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Liu J, Li F, Yang L, Luo S, Deng Y. Gut microbiota and its metabolites regulate insulin resistance: traditional Chinese medicine insights for T2DM. Front Microbiol 2025; 16:1554189. [PMID: 40177494 PMCID: PMC11963813 DOI: 10.3389/fmicb.2025.1554189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 02/27/2025] [Indexed: 04/05/2025] Open
Abstract
The gut microbiota is closely associated with the onset and development of type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and chronic low-grade inflammation. However, despite the widespread use of first-line antidiabetic drugs, IR in diabetes and its complications continue to rise. The gut microbiota and its metabolic products may promote the development of T2DM by exacerbating IR. Therefore, regulating the gut microbiota has become a promising therapeutic strategy, with particular attention given to probiotics, prebiotics, synbiotics, and fecal microbiota transplantation. This review first examines the relationship between gut microbiota and IR in T2DM, summarizing the research progress of microbiota-based therapies in modulating IR. We then delve into how gut microbiota-related metabolic products contribute to IR. Finally, we summarize the research findings on the role of traditional Chinese medicine in regulating the gut microbiota and its metabolic products to improve IR. In conclusion, the gut microbiota and its metabolic products play a crucial role in the pathophysiological process of T2DM by modulating IR, offering new insights into potential therapeutic strategies for T2DM.
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Affiliation(s)
- Jing Liu
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Fuxing Li
- Ningxiang Traditional Chinese Medicine Hospital, Changsha, China
| | - Le Yang
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Shengping Luo
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Yihui Deng
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
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2
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Chen K, Wang H, Yang X, Tang C, Hu G, Gao Z. Targeting gut microbiota as a therapeutic target in T2DM: A review of multi-target interactions of probiotics, prebiotics, postbiotics, and synbiotics with the intestinal barrier. Pharmacol Res 2024; 210:107483. [PMID: 39521027 DOI: 10.1016/j.phrs.2024.107483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/11/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
The global epidemic of type 2 diabetes mellitus (T2DM) imposes a substantial burden on public health and healthcare expenditures, thereby driving the pursuit of cost-effective preventive and therapeutic strategies. Emerging evidence suggests a potential association between dysbiosis of gut microbiota and its metabolites with T2DM, indicating that targeted interventions aimed at modulating gut microbiota may represent a promising therapeutic approach for the management of T2DM. In this review, we concentrated on the multifaceted interactions between the gut microbiota and the intestinal barrier in the context of T2DM. We systematically summarized that the imbalance of beneficial gut microbiota and its metabolites may constitute a viable therapeutic approach for the management of T2DM. Meanwhile, the mechanisms by which gut microbiota interventions, such as probiotics, prebiotics, postbiotics, and synbiotics, synergistically improve insulin resistance in T2DM are summarized. These mechanisms include the restoration of gut microbiota structure, upregulation of intestinal epithelial cell proliferation and differentiation, enhancement of tight junction protein expression, promotion of mucin secretion by goblet cells, and the immunosuppressive functions of regulatory T cells (Treg) and M2 macrophages. Collectively, these actions contribute to the amelioration of the body's metabolic inflammatory status. Our objective is to furnish evidence that supports the clinical application of probiotics, prebiotics, and postbiotics in the management of T2DM.
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Affiliation(s)
- Keyu Chen
- Institute of Metabolic Diseases, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; Department of Endocrinology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Han Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiaofei Yang
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Cheng Tang
- National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for Metabolic Diseases, Beijing Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Guojie Hu
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
| | - Zezheng Gao
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
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3
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Chau GC, Lim JE, Moon K, Kim IS, Um SH. The stimulatory effect of HI 129, a novel indole derivative, on glucose-induced insulin secretion. Biochem Pharmacol 2024; 230:116558. [PMID: 39326678 DOI: 10.1016/j.bcp.2024.116558] [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: 05/27/2024] [Revised: 08/29/2024] [Accepted: 09/24/2024] [Indexed: 09/28/2024]
Abstract
Indole derivatives exhibit a broad spectrum of beneficial effects, encompassing anti-inflammatory, antiviral, antimalarial, anti-diabetic, antioxidant, anti-hepatitis, and antidepressant properties. Here, we describe the potentiation of insulin secretion in pancreatic islets and INS-1 cells through methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-(pyrimidine-2-yl)-1H-indole-3-carboxylate (HI 129), a novel indole derivative. Treatment with HI 129 led to notably decreased ADP/ATP ratios in pancreatic islets and INS-1 cells compared to those in the vehicle-treated controls, indicating a shift in cellular ATP production. Moreover, the augmentation of insulin secretion by HI 129 was closely correlated with its ability to enhance the mitochondrial membrane potential and respiration, partly by reducing the phosphorylation levels of AMP-activated protein kinase (AMPK). Mechanistically, HI 129 enhanced the association between AMPK and β-arrestin-1, critical molecules for glucose-induced insulin secretion. Furthermore, β-arrestin-1 depletion attenuated the effect of HI 129 on glucose-induced insulin secretion, suggesting that HI 129 potentiates insulin secretion via β-arrestin-1/AMPK signaling. These results collectively underscore the potential of HI 129 in enhancing insulin secretion as a novel candidate for improving glucose homeostasis in type 2 diabetes.
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Affiliation(s)
- Gia Cac Chau
- Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea
| | - Ji Eun Lim
- Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea
| | - Kyeongwon Moon
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea
| | - In Su Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea.
| | - Sung Hee Um
- Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea; Biomedical Institute Convergence at Sungkyunkwan University, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, 06351, Korea.
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Byndloss M, Devkota S, Duca F, Niess JH, Nieuwdorp M, Orho-Melander M, Sanz Y, Tremaroli V, Zhao L. The gut microbiota and diabetes: research, translation, and clinical applications - 2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum. Diabetologia 2024; 67:1760-1782. [PMID: 38910152 PMCID: PMC11410996 DOI: 10.1007/s00125-024-06198-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/23/2024] [Indexed: 06/25/2024]
Abstract
This article summarises the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organised by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: (1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g. genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomisation in humans; (2) the highly individualised nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; (3) because single time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and (4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.
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Affiliation(s)
- Mariana Byndloss
- Vanderbilt University Medical Center, Nashville, TN, USA
- Howard Hughes Medical Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Suzanne Devkota
- Cedars-Sinai Medical Center, Human Microbiome Research Institute, Los Angeles, CA, USA
| | | | - Jan Hendrik Niess
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Gastroenterology and Hepatology, University Digestive Healthcare Center, Clarunis, Basel, Switzerland
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Amsterdam Diabeter Center, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Marju Orho-Melander
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Yolanda Sanz
- Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
| | - Valentina Tremaroli
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Liping Zhao
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ, USA
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5
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Huang J, Huang T, Li J. Regulation Mechanism and Potential Value of Active Substances in Spices in Alcohol-Liver-Intestine Axis Health. Int J Mol Sci 2024; 25:3728. [PMID: 38612538 PMCID: PMC11011869 DOI: 10.3390/ijms25073728] [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: 01/23/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Excessive alcohol intake will aggravate the health risk between the liver and intestine and affect the multi-directional information exchange of metabolites between host cells and microbial communities. Because of the side effects of clinical drugs, people tend to explore the intervention value of natural drugs on diseases. As a flavor substance, spices have been proven to have medicinal value, but they are still rare in treating hepatointestinal diseases caused by alcohol. This paper summarized the metabolic transformation of alcohol in the liver and intestine and summarized the potential value of various perfume active substances in improving liver and intestine diseases caused by alcohol. It is also found that bioactive substances in spices can exert antioxidant activity in the liver and intestine environment and reduce the oxidative stress caused by diseases. These substances can interfere with fatty acid synthesis, promote sugar and lipid metabolism, and reduce liver injury caused by steatosis. They can effectively regulate the balance of intestinal flora, promote the production of SCFAs, and restore the intestinal microenvironment.
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Affiliation(s)
- Jianyu Huang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China;
- College of Food and Pharmaceutical Science, Ningbo University, Ningbo 315211, China
| | - Tao Huang
- College of Food and Pharmaceutical Science, Ningbo University, Ningbo 315211, China
| | - Jinjun Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China;
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Wang X, Hu M, Li M, Huan F, Gao R, Wang J. Effects of exposure to 3,6-DBCZ on neurotoxicity and AhR pathway during early life stages of zebrafish (Danio rerio). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 270:115892. [PMID: 38157798 DOI: 10.1016/j.ecoenv.2023.115892] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 12/14/2023] [Accepted: 12/24/2023] [Indexed: 01/03/2024]
Abstract
Polyhalogenated carbazoles (PHCZs) are emerging environmental pollutants, yet limited information is available on their embryotoxicity and neurotoxicity. Therefore, the current work was performed to investigate the adverse effects of 3,6-dibromocarbazole (3,6-DBCZ), a typical PHCZs homolog, on the early life stages of zebrafish larvae. It revealed that the 96-hour post-fertilization (hpf) median lethal concentration (LC50) value of 3,6-DBCZ in zebrafish larvae was determined to be 0.7988 mg/L. Besides, 3,6-DBCZ reduced survival rates at concentrations ≥ 1 mg/L and decreased hatching rates at ≥ 0.25 mg/L at 48 hpf. In behavior tests, it inhibited locomotor activities and reduced the frequency of recorded acceleration states in response to optesthesia (a sudden bright light stimulus) at concentrations ≥ 160 μg/L. Meanwhile, 3,6-DBCZ exposure decreased the frequency of recorded acceleration states in the startle response (tapping mode) at concentrations ≥ 6.4 μg/L. Pathologically, with the transgenic zebrafish model (hb9-eGFP), we observed a strikingly decreased axon length and number in motor neurons after 3,6-DBCZ treatment, which may be ascribed to the activation of the AhR signaling pathway, as evidenced by the molecular docking analysis and Microscale thermophoresis (MST) assay suggested that 3,6-DBCZ binding to AhR-ARNT2 compound proteins. Through interaction with AhR-ARNT, a striking reduction of the anti-oxidative stress (sod1/2, nqo1, nrf2) and neurodevelopment-related genes (elavl3, gfap, mbp, syn2a) were observed after 3,6-DBCZ challenge, accompanied by a marked increased inflammatory genes (TNFβ, IL1β, IL6). Collectively, our findings reveal a previously unrecognized adverse effect of 3,6-DBCZ on zebrafish neurodevelopment and locomotor behaviors, potentially mediated through the activation of the AhR pathway. Furthermore, it provides direct evidence for the toxic concentrations of 3,6-DBCZ and the potential target signaling in zebrafish larvae, which may be beneficial for the risk assessment of the aquatic ecosystems.
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Affiliation(s)
- Xi Wang
- Department of Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Miaoyang Hu
- Department of Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Muhan Li
- Department of Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Fei Huan
- Department of Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Rong Gao
- Department of Hygienic Analysis and Detection, Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Jun Wang
- Department of Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
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Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol (Lausanne) 2023; 14:1169624. [PMID: 37560311 PMCID: PMC10407565 DOI: 10.3389/fendo.2023.1169624] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/05/2023] [Indexed: 08/11/2023] Open
Abstract
The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.
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Affiliation(s)
| | - Van B. Lu
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
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De la Fuente-Muñoz M, De la Fuente-Fernández M, Román-Carmena M, Amor S, Iglesias-de la Cruz MC, García-Laínez G, Llopis S, Martorell P, Verdú D, Serna E, García-Villalón ÁL, Guilera SI, Inarejos-García AM, Granado M. Supplementation with a New Standardized Extract of Green and Black Tea Exerts Antiadipogenic Effects and Prevents Insulin Resistance in Mice with Metabolic Syndrome. Int J Mol Sci 2023; 24:ijms24108521. [PMID: 37239868 DOI: 10.3390/ijms24108521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/25/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
Insulin resistance is one of the main characteristics of metabolic syndrome (MetS) and the main cause of the development of type II diabetes. The high prevalence of this syndrome in recent decades has made it necessary to search for preventive and therapeutic agents, ideally of natural origin, with fewer side effects than conventional pharmacological treatments. Tea is widely known for its medicinal properties, including beneficial effects on weight management and insulin resistance. The aim of this study was to analyze whether a standardized extract of green and black tea (ADM® Complex Tea Extract (CTE)) prevents the development of insulin resistance in mice with MetS. For this purpose, C57BL6/J mice were fed for 20 weeks with a standard diet (Chow), a diet with 56% kcal from fat and sugar (HFHS) or an HFHS diet supplemented with 1.6% CTE. CTE supplementation reduced body weight gain, adiposity and circulating leptin levels. Likewise, CTE also exerted lipolytic and antiadipogenic effects in 3T3-L1 adipocyte cultures and in the C. elegans model. Regarding insulin resistance, CTE supplementation significantly increased plasma adiponectin concentrations and reduced the circulating levels of insulin and the HOMA-IR. Incubation of liver, gastrocnemius muscle and retroperitoneal adipose tissue explants with insulin increased the pAkt/Akt ratio in mice fed with Chow and HFHS + CTE but not in those fed only with HFHS. The greater activation of the PI3K/Akt pathway in response to insulin in mice supplemented with CTE was associated with a decrease in the expression of the proinflammatory markers Mcp-1, IL-6, IL-1β or Tnf-α and with an overexpression of the antioxidant enzymes Sod-1, Gpx-3, Ho-1 and Gsr in these tissues. Moreover, in skeletal muscle, mice treated with CTE showed increased mRNA levels of the aryl hydrocarbon receptor (Ahr), Arnt and Nrf2, suggesting that the CTE's insulin-sensitizing effects could be the result of the activation of this pathway. In conclusion, supplementation with the standardized extract of green and black tea CTE reduces body weight gain, exerts lipolytic and antiadipogenic effects and reduces insulin resistance in mice with MetS through its anti-inflammatory and antioxidant effects.
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Affiliation(s)
- Mario De la Fuente-Muñoz
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | | | - Marta Román-Carmena
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | - Sara Amor
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | | | - Guillermo García-Laínez
- Nutrition Archer Daniels Midland (ADM) Health & Wellness, Biopolis S. L. Parc Cientific, Universitat de València, 46980 Paterna, Spain
| | - Silvia Llopis
- Nutrition Archer Daniels Midland (ADM) Health & Wellness, Biopolis S. L. Parc Cientific, Universitat de València, 46980 Paterna, Spain
| | - Patricia Martorell
- Nutrition Archer Daniels Midland (ADM) Health & Wellness, Biopolis S. L. Parc Cientific, Universitat de València, 46980 Paterna, Spain
| | - David Verdú
- Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Eva Serna
- Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Ángel L García-Villalón
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | - Sonia I Guilera
- R&D Department of Functional Extracts, ADM® Valencia, 46740 Carcaixent, Spain
| | | | - Miriam Granado
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain
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Barta BP, Onhausz B, AL Doghmi A, Szalai Z, Balázs J, Bagyánszki M, Bódi N. Gut region-specific TNFR expression: TNFR2 is more affected than TNFR1 in duodenal myenteric ganglia of diabetic rats. World J Diabetes 2023; 14:48-61. [PMID: 36684383 PMCID: PMC9850801 DOI: 10.4239/wjd.v14.i1.48] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/16/2022] [Accepted: 10/28/2022] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Cytokines are essential in autoimmune inflammatory processes that accompany type 1 diabetes. Tumor necrosis factor alpha plays a key role among others in modulating enteric neuroinflammation, however, it has a dual role in cell degeneration or survival depending on different TNFRs. In general, TNFR1 is believed to trigger apoptosis, while TNFR2 promotes cell regeneration. The importance of the neuronal microenvironment has been recently highlighted in gut region-specific diabetic enteric neuropathy, however, the expression and alterations of different TNFRs in the gastrointestinal tract has not been reported.
AIM To investigate the TNFR1 and TNFR2 expression in myenteric ganglia and their environment in different intestinal segments of diabetic rats.
METHODS Ten weeks after the onset of hyperglycemia, gut segments were taken from the duodenum, ileum and colon of streptozotocin-induced (60 mg/body weight kg i.p.) diabetic (n = 17), insulin-treated diabetic (n = 15) and sex- and age-matched control (n = 15) rats. Myenteric plexus whole-mount preparations were prepared from different gut regions for TNFR1/HuCD or TNFR2/HuCD double-labeling fluorescent immunohistochemistry. TNFR1 and TNFR2 expression was evaluated by post-embedding immunogold electron microscopy on ultrathin sections of myenteric ganglia. TNFRs levels were measured by enzyme-linked immun-osorbent assay in muscle/myenteric plexus-containing (MUSCLE-MP) tissue homogenates from different gut segments and experimental conditions.
RESULTS A distinct region-dependent TNFRs expression was detected in controls. The density of TNFR1-labeling gold particles was lowest, while TNFR2 density was highest in duodenal ganglia and a decreased TNFRs expression from proximal to distal segments was observed in MUSCLE-MP homogenates. In diabetics, the TNFR2 density was only significantly altered in the duodenum with decrease in the ganglia (0.32 ± 0.02 vs 0.45 ± 0.04, P < 0.05), while no significant changes in TNFR1 density was observed. In diabetic MUSCLE-MP homogenates, both TNFRs levels significantly decreased in the duodenum (TNFR1: 4.06 ± 0.65 vs 20.32 ± 3.1, P < 0.001; TNFR2: 11.72 ± 0.39 vs 15.91 ± 1.04, P < 0.01), which markedly influenced the TNFR2/TNFR1 proportion in both the ganglia and their muscular environment. Insulin treatment had controversial effects on TNFR expression.
CONCLUSION Our findings show diabetes-related region-dependent changes in TNFR expression and suggest that TNFR2 is more affected than TNFR1 in myenteric ganglia in the duodenum of type 1 diabetic rats.
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Affiliation(s)
- Bence Pál Barta
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged 6726, Hungary
| | - Benita Onhausz
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged 6726, Hungary
| | - Afnan AL Doghmi
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged 6726, Hungary
| | - Zita Szalai
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged 6726, Hungary
| | - János Balázs
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged 6726, Hungary
| | - Mária Bagyánszki
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged 6726, Hungary
| | - Nikolett Bódi
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged 6726, Hungary
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10
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Huang Y, Liu L, Hao Z, Chen L, Yang Q, Xiong X, Deng Y. Potential roles of gut microbial tryptophan metabolites in the complex pathogenesis of acne vulgaris. Front Microbiol 2022; 13:942027. [PMID: 35966699 PMCID: PMC9363916 DOI: 10.3389/fmicb.2022.942027] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/04/2022] [Indexed: 11/23/2022] Open
Abstract
Acne vulgaris is a chronic inflammatory skin disease in which the influence of gut microbiota has been implicated but without clarification of mechanisms. Gut microbiota may exert such an influence via metabolites, particularly those of tryptophan. End metabolites of tryptophan activate receptors, including aryl hydrocarbon, G protein-coupled, and pregnane X receptors to stabilize the immune microenvironment and intestinal mucosal homeostasis. Any impact on the pathogenesis of acne vulgaris remains unclear. The current review collates recent advances concerning potential roles of tryptophan metabolism in mediating skin inflammation, follicular sebaceous gland function and intestinal permeability, all of which influence the pathogenesis of acne vulgaris. The aim was to improve understanding of the pathogenesis of acne vulgaris and to expose therapeutic opportunities.
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Affiliation(s)
- Yukun Huang
- Department of Dermatology and STD, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lu Liu
- Department of Dermatology and STD, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhenyu Hao
- Department of Dermatology and STD, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lingna Chen
- Department of Dermatology and STD, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qian Yang
- School of Nursing, Chengdu Medical College, Chengdu, China
- *Correspondence: Qian Yang,
| | - Xia Xiong
- Department of Dermatology and STD, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Xia Xiong,
| | - Yongqiong Deng
- Department of Dermatology and STD, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Yongqiong Deng,
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Hu W, Yan G, Ding Q, Cai J, Zhang Z, Zhao Z, Lei H, Zhu YZ. Update of Indoles: Promising molecules for ameliorating metabolic diseases. Biomed Pharmacother 2022; 150:112957. [PMID: 35462330 DOI: 10.1016/j.biopha.2022.112957] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/30/2022] [Accepted: 04/11/2022] [Indexed: 11/15/2022] Open
Abstract
Obesity and metabolic disorders have gradually become public health-threatening problems. The metabolic disorder is a cluster of complex metabolic abnormalities which are featured by dysfunction in glucose and lipid metabolism, and results from the increasing prevalence of visceral obesity. With the core driving factor of insulin resistance, metabolic disorder mainly includes type 2 diabetes mellitus (T2DM), micro and macro-vascular diseases, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and the dysfunction of gut microbiota. Strategies and therapeutic attention are demanded to decrease the high risk of metabolic diseases, from lifestyle changes to drug treatment, especially herbal medicines. Indole is a parent substance of numerous bioactive compounds, and itself can be produced by tryptophan catabolism to stimulate glucagon-like peptide-1 (GLP-1) secretion and inhibit the development of obesity. In addition, in heterocycles drug discovery, the indole scaffold is primarily found in natural compounds with versatile biological activity and plays a prominent role in drug molecules synthesis. In recent decades, plenty of natural or synthesized indole deriviatives have been investigated and elucidated to exert effects on regulating glucose hemeostasis and lipd metabolism. The aim of this review is to trace and emphasize the compounds containing indole scaffold that possess immense potency on preventing metabolic disorders, particularly T2DM, obesity and NAFLD, along with the underlying molecular mechanisms, therefore facilitate a better comprehension of their druggability and application in metabolic diseases.
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Affiliation(s)
- Wei Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Guanyu Yan
- Department of Allergy and Clinical Immunology, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Qian Ding
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Jianghong Cai
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Zhongyi Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Ziming Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Heping Lei
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
| | - Yi Zhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China; Shanghai Key Laboratory of Bioactive Small Molecules, School of Pharmacy, Fudan University, Shanghai, China.
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