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Luca BGD, Almeida PP, Junior RR, Soares DJS, Frantz EDC, Miranda-Alves L, Stockler-Pinto MB, Machado Dos Santos C, Magliano DC. Environmental contamination by bisphenols: From plastic production to modulation of the intestinal morphophysiology in experimental models. Food Chem Toxicol 2025; 197:115280. [PMID: 39923829 DOI: 10.1016/j.fct.2025.115280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/15/2025] [Accepted: 01/24/2025] [Indexed: 02/11/2025]
Abstract
Bisphenols are frequently found in a range of plastic products and have been associated with the development of diseases such as diabetes mellitus type 2 and obesity. These compounds are known as endocrine disruptors and have led to restrictions on their use due to their presence in the environment and their association with non-communicable chronic diseases. The gastrointestinal tract, being the primary site of food and water absorption, is particularly vulnerable to the effects of bisphenols. For this reason, a review of studies showing associations between bisphenols exposure and adverse effects in the gut microbiota, morphology tissue, gut permeability, and on the enteric nervous system was carried out. We have included perinatal studies and in different adult experimental models. The effects of bisphenol exposure on the gut microbiota are complex and varied. Bisphenol exposure generally leads to a decrease in microbial diversity and may impact the integrity of the intestinal barrier, resulting in elevated levels of inflammation, changes in morphological and metabolic characteristics of the gut, modifications in tight junction expression, and changes in goblet cell expression. In addition, bisphenol exposure in the perinatal phase can lead to important intestinal changes, including increased colonic inflammation and decreased colonic paracellular permeability.
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Affiliation(s)
- Beatriz Gouvêa de Luca
- Research Center on Morphology and Metabolism, Biomedical Institute, Federal Fluminense University, Niteroi, RJ, Brazil; Laboratory of Teaching and Research in Histology and Comparative Embryology (LEPHEC), Federal Fluminense University, Niterói, RJ, Brazil; Pathology Graduate Program, Federal Fluminense University (UFF), Niteroi, RJ, Brazil
| | - Patricia Pereira Almeida
- Pathology Graduate Program, Federal Fluminense University (UFF), Niteroi, RJ, Brazil; Nutrition Sciences Graduate Program, Federal Fluminense University (UFF), Niteroi, RJ, Brazil
| | - Reinaldo Röpke Junior
- Laboratory of Experimental Endocrinology (LEEx), Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Endocrinology Graduate Program, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Brazil
| | - Débora Júlia Silva Soares
- Research Center on Morphology and Metabolism, Biomedical Institute, Federal Fluminense University, Niteroi, RJ, Brazil
| | - Eliete Dalla Corte Frantz
- Research Center on Morphology and Metabolism, Biomedical Institute, Federal Fluminense University, Niteroi, RJ, Brazil; Cardiovascular Sciences Graduate Program, Fluminense Federal University (UFF), Niteroi, RJ, Brazil
| | - Leandro Miranda-Alves
- Laboratory of Experimental Endocrinology (LEEx), Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Endocrinology Graduate Program, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Brazil; Pharmacology and Medicinal Chemistry Graduate Program, Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Brazil; Morphological Sciences Graduate Program, Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Brazil
| | - Milena Barcza Stockler-Pinto
- Pathology Graduate Program, Federal Fluminense University (UFF), Niteroi, RJ, Brazil; Nutrition Sciences Graduate Program, Federal Fluminense University (UFF), Niteroi, RJ, Brazil
| | - Clarice Machado Dos Santos
- Laboratory of Teaching and Research in Histology and Comparative Embryology (LEPHEC), Federal Fluminense University, Niterói, RJ, Brazil
| | - D'Angelo Carlo Magliano
- Research Center on Morphology and Metabolism, Biomedical Institute, Federal Fluminense University, Niteroi, RJ, Brazil; Pathology Graduate Program, Federal Fluminense University (UFF), Niteroi, RJ, Brazil; Laboratory of Experimental Endocrinology (LEEx), Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Endocrinology Graduate Program, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Brazil.
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D'Antongiovanni V, Fornai M, Colucci R, Nericcio A, Benvenuti L, Di Salvo C, Segnani C, Pierucci C, Ippolito C, Nemeth ZH, Haskó G, Bernardini N, Antonioli L, Pellegrini C. Enteric glial NLRP3 inflammasome contributes to gut mucosal barrier alterations in a mouse model of diet-induced obesity. Acta Physiol (Oxf) 2025; 241:e14232. [PMID: 39287080 DOI: 10.1111/apha.14232] [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: 03/04/2024] [Revised: 08/12/2024] [Accepted: 09/02/2024] [Indexed: 09/19/2024]
Abstract
AIM In the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs). METHODS Wild-type C57BL/6J and NLRP3-KO (-/-) mice were fed with high-fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP- and NLRP3-positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation. RESULTS HFD mice showed increased body weight, altered IEB integrity, increased GFAP-positive glial cells, and NLRP3 inflammasome hyperactivation. HFD-NLRP3-/- mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase-1/IL-1β signaling. Enteric glial-derived IL-1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL-1β receptor antagonist) and with conditioned medium derived from silenced-NLRP3 glial cells. CONCLUSION HFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase-1/IL-1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity.
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Affiliation(s)
- Vanessa D'Antongiovanni
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Anna Nericcio
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Laura Benvenuti
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Clelia Di Salvo
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cristina Segnani
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Clarissa Pierucci
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Ippolito
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Zoltan H Nemeth
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York, USA
- Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York, USA
| | - Nunzia Bernardini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Carolina Pellegrini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Umemura M, Honda A, Yamashita M, Chida T, Noritake H, Yamamoto K, Honda T, Ichimura-Shimizu M, Tsuneyama K, Miyazaki T, Kurono N, Leung PSC, Gershwin ME, Suda T, Kawata K. High-fat diet modulates bile acid composition and gut microbiota, affecting severe cholangitis and cirrhotic change in murine primary biliary cholangitis. J Autoimmun 2024; 148:103287. [PMID: 39033687 DOI: 10.1016/j.jaut.2024.103287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/11/2024] [Accepted: 07/13/2024] [Indexed: 07/23/2024]
Abstract
Increasing evidence suggests that, in addition to a loss of tolerance, bile acid (BA) modulates the natural history of primary biliary cholangitis (PBC). We focused on the impacts of dietary changes on the immunopathology of PBC, along with alterations in BA composition and gut microbiota. In this study, we have taken advantage of our unique PBC model, a Cyp2c70/Cyp2a12 double knockout (DKO), which includes a human-like BA composition, and develops progressive cholangitis following immunization with the PDC-E2 mimic, 2-octynoic acid (2OA). We compared the effects of a ten-week high-fat diet (HFD) (60 % kcal from fat) and a normal diet (ND) on 2OA-treated DKO mice. Importantly, we report that 2OA-treated DKO mice fed HFD had significantly exacerbated cholangitis, leading to cirrhosis, with increased hepatic expression of Th1 cytokines/chemokines and hepatic fibrotic markers. Serum lithocholic acid (LCA) levels and the ratio of chenodeoxycholic acid (CDCA)-derived BAs to cholic acid-derived BAs were significantly increased by HFD. This was also associated with downregulated expression of key regulators of BA synthesis, including Cyp8b1, Cyp3a11, and Sult2a1. In addition, there were increases in the relative abundances of Acetatifactor and Lactococcus and decreases in Desulfovibrio and Lachnospiraceae_NK4A136_group, which corresponded to the abundances of CDCA and LCA. In conclusion, HFD and HFD-induced alterations in the gut microbiota modulate BA composition and nuclear receptor activation, leading to cirrhotic change in this murine PBC model. These findings have significant implications for understanding the progression of human PBC.
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Affiliation(s)
- Masahiro Umemura
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Akira Honda
- Joint Research Center and Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, 3-20-1Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.
| | - Maho Yamashita
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Takeshi Chida
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Hidenao Noritake
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Mayuko Ichimura-Shimizu
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
| | - Teruo Miyazaki
- Joint Research Center and Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, 3-20-1Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.
| | - Nobuhito Kurono
- Department of Chemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Davis, CA, 95616, USA.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Davis, CA, 95616, USA.
| | - Takafumi Suda
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Kazuhito Kawata
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
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Almeida PP, Brito ML, Thomasi B, Mafra D, Fouque D, Knauf C, Tavares-Gomes AL, Stockler-Pinto MB. Is the enteric nervous system a lost piece of the gut-kidney axis puzzle linked to chronic kidney disease? Life Sci 2024; 351:122793. [PMID: 38848938 DOI: 10.1016/j.lfs.2024.122793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/20/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
The enteric nervous system (ENS) regulates numerous functional and immunological attributes of the gastrointestinal tract. Alterations in ENS cell function have been linked to intestinal outcomes in various metabolic, intestinal, and neurological disorders. Chronic kidney disease (CKD) is associated with a challenging intestinal environment due to gut dysbiosis, which further affects patient quality of life. Although the gut-related repercussions of CKD have been thoroughly investigated, the involvement of the ENS in this puzzle remains unclear. ENS cell dysfunction, such as glial reactivity and alterations in cholinergic signaling in the small intestine and colon, in CKD are associated with a wide range of intestinal pathways and responses in affected patients. This review discusses how the ENS is affected in CKD and how it is involved in gut-related outcomes, including intestinal permeability, inflammation, oxidative stress, and dysmotility.
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Affiliation(s)
| | - Michele Lima Brito
- Pathology Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, Brazil
| | - Beatriz Thomasi
- Department of Physiology, Neuroscience Program, Michigan State University (MSU), East Lansing, MI, USA
| | - Denise Mafra
- Graduate Program in Biological Sciences - Physiology, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Denis Fouque
- Department of Nephrology, Centre Hopitalier Lyon Sud, INSERM 1060, CENS, Université de Lyon, France
| | - Claude Knauf
- INSERM U1220 Institut de Recherche en Santé Digestive, CHU Purpan, Université Toulouse III Paul Sabatier Toulouse, Toulouse, France
| | - Ana Lúcia Tavares-Gomes
- Neurosciences Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, Brazil
| | - Milena Barcza Stockler-Pinto
- Pathology Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, Brazil; INSERM U1220 Institut de Recherche en Santé Digestive, CHU Purpan, Université Toulouse III Paul Sabatier Toulouse, Toulouse, France
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Shetty S, Duesman SJ, Patel S, Huynh P, Toh P, Shroff S, Das A, Chowhan D, Keller B, Alvarez J, Fisher-Foye R, Sebra R, Beaumont K, McAlpine CS, Rajbhandari P, Rajbhandari AK. Sex-specific role of high-fat diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus. Biol Sex Differ 2024; 15:55. [PMID: 39010139 PMCID: PMC11247790 DOI: 10.1186/s13293-024-00628-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 06/11/2024] [Indexed: 07/17/2024] Open
Abstract
BACKGROUND Scientific evidence highlights the influence of biological sex on the relationship between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress concurrently contribute to metabolic dysregulation in both males and females. Our study aimed to investigate the combined effects of high-fat diet (HFD) induced obesity and repeated stress on fear-related behaviors, metabolic, immune, and hypothalamic outcomes in male and female mice. METHODS To investigate this, we used a highly reliable rodent behavioral model that faithfully recapitulates key aspects of post-traumatic stress disorder (PTSD)-like fear. We subjected mice to footshock stressor followed by a weekly singular footshock stressor or no stressor for 14 weeks while on either an HFD or chow diet. At weeks 10 and 14 we conducted glucose tolerance and insulin sensitivity measurements. Additionally, we placed the mice in metabolic chambers to perform indirect calorimetric measurements. Finally, we collected brain and peripheral tissues for cellular analysis. RESULTS We observed that HFD-induced obesity disrupted fear memory extinction, increased glucose intolerance, and affected energy expenditure specifically in male mice. Conversely, female mice on HFD exhibited reduced respiratory exchange ratio (RER), and a significant defect in glucose tolerance only when subjected to repeated stress. Furthermore, the combination of repeated stress and HFD led to sex-specific alterations in proinflammatory markers and hematopoietic stem cells across various peripheral metabolic tissues. Single-nuclei RNA sequencing (snRNAseq) analysis of the ventromedial hypothalamus (VMH) revealed microglial activation in female mice on HFD, while male mice on HFD exhibited astrocytic activation under repeated stress. CONCLUSIONS Overall, our findings provide insights into complex interplay between repeated stress, high-fat diet regimen, and their cumulative effects on health, including their potential contribution to the development of PTSD-like stress and metabolic dysfunctions, emphasizing the need for further research to fully understand these interconnected pathways and their implications for health.
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Affiliation(s)
- Sanutha Shetty
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Samuel J Duesman
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Sanil Patel
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Pacific Huynh
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Pamela Toh
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Sanjana Shroff
- Center for Advanced Genomic Technology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anika Das
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Center for Excellence in Youth Education, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Disha Chowhan
- Center for Advanced Genomic Technology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Benjamin Keller
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Johana Alvarez
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Rachel Fisher-Foye
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Robert Sebra
- Center for Advanced Genomic Technology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kristin Beaumont
- Center for Advanced Genomic Technology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Cameron S McAlpine
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Prashant Rajbhandari
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Disease Mechanism and Therapeutics Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Abha K Rajbhandari
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Arrari F, Jabri MA, Ayari A, Dakhli N, Ben Fayala C, Boubaker S, Sebai H. Amino acid HPLC-FLD analysis of spirulina and its protective mechanism against the combination of obesity and colitis in wistar rats. Heliyon 2024; 10:e30103. [PMID: 38694088 PMCID: PMC11061748 DOI: 10.1016/j.heliyon.2024.e30103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 05/03/2024] Open
Abstract
Objective The cafeteria diet (CD), designed as an experimental diet mimicking the obesogenic diet, may contribute to the pathogenesis of inflammatory bowel diseases (IBD). This study delves into the influence of spirulina (SP) on obesity associated with colitis in Wistar rats. Methods The amino acids composition of SP was analyzed using HPLC-FLD. Animals were equally separated into eight groups, each containing seven animals and treated daily for eight weeks as follows: Control diet (SD), cafeteria diet (CD) group, CD + SP (500 mg/kg) and SD + SP. Ulcerative colitis was provoked by rectal injection of acetic acid (AA) (3 % v/v, 5 ml/kg b.w.) on the last day of treatment in the following groups: SD + AA, SD + AA + SP, CD + AA, and CD + AA + SP. Results Findings revealed that UC and/or CD increased the abdominal fat, weights gain, and colons. Moreover, severe colonic alteration, perturbations in the serum metabolic parameters associated with an oxidative stress state in the colonic mucosa, defined by overproduction of reactive oxygen species (ROS) and increased levels of plasma scavenging activity (PSA). Additionally, obesity exacerbated the severity of AA-induced UC promoting inflammation marked by the overexpression of pro-inflammatory cytokines. Significantly, treatment with SP provided notable protection against inflammation severity, reduced histopathological alterations, attenuated lipid peroxidation (MDA), and enhanced antioxidant enzyme activities (CAT, SOD, and GPX) along with non-enzymatic antioxidants (GSH and SH-G). Conclusions Thus, the antioxidant effects and anti-inflammatory proprieties of SP could be attributed to its richness in amino acids, which could potentially mitigate inflammation severity in obese subjects suffering from ulcerative colitis. These results imply that SP hold promise as a therapeutic agent for managing of UC, particularly in individuals with concomitant obesity. Understanding SP's mechanisms of action may lead novel treatment strategies for inflammatory bowel diseases and hyperlipidemia in medical research.
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Affiliation(s)
- Fatma Arrari
- Université de Jendouba, Institut Supérieur de Biotechnologie de Béja, LR: Physiologie Fonctionnelle et Valorisation des Bio-Ressources, 9000, Béja, Tunisia
| | - Mohamed-Amine Jabri
- Université de Jendouba, Institut Supérieur de Biotechnologie de Béja, LR: Physiologie Fonctionnelle et Valorisation des Bio-Ressources, 9000, Béja, Tunisia
| | - Ala Ayari
- Université de Jendouba, Institut Supérieur de Biotechnologie de Béja, LR: Physiologie Fonctionnelle et Valorisation des Bio-Ressources, 9000, Béja, Tunisia
| | - Nouha Dakhli
- Université de Jendouba, Institut Supérieur de Biotechnologie de Béja, LR: Physiologie Fonctionnelle et Valorisation des Bio-Ressources, 9000, Béja, Tunisia
| | - Chayma Ben Fayala
- Laboratoire d'anatomie Pathologique Humaine et Expérimentale, Institut Pasteur de Tunis, 13, Place Pasteur, Tunis, 1002, Tunisia
| | - Samir Boubaker
- Laboratoire d'anatomie Pathologique Humaine et Expérimentale, Institut Pasteur de Tunis, 13, Place Pasteur, Tunis, 1002, Tunisia
| | - Hichem Sebai
- Université de Jendouba, Institut Supérieur de Biotechnologie de Béja, LR: Physiologie Fonctionnelle et Valorisation des Bio-Ressources, 9000, Béja, Tunisia
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Skrypnik K, Schmidt M, Olejnik-Schmidt A, Harahap IA, Suliburska J. Influence of supplementation with iron and probiotic bacteria Lactobacillus plantarum and Lactobacillus curvatus on selected parameters of inflammatory state in rats on a high-fat iron-deficient diet. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:4411-4424. [PMID: 38339838 DOI: 10.1002/jsfa.13329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/27/2023] [Accepted: 01/23/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND A high-fat (HF) diet, diet iron deficiency and iron supplementation may affect inflammatory parameters. Probiotics influence both iron metabolism and inflammation. We compared the inflammatory state in rats on a HF iron-deficient diet receiving oral iron, Lactobacillus plantarum and Lactobacillus curvatus in different combinations. METHODS This was a two-stage experiment. In groups C (n = 8) and HF (n = 8), rats ate a control or HF diet, respectively, for 16 weeks. In the group HFDEF (n = 48), rats ate a HF iron-deficient diet for 8 weeks (first stage) and were subsequently divided into 6 groups (n = 8 each) receiving the following for a further 8 weeks (second stage): HFDEF - a HF iron-deficient diet; HFDEFFe - a HF iron-deficient diet with iron; HFDEFLp and HFDEFLc - a HF iron-deficient diet with L. plantarum or L. curvatus, respectively; and HFDEFFeLp and HFDEFFeLc - a HF iron-deficient diet with iron and L. plantarum or L. curvatus, respectively. Body composition analysis and blood sampling was performed. Markers of iron status and levels of total antioxidant status (TAS), C-reactive protein (CRP), tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were measured in the blood. RESULTS TAS was higher in the HFDEF group (756.57 ± 489.53 ng mL-1) versus the HFDEFLc group (187.04 ± 47.84 ng mL-1; P = 0.022). No more differences were found between groups, or in TAS, CRP, TNF-α and IL-6 concentrations. Also, no differences were found between groups for alanine and aspartate aminotransferases, glucose, total cholesterol, low- and high-density lipoproteins and triglycerides. TAS level was positively correlated with ferritin concentration, IL-6 with TAS and TNF-α with hepcidin level. CONCLUSIONS Supplementation with L. plantarum, L. curvatus and iron in combinations exerts no influence on inflammatory status, lipid profile, hepatic function and serum fasting glucose in rats on a HF iron-deficient diet. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Katarzyna Skrypnik
- Institute of Human Nutrition and Dietetics, Poznan University of Life Sciences, Poznan, Poland
| | - Marcin Schmidt
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, Poznan, Poland
| | - Agnieszka Olejnik-Schmidt
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, Poznan, Poland
| | - Iskandar Azmy Harahap
- Institute of Human Nutrition and Dietetics, Poznan University of Life Sciences, Poznan, Poland
| | - Joanna Suliburska
- Institute of Human Nutrition and Dietetics, Poznan University of Life Sciences, Poznan, Poland
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Shetty S, Duesman SJ, Patel S, Huyhn P, Shroff S, Das A, Chowhan D, Sebra R, Beaumont K, McAlpine CS, Rajbhandari P, Rajbhandari AK. Sexually dimorphic role of diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.17.567534. [PMID: 38014350 PMCID: PMC10680837 DOI: 10.1101/2023.11.17.567534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Scientific evidence underscores the influence of biological sex on the interplay between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress jointly contribute to metabolic dysregulation in both males and females. To address this gap, our study aimed to investigate the combined effects of a high-fat diet (HFD) and repeated footshock stress on fear-related behaviors and metabolic outcomes in male and female mice. Using a robust rodent model that recapitulates key aspects of post-traumatic stress disorder (PTSD), we subjected mice to footshock stressor followed by weekly reminder footshock stressor or no stressor for 14 weeks while on either an HFD or chow diet. Our findings revealed that HFD impaired fear memory extinction in male mice that received initial stressor but not in female mice. Blood glucose levels were influenced by both diet and sex, with HFD-fed female mice displaying elevated levels that returned to baseline in the absence of stress, a pattern not observed in male mice. Male mice on HFD exhibited higher energy expenditure, while HFD-fed female mice showed a decreased respiratory exchange ratio (RER). Sex-specific alterations in pro-inflammatory markers and abundance of hematopoietic stem cells were observed in chronically stressed mice on an HFD in different peripheral tissues, indicating the manifestation of distinct comorbid disorders. Single-nuclei RNA sequencing of the ventromedial hypothalamus from stressed mice on an HFD provided insights into sex-specific glial cell activation and cell-type-specific transcriptomic changes. In conclusion, our study offers a comprehensive understanding of the intricate interactions between stress, diet, sex, and various physiological and behavioral outcomes, shedding light on a potential brain region coordinating these interactions.
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Affiliation(s)
- Sanutha Shetty
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, NY, New York 10029
| | - Samuel J. Duesman
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, NY, New York 10029
| | - Sanil Patel
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, NY, New York 10029
| | - Pacific Huyhn
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, NY, New York 10029
| | - Sanjana Shroff
- Center for Advanced Genomic Technology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anika Das
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, NY, New York 10029
- Center for Excellence in Youth Education, Icahn School of Medicine at Mount Sinai, NY, New York 10029
| | - Disha Chowhan
- Center for Advanced Genomic Technology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Robert Sebra
- Center for Advanced Genomic Technology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kristin Beaumont
- Center for Advanced Genomic Technology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Cameron S. McAlpine
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, NY, New York 10029
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, NY, New York 10029
| | - Prashant Rajbhandari
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, NY, New York 10029
- Disease Mechanism and Therapeutics Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Senior authors
| | - Abha K. Rajbhandari
- Department of Neuroscience and Psychiatry, Icahn School of Medicine at Mount Sinai, NY, New York 10029
- Senior authors
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9
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Zeng F, Li Y, Zhang X, Feng J, Gu W, Shen L, Huang W. Arctium lappa L. roots inhibit the intestinal inflammation of dietary obese rats through TLR4/NF-κB pathway. Heliyon 2023; 9:e21562. [PMID: 38027866 PMCID: PMC10663856 DOI: 10.1016/j.heliyon.2023.e21562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 10/19/2023] [Accepted: 10/24/2023] [Indexed: 12/01/2023] Open
Abstract
Long-term consumption of Arctium lappa L. roots can lead to weight loss. To explore the relationship between anti-obesity and anti-inflammation, the effects and mechanism of A. lappa L. root powder (ARP) on intestinal inflammation in obese rats were investigated. Dietary obese rats were successfully established by feeding a high-fat and high-sugar diet. The control group (n = 6) consumed a normal diet. The intestines were compared among the groups (each n = 6) with and without the administration of ARP (intragastric 7.5 g/kg·bw/d). Real-time quantitative reverse transcription-polymerase chain reaction and western blotting analysis revealed that ARP effectively inhibited the expression of pro-inflammatory and inflammatory cytokines in the colons of obese rats. These cytokines included interleukin (IL)-1β, IL-8, IL-6, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. The inhibition rates for all these cytokines exceeded 88 %. Moreover, ARP demonstrated the ability to down-regulate key genes involved in Toll-like receptor 4 (TLR4) complexes, namely Tlr4, myeloid differentiation protein-2 (Md2), and myeloid differentiation factor 88 (Myd88), along with downstream signaling molecules such as tumor necrosis factor receptor associated factor 6 (TRAF6) and nuclear factor-κB (NF-κB), with inhibition rates over 81 %. Additionally, ARP was observed to inhibit protein levels of TLR4, NF-κB, IL-1β, and TNF-α in the colons of obese rats, with inhibition rates of 65.6 ± 10.9 %, 84.4 ± 19.9 %, 80.8 ± 14.4 %, and 68.4 ± 17.5 %, respectively. This study confirmed the effectiveness of ARP in inhibiting intestinal inflammation through the blockade of the TLR4/NF-κB signaling pathway. It also suggested that ARP holds potential in improving intestinal health in the context of obesity, implying its possible application in the prevention and treatment of obesity and related metabolic diseases.
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Affiliation(s)
- Feng Zeng
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College, Yangzhou University, Yangzhou, 225000, PR China
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, PR China
| | - Ying Li
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, PR China
| | - Xiaoxiao Zhang
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, PR China
| | - Jin Feng
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, PR China
| | - Wen Gu
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, PR China
| | - Li Shen
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College, Yangzhou University, Yangzhou, 225000, PR China
| | - Wuyang Huang
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College, Yangzhou University, Yangzhou, 225000, PR China
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, PR China
- School of Food and Bioengineering, Jiangsu University, Zhenjiang, 212013, PR China
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10
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Li D, Zhou J, Wang L, Gong Z, Le H, Huang Y, Xu C, Tian C, Cai W, Wu J. Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation. Cell Biosci 2023; 13:186. [PMID: 37789469 PMCID: PMC10548658 DOI: 10.1186/s13578-023-01109-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/18/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND High-fat diet (HFD) is closely associated with the increased prevalence of inflammatory bowel disease (IBD). Excessive gut microbial metabolite deoxycholic acid (DCA) caused by HFD plays significant roles in eliciting intestinal inflammation, however, the mechanism underlining the induction of inflammatory response by DCA has not been fully elucidated. The purpose of this study was to investigate the role of DCA in the triggering of inflammation via affecting CD4+ T cell differentiation. RESULTS Murine CD4+T cells were cultured under Th1, Th2 or Th17-polarizing conditions treated with or without different dosage of DCA, and flowcytometry was conducted to detect the effect of DCA on CD4+ T cell differentiation. Alteration of gene expression in CD4+ T cells upon DCA treatment was determined by RNA-sequencing and qRT-PCR. Bioinformatic analysis, cholesterol metabolic profiling, ChIP assay and immuno-fluorescent staining were further applied to explore the DCA-regulated pathway that involved in CD4+T cell differentiation. The results showed that DCA could dose-dependently promote the differentiation of CD4+ T cell into Th17 linage with pathogenic signature. Mechanistically, DCA stimulated the expression of cholesterol biosynthetic enzymes CYP51 and led to the increased generation of endogenous RORγt agonists, including zymosterol and desmosterol, therefore facilitating Th17 differentiation. Up-regulation of CYP51 by DCA was largely mediated via targeting transcription factor SREBP2 and at least partially through bile acid receptor TGR5. In addition, DCA-supplemented diet significantly increased intestinal Th17 cell infiltration and exacerbated TNBS-induced colitis. Administration of cholestyramine to eliminate fecal bile acid obviously alleviated colonic inflammation accompanied by decreased Th17 cells in HFD-fed mice. CONCLUSIONS Our data establish a link between DCA-induced cholesterol biosynthesis in immune cells and gut inflammation. Modulation of bile acid level or targeting cholesterol metabolic pathway may be potential therapeutic measurements for HFD-related colitis.
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Affiliation(s)
- Dan Li
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jiefei Zhou
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Lingyu Wang
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Zizhen Gong
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Huijuan Le
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ye Huang
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Congfeng Xu
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Chunyan Tian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
- Research Unit of Proteomics-Driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing, China.
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
- Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Jin Wu
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
- Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
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11
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D'Antongiovanni V, Segnani C, Ippolito C, Antonioli L, Colucci R, Fornai M, Bernardini N, Pellegrini C. Pathological Remodeling of the Gut Barrier as a Prodromal Event of High-Fat Diet-Induced Obesity. J Transl Med 2023; 103:100194. [PMID: 37290605 DOI: 10.1016/j.labinv.2023.100194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023] Open
Abstract
Intestinal barrier alterations represent a primum movens in obesity and related intestinal dysfunctions. However, whether gut barrier remodeling represents prodromal events in obesity before weight gain, metabolic alterations, and systemic inflammation remains unclear. Herein, we examined morphologic changes in the gut barrier in a mouse model of high-fat diet (HFD) since the earliest phases of diet assumption. C57BL/6J mice were fed with standard diet (SD) or HFD for 1, 2, 4, or 8 weeks. Remodeling of intestinal epithelial barrier, inflammatory infiltrate, and collagen deposition in the colonic wall was assessed by histochemistry and immunofluorescence analysis. Obese mice displayed increased body and epididymal fat weight along with increased plasma resistin, IL-1β, and IL-6 levels after 8 weeks of HFD. Starting from 1 week of HFD, mice displayed (1) a decreased claudin-1 expression in lining epithelial cells, (2) an altered mucus in goblet cells, (3) an increase in proliferating epithelial cells in colonic crypts, (4) eosinophil infiltration along with an increase in vascular P-selectin, and (5) deposition of collagen fibers. HFD intake is associated with morphologic changes in the large bowel at mucosal and submucosal levels. In particular, the main changes include alterations in the mucous layer and intestinal epithelial barrier integrity and activation of mucosal defense-enhanced fibrotic deposition. These changes represent early events occurring before the development of obesity condition that could contribute to compromising the intestinal mucosal barrier and functions, opening the way for systemic dissemination.
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Affiliation(s)
- Vanessa D'Antongiovanni
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cristina Segnani
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Ippolito
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nunzia Bernardini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Interdepartmental Research Centre "Nutraceuticals and Food for Health," University of Pisa, Pisa, Italy.
| | - Carolina Pellegrini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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12
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Garcia C, Andersen CJ, Blesso CN. The Role of Lipids in the Regulation of Immune Responses. Nutrients 2023; 15:3899. [PMID: 37764683 PMCID: PMC10535783 DOI: 10.3390/nu15183899] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/30/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023] Open
Abstract
Lipid metabolism plays a major role in the regulation of the immune system. Exogenous (dietary and microbial-derived) and endogenous (non-microbial-derived) lipids play a direct role in regulating immune cell activation, differentiation and expansion, and inflammatory phenotypes. Understanding the complexities of lipid-immune interactions may have important implications for human health, as certain lipids or immune pathways may be beneficial in circumstances of acute infection yet detrimental in chronic inflammatory diseases. Further, there are key differences in the lipid effects between specific immune cell types and location (e.g., gut mucosal vs. systemic immune cells), suggesting that the immunomodulatory properties of lipids may be tissue-compartment-specific, although the direct effect of dietary lipids on the mucosal immune system warrants further investigation. Importantly, there is recent evidence to suggest that lipid-immune interactions are dependent on sex, metabolic status, and the gut microbiome in preclinical models. While the lipid-immune relationship has not been adequately established in/translated to humans, research is warranted to evaluate the differences in lipid-immune interactions across individuals and whether the optimization of lipid-immune interactions requires precision nutrition approaches to mitigate or manage disease. In this review, we discuss the mechanisms by which lipids regulate immune responses and the influence of dietary lipids on these processes, highlighting compelling areas for future research.
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Affiliation(s)
| | | | - Christopher N. Blesso
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; (C.G.); (C.J.A.)
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13
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Dietary Supplement, Containing the Dry Extract of Curcumin, Emblica and Cassia, Counteracts Intestinal Inflammation and Enteric Dysmotility Associated with Obesity. Metabolites 2023; 13:metabo13030410. [PMID: 36984850 PMCID: PMC10058382 DOI: 10.3390/metabo13030410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023] Open
Abstract
Intestinal epithelial barrier (IEB) impairment and enteric inflammation are involved in the onset of obesity and gut-related dysmotility. Dietary supplementation with natural plant extracts represents a useful strategy for the management of body weight gain and systemic inflammation associated with obesity. Here, we evaluate the efficacy of a food supplement containing the dry extract of Curcumin, Emblica and Cassia in counteracting enteric inflammation and motor abnormalities in a mouse model of obesity, induced by a high-fat diet (HFD). Male C57BL/6 mice, fed with standard diet (SD) or HFD, were treated with a natural mixture (Curcumin, Emblica and Cassia). After 8 weeks, body weight, BMI, liver and spleen weight, along with metabolic parameters and colonic motor activity were evaluated. Additionally, plasma LBP, fecal calprotectin, colonic levels of MPO and IL-1β, as well as the expression of occludin, TLR-4, MYD88 and NF-κB were investigated. Plant-based food supplement administration (1) counteracted the increase in body weight, BMI and metabolic parameters, along with a reduction in spleen and liver weight; (2) showed strengthening effects on the IEB integrity; and (3) reduced enteric inflammation and oxidative stress, as well as ameliorated the colonic contractile dysfunctions. Natural mixture administration reduced intestinal inflammation and counteracted the intestinal motor dysfunction associated with obesity.
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14
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Cao C, Tan X, Yan H, Shen Q, Hua R, Shao Y, Yao Q. Sleeve gastrectomy decreases high-fat diet induced colonic pro-inflammatory status through the gut microbiota alterations. Front Endocrinol (Lausanne) 2023; 14:1091040. [PMID: 37008903 PMCID: PMC10061349 DOI: 10.3389/fendo.2023.1091040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/13/2023] [Indexed: 02/03/2023] Open
Abstract
Background High-fat diet (HFD) induced obesity is characterized with chronic low-grade inflammation in various tissues and organs among which colon is the first to display pro-inflammatory features associated with alterations of the gut microbiota. Sleeve gastrectomy (SG) is currently one of the most effective treatments for obesity. Although studies reveal that SG results in decreased levels of inflammation in multiple tissues such as liver and adipose tissues, the effects of surgery on obesity related pro-inflammatory status in the colon and its relation to the microbial changes remain unknown. Methods To determine the effects of SG on the colonic pro-inflammatory condition and the gut microbiota, SG was performed on HFD-induced obese mice. To probe the causal relationship between alterations of the gut microbiota and improvements of pro-inflammatory status in the colon following SG, we applied broad-spectrum antibiotics cocktails on mice that received SG to disturb the gut microbial changes. The pro-inflammatory shifts in the colon were assessed based on morphology, macrophage infiltration and expressions of a variety of cytokine genes and tight junction protein genes. The gut microbiota alterations were analyzed using 16s rRNA sequencing. RNA sequencing of colon was conducted to further explore the role of the gut microbiota in amelioration of colonic pro-inflammation following SG at a transcriptional level. Results Although SG did not lead to pronounced changes of colonic morphology and macrophage infiltration in the colon, there were significant decreases in the expressions of several pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-6, IL-18, and IL-23 as well as increased expressions of some tight junction proteins in the colon following SG, suggesting an improvement of pro-inflammatory status. This was accompanied by changing populations of the gut microbiota such as increased richness of Lactobacillus subspecies following SG. Importantly, oral administrations of broad-spectrum antibiotics to delete most intestinal bacteria abrogated surgical effects to relieve colonic pro-inflammation. This was further confirmed by transcriptional analysis of colon indicating that SG regulated inflammation related pathways in a manner that was gut microbiota relevant. Conclusion These results support that SG decreases obesity related colonic pro-inflammatory status through the gut microbial alterations.
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Affiliation(s)
- Chong Cao
- Center for Obesity and Metabolic Surgery, Huashan Hospital of Fudan University, Shanghai, China
| | - Xiaozhuo Tan
- Center for Obesity and Metabolic Surgery, Huashan Hospital of Fudan University, Shanghai, China
| | - Hai Yan
- Center for Obesity and Metabolic Surgery, Huashan Hospital of Fudan University, Shanghai, China
| | - Qiwei Shen
- Center for Obesity and Metabolic Surgery, Huashan Hospital of Fudan University, Shanghai, China
| | - Rong Hua
- Center for Obesity and Metabolic Surgery, Huashan Hospital of Fudan University, Shanghai, China
| | - Yikai Shao
- Center for Obesity and Metabolic Surgery, Huashan Hospital of Fudan University, Shanghai, China
| | - Qiyuan Yao
- Department of General Surgery, Huashan Hospital of Fudan University, Shanghai, China
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15
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Nobiletin protects enteric nerves and ameliorates disordered bowel motility in diet-induced obese mice via increasing Trem2 expression. Biochem Biophys Res Commun 2022; 635:19-29. [DOI: 10.1016/j.bbrc.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 10/01/2022] [Indexed: 11/23/2022]
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16
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Khorsand Zaker BS, Saghebjoo M, Islami F. Effectiveness of high-intensity interval training and high-protein diet on TNF-α protein level in colon tissue of obese male rats: The importance of diet modifying. OBESITY MEDICINE 2022; 31:100403. [DOI: 10.1016/j.obmed.2022.100403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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17
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Cerantola S, Faggin S, Caputi V, Bosi A, Banfi D, Rambaldo A, Porzionato A, Di Liddo R, De Caro R, Savarino EV, Giaroni C, Giron MC. Small intestine neuromuscular dysfunction in a mouse model of dextran sulfate sodium-induced ileitis: Involvement of dopaminergic neurotransmission. Life Sci 2022; 301:120562. [PMID: 35487304 DOI: 10.1016/j.lfs.2022.120562] [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: 02/09/2022] [Revised: 04/06/2022] [Accepted: 04/13/2022] [Indexed: 11/28/2022]
Abstract
AIMS Anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and preclinical models of IBD. Thus, we aimed to evaluate the impact of dextran sodium sulfate (DSS)-induced ileitis on enteric dopaminergic pathways. MATERIALS AND METHODS Male C57/Bl6 mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and were then switched to regular drinking water for 3 days. To measure ileitis severity inflammatory cytokines (IL-1β, TNFα, IL-6) levels were assessed. Changes in ileal muscle tension were isometrically recorded following: 1) cumulative addition of dopamine on basal tone (0.1-1000 μM); ii) 4-Hz electric field stimulation (EFS) in the presence of 30 μM dopamine with/without 10 μM SCH-23390 (dopamine D1 receptor (D1R) antagonist) or 10 μM sulpiride (D2R antagonist). Immunofluorescence distribution of the neuronal HuC/D protein, glial S100β marker, D1R, and dopamine transporter (DAT) were determined in longitudinal-muscle-myenteric plexus whole-mounts (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR. KEY FINDINGS DSS caused an inflammatory process in the small intestine associated to dysmotility and altered barrier permeability, as suggested by decreased fecal output and enhanced stool water content. DSS treatment caused a significant increase of DAT and D1R myenteric immunoreactivity as well as of D1R and D2R mRNA levels, accompanied by a significant reduction of dopamine-mediated relaxation, involving primarily D1-like receptors. SIGNIFICANCE Mouse ileitis affects enteric dopaminergic neurotransmission mainly involving D1R-mediated responses. These findings provide novel information on the participation of dopaminergic pathways in IBD-mediated neuromuscular dysfunction.
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Affiliation(s)
- Silvia Cerantola
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Sofia Faggin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Valentina Caputi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy; Department of Poultry Science, University of Arkansas, Fayetteville, AR 72704, USA
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Anna Rambaldo
- Department of Neuroscience, University of Padova, Padova, Italy
| | | | - Rosa Di Liddo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | | | - Edoardo V Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy; IRCCS San Camillo Hospital, 30126 Venice, Italy.
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18
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Yang S, Wu XL, Wang SQ, Guo XL, Guo FZ, Sun XF. Association of Dietary Energy Intake With Constipation Among Men and Women: Results From the National Health and Nutrition Examination Survey. Front Nutr 2022; 9:856138. [PMID: 35495926 PMCID: PMC9044492 DOI: 10.3389/fnut.2022.856138] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/15/2022] [Indexed: 12/12/2022] Open
Abstract
BackgroundPrevious studies supported that dietary factor was associated with constipation, but the relationship between dietary energy intake and constipation has not been well-studied. Therefore, we aimed to evaluate the prevalence and correlation between energy intake and constipation among men and women.MethodsThese observational analyses included 12,587 adults (≥20 years) from the 2005–2010 cycles of the National Health and Nutrition Examination Surveys (NHANES). Constipation was defined as Bristol Stool Scale Type 1 (separate hard lumps, like nuts) or Type 2 (sausage-like but lumpy). Total energy intake was obtained from the two 24-h dietary recalls and averaged. We used the logistic regression model in Generalized Linear Model (GLM) function, controlling demographic, lifestyle, and dietary factors, to estimate the association between energy intake and constipation among men and women.ResultsThe overall weighted incidence of constipation in this research was 7.4%, the incidence in women and men was 10.4 and 4.3%, respectively. After multivariable adjustment, middle energy consumption correlated with decreased risk of constipation in men (OR:0.5, 95% CI:0.29–0.84), and lower-middle energy intake increased the constipation risk in women (OR: 1.56, 95% CI: 1.15–2.13). High energy consumption was not associated with increased or decreased constipation risk.ConclusionsTo our knowledge, this is the first research to investigate the association between energy intake and constipation; the study demonstrates that appropriate energy consumption can help reduce the risk of constipation in men, and relatively low energy intake is associated with increased constipation risk in women.
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Affiliation(s)
- Shuai Yang
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, China
| | - Xiao-Li Wu
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, China
| | - Shou-Qing Wang
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, China
| | - Xiang-Ling Guo
- Department of Gastroenterology, Jilin Provincial People's Hospital, Changchun, China
| | - Fu-Zheng Guo
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, China
| | - Xiao-Feng Sun
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Xiao-Feng Sun
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19
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Almeida PP, Valdetaro L, Thomasi BBDM, Stockler-Pinto MB, Tavares-Gomes AL. High-fat diets on the enteric nervous system: Possible interactions and mechanisms underlying dysmotility. Obes Rev 2022; 23:e13404. [PMID: 34873814 DOI: 10.1111/obr.13404] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/25/2021] [Accepted: 11/15/2021] [Indexed: 01/09/2023]
Abstract
Obesity is a chronic disease that affects various physiological systems. Among them, the gastrointestinal tract appears to be a main target of this disease. High-fat diet (HFD) animal models can help recapitulate the classic signs of obesity and present a series of gastrointestinal alterations, mainly dysmotility. Because intestinal motility is governed by the enteric nervous system (ENS), enteric neurons, and glial cells have been studied in HFD models. Given the importance of the ENS in general gut physiology, this review aims to discuss the relationship between HFD-induced neuroplasticity and gut dysmotility observed in experimental models. Furthermore, we highlight components of the gut environment that might influence enteric neuroplasticity, including gut microbiota, enteric glio-epithelial unit, serotonin release, immune cells, and disturbances such as inflammation and oxidative stress.
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Affiliation(s)
| | - Luisa Valdetaro
- Postgraduate Program in Neurosciences, Fluminense Federal University, Niterói, Brazil
| | | | - Milena Barcza Stockler-Pinto
- Postgraduate Program in Cardiovascular Sciences, Fluminense Federal University, Niterói, Brazil.,Postgraduate Program in Nutrition Sciences, Fluminense Federal University, Niterói, Brazil
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20
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Brzozowska M, Jana B, Całka J. Effect of NSAIDs Supplementation on the PACAP-, SP- and GAL-Immunoreactive Neurons in the Porcine Jejunum. Int J Mol Sci 2021; 22:ijms222111689. [PMID: 34769120 PMCID: PMC8583865 DOI: 10.3390/ijms222111689] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
Side effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) treatment are a serious limitation of their use in anti-inflammatory therapy. The negative effects of taking NSAIDs include abdominal pain, indigestion nausea as well as serious complications such as bleeding and perforation. The enteric nervous system is involved in regulation of gastrointestinal functions through the release of neurotransmitters. The present study was designed to determine, for the first time, the changes in pituitary adenylate cyclase-activating polypeptide (PACAP), substance P (SP) and galanin (GAL) expression in porcine jejunum after long-term treatment with aspirin, indomethacin and naproxen. The study was performed on 16 immature pigs. The animals were randomly divided into four experimental groups: control, aspirin, indomethacin and naproxen. Control animals were given empty gelatin capsules, while animals in the test groups received selected NSAIDs for 28 days. Next, animals from each group were euthanized. Frozen sections were prepared from collected jejunum and subjected to double immunofluorescence staining. NSAIDs supplementation caused a significant increase in the population of PACAP-, SP- and GAL-containing enteric neurons in the porcine jejunum. Our results suggest the participation of the selected neurotransmitters in regulatory processes of the gastrointestinal function and may indicate the direct toxic effect of NSAIDs on the ENS neurons.
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Affiliation(s)
- Marta Brzozowska
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str. 13, 10-718 Olsztyn, Poland;
- Correspondence: ; Tel.: +48-89-523-44-61
| | - Barbara Jana
- Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima Str. 10, 10-748 Olsztyn, Poland;
| | - Jarosław Całka
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str. 13, 10-718 Olsztyn, Poland;
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21
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Cerantola S, Faggin S, Annaloro G, Mainente F, Filippini R, Savarino EV, Piovan A, Zoccatelli G, Giron MC. Influence of Tilia tomentosa Moench Extract on Mouse Small Intestine Neuromuscular Contractility. Nutrients 2021; 13:nu13103505. [PMID: 34684506 PMCID: PMC8541069 DOI: 10.3390/nu13103505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/28/2021] [Accepted: 10/01/2021] [Indexed: 12/13/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) are characterized by abdominal pain, bloating and bowel disturbances. FGID therapy is primarily symptomatic, including treatment with herbal remedies. Flower extract of Tilia tomentosa Moench (TtM) is occasionally used as an anti-spasmodic in popular medicine. Since its effect on intestinal response is unknown, we evaluated the influence of TtM extract on small intestine contractility. Ileal preparations from C57BL/6J mice were mounted in organ baths to assess changes in muscle tension, following addition of TtM extract (0.5–36 μg/mL) or a vehicle (ethanol). Changes in contractile response to receptor- and non-receptor-mediated stimuli were assessed in ileal preparations pretreated with 12 μg/mL TtM. Alterations in the enteric nervous system neuroglial network were analyzed by confocal immunofluorescence. Increasing addition of TtM induced a marked relaxation in ileal specimens compared to the vehicle. Pretreatment with TtM affected cholinergic and tachykininergic neuromuscular contractions as well as K+-induced smooth muscle depolarization. Following incubation with TtM, a significant reduction in non-adrenergic non-cholinergic-mediated relaxation sensitive to Nω-Nitro-L-arginine methyl ester hydrochloride (pan-nitric oxide synthase inhibitor) was found. In vitro incubation of intestinal specimens with TtM did not affect the myenteric plexus neuroglial network. Our findings show that TtM-induced intestinal relaxation is mediated by nitric oxide pathways, providing a pharmacological basis for the use of TtM in FGIDs.
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Affiliation(s)
- Silvia Cerantola
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (S.F.); (G.A.); (R.F.); (A.P.)
| | - Sofia Faggin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (S.F.); (G.A.); (R.F.); (A.P.)
| | - Gabriela Annaloro
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (S.F.); (G.A.); (R.F.); (A.P.)
| | - Federica Mainente
- Department of Biotechnology, University of Verona, 37134 Verona, Italy; (F.M.); (G.Z.)
| | - Raffaella Filippini
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (S.F.); (G.A.); (R.F.); (A.P.)
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncological and Gastrointestinal Science, University of Padova, 35121 Padova, Italy;
| | - Anna Piovan
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (S.F.); (G.A.); (R.F.); (A.P.)
| | - Gianni Zoccatelli
- Department of Biotechnology, University of Verona, 37134 Verona, Italy; (F.M.); (G.Z.)
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (S.F.); (G.A.); (R.F.); (A.P.)
- IRCCS San Camillo Hospital, 30126 Venice, Italy
- Correspondence: ; Tel.: +39-049-827-5091
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22
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Pellegrini C, Fornai M, Benvenuti L, Colucci R, Caputi V, Palazon-Riquelme P, Giron MC, Nericcio A, Garelli F, D'Antongiovanni V, Segnani C, Ippolito C, Nannipieri M, Lopez-Castejon G, Pelegrin P, Haskó G, Bernardini N, Blandizzi C, Antonioli L. NLRP3 at the crossroads between immune/inflammatory responses and enteric neuroplastic remodelling in a mouse model of diet-induced obesity. Br J Pharmacol 2021; 178:3924-3942. [PMID: 34000757 DOI: 10.1111/bph.15532] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Enteric neurogenic/inflammation contributes to bowel dysmotility in obesity. We examined the role of NLRP3 in colonic neuromuscular dysfunctions in mice with high-fat diet (HFD)-induced obesity. EXPERIMENTAL APPROACH Wild-type C57BL/6J and NLRP3-KO (Nlrp3-/- ) mice were fed with HFD or standard diet for 8 weeks. The activation of inflammasome pathways in colonic tissues from obese mice was assessed. The role of NLRP3 in in vivo colonic transit and in vitro tachykininergic contractions and substance P distribution was evaluated. The effect of substance P on NLRP3 signalling was tested in cultured cells. KEY RESULTS HFD mice displayed increased body and epididymal fat weight, cholesterol levels, plasma resistin levels and plasma and colonic IL-1β levels, colonic inflammasome adaptor protein apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) and caspase-1 mRNA expression and ASC immunopositivity in macrophages. Colonic tachykininergic contractions were enhanced in HFD mice. HFD NLRP3-/- mice developed lower increase in body and epididymal fat weight, cholesterol levels, systemic and bowel inflammation. In HFD Nlrp3-/- mice, the functional alterations of tachykinergic pathways and faecal output were normalized. In THP-1 cells, substance P promoted IL-1β release. This effect was inhibited upon incubation with caspase-1 inhibitor or NK1 antagonist and not observed in ASC-/- cells. CONCLUSION AND IMPLICATIONS In obesity, NLRP3 regulates an interplay between the shaping of enteric immune/inflammatory responses and the activation of substance P/NK1 pathways underlying the onset of colonic dysmotility. Identifying NLRP3 as a therapeutic target for the treatment of bowel symptoms related to obesity.
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Affiliation(s)
- Carolina Pellegrini
- Department of Pharmacy, University of Pisa, Pisa, Italy.,Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Laura Benvenuti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
| | - Valentina Caputi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy.,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Pablo Palazon-Riquelme
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
| | - Anna Nericcio
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
| | - Francesca Garelli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
| | | | - Cristina Segnani
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Ippolito
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Monica Nannipieri
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gloria Lopez-Castejon
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Pablo Pelegrin
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, New York, USA
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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23
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Cerantola S, Caputi V, Contarini G, Mereu M, Bertazzo A, Bosi A, Banfi D, Mantini D, Giaroni C, Giron MC. Dopamine Transporter Genetic Reduction Induces Morpho-Functional Changes in the Enteric Nervous System. Biomedicines 2021; 9:biomedicines9050465. [PMID: 33923250 PMCID: PMC8146213 DOI: 10.3390/biomedicines9050465] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 12/23/2022] Open
Abstract
Antidopaminergic gastrointestinal prokinetics are indeed commonly used to treat gastrointestinal motility disorders, although the precise role of dopaminergic transmission in the gut is still unclear. Since dopamine transporter (DAT) is involved in several brain disorders by modulating extracellular dopamine in the central nervous system, this study evaluated the impact of DAT genetic reduction on the morpho-functional integrity of mouse small intestine enteric nervous system (ENS). In DAT heterozygous (DAT+/-) and wild-type (DAT+/+) mice (14 ± 2 weeks) alterations in small intestinal contractility were evaluated by isometrical assessment of neuromuscular responses to receptor and non-receptor-mediated stimuli. Changes in ENS integrity were studied by real-time PCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations (). DAT genetic reduction resulted in a significant increase in dopamine-mediated effects, primarily via D1 receptor activation, as well as in reduced cholinergic response, sustained by tachykininergic and glutamatergic neurotransmission via NMDA receptors. These functional anomalies were associated to architectural changes in the neurochemical coding and S100β immunoreactivity in small intestine myenteric plexus. Our study provides evidence that genetic-driven DAT defective activity determines anomalies in ENS architecture and neurochemical coding together with ileal dysmotility, highlighting the involvement of dopaminergic system in gut disorders, often associated to neurological conditions.
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Affiliation(s)
- Silvia Cerantola
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
| | - Valentina Caputi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72704, USA
| | - Gabriella Contarini
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95131 Catania, Italy;
| | - Maddalena Mereu
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
| | - Antonella Bertazzo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (C.G.)
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (C.G.)
| | - Dante Mantini
- IRCCS San Camillo Hospital, 30126 Venice, Italy; or
- Motor Control and Neuroplasticity Research Group, KU Leuven, 3000 Leuven, Belgium
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (C.G.)
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
- IRCCS San Camillo Hospital, 30126 Venice, Italy; or
- Correspondence: ; Tel.: +39-049-827-5091; Fax: +39-049-827-5093
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24
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Chen H, Yang H, Deng J, Fan D. Ginsenoside Rk3 Ameliorates Obesity-Induced Colitis by Regulating of Intestinal Flora and the TLR4/NF-κB Signaling Pathway in C57BL/6 Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:3082-3093. [PMID: 33621094 DOI: 10.1021/acs.jafc.0c07805] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Obesity-induced colonic inflammation-stimulated colitis is one of the main causes of colorectal cancer. Dietary phytochemicals are considered to be an effective strategy for relieving obesity-induced inflammatory diseases such as diabetes and colitis. Ginsenoside Rk3 (Rk3) is the main bioactive component of ginseng. Our previous study has demonstrated that Rk3 can effectively alleviate obesity-induced type 2 diabetes, but whether it plays a beneficial role in obesity-induced colitis remains poorly understood. Here, we found that Rk3 intervention repaired the intestinal barrier dysfunction by increasing the expression of the tight junction proteins (zonula occludens-1, claudin, and occludin), and reduced colonic inflammatory cytokine levels, oxidative stress, and macrophage infiltration in high-fat diet-induced mice. Importantly, Rk3 effectively ameliorated the metabolic dysbiosis of intestinal flora with significantly decreased Firmicute/Bacteroidete ratios and suppressed the inflammatory cascade by inhibiting the TLR4/NF-κB signaling pathway. Taken together, our findings indicate that Rk3 can be used as a potential natural anti-inflammatory agent to reduce chronic obesity-induced colitis.
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Affiliation(s)
- Hongwei Chen
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotech & Biomed Research Institute, Northwest University, 229 North Taibai Road, Xi'an 710069, China
| | - Haixia Yang
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
| | - Jianjun Deng
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotech & Biomed Research Institute, Northwest University, 229 North Taibai Road, Xi'an 710069, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China
- Biotech & Biomed Research Institute, Northwest University, 229 North Taibai Road, Xi'an 710069, China
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25
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Wang L, Gong Z, Zhang X, Zhu F, Liu Y, Jin C, Du X, Xu C, Chen Y, Cai W, Tian C, Wu J. Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation. Gut Microbes 2020; 12:1-20. [PMID: 33006494 PMCID: PMC7553752 DOI: 10.1080/19490976.2020.1819155] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
High-fat diet (HFD) leads to systemic low-grade inflammation, which has been involved in the pathogenesis of diverse metabolic and inflammatory diseases. Colon is thought to be the first organ suffering from inflammation under HFD conditions due to the pro-inflammatory macrophages infiltration, however, the mechanisms concerning the induction of pro-inflammatory phenotype of colonic macrophages remains unclear. In this study, we show that HFD increased the percentage of gram-positive bacteria, especially genus Clostridium, and resulted in the significant increment of fecal deoxycholic acid (DCA), a gut microbial metabolite produced by bacteria mainly restricted to genus Clostridium. Notably, reducing gram-positive bacteria with vancomycin diminished fecal DCA and profoundly alleviated pro-inflammatory macrophage infiltration in colon, whereas DCA-supplemented feedings to vancomycin-treated mice provoked obvious pro-inflammatory macrophage infiltration and colonic inflammation. Meanwhile, intra-peritoneal administration of DCA also elicited considerable recruitment of macrophages with pro-inflammatory phenotype. Mechanistically, DCA dose-dependently promoted M1 macrophage polarization and pro-inflammatory cytokines production at least partially through toll-like receptor 2 (TLR2) transactivated by M2 muscarinic acetylcholine receptor (M2-mAchR)/Src pathway. In addition, M2-mAchR mediated increase of TLR2 transcription was mainly achieved via targeting AP-1 transcription factor. Moreover, NF-κB/ERK/JNK signalings downstream of TLR2 are involved in the DCA-induced macrophage polarization. In conclusion, our findings revealed that high level DCA induced by HFD may serve as an initiator to activate macrophages and drive colonic inflammation, thus offer a mechanistic basis that modulation of gut microbiota or intervening specific bile acid receptor signaling could be potential therapeutic approaches for HFD-related inflammatory diseases.
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Affiliation(s)
- Lingyu Wang
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Zizhen Gong
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Xiuyuan Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences(Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Fangxinxing Zhu
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Yuchen Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences(Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Chaozhi Jin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences(Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Xixi Du
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Congfeng Xu
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China,Department of Immunology, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yingwei Chen
- Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China,Wei Cai Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chunyan Tian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences(Beijing), Beijing Institute of Lifeomics, Beijing, China,Chunyan Tian State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing, China
| | - Jin Wu
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China,CONTACT Jin Wu Department of pediatric Surgery, Xinhua hospital, Shanghai Jiaotong University School of Medicine, Shanghai200092, China
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26
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Jiao H, Lim AS, Fazio Coles TE, McQuade RM, Furness JB, Chinnery HR. The effect of high-fat diet-induced metabolic disturbance on corneal neuroimmune features. Exp Eye Res 2020; 201:108298. [PMID: 33069696 DOI: 10.1016/j.exer.2020.108298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 01/10/2023]
Abstract
PURPOSE The highly innervated cornea is susceptible to nerve loss secondary to systemic diseases such as diabetes and metabolic disturbances caused by high-fat diet. In this study, we characterize the effect of high-fat diet on the mouse corneal neuroimmune phenotype, including changes to corneal nerve density and resident immune cells, alongside the clinical assessment of corneal thickness and endothelial cell density. METHODS Male C57Bl6/J mice, aged 10 weeks, were fed a high-fat diet (60 kcal% fat, 5.2 kcal/g) or control diet (10 kcal%, 3.8 kcal/g) for 16 weeks. At the study endpoint, metabolic parameters (HbA1c, weight, fasting glucose, body fat) were measured to confirm metabolic disturbance. Clinical imaging of the anterior segment was performed using optical coherence tomography to measure the corneal epithelial and stromal thickness. Corneal sensory nerves were visualized using flatmount immunostaining and confocal microscopy. The topographical distribution and density of sensory nerves (BIII-tubulin+), intraepithelial CD45+ and MHC- II+ cells, stromal macrophages (IBA1+CD206+) and endothelial cells (ZO-1+) were analysed using FIJI. RESULTS High-fat diet mice had significantly higher blood HbA1c, higher body weight, a higher percentage of body fat and elevated fasting glucose compared to the control diet mice. Corneal epithelial and stromal thickness was similar in both groups. The sum length of the basal nerve plexus was lower in the central and peripheral cornea of mice fed a high-fat diet. In contrast, the sum length of superficial nerve terminals was similar between groups. Epithelial immune cell density was two-fold higher in the central corneas of high-fat diet mice compared to control diet mice. IBA1+CD206+ macrophage density was similar in the anterior stroma of both groups but was significantly higher in the posterior stroma of the peripheral cornea in the high-fat diet mice compared to controls. The percentage of nerve-associated MHC-II+ cells in the epithelium and stroma was higher in HFD mice compared to controls. Endothelial cell density was similar in the corneas of high-fat diet mice compared to controls. CONCLUSION Together with corneal neuropathy, corneal immune cells in mice fed a high-fat diet were differentially affected depending on their topographical distribution and location within cornea, and appeared in closer proximity to epithelial and stromal nerves, suggesting a local neuroimmune disruption induced by systemic metabolic disturbance.
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Affiliation(s)
- Haihan Jiao
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Alicia Sl Lim
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Therese E Fazio Coles
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia
| | - Rachel M McQuade
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia; Department of Medicine, Western Health, Melbourne University, Sunshine, Victoria, Australia
| | - John B Furness
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Holly R Chinnery
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia.
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27
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D’Antongiovanni V, Pellegrini C, Fornai M, Colucci R, Blandizzi C, Antonioli L, Bernardini N. Intestinal epithelial barrier and neuromuscular compartment in health and disease. World J Gastroenterol 2020; 26:1564-1579. [PMID: 32327906 PMCID: PMC7167418 DOI: 10.3748/wjg.v26.i14.1564] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 03/04/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
A number of digestive and extra-digestive disorders, including inflammatory bowel diseases, irritable bowel syndrome, intestinal infections, metabolic syndrome and neuropsychiatric disorders, share a set of clinical features at gastrointestinal level, such as infrequent bowel movements, abdominal distension, constipation and secretory dysfunctions. Several lines of evidence indicate that morphological and molecular changes in intestinal epithelial barrier and enteric neuromuscular compartment contribute to alterations of both bowel motor and secretory functions in digestive and extra-digestive diseases. The present review has been conceived to provide a comprehensive and critical overview of the available knowledge on the morphological and molecular changes occurring in intestinal epithelial barrier and enteric neuromuscular compartment in both digestive and extra-digestive diseases. In addition, our intent was to highlight whether these morphological and molecular alterations could represent a common path (or share some common features) driving the pathophysiology of bowel motor dysfunctions and related symptoms associated with digestive and extra-digestive disorders. This assessment might help to identify novel targets of potential usefulness to develop original pharmacological approaches for the therapeutic management of such disturbances.
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Affiliation(s)
| | | | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
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28
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Antonioli L, D'Antongiovanni V, Pellegrini C, Fornai M, Benvenuti L, di Carlo A, van den Wijngaard R, Caputi V, Cerantola S, Giron MC, Németh ZH, Haskó G, Blandizzi C, Colucci R. Colonic dysmotility associated with high-fat diet-induced obesity: Role of enteric glia. FASEB J 2020; 34:5512-5524. [PMID: 32086846 DOI: 10.1096/fj.201901844r] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 01/30/2020] [Accepted: 02/13/2020] [Indexed: 12/11/2022]
Abstract
The present study was designed to examine the role of enteric glial cells (EGCs) in colonic neuromuscular dysfunctions in a mouse model of high-fat diet (HFD)-induced obesity. C57BL/6J mice were fed with HFD or standard diet (SD) for 1, 2, or 8 weeks. Colonic interleukin (IL)-1β, IL-6, and malondialdehyde (MDA) levels were measured. Expression of occludin in colonic tissues was examined by western blot. Substance P (SP), S100β, GFAP, and phosphorylated mitogen-activated protein kinase 1 (pERK) were assessed in whole mount specimens of colonic plexus by immunohistochemistry. Colonic tachykininergic contractions, elicited by electrical stimulation or exogenous SP, were recorded in the presence or absence of fluorocitrate (FC). To mimic exposure to HFD, cultured EGCs were incubated with palmitate (PA) and/or lipopolysaccharide (LPS). SP and IL-1β levels were assayed in the culture medium by ELISA. HFD mice displayed an increase in colonic IL-1β and MDA, and a reduction of occludin at week 2. These changes occurred to a greater extent at week 8. In vitro electrically evoked tachykininergic contractions were enhanced in HFD mice after 2 or 8 weeks, and they were blunted by FC. Colonic IL-6 levels as well as substance P and S100β density in myenteric ganglia of HFD mice were increased at week 8, but not at week 1 or 2. In cultured EGCs, co-incubation with palmitate plus LPS led to a significant increase in both SP and IL-1β release. HFD-induced obesity is characterized by a hyperactivation of EGCs and is involved in the development of enteric motor disorders through an increase in tachykininergic activity and release of pro-inflammatory mediators.
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Affiliation(s)
- Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | | | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Department of Gastroenterology and Hepatology, Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Laura Benvenuti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Alma di Carlo
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Renè van den Wijngaard
- Department of Gastroenterology and Hepatology, Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Valentina Caputi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Silvia Cerantola
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Zoltán H Németh
- Department of Anesthesiology, Columbia University, New York, NY, USA.,Department of Surgery, Morristown Medical Center, Morristown, NJ, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
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29
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Dou D, Chen QQ, Zhong ZQ, Xia XW, Ding WJ. Regulating the Enteric Nervous System against Obesity in Mice by Electroacupuncture. Neuroimmunomodulation 2020; 27:48-57. [PMID: 32516787 DOI: 10.1159/000506483] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 02/06/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND AND OBJECTIVES The enteric nervous system (ENS) dominates the onset of obesity and has been shown to regulate nutrient absorption and energy metabolism. METHODS AND STUDY DESIGN This study was performed to investigate the role of electroacupuncture in regulating ENS function in obese mice. Obese mice were obtained by high-fat diet. 16S rRNA pyrosequencing, Western blotting, quantitative PCR, and neurotransmitter analysis were used for this purpose. RESULTS Body weight, Lee index, serum lipid, leptin, and adiponectin levels, and other basic indices were significantly ameliorated after electroacupuncture intervention. The pathological ENS scores, serum neurotransmitter levels, and intestinal transit rate were markedly changed in obese mice. Moreover, electroacupuncture promoted the diversity of gut microbiota. No significant differences were observed 21 and 28 days after electroacupuncture. CONCLUSIONS These results suggested ENS may be a new treatment approach to obesity.
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Affiliation(s)
- Ding Dou
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Traditional Chinese Medicine, Zunyi Medical and Pharmaceutical College, Zunyi, China
| | - Qiao Qiao Chen
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhan-Qiong Zhong
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiu-Wen Xia
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei-Jun Ding
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China,
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30
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Ricci C, Baumgartner J, Malan L, Smuts CM. Determining sample size adequacy for animal model studies in nutrition research: limits and ethical challenges of ordinary power calculation procedures. Int J Food Sci Nutr 2019; 71:256-264. [PMID: 31379222 DOI: 10.1080/09637486.2019.1646714] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Animal models are widely used in the field of nutrition research. Scientifically and ethically sound experiments need an adequate number of experimental units. The use of 5-10 units is common, but such sample sizes can be justified for large effect sizes only. We reviewed animal model studies recently published in selected journals in the field of nutrition sciences. We performed a simulation study aimed at determining the adequate sample size for normality assessment. We then performed power calculations for a number of statistical tests commonly found in rodent model studies in nutrition research. Among the selected papers, sample sizes ranged from 6-18 units per group. None of them justified the sample size. However, such sample sizes do not allow for normality testing, thus, graphical approaches should be used. Parametric approaches result in higher statistical power when compared to their non-parametric counterparts. Repeated measures analysis should always be preferred, when possible.
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Affiliation(s)
- Cristian Ricci
- Centre of Excellence for Nutrition (CEN), North-West University, Potchefstroom, South Africa
| | - Jeannine Baumgartner
- Centre of Excellence for Nutrition (CEN), North-West University, Potchefstroom, South Africa
| | - Linda Malan
- Centre of Excellence for Nutrition (CEN), North-West University, Potchefstroom, South Africa
| | - Cornelius M Smuts
- Centre of Excellence for Nutrition (CEN), North-West University, Potchefstroom, South Africa
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31
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Duan Y, Zeng L, Zheng C, Song B, Li F, Kong X, Xu K. Inflammatory Links Between High Fat Diets and Diseases. Front Immunol 2018; 9:2649. [PMID: 30483273 PMCID: PMC6243058 DOI: 10.3389/fimmu.2018.02649] [Citation(s) in RCA: 292] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 10/26/2018] [Indexed: 12/14/2022] Open
Abstract
In recent years, chronic overnutrition, such as consumption of a high-fat diet (HFD), has been increasingly viewed as a significant modifiable risk factor for diseases such as diabetes and certain types of cancer. However, the mechanisms by which HFDs exert adverse effects on human health remains poorly understood. Here, this paper will review the recent scientific literature about HFD-induced inflammation and subsequent development of diseases and cancer, with an emphasis on mechanisms involved. Given the expanding global epidemic of excessive HFD intake, understanding the impacts of a HFD on these medical conditions, gaining great insights into possible underlying mechanisms, and developing effective therapeutic strategies are of great importance.
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Affiliation(s)
- Yehui Duan
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, China
| | - Liming Zeng
- Science College of Jiangxi Agricultural University, Nanchang, China
| | - Changbing Zheng
- Guangdong Provincial Key Laboratory of Animal Nutrition Regulation, South China Agricultural University, Guangzhou, China
| | - Bo Song
- Guangdong Provincial Key Laboratory of Animal Nutrition Regulation, South China Agricultural University, Guangzhou, China
| | - Fengna Li
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, China
| | - Xiangfeng Kong
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, China
| | - Kang Xu
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, China
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