, People's Republic of China
| | - Shui-Han Zhang
- Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410013, Hunan, People's Republic of China
| | - Rong Yu
- Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410013, Hunan, People's Republic of China.
- Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, People's Republic of China.
| | - Jian-Hua Huang
- Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410013, Hunan, People's Republic of China.
- Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, People's Republic of China.
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Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy. Int J Mol Sci 2022; 23:ijms23062995. [PMID: 35328419 PMCID: PMC8951934 DOI: 10.3390/ijms23062995] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/01/2022] [Indexed: 02/04/2023] Open
Abstract
The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care—but also medical prophylactic and therapeutic care in general—to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.
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20
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Chen X, Chen C, Fu X. Hypoglycemic effect of polysaccharide from Astragalus membranaceus on type 2 diabetic mice based on “gut microbiota-mucosal barrier”. Food Funct 2022; 13:10121-10133. [DOI: 10.1039/d2fo02300h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Astragalus membranaceus polysaccharide (APP), the main active constituent possesses numerous bioactivities. In this research, the T2DM model mice was combined with streptozotocin to study the hypoglycemic effect and mechanism of...
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21
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High-Fat Diet Induces Disruption of the Tight Junction-Mediated Paracellular Barrier in the Proximal Small Intestine Before the Onset of Type 2 Diabetes and Endotoxemia. Dig Dis Sci 2021; 66:3359-3374. [PMID: 33104937 DOI: 10.1007/s10620-020-06664-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 10/06/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIM A link between an impaired intestinal barrier, endotoxemia, and the pathogenesis of metabolic diseases, such as type 2 diabetes mellitus (T2DM), has been proposed. In previous work, we have demonstrated that the tight junction (TJ)-mediated intestinal barrier in ileum/colon was marginally changed in prediabetic mice; therefore, it does not seem to mainly contribute to the T2DM onset. In this study, the TJ-mediated epithelial barrier in the duodenum and jejunum was evaluated in mice during the development of type 2 prediabetes. METHODS/RESULTS HF diet induced prediabetes after 60 days associated with a significant rise in intestinal permeability to the small-sized marker Lucifer yellow in these mice, with no histological signs of mucosal inflammation or rupture of the proximal intestine epithelium. As revealed by immunofluorescence, TJ proteins, such as claudins-1, -2, -3, and ZO-1, showed a significant decrease in junctional content in duodenum and jejunum epithelia, already after 15 days of treatment, suggesting a rearrangement of the TJ structure. However, no significant change in total cell content of these proteins was observed in intestinal epithelium homogenates, as assessed by immunoblotting. Despite the changes in intestinal permeability and TJ structure, the prediabetic mice showed similar LPS, zonulin, and TNF-α levels in plasma or adipose tissue, and in intestinal segments as compared to the controls. CONCLUSION Disruption of the TJ-mediated paracellular barrier in the duodenum and jejunum is an early event in prediabetes development, which occurs in the absence of detectable endotoxemia/inflammation and may contribute to the HF diet-induced increase in intestinal permeability.
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Gut Microbiota and Type 2 Diabetes Mellitus: Association, Mechanism, and Translational Applications. Mediators Inflamm 2021; 2021:5110276. [PMID: 34447287 PMCID: PMC8384524 DOI: 10.1155/2021/5110276] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/26/2021] [Indexed: 02/07/2023] Open
Abstract
Gut microbiota has attracted widespread attention due to its crucial role in disease pathophysiology, including type 2 diabetes mellitus (T2DM). Metabolites and bacterial components of gut microbiota affect the initiation and progression of T2DM by regulating inflammation, immunity, and metabolism. Short-chain fatty acids, secondary bile acid, imidazole propionate, branched-chain amino acids, and lipopolysaccharide are the main molecules related to T2DM. Many studies have investigated the role of gut microbiota in T2DM, particularly those butyrate-producing bacteria. Increasing evidence has demonstrated that fecal microbiota transplantation and probiotic capsules are useful strategies in preventing diabetes. In this review, we aim to elucidate the complex association between gut microbiota and T2DM inflammation, metabolism, and immune disorders, the underlying mechanisms, and translational applications of gut microbiota. This review will provide novel insight into developing individualized therapy for T2DM patients based on gut microbiota immunometabolism.
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Taladrid D, González de Llano D, Zorraquín-Peña I, Tamargo A, Silva M, Molinero N, Moreno-Arribas MV, Bartolomé B. Gastrointestinal Digestion of a Grape Pomace Extract: Impact on Intestinal Barrier Permeability and Interaction with Gut Microbiome. Nutrients 2021; 13:nu13072467. [PMID: 34371979 PMCID: PMC8308781 DOI: 10.3390/nu13072467] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 07/16/2021] [Indexed: 01/01/2023] Open
Abstract
Grape pomace (GP) is a winemaking by-product rich in polyphenols and fibre. Supplementation with GP extracts has shown potential benefits against oxidative stress- and inflammation-related pathologies. As a new nutritional target, this paper explores the impact of the ingestion of a grape pomace extract on intestinal barrier functionality. A GP extract was sequentially subjected to gastrointestinal and colonic digestion using the dynamic gastrointestinal simulator (simgi®). This generated two simulated fluids: intestinal-digested extract (IDE) and colonic-digested extract (CDE). The effects of these two fluids on paracellular permeability and the expression of tight junction (TJ) proteins (i.e., zonula occludens-1 (ZO-1) and occludin) were assessed in Caco-2-cell monolayers grown in Transwell® inserts. The IDE fluid significantly (p < 0.001) reduced the paracellular transport of FITC-dextran with respect to the control, whereas no significant differences (p > 0.05) were found for CDE, which could be due, at least partially, to the pro-leaky effect of the colonic digestion medium. Accordant slight increases in the mRNA levels of both ZO-1 and occludin were observed for IDE, but without statistical significance. Additionally, the colonic fermentation of the GP extract promoted the production of short-chain fatty acids (SCFA) and phenolic metabolites and led to changes in the relative abundance of some bacteria that might affect paracellular permeability. Overall, this paper reports first trends about the effects of grape pomace extracts on intestinal permeability that would require further confirmation in future experiments.
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24
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Sathkumara HD, Eaton JL, Field MA, Govan BL, Ketheesan N, Kupz A. A murine model of tuberculosis/type 2 diabetes comorbidity for investigating the microbiome, metabolome and associated immune parameters. Animal Model Exp Med 2021; 4:181-188. [PMID: 34179725 PMCID: PMC8212822 DOI: 10.1002/ame2.12159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/01/2021] [Indexed: 01/02/2023] Open
Abstract
Tuberculosis (TB) is one of the deadliest infectious diseases in the world. The metabolic disease type 2 diabetes (T2D) significantly increases the risk of developing active TB. Effective new TB vaccine candidates and novel therapeutic interventions are required to meet the challenges of global TB eradication. Recent evidence suggests that the microbiota plays a significant role in how the host responds to infection, injury and neoplastic changes. Animal models that closely reflect human physiology are crucial in assessing new treatments and to decipher the underlying immunological defects responsible for increased TB susceptibility in comorbid patients. In this study, using a diet-induced murine T2D model that reflects the etiopathogenesis of clinical T2D and increased TB susceptibility, we investigated how the intestinal microbiota may impact the development of T2D, and how the gut microbial composition changes following a very low-dose aerosol infection with Mycobacterium tuberculosis (Mtb). Our data revealed a substantial intestinal microbiota dysbiosis in T2D mice compared to non-diabetic animals. The observed differences were comparable to previous clinical reports in TB patients, in which it was shown that Mtb infection causes rapid loss of microbial diversity. Furthermore, diversity index and principle component analyses demonstrated distinct clustering of Mtb-infected non-diabetic mice vs. Mtb-infected T2D mice. Our findings support a broad applicability of T2D mice as a tractable small animal model for studying distinct immune parameters, microbiota and the immune-metabolome of TB/T2D comorbidity. This model may also enable answers to be found to critical outstanding questions about targeted interventions of the gut microbiota and the gut-lung axis.
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Affiliation(s)
- Harindra D. Sathkumara
- Centre for Molecular TherapeuticsAustralian Institute of Tropical Health and MedicineJames Cook UniversityCairns & TownsvilleQLDAustralia
| | - Janet L. Eaton
- College of Public Health, Medical and Veterinary SciencesJames Cook UniversityTownsvilleQLDAustralia
| | - Matt A. Field
- Centre for Molecular TherapeuticsAustralian Institute of Tropical Health and MedicineJames Cook UniversityCairns & TownsvilleQLDAustralia
- Centre for Tropical Bioinformatics and Molecular BiologyJames Cook UniversityCairnsQLDAustralia
- John Curtin School of Medical ResearchAustralian National UniversityCanberraACTAustralia
| | - Brenda L. Govan
- Centre for Molecular TherapeuticsAustralian Institute of Tropical Health and MedicineJames Cook UniversityCairns & TownsvilleQLDAustralia
- College of Public Health, Medical and Veterinary SciencesJames Cook UniversityTownsvilleQLDAustralia
| | | | - Andreas Kupz
- Centre for Molecular TherapeuticsAustralian Institute of Tropical Health and MedicineJames Cook UniversityCairns & TownsvilleQLDAustralia
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25
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Liu H, Zhang M, Ma Q, Tian B, Nie C, Chen Z, Li J. Health beneficial effects of resistant starch on diabetes and obesity via regulation of gut microbiota: a review. Food Funct 2021; 11:5749-5767. [PMID: 32602874 DOI: 10.1039/d0fo00855a] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Resistant starch (RS) is well known to prevent type 2 diabetes mellitus (T2DM) and obesity. Recently, attention has been paid to gut microbiota which mediates the RS's impact on T2DM and obesity, while a mechanistic understanding of how RS prevents T2DM and obesity through gut microbiota is not clear yet. Therefore, this review aims at exploring the underlying mechanisms of it. RS prevents T2DM and obesity through gut microbiota by modifying selective microbial composition to produce starch-degrading enzymes, promoting the production of intestinal metabolites, and improving gut barrier function. Therefore, RS possessing good functional features can be used to increase the fiber content of healthier food. Furthermore, achieving highly selective effects on gut microbiota based on the slight differences of RS's chemical structure and focusing on the effects of RS on strain-levels are essential to manipulate the microbiota for human health.
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Affiliation(s)
- Huicui Liu
- College of Food Science and Engineering, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi Province 712100, People's Republic of China.
| | - Min Zhang
- College of Food Science and Engineering, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi Province 712100, People's Republic of China.
| | - Qingyu Ma
- College of Food Science and Engineering, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi Province 712100, People's Republic of China.
| | - Baoming Tian
- College of Food Science and Engineering, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi Province 712100, People's Republic of China.
| | - Chenxi Nie
- College of Food Science and Engineering, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi Province 712100, People's Republic of China.
| | - Zhifei Chen
- College of Food Science and Engineering, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi Province 712100, People's Republic of China.
| | - Juxiu Li
- College of Food Science and Engineering, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi Province 712100, People's Republic of China.
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26
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Zhang Y, Shao F, Guan Z, Luo J, Xiao X, Zhou L. Overexpression of miR-99a Alleviates Intestinal Mucosal Barrier Injury in Rats with Severe Acute Pancreatitis. J Interferon Cytokine Res 2021; 41:72-80. [PMID: 33621134 DOI: 10.1089/jir.2020.0085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Severe acute pancreatitis (SAP), which is characterized by acute onset and high mortality, is complicated with systemic inflammatory response syndrome. This study investigated the molecular mechanism underlying SAP-induced intestinal mucosal barrier injury. SAP was established in rats by retrograde injection of sodium taurocholate (STC) into biliopancreatic duct. Transfection of miR-99a mimic was conducted 24 h before the SAP establishment. Histological properties of pancreatic and intestinal tissues were observed by hematoxylin-eosin staining. The serum levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, procalcitonin (PCT), endotoxin (ET), and diamine oxidase (DAO) were measured by enzyme-linked immunosorbent assay. The expressions of miR-99a, NADPH oxidase (NOX)4, zonula occludens (ZO)-1, occludin, and claudin-1 in pancreatic and the intestinal tissue were determined by quantitative reverse transcription polymerase chain reaction or Western blot. STC injection damaged pancreatic and intestinal tissues of the rats. During the model construction, the serum levels of IL-1β, TNF-α, PCT, ET, and DAO were increased, whereas miR-99a expression in pancreatic and intestinal tissues of the rats was decreased. miR-99a mimic alleviated SAP-induced histological abnormality of pancreatic and intestinal tissues; moreover, it reversed the serum levels of IL-1β, TNF-α, PCT, ET, and DAO increased by SAP, decreased SAP-increased NOX4 expression and increased the expressions of ZO-1, occludin, and claudin-1 previously decreased by SAP in pancreatic and the intestinal tissues. Thus, overexpressed miR-99a could alleviate intestinal mucosal barrier injury in rats with SAP.
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Affiliation(s)
- Yu Zhang
- Department of Critical Care Medicine, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Feifei Shao
- Department of Critical Care Medicine, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Zhihui Guan
- Department of Critical Care Medicine, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Jinming Luo
- Department of Critical Care Medicine, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Xiaorong Xiao
- Department of Critical Care Medicine, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Lingmin Zhou
- Department of Critical Care Medicine, Taizhou First People's Hospital, Taizhou, Zhejiang, China
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Rapa SF, Di Paola R, Cordaro M, Siracusa R, D’Amico R, Fusco R, Autore G, Cuzzocrea S, Stuppner H, Marzocco S. Plumericin Protects against Experimental Inflammatory Bowel Disease by Restoring Intestinal Barrier Function and Reducing Apoptosis. Biomedicines 2021; 9:biomedicines9010067. [PMID: 33445622 PMCID: PMC7826791 DOI: 10.3390/biomedicines9010067] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/08/2021] [Accepted: 01/09/2021] [Indexed: 02/07/2023] Open
Abstract
Intestinal epithelial barrier impairment plays a key pathogenic role in inflammatory bowel diseases (IBDs). In particular, together with oxidative stress, intestinal epithelial barrier alteration is considered as upstream event in ulcerative colitis (UC). In order to identify new products of natural origin with a potential activity for UC treatment, this study evaluated the effects of plumericin, a spirolactone iridoid, present as one of the main bioactive components in the bark of Himatanthus sucuuba (Woodson). Plumericin was evaluated for its ability to improve barrier function and to reduce apoptotic parameters during inflammation, both in intestinal epithelial cells (IEC-6), and in an animal experimental model of 2, 4, 6-dinitrobenzene sulfonic acid (DNBS)-induced colitis. Our results indicated that plumericin increased the expression of adhesion molecules, enhanced IEC-6 cells actin cytoskeleton rearrangement, and promoted their motility. Moreover, plumericin reduced apoptotic parameters in IEC-6. These results were confirmed in vivo. Plumericin reduced the activity of myeloperoxidase, inhibited the expression of ICAM-1, P-selectin, and the formation of PAR, and reduced apoptosis parameters in mice colitis induced by DNBS. These results support a pharmacological potential of plumericin in the treatment of UC, due to its ability to improve the structural integrity of the intestinal epithelium and its barrier function.
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Affiliation(s)
- Shara Francesca Rapa
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (S.F.R.); (G.A.)
| | - Rosanna Di Paola
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Marika Cordaro
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Ramona D’Amico
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Roberta Fusco
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Giuseppina Autore
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (S.F.R.); (G.A.)
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Hermann Stuppner
- Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria;
| | - Stefania Marzocco
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (S.F.R.); (G.A.)
- Correspondence: ; Tel.: +89-969159
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Dash NR, Al Bataineh MT. Metagenomic Analysis of the Gut Microbiome Reveals Enrichment of Menaquinones (Vitamin K2) Pathway in Diabetes Mellitus. Diabetes Metab J 2021; 45:77-85. [PMID: 32431114 PMCID: PMC7850878 DOI: 10.4093/dmj.2019.0202] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 12/11/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with a high prevalence worldwide, especially among overweight and obese populations. T2DM is multifactorial with several genetic and acquired risk factors that lead to insulin resistance. Mounting evidence indicates that alteration of gut microbiome composition contribute to insulin resistance and inflammation. However, the precise link between T2DM and gut microbiome role and composition remains unknown. METHODS We evaluated the metabolic capabilities of the gut microbiome of twelve T2DM and six healthy individuals through shotgun metagenomics using MiSeq platform. RESULTS We identified no significant differences in the overall taxonomic composition between healthy and T2DM subjects when controlling for differences in diet. However, results showed that T2DM enriched in metabolic pathways involved in menaquinone (vitamin K2) superpathway biosynthesis (PWY-5838) as compared to healthy individuals. Covariance analysis between the bacterial genera and metabolic pathways displaying difference in abundance (analysis of variance P<0.05) in T2DM as compared to healthy subjects revealed that genera belonging Firmicutes, Actinobacteria, and Bacteroidetes phyla contribute significantly to vitamin K2 biosynthesis. Further, the microbiome corresponding to T2DM with high glycosylated hemoglobin (HbA1c) (>6.5%) exhibit high abundance of genes involved in lysine biosynthesis and low abundance of genes involved in creatinine degradation as compared to T2DM with lower HbA1c (<6.5%). CONCLUSION The identified differences in metabolic capabilities provide important information that may eventually lead to the development of novel biomarkers and more effective management strategies to treat T2DM.
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Affiliation(s)
- Nihar Ranjan Dash
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Mohammad Tahseen Al Bataineh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical & Health Sciences at University of Sharjah, Sharjah, United Arab Emirates
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29
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Selber-Hnatiw S, Sultana T, Tse W, Abdollahi N, Abdullah S, Al Rahbani J, Alazar D, Alrumhein NJ, Aprikian S, Arshad R, Azuelos JD, Bernadotte D, Beswick N, Chazbey H, Church K, Ciubotaru E, D'Amato L, Del Corpo T, Deng J, Di Giulio BL, Diveeva D, Elahie E, Frank JGM, Furze E, Garner R, Gibbs V, Goldberg-Hall R, Goldman CJ, Goltsios FF, Gorjipour K, Grant T, Greco B, Guliyev N, Habrich A, Hyland H, Ibrahim N, Iozzo T, Jawaheer-Fenaoui A, Jaworski JJ, Jhajj MK, Jones J, Joyette R, Kaudeer S, Kelley S, Kiani S, Koayes M, Kpata AJAAL, Maingot S, Martin S, Mathers K, McCullogh S, McNamara K, Mendonca J, Mohammad K, Momtaz SA, Navaratnarajah T, Nguyen-Duong K, Omran M, Ortiz A, Patel A, Paul-Cole K, Plaisir PA, Porras Marroquin JA, Prevost A, Quach A, Rafal AJ, Ramsarun R, Rhnima S, Rili L, Safir N, Samson E, Sandiford RR, Secondi S, Shahid S, Shahroozi M, Sidibé F, Smith M, Sreng Flores AM, Suarez Ybarra A, Sénéchal R, Taifour T, Tang L, Trapid A, Tremblay Potvin M, Wainberg J, Wang DN, Weissenberg M, White A, Wilkinson G, Williams B, Wilson JR, Zoppi J, Zouboulakis K, Gamberi C. Metabolic networks of the human gut microbiota. MICROBIOLOGY-SGM 2020; 166:96-119. [PMID: 31799915 DOI: 10.1099/mic.0.000853] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The human gut microbiota controls factors that relate to human metabolism with a reach far greater than originally expected. Microbial communities and human (or animal) hosts entertain reciprocal exchanges between various inputs that are largely controlled by the host via its genetic make-up, nutrition and lifestyle. The composition of these microbial communities is fundamental to supply metabolic capabilities beyond those encoded in the host genome, and contributes to hormone and cellular signalling that support the dynamic adaptation to changes in food availability, environment and organismal development. Poor functional exchange between the microbial communities and their human host is associated with dysbiosis, metabolic dysfunction and disease. This review examines the biology of the dynamic relationship between the reciprocal metabolic state of the microbiota-host entity in balance with its environment (i.e. in healthy states), the enzymatic and metabolic changes associated with its imbalance in three well-studied diseases states such as obesity, diabetes and atherosclerosis, and the effects of bariatric surgery and exercise.
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Affiliation(s)
- Susannah Selber-Hnatiw
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Tarin Sultana
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - W Tse
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Niki Abdollahi
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Sheyar Abdullah
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Jalal Al Rahbani
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Diala Alazar
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Nekoula Jean Alrumhein
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Saro Aprikian
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Rimsha Arshad
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Jean-Daniel Azuelos
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Daphney Bernadotte
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Natalie Beswick
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Hana Chazbey
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Kelsey Church
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Emaly Ciubotaru
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Lora D'Amato
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Tavia Del Corpo
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Jasmine Deng
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Briana Laura Di Giulio
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Diana Diveeva
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Elias Elahie
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - James Gordon Marcel Frank
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Emma Furze
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Rebecca Garner
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Vanessa Gibbs
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Rachel Goldberg-Hall
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Chaim Jacob Goldman
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Fani-Fay Goltsios
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Kevin Gorjipour
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Taylor Grant
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Brittany Greco
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Nadir Guliyev
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Andrew Habrich
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Hillary Hyland
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Nabila Ibrahim
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Tania Iozzo
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Anastasia Jawaheer-Fenaoui
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Julia Jane Jaworski
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Maneet Kaur Jhajj
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Jermaine Jones
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Rodney Joyette
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Samad Kaudeer
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Shawn Kelley
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Shayesteh Kiani
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Marylin Koayes
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | | | - Shannon Maingot
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Sara Martin
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Kelly Mathers
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Sean McCullogh
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Kelly McNamara
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - James Mendonca
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Karamat Mohammad
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Sharara Arezo Momtaz
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Thiban Navaratnarajah
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Kathy Nguyen-Duong
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Mustafa Omran
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Angela Ortiz
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Anjali Patel
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Kahlila Paul-Cole
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Paul-Arthur Plaisir
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | | | - Ashlee Prevost
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Angela Quach
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Aries John Rafal
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Rewaparsad Ramsarun
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Sami Rhnima
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Lydia Rili
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Naomi Safir
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Eugenie Samson
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Rebecca Rose Sandiford
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Stefano Secondi
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Stephanie Shahid
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Mojdeh Shahroozi
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Fily Sidibé
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Megan Smith
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Alina Maria Sreng Flores
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Anabel Suarez Ybarra
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Rebecca Sénéchal
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Tarek Taifour
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Lawrence Tang
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Adam Trapid
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Maxim Tremblay Potvin
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Justin Wainberg
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Dani Ni Wang
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Mischa Weissenberg
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Allison White
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Gabrielle Wilkinson
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Brittany Williams
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Joshua Roth Wilson
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Johanna Zoppi
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Katerina Zouboulakis
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
| | - Chiara Gamberi
- Biology Department, Concordia University, 7141 Sherbrooke St W, SP-375-09 Montreal, Quebec, H4B 1R6, Canada
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Saitogullari N, Sayili U, Altunoglu E, Uzun H. Evaluation of serum zonulin level in prediabetic patients. ANNALES D'ENDOCRINOLOGIE 2020; 82:1-7. [PMID: 33278377 DOI: 10.1016/j.ando.2020.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/27/2020] [Accepted: 11/27/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND This study aimed to investigate the relationship between lipopolysaccharide (LPS) and zonulin levels and also to show the effect of acute hyperglycemic stress induced by oral glucose tolerance testing (OGTT) on zonulin levels in pre-diabetic patients. METHODS Four groups were constituted according to the criteria of the American Diabetes Association (ADA), based on OGTT results: control group (n:40); prediabetic group (n:56), divided into two subgroups: impaired fasting glucose group (IFG) (n:36), and impaired glucose tolerance (IGT) + IFG group (n:20) and type-2 diabetes mellitus (T2DM) group (n:45). RESULTS Zonulin and LPS did not significantly differ between the prediabetes and control groups, but were significantly higher in the T2DM group compared to both the prediabetic and the control group (P<0.001). After OGTT, zonulin and LPS were significantly higher in the prediabetes group compared to the control group (P<0.01 and P<0.05, respectively), and significantly lower in the IFG and IFG+IGT groups compared to the T2DM group (P<0.001, P<0.001 and P<0.001, P<0.001, respectively). A positive correlation was detected between fasting zonulin and 2-hour zonulin (r=0.727, P<0.001) and between fasting LPS (r=0.555, P<0.001) and 2-hour LPS (r=0.567, P<0.001) in the prediabetic group. Increased zonulin and LPS levels and the positive correlation between these levels during the prediabetic period although non significant suggests onset of intestinal permeability. CONCLUSIONS During acute hyperglycemia in prediabetic patients, up-regulation of zonulin and LPS may affect intestinal function. The intestines may play a key role in up-regulation of glucose and the pathogenesis of diabetes.
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Affiliation(s)
- Nesrin Saitogullari
- Department of Medical Biochemistry, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpasa, 34303, Istanbul, Turkey
| | - Ugurcan Sayili
- Karakopru District Health Directorate, Republic of Turkey Ministry of Health, Sanliurfa, Turkey
| | - Esma Altunoglu
- Department of Internal Medicine, Istanbul Training and Research Hospital, Health Sciences University, Istanbul, Turkey
| | - Hafize Uzun
- Department of Medical Biochemistry, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpasa, 34303, Istanbul, Turkey.
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31
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The Herbal Medicine Scutellaria-Coptis Alleviates Intestinal Mucosal Barrier Damage in Diabetic Rats by Inhibiting Inflammation and Modulating the Gut Microbiota. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:4568629. [PMID: 33224253 PMCID: PMC7669352 DOI: 10.1155/2020/4568629] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 10/16/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023]
Abstract
Recent studies have confirmed that increased intestinal permeability and gut-origin lipopolysaccharide (LPS) translocation are important causes of metabolic inflammation in type 2 diabetes (T2D), but there are no recognized therapies for targeting this pathological state. Scutellaria baicalensis and Coptis chinensis are a classic herbal pair often used to treat diabetes and various intestinal diseases, and repair of intestinal barrier damage may be at the core of their therapeutic mechanism. This study investigated the effects of oral administration of Scutellaria-Coptis (SC) on the intestinal mucosal barrier in diabetic rats and explored the underlying mechanism from the perspective of anti-inflammatory and gut microbiota-modulatory effects. The main results showed that, in addition to regulating glycolipid metabolism disorders and inhibiting serum inflammatory factors, SC could also upregulate the expression levels of the tight junction proteins claudin-1, occludin, and zonula occludens (ZO-1), significantly improve intestinal epithelial damage, and inhibit excessive LPS translocation into the blood circulation. Furthermore, it was found that SC could reduce the levels of the inflammatory factors interleukin-1β (IL-1β), IL-6, and tumour necrosis factor-α (TNF-α) in intestinal tissue and that the anti-inflammatory effects involved the TLR-4/TRIF and TNFR-1/NF-κB signalling pathways. Moreover, SC had a strong inhibitory effect on some potential enteropathogenic bacteria and LPS-producing bacteria, such as Proteobacteria, Enterobacteriaceae, Enterobacter, Escherichia-Shigella, and Enterococcus, and could also promote the proliferation of butyrate-producing bacteria, such as Lachnospiraceae and Prevotellaceae. Taken together, the hypoglycaemic effects of SC were related to the protection of the intestinal mucosal barrier, and the mechanisms might be related to the inhibition of intestinal inflammation and the regulation of the gut microbiota.
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32
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Noninvasive Biomarkers of Gut Barrier Function in Patients Suffering from Diarrhea Predominant-IBS: An Update. DISEASE MARKERS 2020; 2020:2886268. [PMID: 33110455 PMCID: PMC7582069 DOI: 10.1155/2020/2886268] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 09/23/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
The intestinal barrier plays a crucial role in the absorption of nutrients and in preventing the entry of pathogenic microorganisms and toxic molecules. Several studies have shown a compromised intestinal barrier associated with low-grade inflammation in the small intestinal mucosa in celiac disease, inflammatory bowel disease, and irritable bowel syndrome (IBS), particularly in IBS with diarrhea (IBS-D). In light of these new data, IBS is no longer considered a functional disease but rather a heterogeneous syndrome that has yet to be carefully studied. Therefore, investigating the integrity and function of the intestinal barrier is now essential to improving knowledge of the pathophysiology of IBS-D and to improving the management of IBS-D patients. However, the study of the intestinal barrier must clarify some still unsolved methodological aspects and propose standardised assays before becoming a useful diagnostic tool. In this framework, this review will discuss data about the tests that noninvasively evaluate the integrity and functionality of the human intestinal barrier, paying particular attention to patients with IBS-D, in both clinical and research situations.
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33
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Massier L, Chakaroun R, Tabei S, Crane A, Didt KD, Fallmann J, von Bergen M, Haange SB, Heyne H, Stumvoll M, Gericke M, Dietrich A, Blüher M, Musat N, Kovacs P. Adipose tissue derived bacteria are associated with inflammation in obesity and type 2 diabetes. Gut 2020; 69:1796-1806. [PMID: 32317332 DOI: 10.1136/gutjnl-2019-320118] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 03/31/2020] [Accepted: 03/31/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Bacterial translocation to various organs including human adipose tissue (AT) due to increased intestinal permeability remains poorly understood. We hypothesised that: (1) bacterial presence is highly tissue specific and (2) related in composition and quantity to immune inflammatory and metabolic burden. DESIGN We quantified and sequenced the bacterial 16S rRNA gene in blood and AT samples (omental, mesenteric and subcutaneous) of 75 subjects with obesity with or without type 2 diabetes (T2D) and used catalysed reporter deposition (CARD) - fluorescence in situ hybridisation (FISH) to detect bacteria in AT. RESULTS Under stringent experimental and bioinformatic control for contaminants, bacterial DNA was detected in blood and omental, subcutaneous and mesenteric AT samples in the range of 0.1 to 5 pg/µg DNA isolate. Moreover, CARD-FISH allowed the detection of living, AT-borne bacteria. Proteobacteria and Firmicutes were the predominant phyla, and bacterial quantity was associated with immune cell infiltration, inflammatory and metabolic parameters in a tissue-specific manner. Bacterial composition differed between subjects with and without T2D and was associated with related clinical measures, including systemic and tissues-specific inflammatory markers. Finally, treatment of adipocytes with bacterial DNA in vitro stimulated the expression of TNFA and IL6. CONCLUSIONS Our study provides contaminant aware evidence for the presence of bacteria and bacterial DNA in several ATs in obesity and T2D and suggests an important role of bacteria in initiating and sustaining local AT subclinical inflammation and therefore impacting metabolic sequelae of obesity.
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Affiliation(s)
- Lucas Massier
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.,IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Rima Chakaroun
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.,IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Shirin Tabei
- IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Alyce Crane
- IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Konrad David Didt
- IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Jörg Fallmann
- Department of Computer Science and Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Center for Environmental Research GmbH - UFZ, Leipzig, Germany
| | - Sven-Bastiaan Haange
- Department of Molecular Systems Biology, Helmholtz Center for Environmental Research GmbH - UFZ, Leipzig, Germany
| | - Henrike Heyne
- IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany.,Institute of Human Genetics, University of Leipzig, Leipzig, Germany.,Broad Institute of MIT and Harvard, Boston, Massachusetts, USA
| | - Michael Stumvoll
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.,IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Martin Gericke
- IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany.,Institute of Anatomy and Cell Biology, Martin-Luther University Halle-Wittenberg, Halle, Germany.,Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Arne Dietrich
- IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany.,University Hospital Leipzig, Clinic for Visceral, Transplantation and Thorax and Vascular Surgery, University of Leipzig, Leipzig, Germany
| | - Matthias Blüher
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.,IFB AdiposityDiseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Niculina Musat
- Department of Isotope Biogeochemistry, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany
| | - Peter Kovacs
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
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Schoultz I, Keita ÅV. The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability. Cells 2020; 9:1909. [PMID: 32824536 PMCID: PMC7463717 DOI: 10.3390/cells9081909] [Citation(s) in RCA: 280] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 02/08/2023] Open
Abstract
The intestinal barrier is essential in human health and constitutes the interface between the outside and the internal milieu of the body. A functional intestinal barrier allows absorption of nutrients and fluids but simultaneously prevents harmful substances like toxins and bacteria from crossing the intestinal epithelium and reaching the body. An altered intestinal permeability, a sign of a perturbed barrier function, has during the last decade been associated with several chronic conditions, including diseases originating in the gastrointestinal tract but also diseases such as Alzheimer and Parkinson disease. This has led to an intensified interest from researchers with diverse backgrounds to perform functional studies of the intestinal barrier in different conditions. Intestinal permeability is defined as the passage of a solute through a simple membrane and can be measured by recording the passage of permeability markers over the epithelium via the paracellular or the transcellular route. The methodological tools to investigate the gut barrier function are rapidly expanding and new methodological approaches are being developed. Here we outline and discuss, in vivo, in vitro and ex vivo techniques and how these methods can be utilized for thorough investigation of the intestinal barrier.
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Affiliation(s)
- Ida Schoultz
- Faculty of Medicine and Health, School of Medical Sciences, Örebro University, 703 62 Örebro, Sweden;
| | - Åsa V. Keita
- Department of Biomedical and Clinical Sciences, Linköping University, 581 85 Linköping, Sweden
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35
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Robertson MD. Prebiotics and type 2 diabetes: targeting the gut microbiota for improved glycaemic control? PRACTICAL DIABETES 2020. [DOI: 10.1002/pdi.2285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- M Denise Robertson
- Reader in Nutritional Physiology, Department of Nutritional Sciences, University of Surrey Guildford UK
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36
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Chakaroun RM, Massier L, Kovacs P. Gut Microbiome, Intestinal Permeability, and Tissue Bacteria in Metabolic Disease: Perpetrators or Bystanders? Nutrients 2020; 12:E1082. [PMID: 32295104 PMCID: PMC7230435 DOI: 10.3390/nu12041082] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
The emerging evidence on the interconnectedness between the gut microbiome and host metabolism has led to a paradigm shift in the study of metabolic diseases such as obesity and type 2 diabetes with implications on both underlying pathophysiology and potential treatment. Mounting preclinical and clinical evidence of gut microbiota shifts, increased intestinal permeability in metabolic disease, and the critical positioning of the intestinal barrier at the interface between environment and internal milieu have led to the rekindling of the "leaky gut" concept. Although increased circulation of surrogate markers and directly measurable intestinal permeability have been linked to increased systemic inflammation in metabolic disease, mechanistic models behind this phenomenon are underdeveloped. Given repeated observations of microorganisms in several tissues with congruent phylogenetic findings, we review current evidence on these unanticipated niches, focusing specifically on the interaction between gut permeability and intestinal as well as extra-intestinal bacteria and their joint contributions to systemic inflammation and metabolism. We further address limitations of current studies and suggest strategies drawing on standard techniques for permeability measurement, recent advancements in microbial culture independent techniques and computational methodologies to robustly develop these concepts, which may be of considerable value for the development of prevention and treatment strategies.
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Affiliation(s)
- Rima M. Chakaroun
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany; (L.M.); (P.K.)
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37
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Zhang X, Cui X, Jin X, Han F, Wang J, Yang X, Xu J, Shan C, Gao Z, Li X, Zuo M, Yang J, Chang B. Preventive Role of Salsalate in Diabetes Is Associated With Reducing Intestinal Inflammation Through Improvement of Gut Dysbiosis in ZDF Rats. Front Pharmacol 2020; 11:300. [PMID: 32265702 PMCID: PMC7096544 DOI: 10.3389/fphar.2020.00300] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 02/28/2020] [Indexed: 12/21/2022] Open
Abstract
A safe and effective approach is needed to prevent and reduce the incidence of diabetes worldwide. The hypoglycemic efficacy of salicylic acid (salsalate, SAL), which has anti-inflammatory properties, has been empirically demonstrated in studies conducted at the Joslin Diabetes Center and elsewhere. Here, we investigated the potential role of SAL in preventing the onset of diabetes in Zucker diabetic fatty (ZDF) rats and attempted to elucidate its underlying mechanisms. ZDF and Zucker lean (ZL) rats were administered a high-fat diet with or without SAL intervention, and their relative rates of diabetes were compared. Our results showed that all rats in the placebo group developed diabetes, whereas only 10% of the SAL-treated rats presented with impaired glucose tolerance (IGT). None of the latter progressed to diabetes. Relative to the untreated rats, SAL lowered plasma glucagon and insulin while improving insulin sensitivity and β-cell function. SAL may protect against hyperglycemia by increasing the microbial diversity, ameliorating gut dysbiosis, restoring intestinal epithelial cell connections, inhibiting endotoxin influx into the blood, and attenuating inflammation. Together, these findings suggest that SAL may be a candidate prophylactic therapy against diabetes. The protective role of SAL may be attributed to its ability to reduce intestinal inflammation and improve gut dysbiosis.
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Affiliation(s)
- Xinrong Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiao Cui
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiaofang Jin
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Fei Han
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Jingyu Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiaoyun Yang
- Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Jie Xu
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Chunyan Shan
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Zhongai Gao
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiaochen Li
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Minxia Zuo
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Juhong Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Baocheng Chang
- NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
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38
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Sharma S, Tripathi P, Sharma J, Dixit A. Flavonoids modulate tight junction barrier functions in hyperglycemic human intestinal Caco-2 cells. Nutrition 2020; 78:110792. [PMID: 32473529 DOI: 10.1016/j.nut.2020.110792] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/01/2020] [Accepted: 02/27/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Diabetes mellitus is a chronic disease requiring lifelong medical attention. With hundreds of millions suffering worldwide and a rapidly rising incidence, diabetes mellitus poses a great burden on health care systems. Recent studies investigating the underlying mechanisms involved in disease development in diabetes point to the role of the dysregulation of the intestinal barrier. Hyperglycemia-mediated tight junction deformity is known to contribute to leaky gut in various metabolic disorders. The present study aimed to investigate the role of oxidative stress on intestinal epithelial tight junction (TJ) barrier functions in hyperglycemia. Because many flavonoids are known to influence the cellular redox state, exploring these flavonoids may help to understand the role of TJ barrier in hyperglycemia-mediated oxidative stress, which in turn might unfold the association of oxidative stress and dysfunction of barrier-forming TJs. METHODS Caco-2 cells were stimulated with high glucose (HG), with or without flavonoids (quercetin, morin, naringenin), for 24 h. We determined cellular viability, levels of reactive oxygen species, and mitochondrial membrane potential in flavonoids treated HG-Caco-2 cells. The levels of the proinflammatory cytokines, glucose uptake, and expression of glucose transporters were determined on flavonoids treatment. We investigated the effect of flavonoids on TJs functions by measuring transepithelial electrical resistance (a TJ integrity marker), membrane permeability using tracer compounds, and the expressions levels of TJs related molecules on hyperglycemic Caco-2 cell monolayers. RESULTS We found that high glucose treatment resulted in reduced cell viability, increased reactive oxygen species production, measurable mitochondrial dysfunction, and decreased transepithelial electrical resistance, with increased membrane permeability. Treatment with the test flavonoids produced increased cell viability and reduced glucose uptake of HG-Caco-2 cells. A concomitant decrease in reactive oxygen species production, proinflammatory cytokines, and Glut-associated genes and proteins were identified with flavonoid treatment. Flavonoids prevented derangement of TJs protein interaction and stabilized membrane permeability. CONCLUSIONS These findings indicate that flavonoids confer protection against hyperglycemia-mediated oxidative stress and enhance intestinal barrier functions by modulating underlying intracellular molecular mechanisms.
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Affiliation(s)
- Sapna Sharma
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Prabhanshu Tripathi
- Translational Health Science, and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - Jeetesh Sharma
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Aparna Dixit
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
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Wieërs G, Belkhir L, Enaud R, Leclercq S, Philippart de Foy JM, Dequenne I, de Timary P, Cani PD. How Probiotics Affect the Microbiota. Front Cell Infect Microbiol 2020; 9:454. [PMID: 32010640 PMCID: PMC6974441 DOI: 10.3389/fcimb.2019.00454] [Citation(s) in RCA: 293] [Impact Index Per Article: 58.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 12/13/2019] [Indexed: 12/15/2022] Open
Abstract
Probiotics have been used to treat a variety of diseases for decades; however, what is the rationale for their application? Such a treatment was first proposed in the early nineteenth century based on observations of decreased bifidobacterial populations in children suffering from diarrhea, suggesting that oral intake of bifidobacteria could replete this subpopulation of the microbiota and improve health. Since then, studies have shown modifications in the gut or skin microbiota in the course of a variety of diseases and suggested positive effects of certain probiotics. Most studies failed to report any impact on the microbiota. The impact of probiotics as well as of bacteria colonizing food does not reside in their ability to graft in the microbiota but rather in sharing genes and metabolites, supporting challenged microbiota, and directly influencing epithelial and immune cells. Such observations argue that probiotics could be associated with conventional drugs for insulin resistance, infectious diseases, inflammatory diseases, and psychiatric disorders and could also interfere with drug metabolism. Nevertheless, in the context of a plethora of probiotic strains and associations produced in conditions that do not allow direct comparisons, it remains difficult to know whether a patient would benefit from taking a particular probiotic. In other words, although several mechanisms are observed when studying a single probiotic strain, not all individual strains are expected to share the same effects. To clarify the role of probiotics in the clinic, we explored the relation between probiotics and the gut and skin microbiota.
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Affiliation(s)
- Grégoire Wieërs
- Service de Médecine Interne Générale, Clinique Saint Pierre, Ottignies, Belgium
| | - Leila Belkhir
- Service de Médecine Interne et Maladies Infectieuses, Cliniques Universitaires Saint Luc, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Raphaël Enaud
- CHU Bordeaux, CRCM Pédiatrique, CIC 1401, Université de Bordeaux, INSERM, CRCTB, U1045, CHU Bordeaux, Bordeaux, France
| | - Sophie Leclercq
- Institute of Neuroscience and Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | | | | | - Philippe de Timary
- Service de Psychiatrie, Cliniques Universitaires Saint Luc, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Patrice D. Cani
- Walloon Excellence in Life Sciences and BIOtechnology, Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
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40
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Warmbrunn MV, Herrema H, Aron-Wisnewsky J, Soeters MR, Van Raalte DH, Nieuwdorp M. Gut microbiota: a promising target against cardiometabolic diseases. Expert Rev Endocrinol Metab 2020; 15:13-27. [PMID: 32066294 DOI: 10.1080/17446651.2020.1720511] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 01/21/2020] [Indexed: 02/06/2023]
Abstract
Introduction: Cardiometabolic diseases (CMD) are a group of interrelated disorders such as metabolic syndrome, type 2 diabetes mellitus and cardiovascular diseases (CVD). As the prevalence of these diseases increases globally, efficient new strategies are necessary to target CMD and modifiable risk factors. In the past decade, evidence has accumulated regarding the influence of gut microbiota (GM) on CMD, providing new targets for therapeutic interventions.Areas covered: This narrative review discusses the pathophysiologic link between CMD, GM, and potential microbiota-based targets against atherosclerosis and modifiable risk factors for atherosclerosis. Low-grade inflammation can be induced through GM and its derived metabolites. CMD are influenced by GM and microbiota-derived metabolites such as short-chain fatty acids (SCFA), secondary bile acids, trimethylamine N-oxide (TMAO), and the composition of GM can modulate host metabolism. All of the above can lead to promising therapeutic targets.Expert opinion: Most data are derived from animal models or human association studies; therefore, more translational and interventional research in humans is necessary to validate these promising findings. Reproduced findings such as aberrant microbiota patterns or circulating biomarkers could be targeted depending on individual metabolic profiles, moving toward personalized medicine in CMD.
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Affiliation(s)
- Moritz V Warmbrunn
- Department of Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
| | - Hilde Herrema
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
| | - Judith Aron-Wisnewsky
- Department of Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
- Sorbonne Université, INSERM, Nutrition and Obesities; Systemic Approaches (Nutriomics), Paris, France
- Assistance Publique Hôpitaux De Paris, Pitie-Salpêtrière Hospital, Nutrition Department, Paris, France
| | - Maarten R Soeters
- Department of Endocrinology and Metabolism, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
| | - Daniel H Van Raalte
- Department of Internal Medicine, Diabetes Center, Amsterdam UMC, Location VUMC at Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam UMC, ICar at Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Max Nieuwdorp
- Department of Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, The Netherlands
- Department of Internal Medicine, Diabetes Center, Amsterdam UMC, Location VUMC at Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam UMC, ICar at Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Horvath A, Leber B, Feldbacher N, Tripolt N, Rainer F, Blesl A, Trieb M, Marsche G, Sourij H, Stadlbauer V. Effects of a multispecies synbiotic on glucose metabolism, lipid marker, gut microbiome composition, gut permeability, and quality of life in diabesity: a randomized, double-blind, placebo-controlled pilot study. Eur J Nutr 2019; 59:2969-2983. [PMID: 31729622 PMCID: PMC7501130 DOI: 10.1007/s00394-019-02135-w] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/04/2019] [Indexed: 01/08/2023]
Abstract
Purpose Diabesity, the combination of obesity and type 2 diabetes, is an ever-growing global health burden. Diabesity-associated dysbiosis of the intestinal microbiome has gained attention as a potential driver of disease and, therefore, a possible therapeutic target by means of pro- or prebiotic supplementation. This study tested the effects of a multispecies synbiotic (i.e. a combination of probiotics and prebiotics) on glucose metabolism, gut microbiota, gut permeability, neutrophil function and quality of life in treatment-experienced diabesity patients. Methods A randomized, double-blind, placebo-controlled pilot study with 26 diabesity patients was conducted in which patients received a daily dose of a multispecies probiotic and a prebiotic (or a placebo) for 6 months. Results There were no changes in glucose metabolism or mixed meal tolerance test responses throughout the study. The analysis of secondary outcomes revealed beneficial effects on hip circumference [− 1 (95% CI − 4; 3) vs +3 (− 1; 8) cm, synbiotics vs. placebo, respectively, p = 0.04], serum zonulin [− 0.04 (− 0.2; 0.1) vs +0.3 (− 0.05; 0.6) ng/ml, p = 0.004)] and the physical role item of the SF36 quality of life assessment [+ 5.4 (− 1.7; 12.5) vs − 5.0 (− 10.1; 0.2) points, p = 0.02] after 3 months of intervention, and lipoprotein (a) [− 2.1 (− 5.7; 1.6) vs +3.4 (− 0.9; 7.9) mg/dl, p = 0.02] after 6 months. There were no significant differences in alpha or beta diversity of the microbiome between groups or time points. Conclusions Glucose metabolism as the primary outcome was unchanged during the intervention with a multispecies synbiotic in patients with diabesity. Nevertheless, synbiotics improved some symptoms and biomarkers of type 2 diabetes and aspects of quality of life suggesting a potential role as adjuvant tool in the management of diabesity. Graphic abstract ![]()
Electronic supplementary material The online version of this article (10.1007/s00394-019-02135-w) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Angela Horvath
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria. .,Center for Biomarker Research in Medicine (CBmed), Stiftingtalstrasse 5, 8010, Graz, Austria.
| | - Bettina Leber
- Division of Transplantation Surgery, Medical University of Graz, Auenbruggerplatz 29, 8036, Graz, Austria
| | - Nicole Feldbacher
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Center for Biomarker Research in Medicine (CBmed), Stiftingtalstrasse 5, 8010, Graz, Austria
| | - Norbert Tripolt
- Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Florian Rainer
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Andreas Blesl
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Markus Trieb
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria
| | - Gunther Marsche
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria
| | - Harald Sourij
- Center for Biomarker Research in Medicine (CBmed), Stiftingtalstrasse 5, 8010, Graz, Austria.,Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Zayed Center for Health Sciences (ZCHS), UAE University, Al-Ain, UAE
| | - Vanessa Stadlbauer
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
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Attaye I, Pinto-Sietsma SJ, Herrema H, Nieuwdorp M. A Crucial Role for Diet in the Relationship Between Gut Microbiota and Cardiometabolic Disease. Annu Rev Med 2019; 71:149-161. [PMID: 31479620 DOI: 10.1146/annurev-med-062218-023720] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cardiometabolic disease (CMD), such as type 2 diabetes mellitus and cardiovascular disease, contributes significantly to morbidity and mortality on a global scale. The gut microbiota has emerged as a potential target to beneficially modulate CMD risk, possibly via dietary interventions. Dietary interventions have been shown to considerably alter gut microbiota composition and function. Moreover, several diet-derived microbial metabolites are able to modulate human metabolism and thereby alter CMD risk. Dietary interventions that affect gut microbiota composition and function are therefore a promising, novel, and cost-efficient method to reduce CMD risk. Studies suggest that fermentable carbohydrates can beneficially alter gut microbiota composition and function, whereas high animal protein and high fat intake negatively impact gut microbiota function and composition. This review focuses on the role of macronutrients (i.e., carbohydrate, protein, and fat) and dietary patterns (e.g., vegetarian/vegan and Mediterranean diet) in gut microbiota composition and function in the context of CMD.
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Affiliation(s)
- Ilias Attaye
- Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; .,Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, University Medical Centers, 1081 HV Amsterdam, The Netherlands
| | - Sara-Joan Pinto-Sietsma
- Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; .,Department of Clinical Epidemiology and Biostatistics, University Medical Centers, 1081 HV Amsterdam, The Netherlands
| | - Hilde Herrema
- Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, University Medical Centers, 1081 HV Amsterdam, The Netherlands
| | - Max Nieuwdorp
- Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; .,Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, University Medical Centers, 1081 HV Amsterdam, The Netherlands.,Department of Internal Medicine, Amsterdam Diabetes Center, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.,Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
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43
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Li L, Rao S, Cheng Y, Zhuo X, Deng C, Xu N, Zhang H, Yang L. Microbial osteoporosis: The interplay between the gut microbiota and bones via host metabolism and immunity. Microbiologyopen 2019; 8:e00810. [PMID: 31001921 PMCID: PMC6692530 DOI: 10.1002/mbo3.810] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 01/09/2019] [Accepted: 01/11/2019] [Indexed: 01/15/2023] Open
Abstract
The complex relationship between intestinal microbiota and host is a novel field in recent years. A large number of studies are being conducted on the relationship between intestinal microbiota and bone metabolism. Bone metabolism consisted of bone absorption and formation exists in the whole process of human growth and development. The nutrient components, inflammatory factors, and hormone environment play important roles in bone metabolism. Recently, intestinal microbiota has been found to influence bone metabolism via influencing the host metabolism, immune function, and hormone secretion. Here, we searched relevant literature on Pubmed and reviewed the effect of intestinal microbiota on bone metabolism through the three aspects, which may provide new ideas and targets for the clinical treatment of osteoporosis.
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Affiliation(s)
- Lishan Li
- Department of endocrinology and metabolismZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Shitao Rao
- School of Biomedical SciencesCUHKShatin, N.THong Kong SARChina
| | - Yanzhen Cheng
- Department of endocrinology and metabolismZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Xiaoyun Zhuo
- Department of endocrinology and metabolismZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Caihong Deng
- Department of endocrinology and metabolismZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Ningning Xu
- Department of endocrinology and metabolismZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Hua Zhang
- Department of endocrinology and metabolismZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Li Yang
- Department of endocrinology and metabolismZhujiang HospitalSouthern Medical UniversityGuangzhouChina
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44
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Webb DL. Tests of intestinal mucosal hyperpermeability: Many diseases, many biomarkers and a bright future. Best Pract Res Clin Gastroenterol 2019; 40-41:101636. [PMID: 31594645 DOI: 10.1016/j.bpg.2019.101636] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 07/18/2019] [Indexed: 01/31/2023]
Abstract
The number of disorders now linked to increased intestinal mucosal permeability implies that a substantial percent of the population is affected. Drug interventions targeting reduced tight junctional permeability are being pursued. Although hyper-permeability in itself is not a clinically recognized disease entity, its relationship to disease processes has driven interest in measuring, and even monitoring mucosal permeability in vivo. Along with improved knowledge of gut barrier physiology, advances have been made in tests and biomarkers of barrier function. Drawing from our experiences in the past decade, considerations and challenges faced in assessing in vivo intestinal permeability are discussed herein, along with indications of what the future might hold.
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Affiliation(s)
- Dominic-Luc Webb
- Gastroenterology and Hepatology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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45
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Camilleri M, Lyle BJ, Madsen KL, Sonnenburg J, Verbeke K, Wu GD. Role for diet in normal gut barrier function: developing guidance within the framework of food-labeling regulations. Am J Physiol Gastrointest Liver Physiol 2019; 317:G17-G39. [PMID: 31125257 PMCID: PMC6689735 DOI: 10.1152/ajpgi.00063.2019] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, as it facilitates passage of injurious factors such as lipopolysaccharide, peptidoglycan, whole bacteria, and other toxins to traverse the barrier to damage the intestine or enter the portal circulation. Currently available evidence in animal models and in vitro systems has shown that certain dietary interventions can be used to reinforce the intestinal barrier to prevent the development of disease. The relevance of these studies to human health is unknown. Herein, we define the components of the intestinal barrier, review available modalities to assess its structure and function in humans, and review the available evidence in model systems or perturbations in humans that diet can be used to fortify intestinal barrier function. Acknowledging the technical challenges and the present gaps in knowledge, we provide a conceptual framework by which evidence could be developed to support the notion that diet can reinforce human intestinal barrier function to restore normal function and potentially reduce the risk for disease. Such evidence would provide information on the development of healthier diets and serve to provide a framework by which federal agencies such as the US Food and Drug Administration can evaluate evidence linking diet with normal human structure/function claims focused on reducing risk of disease in the general public.
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Affiliation(s)
- Michael Camilleri
- 1Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Barbara J. Lyle
- 2International Life Sciences Institute North America, Washington, DC,3School of Professional Studies, Northwestern University, Evanston, Illinois
| | - Karen L. Madsen
- 4Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Justin Sonnenburg
- 5Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California
| | - Kristin Verbeke
- 6Translational Research in Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Gary D. Wu
- 7Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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de Brito Alves JL, de Oliveira Y, Carvalho NNC, Cavalcante RGS, Pereira Lira MM, Nascimento LCPD, Magnani M, Vidal H, Braga VDA, de Souza EL. Gut microbiota and probiotic intervention as a promising therapeutic for pregnant women with cardiometabolic disorders: Present and future directions. Pharmacol Res 2019; 145:104252. [PMID: 31054952 DOI: 10.1016/j.phrs.2019.104252] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 04/10/2019] [Accepted: 04/30/2019] [Indexed: 12/12/2022]
Abstract
Maternal cardiometabolic disorders, such as gestational diabetes mellitus, pre-eclampsia, obesity, and dyslipidemia, are the most common conditions that predispose offspring to risk for future cardiometabolic diseases, needing appropriate therapeutic approach. The implications of microbiota in the pathophysiology of maternal cardiometabolic disorders are progressively emerging and probiotics may be a simple and safe therapeutic strategy for maternal cardiometabolic management. In this review, we argue the importance of cardiometabolic dysfunction during pregnancy and/or lactation on the offspring risk for cardiometabolic disease in later life. In addition, we comprehensively discuss the microbial diversity observed in maternal cardiometabolic disorders and we present the main findings on probiotic intervention as a potential strategy for management of maternal cardiometabolic disorders. Current data reveal that gut microbiota may be transmitted from mother to offspring. Whether targeting microbiota with probiotic intervention during the periconceptional period prevents or delays the onset of cardiometabolic disorders in adult offspring should be tested in future clinical trials.
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Affiliation(s)
- José Luiz de Brito Alves
- Department of Nutrition, Health Sciences Center, Federal University of Paraíba, João Pessoa, Brazil.
| | - Yohanna de Oliveira
- Department of Nutrition, Health Sciences Center, Federal University of Paraíba, João Pessoa, Brazil
| | | | | | | | | | - Marciane Magnani
- Department of Food Engineering, Technology Center, Federal University of Paraiba, Joao Pessoa, Brazil
| | - Hubert Vidal
- Univ-Lyon, CarMeN(Cardio, Metabolism,Diabetes and Nutrition) Laboratory, INSERM U1060, INRA U1397, Université Claude Bernard Lyon 1, INSA Lyon, Oullins, France
| | - Valdir de Andrade Braga
- Department of Biotechnology, Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil
| | - Evandro Leite de Souza
- Department of Nutrition, Health Sciences Center, Federal University of Paraíba, João Pessoa, Brazil
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Wensveen FM, Šestan M, Turk Wensveen T, Polić B. 'Beauty and the beast' in infection: How immune-endocrine interactions regulate systemic metabolism in the context of infection. Eur J Immunol 2019; 49:982-995. [PMID: 31106860 DOI: 10.1002/eji.201847895] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/28/2019] [Accepted: 05/17/2019] [Indexed: 02/07/2023]
Abstract
The immune and endocrine systems ensure two vital functions in the body. The immune system protects us from lethal pathogens, whereas the endocrine system ensures proper metabolic function of peripheral organs by regulating systemic homeostasis. These two systems were long thought to operate independently. The immune system uses cytokines and immune receptors, whereas the endocrine system uses hormones to regulate metabolism. However, recent findings show that the immune and endocrine systems closely interact, especially regarding regulation of glucose metabolism. In response to pathogen encounter, cytokines modify responsiveness of peripheral organs to endocrine signals, resulting in altered levels of blood hormones such as insulin, which promotes the ability of the body to fight infection. Here we provide an overview of recent literature describing various mechanisms, which the immune system utilizes to modify endocrine regulation of systemic metabolism. Moreover, we will describe how these immune-endocrine interactions derail in the context of obesity. From a clinical perspective we will elaborate how infection and obesity aggravate the development of metabolic diseases such as diabetes mellitus type 2 in humans. In summary, this review provides a comprehensive overview of immune-induced changes in systemic metabolism following infection, with a focus on regulation of glucose metabolism.
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Affiliation(s)
- Felix M Wensveen
- Department of Histology and Embryology, University of Rijeka School of Medicine, Rijeka, Croatia
| | - Marko Šestan
- Department of Histology and Embryology, University of Rijeka School of Medicine, Rijeka, Croatia
| | - Tamara Turk Wensveen
- Department of Endocrinology, Diabetes and Metabolic Diseases, Clinical hospital center Rijeka, Rijeka, Croatia
| | - Bojan Polić
- Department of Histology and Embryology, University of Rijeka School of Medicine, Rijeka, Croatia
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Pedersen C, Ijaz UZ, Gallagher E, Horton F, Ellis RJ, Jaiyeola E, Duparc T, Russell-Jones D, Hinton P, Cani PD, La Ragione RM, Robertson MD. Fecal Enterobacteriales enrichment is associated with increased in vivo intestinal permeability in humans. Physiol Rep 2019; 6:e13649. [PMID: 29611319 PMCID: PMC5880877 DOI: 10.14814/phy2.13649] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 02/02/2018] [Accepted: 02/08/2018] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes (T2D) has been linked with increased intestinal permeability, but the clinical significance of this phenomenon remains unknown. The objective of this study was to investigate the potential link between glucose control, intestinal permeability, diet and intestinal microbiota in patients with T2D. Thirty‐two males with well‐controlled T2D and 30 age‐matched male controls without diabetes were enrolled in a case–control study. Metabolic parameters, inflammatory markers, endotoxemia, and intestinal microbiota in individuals subdivided into high (HP) and normal (LP) colonic permeability groups, were the main outcomes. In T2D, the HP group had significantly higher fasting glucose (P = 0.034) and plasma nonesterified fatty acid levels (P = 0.049) compared with the LP group. Increased colonic permeability was also linked with altered abundances of selected microbial taxa. The microbiota of both T2D and control HP groups was enriched with Enterobacteriales. In conclusion, high intestinal permeability was associated with poorer fasting glucose control in T2D patients and changes in some microbial taxa in both T2D patients and nondiabetic controls. Therefore, enrichment in the gram‐negative order Enterobacteriales may characterize impaired colonic permeability prior to/independently from a disruption in glucose tolerance.
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Affiliation(s)
- Camilla Pedersen
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Umer Z Ijaz
- School of Engineering, University of Glasgow, Glasgow, United Kingdom
| | - Edith Gallagher
- Medical Physics - Nuclear Medicine, Royal Surrey County Hospital, Guildford, United Kingdom
| | - Felicity Horton
- Medical Physics - Nuclear Medicine, Royal Surrey County Hospital, Guildford, United Kingdom
| | | | - Etana Jaiyeola
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Thibaut Duparc
- WELBIO - Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - David Russell-Jones
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.,CEDAR Centre, Royal Surrey County Hospital, Guildford, United Kingdom
| | - Paul Hinton
- Medical Physics - Nuclear Medicine, Royal Surrey County Hospital, Guildford, United Kingdom
| | - Patrice D Cani
- WELBIO - Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Roberto M La Ragione
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - M Denise Robertson
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
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Modestino AE, Skowronski EA, Pruitt C, Taub PR, Herbst K, Schmid-Schönbein GW, Heller MJ, Mills PJ. Elevated Resting and Postprandial Digestive Proteolytic Activity in Peripheral Blood of Individuals With Type-2 Diabetes Mellitus, With Uncontrolled Cleavage of Insulin Receptors. J Am Coll Nutr 2019; 38:485-492. [PMID: 30964398 DOI: 10.1080/07315724.2018.1545611] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Objective: To examine resting and postprandial peripheral protease activity in healthy controls and individuals with type 2 diabetes mellitus (T2DM) and pre-T2DM. Methods: Individuals with T2DM or pre-T2DM and healthy controls (mean age 55.8 years) were studied before and for a span of 300 minutes following a single high-calorie McDonald's breakfast. Metalloproteases-2/-9 (MMP-2/-9), elastase, and trypsin activities were assessed in whole blood before and following the meal using a novel high-precision electrophoretic platform. Also assessed were circulating levels of inflammatory biomarkers and insulin receptor density on peripheral blood mononuclear cells (PBMCs) in relationship to protease activity. Results: Premeal MMP-2/-9 and elastase activity levels in T2DM and in pre-T2DM participants were significantly elevated as compared to controls. The T2DM group showed a significant increase in elastase activity 15 minutes after the meal; elastase activity continued to increase to the 30-minute time point (p < 0.01). In control participants, MMP-2/-9, elastase, and trypsin were significantly increased at 15 minutes after the meal (p < 0.05) and returned to premeal values within a period of approximately 30 to 60 minutes post meal. PBMCs incubated for 1 hour with plasma from T2DM and pre-T2DM participants had significantly lower levels of insulin receptor density compared to those incubated with plasma from control participants (p < 0.001). Conclusions: The results of this study suggest that individuals with T2DM and pre-T2DM have higher resting systemic protease activity than nonsymptomatic controls. A single high-calorie/high-carbohydrate meal results in further elevations of protease activity in the systemic circulation of T2DM and pre-T2DM, as well as in healthy controls. The protease activity in turn can lead to a downregulation of insulin receptor density, potentially supporting a state of insulin resistance.
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Affiliation(s)
- Augusta E Modestino
- a Department of Bioengineering, University of California San Diego , La Jolla , California , USA.,b Knight Cancer Center, Center for Early Cancer Detection (CEDAR), Oregon Health Sciences University , Portland , Oregon, USA
| | - Elaine A Skowronski
- c Department of Nanoengineering, University of California San Diego , La Jolla , California , USA
| | - Chris Pruitt
- d Department of Family Medicine and Public Health, University of California San Diego , La Jolla , California , USA
| | - Pam R Taub
- e Department of Medicine, University of California San Diego , La Jolla , California , USA
| | - Karen Herbst
- f Department of Medicine, The University of Arizona Health Sciences , Tucson , Arizona , USA
| | - Geert W Schmid-Schönbein
- a Department of Bioengineering, University of California San Diego , La Jolla , California , USA
| | - Michael J Heller
- a Department of Bioengineering, University of California San Diego , La Jolla , California , USA.,b Knight Cancer Center, Center for Early Cancer Detection (CEDAR), Oregon Health Sciences University , Portland , Oregon, USA
| | - Paul J Mills
- d Department of Family Medicine and Public Health, University of California San Diego , La Jolla , California , USA
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50
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Shen L, Ao L, Xu H, Shi J, You D, Yu X, Xu W, Sun J, Wang F. Poor short-term glycemic control in patients with type 2 diabetes impairs the intestinal mucosal barrier: a prospective, single-center, observational study. BMC Endocr Disord 2019; 19:29. [PMID: 30849982 PMCID: PMC6408809 DOI: 10.1186/s12902-019-0354-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 02/25/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND To determine the relation between daily glycemic fluturation and the intestinal mucosal barrier dysfunction in type 2 diabetes mellitus (T2DM). METHODS Totally 66 patients with T2DM were enrolled, 33 healthy volunteers were also recruited according to the enrolled patients' gender and age in a ratio of 2: 1. Patients were bisected by the median of endotoxins level into low(< 12.31 μ/l, n = 33) and high(≥12.31 μ/l, n = 33) blood endotoxin groups. Clinical data and blood glucose fluctuations were compared between groups. Multivariate regression analysis was used to determine the independent factors affecting the intestinal mucosal barrier. RESULTS Serum endotoxin [12.1 (4.2~22.0) vs 3.2 (1.3~6.0), P < 0.001] and fasting blood glucose levels [9.8 ± 3.6 vs 5.4 ± 0.7, P < 0.001] were significantly higher in patients with T2DM than the control group. The standard deviation of blood glucose (SDBG) within 1 day [2.9 (2.0~3.3) vs. 2.1 (1.6~2.5), P = 0.012] and the largest amplitude of glycemic excursions (LAGE) [7.5 (5.4~8.9) vs. 5.9 (4.3~7.4), P = 0.034] were higher in the high endotoxin group than in the low endotoxin group. A multiple linear stepwise regression revealed a positive correlation between SDBG with endotoxin (standard partial regression coefficient = 0.255, P = 0.039). CONCLUSIONS T2DM patients who incapable of maintaining stable blood glucose level are at a higher risk to associated with intestinal mucosal barrier injury.
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Affiliation(s)
- Lijuan Shen
- Department of Clinical Laboratory, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, No.1, Chengbei Rd, Jiading District, Shanghai, 201800, China
| | - Li Ao
- Department of Endocrinology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, 201800, China
| | - Haoben Xu
- Anting Town Community Healthcare Center of Jiading District, Shanghai, 201805, China
| | - Junfeng Shi
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China
| | - Dali You
- Department of Critical Care Medicine, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, No.1, Chengbei Rd, Jiading District, Shanghai, 201800, China
| | - Xiuwen Yu
- Department of Clinical Laboratory, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, No.1, Chengbei Rd, Jiading District, Shanghai, 201800, China
| | - Weixin Xu
- Department of Clinical Laboratory, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, No.1, Chengbei Rd, Jiading District, Shanghai, 201800, China
| | - Jie Sun
- Department of Clinical Laboratory, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, No.1, Chengbei Rd, Jiading District, Shanghai, 201800, China.
| | - Fei Wang
- Department of Critical Care Medicine, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, No.1, Chengbei Rd, Jiading District, Shanghai, 201800, China.
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