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Sundararaman L, Gouda D, Kumar A, Sundararaman S, Goudra B. Glucagon-like Peptide-1 Receptor Agonists: Exciting Avenues Beyond Weight Loss. J Clin Med 2025; 14:1978. [PMID: 40142784 PMCID: PMC11943310 DOI: 10.3390/jcm14061978] [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: 02/05/2025] [Revised: 03/03/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
The last two decades have proffered many remarkable choices in managing type 1 and type 2 diabetes mellitus. Leading the list are glucagon-like peptide-1 receptor agonists (GLP1RAs), the first of which, exenatide, was approved by the FDA in 2005. Two other major classes of drugs have also entered the market: dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly known as gliptins and approved in 2006, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, with the first approval occurring in 2013. These drugs have revolutionized the treatment of diabetes. Additionally, on the horizon, the once-weekly basal insulin analog insulin icodec and the once-weekly combination of insulin icodec and semaglutide are expected to be available in the future. Beyond glycemic control, GLP1RAs have exhibited benefits in conditions associated with diabetes, including hypertension, dyslipidemia, non-alcoholic steatohepatitis, as well as in neurodegenerative diseases such as Alzheimer's disease. Additionally, emerging research suggests potential roles in certain types of cancer, infertility, and associative learning. Major cardiovascular events seem to be lower in patients on GLP1RAs. While some evidence is robust, other findings remain tenuous. It is important that clinicians are familiar with current research in order to provide optimal evidence-based care to patients. In the not-too-distant future, there may be a case to prescribe these drugs for benefits outside diabetes.
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Affiliation(s)
- Lalitha Sundararaman
- Department of Anesthesiology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, USA;
| | - Divakara Gouda
- Inspira Health Network, 155 Bridgeton Pike ste c, Mullica Hill, NJ 08062, USA;
| | - Anil Kumar
- Department of Diabetes and Endocrinology, Karnataka Institute of Endocrinology and Research Bangalore, Binnamangala, Stage 1, Indiranagar, Bengaluru 560038, Karnataka, India;
| | - Sumithra Sundararaman
- Prana Holistic Center for Fertility and Integrated Medicine, 74/198, St’Mary’s Road, Opp. St’ Mary’s Church, Trustpakkam, Abiramapuram, Chennai 600018, Tamil Nadu, India;
| | - Basavana Goudra
- Department of Anesthesiology, Sidney Kimmel Medical College, Jefferson Health, 111 S 11th Street, #8280, Philadelphia, PA 19107, USA
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He Y, Xu B, Zhang M, Chen D, Wu S, Gao J, Liu Y, Zhang Z, Kuang J, Fang Q. Advances in GLP-1 receptor agonists for pain treatment and their future potential. J Headache Pain 2025; 26:46. [PMID: 40016636 PMCID: PMC11869436 DOI: 10.1186/s10194-025-01979-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 02/13/2025] [Indexed: 03/01/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show substantial efficacy in regulating blood glucose levels and lipid metabolism, initially as an effective treatment for diabetes mellitus. In recent years, GLP-1RAs have become a focal point in the medical community due to their innovative treatment mechanisms, robust therapeutic efficacy, and expansive development prospects. Notably, GLP-1RAs benefit pain management through their neuroprotective and metabolic regulatory properties, such as inhibiting inflammation responses and oxidative stress, promoting β-endorphin release and modulating several other crucial biological pathways. Hence GLP-1RAs hold promise for repurposing as treatments for pain disorders. In this narrative review, we thoroughly trace the current preclinical and clinical evidence of seven pain modalities, including inflammatory pain, osteoarthritis, visceral pain, neuropathic pain, diabetic neuropathy, cancer pain and headache, to support the efficacy and underlying biological mechanisms of GLP-1RAs as therapeutic agents for pain suffering. Despite these promising findings, further research is necessary to establish their long-term efficacy, optimal dosing strategies, and potential synergistic interactions of GLP-1RAs with existing pain management therapies. Future clinical trials should aim to distinguish the direct analgesic effects of GLP-1RAs from their metabolic benefits and explore their broader applications in pain conditions. The ongoing exploration of new indications for GLP-1RAs further highlights their transformative potential in advancing medical treatments across diverse clinical fields.
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Affiliation(s)
- Yongtao He
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Biao Xu
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Mengna Zhang
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Dan Chen
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Shuyuan Wu
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Jie Gao
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Yongpeng Liu
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Zixin Zhang
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Junzhe Kuang
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Quan Fang
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China.
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Funayama T, Nozu T, Ishioh M, Igarashi S, Tanaka H, Sumi C, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Takahashi S, Okumura T. Splenectomy prevents brain orexin, ghrelin, or oxytocin but not GLP-1-induced improvement of intestinal barrier function in rats. Neurogastroenterol Motil 2025; 37:e14949. [PMID: 39450642 DOI: 10.1111/nmo.14949] [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: 05/21/2024] [Revised: 09/30/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND Accumulating evidence has suggested that neuropeptides such as orexin, ghrelin, or oxytocin act centrally in the brain to regulate intestinal barrier function through the vagus nerve. It has been reported that the vagal cholinergic anti-inflammatory pathway was blocked by splenectomy. In the present study, we therefore examined the effect of splenectomy on neuropeptides-induced improvement of increased intestinal permeability. METHODS Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min spectrophotometrically in rats. RESULTS Splenectomy increased colonic permeability. The increased permeability by splenectomy was significantly blocked by vagal activation induced by carbachol or 2-deoxy-d-glucose which was prevented by atropine, suggesting vagal activation could prevent colonic hyperpermeability in splenectomized rats. In the splenectomized rats, intracisternal injection of orexin, ghrelin, oxytocin, or butyrate failed to inhibit increased colonic permeability while intracisternal glucagon-like peptide-1 (GLP-1) analogue, liraglutide, potently blocked the increased colonic permeability in a dose-dependent manner. The liraglutide-induced improvement of increased colonic permeability was blocked by atropine in splenectomized rats. Intracisternal injection of GLP-1 receptor antagonist attenuated 2-deoxy-d-glucose-induced improvement of colonic hyperpermeability in splenectomized rats. CONCLUSION The present results suggested that the spleen is important in the improvement of intestinal barrier function by brain orexin, ghrelin or oxytocin, and butyrate. On the other hand, GLP-1 acts centrally in the brain to improve colonic hyperpermeability in a spleen-independent manner. All these results suggest that dual mechanisms (spleen dependent or independent) may exist for the brain-gut regulation in intestinal barrier function.
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Affiliation(s)
- Takuya Funayama
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Tsukasa Nozu
- Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Masatomo Ishioh
- Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Sho Igarashi
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Tanaka
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Chihiro Sumi
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Takeshi Saito
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yasumichi Toki
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Mayumi Hatayama
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Masayo Yamamoto
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Motohiro Shindo
- Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
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Stanton EW, Manasyan A, Banerjee R, Hong K, Koesters E, Daar DA. Glucagon-Like Peptide-1 Agonists: A Practical Overview for Plastic and Reconstructive Surgeons. Ann Plast Surg 2025; 94:121-127. [PMID: 39293069 DOI: 10.1097/sap.0000000000004089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2024]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) agonists, such as exenatide, liraglutide, dulaglutide, semaglutide, and tirzepatide, effectively manage type 2 diabetes by promoting insulin release, suppressing glucagon secretion, and enhancing glucose metabolism. They also aid weight reduction and cardiovascular health, potentially broadening their therapeutic scope. In plastic surgery, they hold promise for perioperative weight management and glycemic control, potentially impacting surgical outcomes. METHODS A comprehensive review was conducted to assess GLP-1 agonists' utilization in plastic surgery. We analyzed relevant studies, meta-analyses, and trials to evaluate their benefits and limitations across surgical contexts, focusing on weight reduction, glycemic control, cardiovascular risk factors, and potential complications. RESULTS Studies demonstrate GLP-1 agonists' versatility, spanning weight management, cardiovascular health, neurological disorders, and metabolic dysfunction-associated liver diseases. Comparative analyses highlight variations in glycemic control, weight loss, and cardiometabolic risk. Meta-analyses reveal significant reductions in hemoglobin A1C levels, especially with high-dose semaglutide (2 mg) and tirzepatide (15 mg). However, increased dosing may lead to gastrointestinal side effects and serious complications like pancreatitis and bowel obstruction. Notably, GLP-1 agonists' efficacy in weight reduction and glycemic control may impact perioperative management in plastic surgery, potentially expanding surgical candidacy for procedures like autologous flap-based breast reconstruction and influencing outcomes related to lymphedema. Concerns persist regarding venous thromboembolism and delayed gastric emptying, necessitating further investigation into bleeding and aspiration risk with anesthesia. CONCLUSIONS GLP-1 agonists offer advantages in perioperative weight management and glycemic control in plastic surgery patients. They may broaden surgical candidacy and mitigate lymphedema risk but require careful consideration of complications, particularly perioperative aspiration risk. Future research should focus on their specific impacts on surgical outcomes to optimize their integration into perioperative protocols effectively. Despite challenges, GLP-1 agonists promise to enhance surgical outcomes and patient care in plastic surgery.
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Affiliation(s)
| | - Artur Manasyan
- From the Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Rakhi Banerjee
- From the Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Kurt Hong
- Division of Internal Medicine, Keck School of Medicine of USC, Los Angeles, CA
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Gul U, Aung T, Martin M, Farrukh DN, Shah PC, Lovely ZS, Marroquín León E, Alansaari M, Maini S, Fariduddin MM, Ullah A, Nazir Z. A Comprehensive Review of the Role of GLP-1 Agonists in Weight Management and Their Effect on Metabolic Parameters Such as Blood Glucose, Cholesterol, and Blood Pressure. Cureus 2024; 16:e76519. [PMID: 39872560 PMCID: PMC11771532 DOI: 10.7759/cureus.76519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2024] [Indexed: 01/30/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been developed to manage type 2 diabetes mellitus. Although, in the last 10 years, the use of GLP-1 RAs, especially semaglutide and liraglutide, has increased, its clinical implications and how it affects metabolic parameters have yet to be fully consolidated. This narrative review explores the metabolic effects of GLP-1 RAs in weight management, blood glucose, cardiovascular health, lipid profiles, and blood pressure. Data were collected by comparing GLP-1 RAs, such as semaglutide, liraglutide, tripeptide, and exenatide, as well as comparing them to a baseline treatment group. GLP-1 RAs have shown consistent results in managing blood glucose levels by lowering HbA1c with minimal hypoglycemic risk and increasing insulin production and synthesis. GLP-1 RAs have been found to improve overall cardiovascular health and reduce major adverse cardiovascular events (MACE) by improving the endothelial function of the vasculature and lowering ANP (atrial natriuretic peptide) production, leading to reduced blood pressure. In addition to the cardiovascular benefits, GLP-1 RAs have a varying effect on lipid profiles, finding statistically significant results for low-density lipoprotein cholesterol levels. In conjunction with all the effects, GLP-1 RAs have been found to lower weight and aid in weight management.
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Affiliation(s)
- Ushna Gul
- Internal Medicine, Khyber Medical College, Peshawar, PAK
| | - Thandar Aung
- Accident and Emergency, St. Ann's Bay Hospital, St. Ann's Bay, JAM
| | - Mehwish Martin
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | | | - Pari C Shah
- Family Medicine, Northeast Ohio Medical University, Xenia, USA
| | - Zeenia S Lovely
- Emergency, Kerala University of Health and Sciences, Cochin, IND
| | | | - Mohamed Alansaari
- Internal Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, IRL
| | - Shriya Maini
- Internal Medicine, Dayanand Medical College and Hospital, Punjab, IND
| | | | | | - Zahra Nazir
- Internal Medicine, Combined Military Hospital, Quetta, PAK
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Sørum ME, Gang AO, Tholstrup DM, Gudbrandsdottir S, Kissow H, Kornblit B, Müller K, Knop FK. Semaglutide treatment for PRevention Of Toxicity in high-dosE Chemotherapy with autologous haematopoietic stem-cell Transplantation (PROTECT): study protocol for a randomised, double-blind, placebo-controlled, investigator-initiated study. BMJ Open 2024; 14:e089862. [PMID: 39384243 PMCID: PMC11474865 DOI: 10.1136/bmjopen-2024-089862] [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: 06/11/2024] [Accepted: 09/17/2024] [Indexed: 10/11/2024] Open
Abstract
INTRODUCTION Cancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is no effective prophylaxis against this. Glucagon-like peptide 1 (GLP-1), a well-known regulator of blood glucose, has been suggested in mouse studies to possess trophic effects on gut epithelial cells as well as anti-inflammatory properties. In line with this, endogenous GLP-1 levels have been shown to be inversely correlated with toxicities after haematopoietic stem cell transplantation (HSCT) and treatment with a GLP-1 receptor agonist (GLP-1RA) was shown to limit chemotherapy-induced mucositis in rodents. This present study investigates the effects of the GLP-1RA semaglutide on GI mucositis severity score in patients with lymphoma undergoing high-dose chemotherapy followed by autologous (auto) HSCT. METHODS AND ANALYSIS This is a randomised, double-blind, placebo-controlled, two-centre investigator-initiated clinical study. Forty adult patients with malignant lymphoma referred for auto-HSCT will be randomised in a 1:1 manner to receive either semaglutide or placebo once-weekly for 8 weeks. This includes a run-in period of 3-4 weeks with semaglutide 0.25 mg prior to high-dose chemotherapy treatment followed by a period of 4-5 weeks with semaglutide 0.5 mg including the 1 week of high-dose chemotherapy treatment. Clinical assessment of endpoint measurements and safety will be performed weekly during treatment and in a follow-up period of 10 weeks. The primary endpoint is GI mucositis severity (mean severity grade (0-II) during week 1-4 after auto-HSCT). Secondary endpoints include C-reactive protein increment, quality of life and safety. Fever, bacteraemia, antibiotic use, weight loss, morphine consumption, duration of hospitalisation, use of parenteral nutrition, change in muscle mass and clinical and laboratory evidence of organ toxicities will also be assessed. ETHICS AND DISSEMINATION The study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Danish National Medical Research Ethics Committee (EU CT #2022-502139-20-00) and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark's good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and international scientific meetings and in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER NCT06449625.
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Affiliation(s)
- Maria Ebbesen Sørum
- Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne Ortved Gang
- Department of Haematology, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | | | - Sif Gudbrandsdottir
- Department of Haematology, Zealand University Hospital Roskilde, Roskilde, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Brian Kornblit
- Department of Haematology, Copenhagen University Hospital, Copenhagen, Denmark
| | - Klaus Müller
- Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark
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Halloum W, Dughem YA, Beier D, Pellesi L. Glucagon-like peptide-1 (GLP-1) receptor agonists for headache and pain disorders: a systematic review. J Headache Pain 2024; 25:112. [PMID: 38997662 PMCID: PMC11241973 DOI: 10.1186/s10194-024-01821-3] [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: 06/17/2024] [Accepted: 07/03/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) plays a crucial role in metabolic disorders by enhancing insulin secretion, inhibiting glucagon release, and slowing gastric emptying, thereby improving glycemic control. In recent years, GLP-1 role in neuronal pathways has expanded its therapeutic potential. We aim to comprehensively evaluate the relevance of GLP-1 in headache and pain disorders. METHODS A systematic literature search was conducted on PubMed and Embase (Ovid) databases using the search terms "GLP-1" and "pain". Animal and human studies published in English language were included. Abstracts, reviews, and articles on other disorders than "pain" were excluded. RESULTS The search strategy identified 833 hits, of which 42 studies were included in the final review. The studies were categorized into four groups: inflammatory pain and osteoarthritis, headaches, neuropathic pain and diabetic neuropathy, and visceral pain and irritable bowel syndrome. GLP-1 receptor (GLP-1R) agonists, like liraglutide, have shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory and neuropathic pain. GLP-1 is involved in migraine mechanisms and GLP-1R agonists are beneficial in individuals with idiopathic intracranial hypertension. Additionally, GLP-1R agonists reduce visceral hypersensitivity and ameliorate symptoms in patients with irritable bowel syndrome. CONCLUSIONS The therapeutic scope of GLP-1R agonists is expanding beyond traditional metabolic targets, highlighting its potential for headache and pain disorders. Engineering bimodal molecules that integrate GLP-1R agonism with specific pain-related mechanisms may offer innovative therapeutic options.
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Affiliation(s)
- Wael Halloum
- Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Campusvej 55, Odense, 5230, Denmark
| | - Yousef Al Dughem
- Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Campusvej 55, Odense, 5230, Denmark
| | - Dagmar Beier
- Department of Neurology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Lanfranco Pellesi
- Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Campusvej 55, Odense, 5230, Denmark.
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Wang K, Lai W, Min T, Wei J, Bai Y, Cao H, Guo J, Su Z. The Effect of Enteric-Derived Lipopolysaccharides on Obesity. Int J Mol Sci 2024; 25:4305. [PMID: 38673890 PMCID: PMC11050189 DOI: 10.3390/ijms25084305] [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: 03/11/2024] [Revised: 04/11/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Endotoxin is a general term for toxic substances in Gram-negative bacteria, whose damaging effects are mainly derived from the lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, and is a strong pyrogen. Obesity is a chronic, low-grade inflammatory condition, and LPS are thought to trigger and exacerbate it. The gut flora is the largest source of LPS in the body, and it is increasingly believed that altered intestinal microorganisms can play an essential role in the pathology of different diseases. Today, the complex axis linking gut flora to inflammatory states and adiposity has not been well elucidated. This review summarises the evidence for an interconnection between LPS, obesity, and gut flora, further expanding our understanding of LPS as a mediator of low-grade inflammatory disease and contributing to lessening the effects of obesity and related metabolic disorders. As well as providing targets associated with LPS, obesity, and gut flora, it is hoped that interventions that combine targets with gut flora address the individual differences in gut flora treatment.
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Affiliation(s)
- Kai Wang
- Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; (K.W.); (W.L.); (T.M.); (J.W.)
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Weiwen Lai
- Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; (K.W.); (W.L.); (T.M.); (J.W.)
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Tianqi Min
- Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; (K.W.); (W.L.); (T.M.); (J.W.)
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jintao Wei
- Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; (K.W.); (W.L.); (T.M.); (J.W.)
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China;
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China;
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengquan Su
- Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; (K.W.); (W.L.); (T.M.); (J.W.)
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
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Smits MM, Dreyer SIL, Hunt JE, Drzazga AK, Modvig IM, Holst JJ, Kissow H. Indole-3-carboxyaldehyde does not reverse the intestinal effects of fiber-free diet in mice. Front Endocrinol (Lausanne) 2024; 15:1362711. [PMID: 38586454 PMCID: PMC10995233 DOI: 10.3389/fendo.2024.1362711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/26/2024] [Indexed: 04/09/2024] Open
Abstract
Objective Fiber-free diet impairs intestinal and colonic health in mice, in parallel with a reduction in glucagon like peptide-1 (GLP-1) levels. Endogenous GLP-1 is important for intestinal growth and maintenance of the intestinal integrity. We aimed to investigate whether fiber-free diet reduces luminal content of metabolites which, upon supplementation, could increase GLP-1 secretion and restore the adverse effects of fiber-free diet. Methods Untargeted metabolomics (LC-MS) was performed on colonic content of mice fed a fiber-free diet, identifying a metabolite of particular interest: indole-3-carboxyaldehyde (I3A). We exposed cultured GLUTag cells to I3A, and measured cumulative GLP-1 secretion. Isolated colon perfusions were performed in male C57BL/6JRj mice and Wistar rats. I3A was administered luminally or vascularly, and GLP-1 was measured in portal vein effluent. Finally, female C57BL/6JRJ mice were fed chow or fiber-free diet, with I3A or vehicle by oral gavage. After 10 days, plasma GLP-1 (ELISA) and intestinal permeability (FITC-dextran) were measured, animals were sacrificed and organs removed for histology. Results Mice fed a fiber-free diet had significantly lower I3A in their colonic content compared to a control diet (7883 ± 3375 AU, p=0.04). GLP-1 secretion from GLUTag cells was unchanged after five minutes of exposure to I3A. However, GLP-1 levels increased after 120 minutes of exposure to 1 mM (60% increase, p=0.016) and 5 mM (89% increase, p=0.0025) I3A. In contrast, 48 h exposure to 1 mM decreased GLP-1 secretion (51% decrease, p<0.001) and viability. In isolated perfused mouse and rat colon, I3A applied into the luminal or vascular side did not affect GLP-1 secretion. Mice fed a fiber-free diet tended to weigh less compared to chow fed mice; and the small intestine and colon were significantly smaller. No differences were seen in crypt depth, villus length, mucosal area, and intestinal permeability. Supplementing I3A did not affect body weight, morphology or plasma GLP-1 levels. Conclusions Fiber-free diet lowered colonic content of I3A in mice. I3A stimulates GLP-1 secretion in vitro, but not in animal studies. Moreover, it has no evident beneficial effect on intestinal health when administered in vivo.
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Affiliation(s)
- Mark M. Smits
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Serafina I. L. Dreyer
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jenna E. Hunt
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anna K. Drzazga
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Lodz, Poland
| | - Ida M. Modvig
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J. Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Wang W, Zhang C, Zhang H, Li L, Fan T, Jin Z. The alleviating effect and mechanism of GLP-1 on ulcerative colitis. Aging (Albany NY) 2023; 15:8044-8060. [PMID: 37595257 PMCID: PMC10496996 DOI: 10.18632/aging.204953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 07/17/2023] [Indexed: 08/20/2023]
Abstract
Ulcerative Colitis (UC) is a major type of chronic inflammatory bowel disease of the colonic mucosa and exhibits progressive morbidity. The incidence and prevalence of UC is increasing worldwide. The global burden of UC, which can substantially reduce quality of life, is clearly increasing. These data highlight the need for research into prevention of UC and innovations in health-care systems to manage this complex and costly disease. Glucagon-like peptide-1 (GLP-1), a new antidiabetic drug, is used to treat Type 2 Diabetes Mellitus (T2DM). Accumulating evidence suggests that GLP-1 has additional roles other than glucose-lowering effects. Despite the abundance of GLP-1 research, studies in UC have been less consistent, especially body weight; for example, body weight, colon length, colon injury score, intestinal microbiota, remain to be studied further. To date, the molecular mechanism of the protective effect of GLP-1 on UC remains obscure. The effect of GLP-1 was studied by using a dextran sulfate sodium (DSS)-induced colitic mice and lipopolysaccharide (LPS) treated RAW264.7 cells (macrophage cell line) under in vivo and in vitro conditions, respectively. Our results indicate that GLP-1 significantly relieves ulcerative colitis as it represses the production of proinflammatory mediators. In addition, GLP-1 blocks the activation of the protein kinase B (AKT)/nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways. GLP-1 also alleviates DSS-induced injury to the intestinal mucosa and dysbiosis of gut microbiota. Altogether, GLP-1 has protection effect on ulcerative colitis. Thus, GLP-1 can be considered as a potential therapeutic candidate for the treatment of UC.
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Affiliation(s)
- Wenrui Wang
- Department of Hepatopancreatobiliary Medicine, Digestive Diseases Center, The Second Hospital, Jilin University, Changchun 130000, PR China
| | - Chuan Zhang
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun 130000, PR China
| | - Haolong Zhang
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union, Hospital of Jilin University, Changchun 130000, PR China
| | - Luyao Li
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun 130000, PR China
| | - Tingting Fan
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun 130000, PR China
| | - Zhenjing Jin
- Department of Hepatopancreatobiliary Medicine, Digestive Diseases Center, The Second Hospital, Jilin University, Changchun 130000, PR China
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11
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Igarashi S, Nozu T, Ishioh M, Funayama T, Sumi C, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Tanabe H, Okumura T. Ghrelin prevents lethality in a rat endotoxemic model through central effects on the vagal pathway and adenosine A2B signaling : Brain ghrelin and anti-septic action. J Physiol Biochem 2023:10.1007/s13105-023-00962-4. [PMID: 37099079 DOI: 10.1007/s13105-023-00962-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 04/17/2023] [Indexed: 04/27/2023]
Abstract
Accumulating evidence suggest that ghrelin plays a role as an antiseptic peptide. The present study aimed to clarify whether the brain may be implicated ghrelin's antiseptic action. We examined the effect of brain ghrelin on survival in a novel endotoxemic model achieved by treating rats with lipopolysaccharide (LPS) and colchicine. The observation of survival stopped three days after chemicals' injection or at death. Intracisternal ghrelin dose-dependently reduced lethality in the endotoxemic model; meanwhile, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin injection affected the mortality rate. The brain ghrelin-induced lethality reduction was significantly blocked by surgical vagotomy. Moreover, intracisternal injection of a ghrelin receptor antagonist blocked the improved survival achieved by intracisternal ghrelin injection or intravenous 2-deoxy-d-glucose administration. Intracisternal injection of an adenosine A2B receptor agonist reduced the lethality and the ghrelin-induced improvement of survival was blocked by adenosine A2B receptor antagonist. I addition, intracisternal ghrelin significantly blocked the colonic hyperpermeability produced by LPS and colchicine. These results suggest that ghrelin acts centrally to reduce endotoxemic lethality. Accordingly, activation of the vagal pathway and adenosine A2B receptors in the brain may be implicated in the ghrelin-induced increased survival. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the decreased septic lethality caused by brain ghrelin.
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Affiliation(s)
- Sho Igarashi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan
| | - Masatomo Ishioh
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Takuya Funayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Chihiro Sumi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Takeshi Saito
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Yasumichi Toki
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Mayumi Hatayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Masayo Yamamoto
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Motohiro Shindo
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Hiroki Tanabe
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
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12
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Arvanitakis K, Koufakis T, Popovic D, Maltese G, Mustafa O, Doumas M, Giouleme O, Kotsa K, Germanidis G. GLP-1 Receptor Agonists in Obese Patients with Inflammatory Bowel Disease: from Molecular Mechanisms to Clinical Considerations and Practical Recommendations for Safe and Effective Use. Curr Obes Rep 2023:10.1007/s13679-023-00506-3. [PMID: 37081371 DOI: 10.1007/s13679-023-00506-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/09/2023] [Indexed: 04/22/2023]
Abstract
PURPOSE OF REVIEW To discuss current literature and provide practical recommendations for the safe and effective use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in people with inflammatory bowel disease (IBD) and type 2 diabetes (T2D) and/or obesity. The molecular mechanisms that justify the potential benefits of GLP-1 RA in IBD and the links between IBD, obesity, and cardiovascular disease are also discussed. RECENT FINDINGS Preliminary data suggest that GLP-1 RA can modulate crucial pathways in the pathogenesis of IBD, such as chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, setting the stage for human trials to investigate the role of these agents in the treatment of IBD among people with or without diabetes and obesity. However, gastrointestinal side effects related to GLP-1 RA need appropriate clinical management to mitigate risks and maximize the benefits of therapy in people with IBD. GLP-1 RA originally emerged as drugs for the treatment of hyperglycemia and are currently licensed for the management of T2D and/or overweight/obesity. However, their wealth of pleiotropic actions soon raised expectations that they might confer benefits on non-metabolic disorders. Future studies are expected to clarify whether GLP-1 RA deserve an adjunct place in the arsenal of drugs against IBD.
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Affiliation(s)
- Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Djordje Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Giuseppe Maltese
- Department of Diabetes and Endocrinology, Epsom & St Helier University Hospitals, Surrey, SM5 1AA, UK
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences & Medicine, King's College, London, UK
| | - Omar Mustafa
- Department of Diabetes, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
- King's College London, London, UK
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Olga Giouleme
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece.
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece.
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13
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Funayama T, Nozu T, Ishioh M, Igarashi S, Sumi C, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Tanabe H, Okumura T. Centrally administered GLP-1 analogue improves intestinal barrier function through the brain orexin and the vagal pathway in rats. Brain Res 2023; 1809:148371. [PMID: 37076092 DOI: 10.1016/j.brainres.2023.148371] [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: 02/13/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023]
Abstract
Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9-39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.
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Affiliation(s)
- Takuya Funayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Masatomo Ishioh
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Sho Igarashi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Chihiro Sumi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Takeshi Saito
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Yasumichi Toki
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Mayumi Hatayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Masayo Yamamoto
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Motohiro Shindo
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Hiroki Tanabe
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan.
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14
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Bischoff SC, Ockenga J, Eshraghian A, Barazzoni R, Busetto L, Campmans-Kuijpers M, Cardinale V, Chermesh I, Kani HT, Khannoussi W, Lacaze L, Léon-Sanz M, Mendive JM, Müller MW, Tacke F, Thorell A, Vranesic Bender D, Weimann A, Cuerda C. Practical guideline on obesity care in patients with gastrointestinal and liver diseases - Joint ESPEN/UEG guideline. Clin Nutr 2023; 42:987-1024. [PMID: 37146466 DOI: 10.1016/j.clnu.2023.03.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 05/07/2023]
Abstract
BACKGROUND Patients with chronic gastrointestinal disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean gastrointestinal patients. The present guideline addresses this question according to current knowledge and evidence. OBJECTIVE The present practical guideline is intended for clinicians and practitioners in general medicine, gastroenterology, surgery and other obesity management, including dietitians and focuses on obesity care in patients with chronic gastrointestinal diseases. METHODS The present practical guideline is the shortened version of a previously published scientific guideline developed according to the standard operating procedure for ESPEN guidelines. The content has been re-structured and transformed into flow-charts that allow a quick navigation through the text. RESULTS In 100 recommendations (3× A, 33× B, 24 × 0, 40× GPP, all with a consensus grade of 90% or more) care of gastrointestinal patients with obesity - including sarcopenic obesity - is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially metabolic associated liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician. CONCLUSION The present practical guideline offers in a condensed way evidence-based advice how to care for patients with chronic gastrointestinal diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.
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Affiliation(s)
- Stephan C Bischoff
- Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
| | - Johann Ockenga
- Medizinische Klinik II, Klinikum Bremen-Mitte, Bremen FRG, Bremen, Germany.
| | - Ahad Eshraghian
- Department of Gastroenterology and Hepatology, Avicenna Hospital, Shiraz, Iran.
| | - Rocco Barazzoni
- Department of Medical, Technological and Translational Sciences, University of Trieste, Ospedale di Cattinara, Trieste, Italy.
| | - Luca Busetto
- Department of Medicine, University of Padova, Padova, Italy.
| | - Marjo Campmans-Kuijpers
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, the Netherlands.
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
| | - Irit Chermesh
- Department of Gastroenterology, Rambam Health Care Campus, Affiliated with Technion-Israel Institute of Technology, Haifa, Israel.
| | - Haluk Tarik Kani
- Department of Gastroenterology, Marmara University, School of Medicine, Istanbul, Turkey.
| | - Wafaa Khannoussi
- Hepato-Gastroenterology Department, Mohammed VI University Hospital, Oujda, Morocco; and Laboratoire de Recherche des Maladies Digestives (LARMAD), Mohammed the First University, Oujda, Morocco.
| | - Laurence Lacaze
- Department of General Surgery, Mantes-la-Jolie Hospital, Mantes-la-Jolie, France.
| | - Miguel Léon-Sanz
- Department of Endocrinology and Nutrition, University Hospital Doce de Octubre, Medical School, University Complutense, Madrid, Spain.
| | - Juan M Mendive
- La Mina Primary Care Academic Health Centre, Catalan Institute of Health (ICS), University of Barcelona, Barcelona, Spain.
| | - Michael W Müller
- Department of General and Visceral Surgery, Regionale Kliniken Holding, Kliniken Ludwigsburg-Bietigheim gGmbH, Krankenhaus Bietigheim, Bietigheim-Bissingen, Germany.
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| | - Anders Thorell
- Department of Clinical Science, Danderyds Hospital, Karolinska Institutet & Department of Surgery, Ersta Hospital, Stockholm, Sweden.
| | - Darija Vranesic Bender
- Unit of Clinical Nutrition, Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia.
| | - Arved Weimann
- Department of General, Visceral and Oncological Surgery, St. George Hospital, Leipzig, Germany.
| | - Cristina Cuerda
- Departamento de Medicina, Universidad Complutense de Madrid, Nutrition Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
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15
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Lebrun LJ, Dusuel A, Xolin M, Le Guern N, Grober J. Activation of TLRs Triggers GLP-1 Secretion in Mice. Int J Mol Sci 2023; 24:5333. [PMID: 36982420 PMCID: PMC10049702 DOI: 10.3390/ijms24065333] [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: 02/01/2023] [Revised: 03/03/2023] [Accepted: 03/05/2023] [Indexed: 03/14/2023] Open
Abstract
The gastrointestinal tract constitutes a large interface with the inner body and is a crucial barrier against gut microbiota and other pathogens. As soon as this barrier is damaged, pathogen-associated molecular patterns (PAMPs) are recognized by immune system receptors, including toll-like receptors (TLRs). Glucagon-like peptide 1 (GLP-1) is an incretin that was originally involved in glucose metabolism and recently shown to be rapidly and strongly induced by luminal lipopolysaccharides (LPS) through TLR4 activation. In order to investigate whether the activation of TLRs other than TLR4 also increases GLP-1 secretion, we used a polymicrobial infection model through cecal ligation puncture (CLP) in wild-type and TLR4-deficient mice. TLR pathways were assessed by intraperitoneal injection of specific TLR agonists in mice. Our results show that CLP induces GLP-1 secretion both in wild-type and TLR4-deficient mice. CLP and TLR agonists increase gut and systemic inflammation. Thus, the activation of different TLRs increases GLP-1 secretion. This study highlights for the first time that, in addition to an increased inflammatory status, CLP and TLR agonists also strongly induce total GLP-1 secretion. Microbial-induced GLP-1 secretion is therefore not only a TLR4/LPS-cascade.
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Affiliation(s)
- Lorène J. Lebrun
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
- Institut Agro Dijon, 21000 Dijon, France
| | - Alois Dusuel
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Marion Xolin
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Naig Le Guern
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Jacques Grober
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
- Institut Agro Dijon, 21000 Dijon, France
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16
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Ishioh M, Nozu T, Miyagishi S, Igarashi S, Funayama T, Ohhira M, Okumura T. Activation of basal forebrain cholinergic neurons improves colonic hyperpermeability through the vagus nerve and adenosine A2B receptors in rats. Biochem Pharmacol 2022; 206:115331. [PMID: 36330948 DOI: 10.1016/j.bcp.2022.115331] [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: 07/08/2022] [Revised: 10/20/2022] [Accepted: 10/24/2022] [Indexed: 12/14/2022]
Abstract
Intestinal barrier dysfunction, a leaky gut, contributes to the pathophysiology of various diseases such as dementia and irritable bowel syndrome (IBS). We recently clarified that orexin, ghrelin, or adenosine A2B signaling in the brain improved leaky gut through the vagus nerve. The present study was performed to clarify whether basal forebrain cholinergic neurons (BFCNs) are implicated in the central regulation of intestinal barrier function. We activated BFCNs using benzyl quinolone carboxylic acid (BQCA), a positive muscarinic M1 allosteric modulator, and evaluated colonic permeability by quantifying the absorbed Evans blue in rat colonic tissue. Intracisternal (not intraperitoneal) injection of BQCA blocked the increased colonic permeability in response to lipopolysaccharide. Vagotomy blocked BQCA-induced improvement of colonic hyperpermeability. Intracisternally administered pirenzepine, a muscarinic M1 selective antagonist, prevented intestinal barrier function improvement by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Adenosine A2B receptor antagonist but not dopamine or opioid receptor antagonist prevented BQCA-induced blockade of colonic hyperpermeability. Additionally, intracisternal injection of pirenzepine blocked orexin- or butyrate-induced intestinal barrier function improvement. These results suggest that BFCNs improve leaky gut through adenosine A2B signaling and the vagal pathway. Furthermore, BFCNs mediate orexin- or butyrate-induced intestinal barrier function improvement. Since BFCNs play a role in cognitive function and a leaky gut is associated with dementia, the present finding may lead us to speculate that BFCNs are involved in the development of dementia by regulating intestinal barrier function.
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Affiliation(s)
- Masatomo Ishioh
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Saori Miyagishi
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Sho Igarashi
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Takuya Funayama
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Masumi Ohhira
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan; Center for Medical Education, Asahikawa Medical University, Japan
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17
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Abdalqadir N, Adeli K. GLP-1 and GLP-2 Orchestrate Intestine Integrity, Gut Microbiota, and Immune System Crosstalk. Microorganisms 2022; 10:2061. [PMID: 36296337 PMCID: PMC9610230 DOI: 10.3390/microorganisms10102061] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 12/15/2022] Open
Abstract
The intestine represents the body's largest interface between internal organs and external environments except for its nutrient and fluid absorption functions. It has the ability to sense numerous endogenous and exogenous signals from both apical and basolateral surfaces and respond through endocrine and neuronal signaling to maintain metabolic homeostasis and energy expenditure. The intestine also harbours the largest population of microbes that interact with the host to maintain human health and diseases. Furthermore, the gut is known as the largest endocrine gland, secreting over 100 peptides and other molecules that act as signaling molecules to regulate human nutrition and physiology. Among these gut-derived hormones, glucagon-like peptide 1 (GLP-1) and -2 have received the most attention due to their critical role in intestinal function and food absorption as well as their application as key drug targets. In this review, we highlight the current state of the literature that has brought into light the importance of GLP-1 and GLP-2 in orchestrating intestine-microbiota-immune system crosstalk to maintain intestinal barrier integrity, inflammation, and metabolic homeostasis.
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Affiliation(s)
- Nyan Abdalqadir
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1H3, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biology, College of Science, University of Sulaimani, Sulaymaniyah 46001, Iraq
| | - Khosrow Adeli
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1H3, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
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18
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Yu L, Li Y. Involvement of Intestinal Enteroendocrine Cells in Neurological and Psychiatric Disorders. Biomedicines 2022; 10:biomedicines10102577. [PMID: 36289839 PMCID: PMC9599815 DOI: 10.3390/biomedicines10102577] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/21/2022] [Accepted: 09/21/2022] [Indexed: 11/24/2022] Open
Abstract
Neurological and psychiatric patients have increased dramatically in number in the past few decades. However, effective treatments for these diseases and disorders are limited due to heterogeneous and unclear pathogenic mechanisms. Therefore, further exploration of the biological aspects of the disease, and the identification of novel targets to develop alternative treatment strategies, is urgently required. Systems-level investigations have indicated the potential involvement of the brain–gut axis and intestinal microbiota in the pathogenesis and regulation of neurological and psychiatric disorders. While intestinal microbiota is crucial for maintaining host physiology, some important sensory and regulatory cells in the host should not be overlooked. Intestinal epithelial enteroendocrine cells (EECs) residing in the epithelium throughout intestine are the key regulators orchestrating the communication along the brain-gut-microbiota axis. On one hand, EECs sense changes in luminal microorganisms via microbial metabolites; on the other hand, they communicate with host body systems via neuroendocrine molecules. Therefore, EECs are believed to play important roles in neurological and psychiatric disorders. This review highlights the involvement of EECs and subtype cells, via secretion of endocrine molecules, in the development and regulation of neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, visceral pain, neuropathic pain, and depression. Moreover, the current paper summarizes the potential mechanism of EECs in contributing to disease pathogenesis. Examination of these mechanisms may inspire and lead to the development of new aspects of treatment strategies for neurological and psychiatric disorders in the future.
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Affiliation(s)
- Liangen Yu
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716, USA
| | - Yihang Li
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716, USA
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Correspondence:
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19
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Okumura T, Nozu T, Ishioh M, Igarashi S, Funayama T, Kumei S, Ohhira M. Oxytocin acts centrally in the brain to improve leaky gut through the vagus nerve and a cannabinoid signaling in rats. Physiol Behav 2022; 254:113914. [PMID: 35839845 DOI: 10.1016/j.physbeh.2022.113914] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 10/17/2022]
Abstract
Brain oxytocin plays a role in gastrointestinal functions. Among them, oxytocin acts centrally to modulate gastrointestinal motility and visceral sensation. Intestinal barrier function, one of important gut functions, is also regulated by the central nervous system. Little is, however, known about a role of central oxytocin in the regulation of intestinal barrier function. The present study was performed to clarify whether brain oxytocin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of oxytocin dose-dependently abolished increased colonic permeability in response to lipopolysaccharide while intraperitoneal injection of oxytocin at the same dose failed to block it. Either atropine or surgical vagotomy blocked the central oxytocin-induced improvement of colonic hyperpermeability. Cannabinoid 1 receptor antagonist but not adenosine or opioid receptor antagonist prevented the central oxytocin-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of oxytocin receptor antagonist blocked the ghrelin- or orexin-induced improvement of intestinal barrier function. These results suggest that oxytocin acts centrally in the brain to reduce colonic hyperpermeability. The vagal cholinergic pathway or cannabinoid 1 receptor signaling plays a vital role in the process. The oxytocin-induced improvement of colonic hyperpermeability mediates the central ghrelin- or orexin-induced improvement of intestinal barrier function. We would therefore suggest that activation of central oxytocin signaling may be useful for leaky gut-related diseases such as irritable bowel syndrome and autism.
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Affiliation(s)
- Toshikatsu Okumura
- Division of Metabolism, Asahikawa Medical University, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Masatomo Ishioh
- Division of Metabolism, Asahikawa Medical University, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Sho Igarashi
- Division of Metabolism, Asahikawa Medical University, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Takuya Funayama
- Division of Metabolism, Asahikawa Medical University, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Shima Kumei
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Masumi Ohhira
- Department of General Medicine, Asahikawa Medical University, Japan
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20
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Bischoff SC, Barazzoni R, Busetto L, Campmans‐Kuijpers M, Cardinale V, Chermesh I, Eshraghian A, Kani HT, Khannoussi W, Lacaze L, Léon‐Sanz M, Mendive JM, Müller MW, Ockenga J, Tacke F, Thorell A, Vranesic Bender D, Weimann A, Cuerda C. European guideline on obesity care in patients with gastrointestinal and liver diseases - Joint European Society for Clinical Nutrition and Metabolism / United European Gastroenterology guideline. United European Gastroenterol J 2022; 10:663-720. [PMID: 35959597 PMCID: PMC9486502 DOI: 10.1002/ueg2.12280] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Patients with chronic gastrointestinal (GI) disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean GI patients. The present guideline addresses this question according to current knowledge and evidence. OBJECTIVE The objective of the guideline is to give advice to all professionals working in the field of gastroenterology care including physicians, surgeons, dietitians and others how to handle patients with GI disease and obesity. METHODS The present guideline was developed according to the standard operating procedure for European Society for Clinical Nutrition and Metabolism guidelines, following the Scottish Intercollegiate Guidelines Network grading system (A, B, 0, and good practice point [GPP]). The procedure included an online voting (Delphi) and a final consensus conference. RESULTS In 100 recommendations (3x A, 33x B, 24x 0, 40x GPP, all with a consensus grade of 90% or more) care of GI patients with obesity - including sarcopenic obesity - is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially fatty liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician. CONCLUSION The present guideline offers for the first time evidence-based advice how to care for patients with chronic GI diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.
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Affiliation(s)
| | - Rocco Barazzoni
- Department of Medical, Technological and Translational SciencesUniversity of TriesteTriesteItaly
| | - Luca Busetto
- Department of MedicineUniversity of PadovaPadovaItaly
| | - Marjo Campmans‐Kuijpers
- Department of Gastroenterology and HepatologyUniversity Medical Centre GroningenGroningenThe Netherlands
| | - Vincenzo Cardinale
- Department of Medico‐Surgical Sciences and BiotechnologiesSapienza University of RomeRomeItaly
| | - Irit Chermesh
- Department of GastroenterologyRambam Health Care CampusAffiliated with Technion‐Israel Institute of TechnologyHaifaIsrael
| | - Ahad Eshraghian
- Department of Gastroenterology and HepatologyAvicenna HospitalShirazIran
| | - Haluk Tarik Kani
- Department of GastroenterologyMarmara UniversitySchool of MedicineIstanbulTurkey
| | - Wafaa Khannoussi
- Hepato‐Gastroenterology DepartmentMohammed VI University HospitalOujdaMorocco
- Laboratoire de Recherche des Maladies Digestives (LARMAD)Mohammed the First UniversityOujdaMorocco
| | - Laurence Lacaze
- Department of NutritionRennes HospitalRennesFrance
- Department of general surgeryMantes‐la‐Jolie HospitalFrance
- Department of clinical nutritionPaul Brousse‐Hospital, VillejuifFrance
| | - Miguel Léon‐Sanz
- Department of Endocrinology and NutritionUniversity Hospital Doce de OctubreMedical SchoolUniversity ComplutenseMadridSpain
| | - Juan M. Mendive
- La Mina Primary Care Academic Health Centre. Catalan Institute of Health (ICS)University of BarcelonaBarcelonaSpain
| | - Michael W. Müller
- Department of General and Visceral SurgeryRegionale Kliniken HoldingKliniken Ludwigsburg‐Bietigheim gGmbHBietigheim‐BissingenGermany
| | - Johann Ockenga
- Medizinische Klinik IIKlinikum Bremen‐MitteBremenGermany
| | - Frank Tacke
- Department of Hepatology & GastroenterologyCharité Universitätsmedizin BerlinCampus Virchow‐Klinikum and Campus Charité MitteBerlinGermany
| | - Anders Thorell
- Department of Clinical ScienceDanderyds HospitalKarolinska InstitutetStockholmSweden
- Department of SurgeryErsta HospitalStockholmSweden
| | - Darija Vranesic Bender
- Department of Internal MedicineUnit of Clinical NutritionUniversity Hospital Centre ZagrebZagrebCroatia
| | - Arved Weimann
- Department of General, Visceral and Oncological SurgerySt. George HospitalLeipzigGermany
| | - Cristina Cuerda
- Departamento de MedicinaUniversidad Complutense de MadridNutrition UnitHospital General Universitario Gregorio MarañónMadridSpain
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21
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Bischoff SC, Barazzoni R, Busetto L, Campmans-Kuijpers M, Cardinale V, Chermesh I, Eshraghian A, Kani HT, Khannoussi W, Lacaze L, Léon-Sanz M, Mendive JM, Müller MW, Ockenga J, Tacke F, Thorell A, Vranesic Bender D, Weimann A, Cuerda C. European guideline on obesity care in patients with gastrointestinal and liver diseases - Joint ESPEN/UEG guideline. Clin Nutr 2022; 41:2364-2405. [PMID: 35970666 DOI: 10.1016/j.clnu.2022.07.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 07/03/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Patients with chronic gastrointestinal (GI) disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean GI patients. The present guideline addresses this question according to current knowledge and evidence. OBJECTIVE The objective of the guideline is to give advice to all professionals working in the field of gastroenterology care including physicians, surgeons, dietitians and others how to handle patients with GI disease and obesity. METHODS The present guideline was developed according to the standard operating procedure for ESPEN guidelines, following the Scottish Intercollegiate Guidelines Network (SIGN) grading system (A, B, 0, and good practice point (GPP)). The procedure included an online voting (Delphi) and a final consensus conference. RESULTS In 100 recommendations (3x A, 33x B, 24x 0, 40x GPP, all with a consensus grade of 90% or more) care of GI patients with obesity - including sarcopenic obesity - is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially fatty liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician. CONCLUSION The present guideline offers for the first time evidence-based advice how to care for patients with chronic GI diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.
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Affiliation(s)
- Stephan C Bischoff
- Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
| | - Rocco Barazzoni
- Department of Medical, Technological and Translational Sciences, University of Trieste, Ospedale di Cattinara, Trieste, Italy.
| | - Luca Busetto
- Department of Medicine, University of Padova, Padova, Italy.
| | - Marjo Campmans-Kuijpers
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, the Netherlands.
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
| | - Irit Chermesh
- Department of Gastroenterology, Rambam Health Care Campus, Affiliated with Technion-Israel Institute of Technology, Haifa, Israel.
| | - Ahad Eshraghian
- Department of Gastroenterology and Hepatology, Avicenna Hospital, Shiraz, Iran.
| | - Haluk Tarik Kani
- Department of Gastroenterology, Marmara University, School of Medicine, Istanbul, Turkey.
| | - Wafaa Khannoussi
- Hepato-Gastroenterology Department, Mohammed VI University Hospital, Oujda, Morocco; Laboratoire de Recherche des Maladies Digestives (LARMAD), Mohammed the First University, Oujda, Morocco.
| | - Laurence Lacaze
- Department of General Surgery, Mantes-la-Jolie Hospital, Mantes-la-Jolie, France; Department of Clinical Nutrition, Paul-Brousse-Hospital, Villejuif, France.
| | - Miguel Léon-Sanz
- Department of Endocrinology and Nutrition, University Hospital Doce de Octubre, Medical School, University Complutense, Madrid, Spain.
| | - Juan M Mendive
- La Mina Primary Care Academic Health Centre, Catalan Institute of Health (ICS), University of Barcelona, Barcelona, Spain.
| | - Michael W Müller
- Department of General and Visceral Surgery, Regionale Kliniken Holding, Kliniken Ludwigsburg-Bietigheim GGmbH, Krankenhaus Bietigheim, Bietigheim-Bissingen, Germany.
| | - Johann Ockenga
- Medizinische Klinik II, Klinikum Bremen-Mitte, Bremen FRG, Bremen, Germany.
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| | - Anders Thorell
- Department of Clinical Science, Danderyds Hospital, Karolinska Institutet & Department of Surgery, Ersta Hospital, Stockholm, Sweden.
| | - Darija Vranesic Bender
- Unit of Clinical Nutrition, Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia.
| | - Arved Weimann
- Department of General, Visceral and Oncological Surgery, St. George Hospital, Leipzig, Germany.
| | - Cristina Cuerda
- Departamento de Medicina, Universidad Complutense de Madrid, Nutrition Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
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22
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Su Y, Liu N, Zhang Z, Hao L, Ma J, Yuan Y, Shi M, Liu J, Zhao Z, Zhang Z, Holscher C. Cholecystokinin and glucagon-like peptide-1 analogues regulate intestinal tight junction, inflammation, dopaminergic neurons and α-synuclein accumulation in the colon of two Parkinson's disease mouse models. Eur J Pharmacol 2022; 926:175029. [DOI: 10.1016/j.ejphar.2022.175029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/03/2022]
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23
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Nozu T, Okumura T. Pathophysiological Commonality Between Irritable Bowel Syndrome and Metabolic Syndrome: Role of Corticotropin-releasing Factor-Toll-like Receptor 4-Proinflammatory Cytokine Signaling. J Neurogastroenterol Motil 2022; 28:173-184. [PMID: 35189599 PMCID: PMC8978123 DOI: 10.5056/jnm21002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 08/26/2021] [Accepted: 10/11/2021] [Indexed: 11/20/2022] Open
Abstract
Irritable bowel syndrome (IBS) displays chronic abdominal pain with altered defecation. Most of the patients develop visceral hypersensitivity possibly resulting from impaired gut barrier and altered gut microbiota. We previously demonstrated that colonic hyperpermeability with visceral hypersensitivity in animal IBS models, which is mediated via corticotropin-releasing factor (CRF)-Toll-like receptor 4 (TLR4)-proinflammatory cytokine signaling. CRF impairs gut barrier via TLR4. Leaky gut induces bacterial translocation resulting in dysbiosis, and increases lipopolysaccharide (LPS). Activation of TLR4 by LPS increases the production of proinflammatory cytokines, which activate visceral sensory neurons to induce visceral hypersensitivity. LPS also activates CRF receptors to further increase gut permeability. Metabolic syndrome (MS) is a cluster of cardiovascular risk factors, including insulin resistance, obesity, dyslipidemia, and hypertension, and recently several researchers suggest the possibility that impaired gut barrier and dysbiosis with low-grade systemic inflammation are involved in MS. Moreover, TLR4-proinflammatory cytokine contributes to the development of insulin resistance and obesity. Thus, the existence of pathophysiological commonality between IBS and MS is expected. This review discusses the potential mechanisms of IBS and MS with reference to gut barrier and microbiota, and explores the possibility of existence of pathophysiological link between these diseases with a focus on CRF, TLR4, and proinflammatory cytokine signaling. We also review epidemiological data supporting this possibility, and discuss the potential of therapeutic application of the drugs used for MS to IBS treatment. This notion may pave the way for exploring novel therapeutic approaches for these disorders.
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Affiliation(s)
- Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.,Center for Medical Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.,Department of General Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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24
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Srikrishnaraj A, Jeong H, Brubaker PL. Complementary and antagonistic effects of combined glucagon-like peptide-2 and glucagon-like peptide-1 receptor agonist administration on parameters relevant to short bowel syndrome. JPEN J Parenter Enteral Nutr 2021; 46:1361-1370. [PMID: 34826336 DOI: 10.1002/jpen.2307] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Short Bowel Syndrome (SBS) is characterized by debilitating malabsorption requiring parenteral nutrition. The intestinotrophic glucagon-like peptide-2 receptor agonist, h[Gly2]GLP2, is currently used to treat patients with SBS. Recent evidence suggests that GLP-1 receptor agonists such as Exendin-4 (Ex4) may also be beneficial in SBS given their ability to increase intestinal growth and delay gastric emptying (GE). METHODS Intestinal growth, body weight (BW), food intake (FI), GE, gastrointestinal (GI) transit, intestinal permeability, and glucose tolerance were investigated in male and female C57/BL6 mice following vehicle, h[Gly2]GLP2 or Ex4 treatment, alone or in combination at "low", "medium", and "high" doses (0.1, 0.5, 1.0 and 0.01, 0.05, 0.1 μg/g, respectively). RESULTS Only the h[Gly2]GLP2 low/Ex4 high-dose combination increased small intestinal (SI) weight, in an additive manner, compared to vehicle and both mono-agonists (P<0.01-0.001), via increases in villus height (P<0.01) and SI length (P<0.05), respectively. This combination had no effects on BW, FI and fat, liver, spleen, heart and kidney weights, but reduced GI transit (P<0.001) compared to low-dose h[Gly2]GLP2 mono-treatment, and abrogated the inhibitory effects of high-dose Ex4 on GE (P<0.01) and of low-dose h[Gly2]GLP2 on intestinal permeability (P<0.05). Ex4-induced improvements in glucose homeostasis were maintained upon combination with h[Gly2]GLP2 (P<0.001). CONCLUSIONS These findings suggest that combining specific doses of GLP-2-based therapies and GLP-1 receptor agonists additively improves SI growth and GI transit without detrimental effects on BW, FI, GE, and glucose homeostasis, and may therefore be a useful approach to the treatment of patients with SBS. This article is protected by copyright. All rights reserved.
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Affiliation(s)
| | - Hyerin Jeong
- Departments of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Patricia L Brubaker
- Departments of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.,Departments of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada
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25
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Radbakhsh S, Atkin SL, Simental-Mendia LE, Sahebkar A. The role of incretins and incretin-based drugs in autoimmune diseases. Int Immunopharmacol 2021; 98:107845. [PMID: 34126341 DOI: 10.1016/j.intimp.2021.107845] [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: 03/10/2021] [Revised: 05/25/2021] [Accepted: 05/31/2021] [Indexed: 02/07/2023]
Abstract
Incretin hormones, including glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP), are gastrointestinal peptides secreted from enteroendocrine cells. These hormones play significant roles in many physiological processes via binding to G-protein coupled receptors (GPCRs) on different organs and tissues; one of them is the immunomodulatory effect on the immune system and its molecular components such as cytokines and chemokines. Anti-inflammatory effects of incretins and dependent molecules involving long-acting analogs and DPP4 inhibitors through regulation of T and B cell activation may attenuate autoimmune diseases caused by immune system disorders in mistakenly recognizing self as the foreign agent. In this review, we investigate incretin effects on the immune system response and the potential benefits of incretin-based therapy for treating autoimmune diseases.
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Affiliation(s)
- Shabnam Radbakhsh
- Department of Medical Biotechnology and Nanotechnology, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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26
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Hunt JE, Holst JJ, Jeppesen PB, Kissow H. GLP-1 and Intestinal Diseases. Biomedicines 2021; 9:biomedicines9040383. [PMID: 33916501 PMCID: PMC8067135 DOI: 10.3390/biomedicines9040383] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/22/2021] [Accepted: 04/01/2021] [Indexed: 12/18/2022] Open
Abstract
Accumulating evidence implicates glucagon-like peptide-1 (GLP-1) to have, beyond glucose maintenance, a beneficial role in the gastrointestinal tract. Here, we review emerging data investigating GLP-1 as a novel treatment for intestinal diseases, including inflammatory bowel diseases, short-bowel syndrome, intestinal toxicities and coeliac disease. Possible beneficial mechanisms for these diseases include GLP-1′s influence on gastric emptying, its anti-inflammatory properties and its intestinotrophic effect. The current knowledge basis derives from the available GLP-1 agonist treatments in experimental animals and small clinical trials. However, new novel strategies including dual GLP-1/GLP-2 agonists are also in development for the treatment of intestinal diseases.
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Affiliation(s)
- Jenna Elizabeth Hunt
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (J.E.H.); (J.J.H.)
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (J.E.H.); (J.J.H.)
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Palle Bekker Jeppesen
- Department of Medical Gastroenterology and Hepatology, Rigshospitalet, 2200 Copenhagen, Denmark;
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (J.E.H.); (J.J.H.)
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Correspondence:
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27
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Ishioh M, Nozu T, Igarashi S, Tanabe H, Kumei S, Ohhira M, Takakusaki K, Okumura T. Activation of central adenosine A2B receptors mediate brain ghrelin-induced improvement of intestinal barrier function through the vagus nerve in rats. Exp Neurol 2021; 341:113708. [PMID: 33771554 DOI: 10.1016/j.expneurol.2021.113708] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/15/2021] [Accepted: 03/21/2021] [Indexed: 11/16/2022]
Abstract
Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.
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Affiliation(s)
- Masatomo Ishioh
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Sho Igarashi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Hiroki Tanabe
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan
| | - Shima Kumei
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Masumi Ohhira
- Department of General Medicine, Asahikawa Medical University, Japan
| | - Kaoru Takakusaki
- Division of Neuroscience, Department of Physiology, Asahikawa Medical University, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
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28
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Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, Xue H, Liu Y, Zhang Y. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne) 2021; 12:721135. [PMID: 34497589 PMCID: PMC8419463 DOI: 10.3389/fendo.2021.721135] [Citation(s) in RCA: 182] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.
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Affiliation(s)
- Xin Zhao
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Minghe Wang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Zhitong Wen
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Zhihong Lu
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Lijuan Cui
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Chao Fu
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Huan Xue
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
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Abstract
This paper is the forty-first consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2018 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (2), the roles of these opioid peptides and receptors in pain and analgesia in animals (3) and humans (4), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (5), opioid peptide and receptor involvement in tolerance and dependence (6), stress and social status (7), learning and memory (8), eating and drinking (9), drug abuse and alcohol (10), sexual activity and hormones, pregnancy, development and endocrinology (11), mental illness and mood (12), seizures and neurologic disorders (13), electrical-related activity and neurophysiology (14), general activity and locomotion (15), gastrointestinal, renal and hepatic functions (16), cardiovascular responses (17), respiration and thermoregulation (18), and immunological responses (19).
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Affiliation(s)
- Richard J Bodnar
- Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, Flushing, NY, 11367, United States.
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30
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Nguyen M, Tavernier A, Gautier T, Aho S, Morgant MC, Bouhemad B, Guinot PG, Grober J. Glucagon-like peptide-1 is associated with poor clinical outcome, lipopolysaccharide translocation and inflammation in patients undergoing cardiac surgery with cardiopulmonary bypass. Cytokine 2020; 133:155182. [DOI: 10.1016/j.cyto.2020.155182] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/08/2020] [Accepted: 06/15/2020] [Indexed: 12/12/2022]
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31
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Cui X, Zhao X, Wang Y, Yang Y, Zhang H. Glucagon‑like peptide‑1 analogue exendin‑4 modulates serotonin transporter expression in intestinal epithelial cells. Mol Med Rep 2020; 21:1934-1940. [PMID: 32319618 PMCID: PMC7057813 DOI: 10.3892/mmr.2020.10976] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023] Open
Abstract
Serotonin-selective reuptake transporter (SERT) regulates extracellular availability of serotonin (5-hydroxytryptamine; 5-HT) and participates in the pathogenesis of functional disorders. Colonic SERT expression is decreased in colonic sensitized rats, and the glucagon-like peptide-1 analogue, exendin-4, reduces visceral hypersensitivity by decreasing 5-HT levels and increasing SERT expression. The present in vitro study aimed to further investigate the effects of exendin-4 on SERT expression, and to examine the role of GLP-1 and its receptor in the regulation of 5-HT. SERT mRNA and protein expression levels were detected by reverse transcription-quantitative PCR and western blotting. A [3H]−5-HT reuptake experiment was performed in IEC-6 rat intestinal epithelial cells treated with exendin-4. Effects on the adenosine cyclophosphate (AC)/PKA pathway were examined by variously treating cells with the AC activator forskolin, the protein kinase A (PKA) inhibitor H89 and the AC inhibitor SQ22536. Exendin-4 treatment upregulated SERT expression and enhanced 5-HT reuptake in IEC-6 cells. Also, PKA activity in IEC-6 cells was increased by both exendin-4 and forskolin, whereas these effects were abolished by the pre-treatment of exendin-9, which is a GLP-1R inhibitor, SQ22536 and H89. In conclusion, exendin-4 may be associated with the upregulation of SERT expression via the AC/PKA signaling pathway.
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Affiliation(s)
- Xiufang Cui
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xiaojing Zhao
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Ying Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yan Yang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hongjie Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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32
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Abstract
The regulation of glycemia is under a tight neuronal detection of glucose levels performed by the gut-brain axis and an efficient efferent neuronal message sent to the peripheral organs, as the pancreas to induce insulin and inhibit glucagon secretions. The neuronal detection of glucose levels is performed by the autonomic nervous system including the enteric nervous system and the vagus nerve innervating the gastro-intestinal tractus, from the mouth to the anus. A dysregulation of this detection leads to the one of the most important current health issue around the world i.e. diabetes mellitus. Furthemore, the consequences of diabetes mellitus on neuronal homeostasis and activities participate to the aggravation of the disease establishing a viscious circle. Prokaryotic cells as bacteria, reside in our gut. The strong relationship between prokaryotic cells and our eukaryotic cells has been established long ago, and prokaryotic and eukaryotic cells in our body have evolved synbiotically. For the last decades, studies demonstrated the critical role of the gut microbiota on the metabolic control and how its shift can induce diseases such as diabetes. Despite an important increase of knowledge, few is known about 1) how the gut microbiota influences the neuronal detection of glucose and 2) how the diabetes mellitus-induced gut microbiota shift observed participates to the alterations of autonomic nervous system and the gut-brain axis activity.
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Affiliation(s)
- Estelle Grasset
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345, Gothenburg, Sweden.
| | - Remy Burcelin
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France
- Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2 : 'Intestinal Risk Factors, Diabetes, Université Paul Sabatier (UPS), Dyslipidemia', F-31432, Toulouse, Cedex 4, France
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33
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Glucagon-like peptide-1 receptor activation alleviates lipopolysaccharide-induced acute lung injury in mice via maintenance of endothelial barrier function. J Transl Med 2019; 99:577-587. [PMID: 30659271 DOI: 10.1038/s41374-018-0170-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/25/2018] [Accepted: 11/08/2018] [Indexed: 11/09/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1), which is well known for regulating glucose homeostasis, exhibits multiple actions in cardiovascular disorders and renal injury. However, little is known about the effect of GLP-1 receptor (GLP-1R) activation on acute lung injury (ALI). In this study, we investigated the effect of GLP-1R on ALI and the potential underlying mechanisms with the selective agonist liraglutide. Our results show that GLP-1 levels decreased in serum, though they increased in bronchoalveolar lavage fluid (BALF) and lung tissue in a mouse model of lipopolysaccharide (LPS)-induced ALI. Liraglutide prevented LPS-induced polymorphonuclear neutrophil (PMN) extravasation, lung injury, and alveolar-capillary barrier dysfunction. In cultured human pulmonary microvascular endothelial cells (HPMECs), liraglutide protected against LPS-induced endothelial barrier injury by restoring intercellular tight junctions and adherens junctions. Moreover, liraglutide prevented PMN-endothelial adhesion by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and thereafter suppressed PMN transendothelial migration. Furthermore, liraglutide suppressed LPS-induced activation of Rho/NF-κB signaling in HPMECs. In conclusion, our results show that GLP-1R activation protects mice from LPS-induced ALI by maintaining functional endothelial barrier and inhibiting PMN extravasation. These results also suggest that GLP-1R may be a potential therapeutic target for the treatment of ALI.
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Kyriachenko Y, Falalyeyeva T, Korotkyi O, Molochek N, Kobyliak N. Crosstalk between gut microbiota and antidiabetic drug action. World J Diabetes 2019; 10:154-168. [PMID: 30891151 PMCID: PMC6422856 DOI: 10.4239/wjd.v10.i3.154] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 03/10/2019] [Accepted: 03/11/2019] [Indexed: 02/05/2023] Open
Abstract
Type 2 diabetes (T2D) is a disorder characterized by chronic inflated blood glucose levels (hyperglycemia), at first due to insulin resistance and unregulated insulin secretion but with tendency towards global spreading. The gut microbiota is recognized to have an influence on T2D, although surveys have not formed a clear overview to date. Because of the interactions between gut microbiota and host homeostasis, intestinal bacteria are believed to play a large role in various diseases, including metabolic syndrome, obesity and associated disease. In this review, we highlight the animal and human studies which have elucidated the roles of metformin, α-glucosidase inhibitors, glucagon-like peptide-1 agonists, peroxisome proliferator-activated receptors γ agonists, inhibitors of dipeptidyl peptidase-4, sodium/glucose cotransporter inhibitors, and other less studied medications on gut microbiota. This review is dedicated to one of the most widespread diseases, T2D, and the currently used antidiabetic drugs and most promising new findings. In general, the gut microbiota has been shown to have an influence on host metabolism, food consumption, satiety, glucose homoeostasis, and weight gain. Altered intestinal microbiota composition has been noticed in cardiovascular diseases, colon cancer, rheumatoid arthritis, T2D, and obesity. Therefore, the main effect of antidiabetic drugs is on the microbiome composition, basically increasing the short-chain fatty acids-producing bacteria, responsible for losing weight and suppressing inflammation.
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Affiliation(s)
- Yevheniia Kyriachenko
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Tetyana Falalyeyeva
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Oleksandr Korotkyi
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Nataliia Molochek
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Nazarii Kobyliak
- Endocrinology Department, Bogomolets National Medical University, Kyiv 01601, Ukraine
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35
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Ebbesen MS, Kissow H, Hartmann B, Grell K, Gørløv JS, Kielsen K, Holst JJ, Müller K. Glucagon-Like Peptide-1 Is a Marker of Systemic Inflammation in Patients Treated with High-Dose Chemotherapy and Autologous Stem Cell Transplantation. Biol Blood Marrow Transplant 2019; 25:1085-1091. [PMID: 30731250 DOI: 10.1016/j.bbmt.2019.01.036] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/31/2019] [Indexed: 12/12/2022]
Abstract
Autologous stem cell transplantation (ASCT) is challenged by side effects that may be propagated by chemotherapy-induced mucositis, resulting in bacterial translocation and systemic inflammation. Because gastrointestinal damage appears as an early event in this cascade of reactions, we hypothesized that markers reflecting damage to the intestinal barrier could serve as early predictive markers of toxicity. Glucagon-like peptide-1 (GLP-1), a well-known regulator of blood glucose, has been found to promote intestinal growth and repair in animal studies. We investigated fasting GLP-1 plasma levels in 66 adults undergoing ASCT for lymphoma and multiple myeloma. GLP-1 increased significantly after chemotherapy, reaching peak levels at day +7 post-transplant (median, 8 pmol/L [interquartile range, 4 to 12] before conditioning versus 10 pmol/L [interquartile range, 6 to 17] at day +7; P = .007). The magnitude of the GLP-1 increase was related to the intensity of conditioning. GLP-1 at the day of transplantation (day 0) was positively associated with peak C-reactive protein (CRP) levels (46 mg/L per GLP-1 doubling, P < .001) and increase in days with fever (32% per GLP-1 doubling, P = .0058). Patients with GLP-1 above the median at day 0 had higher CRP levels from days +3 to +10 post-transplant than patients with lower GLP-1 (P ≤ .041) with peak values of 238 versus 129 mg/L, respectively. This study, which represents the first clinical investigation of fasting GLP-1 in relation to high-dose chemotherapy, provides evidence that GLP-1 plays a role in regulation of mucosal defenses. Fasting GLP-1 levels may serve as an early predictor of systemic inflammation and fever in patients receiving high-dose chemotherapy.
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Affiliation(s)
- Maria Schou Ebbesen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
| | - Hannelouise Kissow
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Kathrine Grell
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Katrine Kielsen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; Institute for Inflammation Research, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; Institute for Inflammation Research, University Hospital Rigshospitalet, Copenhagen, Denmark
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36
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Stengel A, Taché Y. Gut-Brain Neuroendocrine Signaling Under Conditions of Stress-Focus on Food Intake-Regulatory Mediators. Front Endocrinol (Lausanne) 2018; 9:498. [PMID: 30210455 PMCID: PMC6122076 DOI: 10.3389/fendo.2018.00498] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/08/2018] [Indexed: 12/12/2022] Open
Abstract
The gut-brain axis represents a bidirectional communication route between the gut and the central nervous system comprised of neuronal as well as humoral signaling. This system plays an important role in the regulation of gastrointestinal as well as homeostatic functions such as hunger and satiety. Recent years also witnessed an increased knowledge on the modulation of this axis under conditions of exogenous or endogenous stressors. The present review will discuss the alterations of neuroendocrine gut-brain signaling under conditions of stress and the respective implications for the regulation of food intake.
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Affiliation(s)
- Andreas Stengel
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
- Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Yvette Taché
- CURE/Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- VA Greater Los Angeles Health Care System, Los Angeles, CA, United States
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37
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Olivares M, Schüppel V, Hassan AM, Beaumont M, Neyrinck AM, Bindels LB, Benítez-Páez A, Sanz Y, Haller D, Holzer P, Delzenne NM. The Potential Role of the Dipeptidyl Peptidase-4-Like Activity From the Gut Microbiota on the Host Health. Front Microbiol 2018; 9:1900. [PMID: 30186247 PMCID: PMC6113382 DOI: 10.3389/fmicb.2018.01900] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 07/27/2018] [Indexed: 12/16/2022] Open
Abstract
The Dipeptidyl peptidase-4 (DPP-4) activity influences metabolic, behavioral and intestinal disorders through the cleavage of key hormones and peptides. Some studies describe the existence of human DPP-4 homologs in commensal bacteria, for instance in Prevotella or Lactobacillus. However, the role of the gut microbiota as a source of DPP-4-like activity has never been investigated. Through the comparison of the DPP-4 activity in the cecal content of germ-free mice (GFM) and gnotobiotic mice colonized with the gut microbiota of a healthy subject, we bring the proof of concept that a significant DPP-4-like activity occurs in the microbiota. By analyzing the existing literature, we propose that DPP-4-like activity encoded by the intestinal microbiome could constitute a novel mechanism to modulate protein digestion as well as host metabolism and behavior.
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Affiliation(s)
- Marta Olivares
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Valentina Schüppel
- ZIEL Institute for Food and Health, Technical University of Munich, Freising-Weihenstephan, Germany.,Chair of Nutrition and Immunology, Technical University of Munich, Freising-Weihenstephan, Germany
| | - Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Pharmacology Section, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Martin Beaumont
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Alfonso Benítez-Páez
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain
| | - Yolanda Sanz
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain
| | - Dirk Haller
- ZIEL Institute for Food and Health, Technical University of Munich, Freising-Weihenstephan, Germany.,Chair of Nutrition and Immunology, Technical University of Munich, Freising-Weihenstephan, Germany
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Pharmacology Section, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
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38
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Holzer P, Farzi A, Hassan AM, Zenz G, Jačan A, Reichmann F. Visceral Inflammation and Immune Activation Stress the Brain. Front Immunol 2017; 8:1613. [PMID: 29213271 PMCID: PMC5702648 DOI: 10.3389/fimmu.2017.01613] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 11/07/2017] [Indexed: 12/20/2022] Open
Abstract
Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut-brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut-brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention.
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Affiliation(s)
- Peter Holzer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Geraldine Zenz
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Angela Jačan
- CBmed GmbH-Center for Biomarker Research in Medicine, Graz, Austria
| | - Florian Reichmann
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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