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Zhao X, Qiu Y, Liang L, Fu X. Interkingdom signaling between gastrointestinal hormones and the gut microbiome. Gut Microbes 2025; 17:2456592. [PMID: 39851261 PMCID: PMC11776477 DOI: 10.1080/19490976.2025.2456592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 08/12/2024] [Accepted: 01/02/2025] [Indexed: 01/26/2025] Open
Abstract
The interplay between the gut microbiota and gastrointestinal hormones plays a pivotal role in the health of the host and the development of diseases. As a vital component of the intestinal microecosystem, the gut microbiota influences the synthesis and release of many gastrointestinal hormones through mechanisms such as modulating the intestinal environment, producing metabolites, impacting mucosal barriers, generating immune and inflammatory responses, and releasing neurotransmitters. Conversely, gastrointestinal hormones exert feedback regulation on the gut microbiota by modulating the intestinal environment, nutrient absorption and utilization, and the bacterial biological behavior and composition. The distributions of the gut microbiota and gastrointestinal hormones are anatomically intertwined, and close interactions between the gut microbiota and gastrointestinal hormones are crucial for maintaining gastrointestinal homeostasis. Interventions leveraging the interplay between the gut microbiota and gastrointestinal hormones have been employed in the clinical management of metabolic diseases and inflammatory bowel diseases, such as bariatric surgery and fecal microbiota transplantation, offering promising targets for the treatment of dysbiosis-related diseases.
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Affiliation(s)
- Xinyu Zhao
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Ye Qiu
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Lanfan Liang
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Xiangsheng Fu
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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2
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Wongkrasant P, Wallace LE, MacNaughton WK, Sharkey KA. Fructooligosaccharides slow colonic motility and activate myenteric neurons via calcium sensing and 5-HT 3 receptors in the proximal colon. Am J Physiol Gastrointest Liver Physiol 2025; 328:G734-G745. [PMID: 40279204 DOI: 10.1152/ajpgi.00039.2025] [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: 02/04/2025] [Revised: 03/05/2025] [Accepted: 04/10/2025] [Indexed: 04/27/2025]
Abstract
Calcium-sensing receptors (CaSR) regulate a variety of functions in the gastrointestinal tract. Recently, prebiotic-independent effects of fructooligosaccharides (FOS) on epithelial barrier function were found to be mediated by CaSR. Here, we tested the hypothesis that FOS acts via the CaSR to regulate colonic motility and neuronal activity in the enteric nervous system. Using immunohistochemistry, we determined that CaSR were localized on the colonic epithelium of the mouse proximal colon and that a small proportion of enterochromaffin cells coexpress CaSR. We demonstrated that intraluminal administration of FOS slows colonic motility in vivo in male and female mice, an effect that is mediated by both CaSR and 5-HT3 receptors. We assessed neuronal activity in response to luminally perfused FOS in intact segments of the proximal colon from male and female mice expressing a genetically encoded fluorescent calcium reporter in intrinsic primary afferent neurons (Calb1-GCaMP6 mice) or in all enteric neurons (Wnt1-GCaMP6 mice) using live cell confocal imaging. In both Calb1-GCaMP6 mice and Wnt1-GCaMP6 mice, intraluminal FOS perfusion induced a sustained elevation of intracellular Ca2+ in neurons of the myenteric plexus. This effect was sensitive to tetrodotoxin and mediated by CaSR and 5-HT3 receptors. Serosal application of FOS was without effect. Our results demonstrate that FOS acts acutely to slow colonic motility in vivo and activates the enteric nervous system via CaSR and 5-HT3 receptors.NEW & NOTEWORTHY Calcium-sensing receptors regulate a variety of functions in the gastrointestinal tract. Here, we demonstrate a novel action of fructooligosaccharides to regulate colonic motility in vivo and activate the enteric nervous system. These effects are mediated by calcium-sensing and 5-HT3 receptors.
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Affiliation(s)
- Preedajit Wongkrasant
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Laurie E Wallace
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Wallace K MacNaughton
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keith A Sharkey
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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3
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Romaní‐Pérez M, Líebana‐García R, Flor‐Duro A, Bonillo‐Jiménez D, Bullich‐Vilarrubias C, Olivares M, Sanz Y. Obesity and the gut microbiota: implications of neuroendocrine and immune signaling. FEBS J 2025; 292:1397-1420. [PMID: 39159270 PMCID: PMC11927058 DOI: 10.1111/febs.17249] [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: 12/06/2023] [Revised: 06/29/2024] [Accepted: 08/06/2024] [Indexed: 08/21/2024]
Abstract
Obesity is a major health challenge due to its high prevalence and associated comorbidities. The excessive intake of a diet rich in fat and sugars leads to a persistent imbalance between energy intake and energy expenditure, which increases adiposity. Here, we provide an update on relevant diet-microbe-host interactions contributing to or protecting from obesity. In particular, we focus on how unhealthy diets shape the gut microbiota and thus impact crucial intestinal neuroendocrine and immune system functions. We describe how these interactions promote dysfunction in gut-to-brain neuroendocrine pathways involved in food intake control and postprandial metabolism and elevate the intestinal proinflammatory tone, promoting obesity and metabolic complications. In addition, we provide examples of how this knowledge may inspire microbiome-based interventions, such as fecal microbiota transplants, probiotics, and biotherapeutics, to effectively combat obesity-related disorders. We also discuss the current limitations and gaps in knowledge of gut microbiota research in obesity.
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Affiliation(s)
- Marina Romaní‐Pérez
- Institute of Agrochemistry and Food TechnologySpanish National Research Council (IATA‐CSIC)ValenciaSpain
| | - Rebeca Líebana‐García
- Institute of Agrochemistry and Food TechnologySpanish National Research Council (IATA‐CSIC)ValenciaSpain
| | - Alejandra Flor‐Duro
- Institute of Agrochemistry and Food TechnologySpanish National Research Council (IATA‐CSIC)ValenciaSpain
| | - Daniel Bonillo‐Jiménez
- Institute of Agrochemistry and Food TechnologySpanish National Research Council (IATA‐CSIC)ValenciaSpain
| | - Clara Bullich‐Vilarrubias
- Institute of Agrochemistry and Food TechnologySpanish National Research Council (IATA‐CSIC)ValenciaSpain
| | - Marta Olivares
- Institute of Agrochemistry and Food TechnologySpanish National Research Council (IATA‐CSIC)ValenciaSpain
| | - Yolanda Sanz
- Institute of Agrochemistry and Food TechnologySpanish National Research Council (IATA‐CSIC)ValenciaSpain
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4
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Chao J, Coleman RA, Keating DJ, Martin AM. Gut Microbiome Regulation of Gut Hormone Secretion. Endocrinology 2025; 166:bqaf004. [PMID: 40037297 PMCID: PMC11879239 DOI: 10.1210/endocr/bqaf004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Indexed: 03/06/2025]
Abstract
The gut microbiome, comprising bacteria, viruses, fungi, and bacteriophages, is one of the largest microbial ecosystems in the human body and plays a crucial role in various physiological processes. This review explores the interaction between the gut microbiome and enteroendocrine cells (EECs), specialized hormone-secreting cells within the intestinal epithelium. EECs, which constitute less than 1% of intestinal epithelial cells, are key regulators of gut-brain communication, energy metabolism, gut motility, and satiety. Recent evidence shows that gut microbiota directly influence EEC function, maturation, and hormone secretion. For instance, commensal bacteria regulate the production of hormones like glucagon-like peptide 1 and peptide YY by modulating gene expression and vesicle cycling in EE cells. Additionally, metabolites such as short-chain fatty acids, derived from microbial fermentation, play a central role in regulating EEC signaling pathways that affect metabolism, gut motility, and immune responses. Furthermore, the interplay between gut microbiota, EECs, and metabolic diseases, such as obesity and diabetes, is examined, emphasizing the microbiome's dual role in promoting health and contributing to disease states. This intricate relationship between the gut microbiome and EECs offers new insights into potential therapeutic strategies for metabolic and gut disorders.
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Affiliation(s)
- Jessica Chao
- Gut Hormones in Health and Disease Lab, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
| | - Rosemary A Coleman
- Gut Hormones in Health and Disease Lab, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
| | - Damien J Keating
- Gut Sensory Systems Group, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
| | - Alyce M Martin
- Gut Hormones in Health and Disease Lab, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
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5
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La H, Kim J, Kim DH, Kim SH, Singh P, Nam G, Moon K, Kim I, Kim IS. Discovery of 1,4-Disubstituted Cyclohexene Analogues as Selective GPR119 Agonists for the Treatment of Type 2 Diabetes. J Med Chem 2025; 68:4619-4634. [PMID: 39853173 DOI: 10.1021/acs.jmedchem.4c02655] [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: 01/26/2025]
Abstract
GPR119 has emerged as a promising target for treating type 2 diabetes and associated obesity, as its stimulation induces the secretion of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide in the intestinal tract as well as the glucose-dependent release of insulin in pancreatic β-cells. We describe the design and synthesis of novel GPR119 agonists containing a 1,4-disubstituted cyclohexene scaffold. Compound 21b displayed nanomolar potency (EC50 = 3.8 nM) for hGPR119 activation and demonstrated a hypoglycemic efficacy of 17.0% in an oral glucose tolerance test. The hypoglycemic effect of compound 21b, compared to sitagliptin, a DPP-4 inhibitor, showed the relatively higher efficacy in both FATZO and db/db mice. Additionally, compound 21b exhibited a significant reduction in body weight in a female diet-induced obese rat model, comparable to that of metformin. Furthermore, in vivo pharmacokinetic experiments revealed that compound 21b is a potential candidate for the treatment of type 2 diabetes and obesity.
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Affiliation(s)
- Hyunhwa La
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
- Medicinal Chemistry Research Team, New Drug Discovery Lab., Hyundai Pharmaceutical Co. Ltd., Suwon 16229, Republic of Korea
| | - Jinwoong Kim
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea
- Medicinal Chemistry Research Team, New Drug Discovery Lab., Hyundai Pharmaceutical Co. Ltd., Suwon 16229, Republic of Korea
| | - Dae-Hoon Kim
- Nonclinical Research Team, New Drug Discovery Lab., Hyundai Pharmaceutical Co. Ltd., Yongin 17089, Republic of Korea
| | - Seong-Heon Kim
- Medicinal Chemistry Research Team, New Drug Discovery Lab., Hyundai Pharmaceutical Co. Ltd., Suwon 16229, Republic of Korea
- Nonclinical Research Team, New Drug Discovery Lab., Hyundai Pharmaceutical Co. Ltd., Yongin 17089, Republic of Korea
| | - Pargat Singh
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Gibeom Nam
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Kyeongwon Moon
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Ikyon Kim
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea
| | - In Su Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
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6
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Zhang M, Zhu L, Zhang H, Wang X, Liu T, Wu G. Targeted discovery of pea protein-derived GLP-1-secreting peptides by CaSR activation-based molecular docking and their digestive stability. Food Chem 2025; 464:141569. [PMID: 39418954 DOI: 10.1016/j.foodchem.2024.141569] [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: 01/30/2024] [Revised: 09/11/2024] [Accepted: 10/05/2024] [Indexed: 10/19/2024]
Abstract
Dietary proteins could stimulate Glucagon-like peptide 1 (GLP-1) secretion. However, only a few food-derived GLP-1-secreting peptides have been identified. Herein, three GLP-1-secreting peptides were identified from pea protein hydrolysate (PPH) by calcium-sensing receptor (CaSR) activation-based molecular docking. PPH-triggered GLP-1 secretion was mediated by CaSR activation. A total of 4221 peptides were sequenced from PPH through peptidomic analysis. Subsequently, three GLP-1-secreting peptides, including RFY, FEPF, and FLFK, were screened by CaSR activation-based molecular docking, and peptide-induced GLP-1 secretion were mediated by CaSR activation. More importantly, FEPF and FLFK exhibited good digestive stability. The molecular docking suggested that binding energy between peptides and CaSR was negatively correlated with their ability to stimulate GLP-1 secretion, and some binding sites in CaSR, such as Asn102 and Tyr218, play a crucial role in stimulating GLP-1 secretion. Our findings suggest that the targeted discovery of pea protein-derived GLP-1-secreting peptides through CaSR activation-based molecular docking is an effective strategy.
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Affiliation(s)
- Mingkai Zhang
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - Ling Zhu
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China.
| | - Hui Zhang
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China.
| | - Xingguo Wang
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - Tongtong Liu
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - Gangcheng Wu
- National Engineering Research Center for Functional Food, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
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7
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Abdelaziz A, El-Far YM, Abdel-Rahman N. Citronellal Alleviates Insulin Resistance in High-Fat Diet/Streptozocin Model: Role of Asprosin/Olfactory Receptor Axis. Mol Nutr Food Res 2025; 69:e202400654. [PMID: 39821628 DOI: 10.1002/mnfr.202400654] [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: 08/16/2024] [Revised: 12/10/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
Ectopic olfactory receptors are expressed in nonolfactory tissues and perform diverse roles including regulation of glucose homeostasis. We explored the effect of citronellal treatment on olfactory receptor 4M1 subtype (OR4M1) signaling in insulin resistance and Type II diabetes in rats. We aimed to validate the anti-diabetic effect of citronellal through Asprosin/OR4M1 modulation. Exploring new antidiabetics and pharmacological targets is important to improve quality of life and limit complications. The model was established in Sprague-Dawley rats by a high-fat diet for 4 weeks followed by a single low-dose streptozotocin (STZ) (35 mg/kg/ip). One week after STZ injection, oral citronellal (100 mg/kg) was administered for 4 weeks. Citronellal lowered serum glucose and triglycerides and ameliorated OGTT and HOMA-IR results. Docking results revealed that citronellal blocked the Asprosin binding site at OR4M1. The hepatic expression of OR4M1 and Asprosin was reduced. Citronellal lowered cAMP levels causing attenuated levels of protein kinase A and downstream gluconeogenic enzymes: glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Citronellal also inhibited the expression of hepatic TLR-4 and inhibited JNK phosphorylation. Citronellal attenuated hepatic levels of NF-κB, p-NF-κB, and downstream proteins MCP-1 and TNF-α. These results suggest that citronellal alleviates insulin resistance by mitigating Asprosin/OR4M1 and Asprosin/TLR4/JNK signaling.
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Affiliation(s)
- Aya Abdelaziz
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Yousra M El-Far
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Noha Abdel-Rahman
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Yoshinari Y, Nishimura T, Yoshii T, Kondo S, Tanimoto H, Kobayashi T, Matsuyama M, Niwa R. A high-protein diet-responsive gut hormone regulates behavioral and metabolic optimization in Drosophila melanogaster. Nat Commun 2024; 15:10819. [PMID: 39737959 PMCID: PMC11685984 DOI: 10.1038/s41467-024-55050-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 11/27/2024] [Indexed: 01/01/2025] Open
Abstract
Protein is essential for all living organisms; however, excessive protein intake can have adverse effects, such as hyperammonemia. Although mechanisms responding to protein deficiency are well-studied, there is a significant gap in our understanding of how organisms adaptively suppress excessive protein intake. In the present study, utilizing the fruit fly, Drosophila melanogaster, we discover that the peptide hormone CCHamide1 (CCHa1), secreted by enteroendocrine cells in response to a high-protein diet (HPD), is vital for suppressing overconsumption of protein. Gut-derived CCHa1 is received by a small subset of enteric neurons that produce short neuropeptide F, thereby modulating protein-specific satiety. Importantly, impairment of the CCHa1-mediated gut-enteric neuronal axis results in ammonia accumulation and a shortened lifespan under HPD conditions. Collectively, our findings unravel the crosstalk of gut hormone and neuronal pathways that orchestrate physiological responses to prevent and adapt to dietary protein overload.
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Affiliation(s)
- Yuto Yoshinari
- Metabolic Regulation and Genetics, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8577, Japan.
| | - Takashi Nishimura
- Metabolic Regulation and Genetics, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
| | - Taishi Yoshii
- Graduate School of Environmental, Life, Natural Science and Technology, Okayama University, Okayama, Japan
| | - Shu Kondo
- Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo, Japan
- Invertebrate Genetics Laboratory, National Institute of Genetics, Mishima, Japan
| | - Hiromu Tanimoto
- Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Tomoe Kobayashi
- Division of Molecular Genetics, Shigei Medical Research Institute, Okayama, Japan
| | - Makoto Matsuyama
- Division of Molecular Genetics, Shigei Medical Research Institute, Okayama, Japan
| | - Ryusuke Niwa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8577, Japan.
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Conley JM, Jochim A, Evans-Molina C, Watts VJ, Ren H. G Protein-Coupled Receptor 17 Inhibits Glucagon-like Peptide-1 Secretion via a Gi/o-Dependent Mechanism in Enteroendocrine Cells. Biomolecules 2024; 15:9. [PMID: 39858405 PMCID: PMC11762167 DOI: 10.3390/biom15010009] [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: 11/25/2024] [Revised: 12/22/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025] Open
Abstract
Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. However, the GPR17-mediated molecular signaling pathways in EECs have yet to be fully deciphered. Here, we expressed the human GPR17 long isoform (hGPR17L) in GLUTag cells, a murine EEC line, and we used the GPR17 synthetic agonist MDL29,951 together with pharmacological probes and genetic approaches to quantitatively assess the contribution of GPR17 signaling to GLP-1 secretion. Constitutive hGPR17L activity inhibited GLP-1 secretion, and MDL29,951 treatment further inhibited this secretion, which was attenuated by treatment with the GPR17 antagonist HAMI3379. MDL29,951 promoted both Gi/o and Gq protein coupling to mediate cyclic AMP (cAMP) and calcium signaling. hGPR17L regulation of GLP-1 secretion appeared to be Gq-independent and dependent upon Gi/o signaling, but was not correlated with MDL29,951-induced whole-cell cAMP signaling. Our studies revealed key signaling mechanisms underlying the role of GPR17 in regulating GLP-1 secretion and suggest future opportunities for pharmacologically targeting GPR17 with inverse agonists to maximize GLP-1 secretion.
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Affiliation(s)
- Jason M. Conley
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (J.M.C.); (A.J.); (C.E.-M.)
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Alexander Jochim
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (J.M.C.); (A.J.); (C.E.-M.)
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Carmella Evans-Molina
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (J.M.C.); (A.J.); (C.E.-M.)
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Val J. Watts
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA;
| | - Hongxia Ren
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (J.M.C.); (A.J.); (C.E.-M.)
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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10
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Conley JM, Jochim A, Evans-Molina C, Watts VJ, Ren H. G protein-coupled receptor 17 inhibits glucagon-like peptide-1 secretion via a Gi/o-dependent mechanism in enteroendocrine cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.13.623413. [PMID: 39605686 PMCID: PMC11601441 DOI: 10.1101/2024.11.13.623413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. However, the GPR17-mediated molecular signaling pathways in EECs have yet to be fully deciphered. Here, we expressed the human GPR17 long isoform (hGPR17L) in GLUTag cells, a murine EEC line, and we used the GPR17 synthetic agonist MDL29,951 together with pharmacological probes and genetic approaches to quantitatively assess the contribution of GPR17 signaling to GLP-1 secretion. Constitutive hGPR17L activity inhibited GLP-1 secretion, and MDL29,951 treatment further inhibited this secretion, which was attenuated by treatment with the GPR17 antagonist HAMI3379. MDL29,951 promoted both Gi/o and Gq protein coupling to mediate cyclic AMP (cAMP) and calcium signaling. hGPR17L regulation of GLP-1 secretion was Gq-independent and dependent upon Gi/o signaling, but was not correlated with MDL29,951-induced whole-cell cAMP signaling. Our studies revealed key signaling mechanisms underlying the role of GPR17 in regulating GLP-1 secretion and suggest future opportunities for pharmacologically targeting GPR17 with inverse agonists to maximize GLP-1 secretion.
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Affiliation(s)
- Jason M. Conley
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Alexander Jochim
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Carmella Evans-Molina
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
- Roudebush VA Medical Center, Indianapolis, IN 46202
| | - Val J. Watts
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907
| | - Hongxia Ren
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202
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11
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Oteng AB, Liu L, Cui Y, Gavrilova O, Lu H, Chen M, Weinstein LS, Campbell JE, Lewis JE, Gribble FM, Reimann F, Wess J. Activation of Gs signaling in mouse enteroendocrine K cells greatly improves obesity- and diabetes-related metabolic deficits. J Clin Invest 2024; 134:e182325. [PMID: 39436694 DOI: 10.1172/jci182325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 10/15/2024] [Indexed: 10/25/2024] Open
Abstract
Following a meal, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the 2 major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L and K cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K cells. GPCRs couple to 1 or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the α-subunit of Gs, selectively in K cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K cell-specific Gnas-KO mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.
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Affiliation(s)
- Antwi-Boasiako Oteng
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
- Center for Research on Genomics and Global Health (CRGGH), National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA
| | - Liu Liu
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
| | - Yinghong Cui
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
| | | | - Huiyan Lu
- Mouse Transgenic Core Facility, NIDDK, NIH, Bethesda, Maryland, USA
| | - Min Chen
- Signal Transduction Section, Metabolic Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
| | - Lee S Weinstein
- Signal Transduction Section, Metabolic Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Jo E Lewis
- MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Fiona M Gribble
- MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Frank Reimann
- MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Jürgen Wess
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
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12
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McRae AN, Ticho AL, Liu Y, Ricardo-Silgado ML, Mangena NN, Jassir FF, Gonzalez-Izundegui D, Calderon G, Rohakhtar FR, Simon V, Li Y, Leggett C, Hurtado D, LaRusso N, Acosta AJ. Regulator of G-protein signaling expression in human intestinal enteroendocrine cells and potential role in satiety hormone secretion in health and obesity. EBioMedicine 2024; 107:105283. [PMID: 39142076 PMCID: PMC11367526 DOI: 10.1016/j.ebiom.2024.105283] [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: 03/02/2023] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Gut L-type enteroendocrine cells (EECs) are intestinal chemosensory cells that secrete satiety hormones GLP-1 and PYY in response to activation of G-protein coupled receptors (GPCRs) by luminal components of nutrient digestion and microbial fermentation. Regulator of G-protein Signaling (RGS) proteins are negative regulators of GPCR signaling. The expression profile of RGS in EECs, and their potential role in satiety hormone secretion and obesity is unknown. METHODS Transcriptomic profiling of RGS was completed in native colonic EECs was completed using single-cell RNA sequencing (scRNA-Seq) in lean and obesity, and human jejunal EECs with data obtained from a publicly available RNAseq dataset (GSE114853). RGS validation studies were completed using whole mucosal intestinal tissue obtained during endoscopy in 61 patients (n = 42 OB, n = 19 Lean); a subset of patients' postprandial plasma was assayed for GLP-1 and PYY. Ex vivo human intestinal cultures and in vitro NCI-H716 cells overexpressing RGS9 were exposed to GLP-1 secretagogues in conjunction with a nonselective RGS-inhibitor and assayed for GLP-1 secretion. FINDINGS Transcriptomic profiling of colonic and jejunal enteroendocrine cells revealed a unique RGS expression profile in EECs, and further within GLP-1+ L-type EECs. In obesity the RGS expression profile was altered in colonic EECs. Human gut RGS9 expression correlated positively with BMI and negatively with postprandial GLP-1 and PYY. RGS inhibition in human intestinal cultures increased GLP-1 release from EECs ex vivo. NCI-H716 cells overexpressing RGS9 displayed defective nutrient-stimulated GLP-1 secretion. INTERPRETATION This study introduces the expression profile of RGS in human EECs, alterations in obesity, and suggests a role for RGS proteins as modulators of GLP-1 and PYY secretion from intestinal EECs. FUNDING AA is supported by the NIH(C-Sig P30DK84567, K23 DK114460), a Pilot Award from the Mayo Clinic Center for Biomedical Discovery, and a Translational Product Development Fund from The Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice in partnership with the University of Minnesota Clinical and Translational Science Institute.
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Affiliation(s)
- Alison N McRae
- Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Alexander L Ticho
- Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yuanhang Liu
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Maria Laura Ricardo-Silgado
- Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Nothando N Mangena
- Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Fauzi Feris Jassir
- Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Daniel Gonzalez-Izundegui
- Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Gerardo Calderon
- Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Vernadette Simon
- Center for Individualized Medicine (CIM), Mayo Clinic, Rochester, MN, USA
| | - Ying Li
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Cadman Leggett
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Daniela Hurtado
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition Mayo Clinic, Jacksonville, FL, USA
| | - Nicholas LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Andres J Acosta
- Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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13
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Goy B, Berkenou J, Rothenbuhler A, Audrain C, Linglart A, Dubern B. Characterization of Digestive Manifestations in Patients with Impaired PTH/PTHrP Signaling Disorder/Pseudohypoparathyroidism. Horm Res Paediatr 2024:1-8. [PMID: 39154638 DOI: 10.1159/000539995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 06/19/2024] [Indexed: 08/20/2024] Open
Abstract
INTRODUCTION Pseudohypoparathyroidism, newly classified as inactivating PTH/PTHrP signaling disorder (iPPSD) type 2 or type 3, is a rare disease caused by defects in the GNAS imprinted gene that encodes Gsα. The most common phenotype comprises resistance to hormones binding to G protein-coupled receptors such as PTH, PTHrP, or TSH, subcutaneous ossifications, short stature, brachydactyly, and early onset obesity. Uncommon features have been described including sleep apnea, asthma, and resistance to calcitonin. At the national French reference center for rare calcium and phosphate metabolism diseases, a large cohort of patients with iPPSD type 2 and type 3 is followed. Interestingly, digestive manifestations and in particular intractable constipation were regularly reported by families of children with iPPSD type 2 or type 3. OBJECTIVE The aim of our study was therefore to specify the frequency and characteristics of digestive manifestations in children followed up for iPPSD2 or iPPSD3 in our reference center. MATERIAL AND METHODS Thirty-six patients aged between 2 and 18 years (32 followed up for iPPSD2 and 4 for iPPSD3) were included. Parents completed a specific questionnaire to assess any digestive disorders in their child. The diagnosis of constipation was established using the Bristol visual scale in the event of a score of less than 2 according to stool appearance. RESULTS Parents reported constipation through the questionnaires in 22/36 (over 60%) of the children. It was the most frequently reported digestive disorder. Among these 22 children, 19 (87%) had a Bristol score for stool shape and texture between 1 and 2 on a scale of 7, confirming constipation. Dedicated treatment had been initiated for 10 (55%) of them, yet only 3 families (16%) considered this treatment effective. Neonatal vomiting and eating disorders, such as lack of satiety or food selectivity, were also noted in 18 (50%) of patients, as was gastroesophageal reflux present in the neonatal period in 14 (40%) of children. There were no significant differences according to the type of iPPSD or patient age. CONCLUSION Our work shows for the first time that digestive manifestations, including constipation, occur frequently in children followed for iPPSD, suggesting a potential role of Gsα and G protein receptors in the digestive tract. It is well known that constipation and digestive symptoms alter quality of life. Early management is therefore essential to improve the quality of life of children followed for iPPSD. Our data need to be confirmed on a larger cohort.
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Affiliation(s)
- Bérénice Goy
- Pediatric Nutrition and Gastroenterology Department, Reference Center for Rare Disorders, PRADORT (Syndrome de PRADer-Willi et autres Obésités Rares avec Troubles du comportement alimentaire), Trousseau Hospital, AP-HP, Sorbonne University, Paris, France
| | - Jugurtha Berkenou
- AP-HP, Department of Endocrinology and Diabetology for Children and Department of Adolescent Medicine, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR and Platform of expertise for rare diseases Paris-Saclay, Paris-Saclay University Hospital, Le Kremlin-Bicêtre, France
| | - Anya Rothenbuhler
- AP-HP, Department of Endocrinology and Diabetology for Children and Department of Adolescent Medicine, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR and Platform of expertise for rare diseases Paris-Saclay, Paris-Saclay University Hospital, Le Kremlin-Bicêtre, France
| | - Christelle Audrain
- AP-HP, Department of Endocrinology and Diabetology for Children and Department of Adolescent Medicine, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR and Platform of expertise for rare diseases Paris-Saclay, Paris-Saclay University Hospital, Le Kremlin-Bicêtre, France
| | - Agnès Linglart
- AP-HP, Department of Endocrinology and Diabetology for Children and Department of Adolescent Medicine, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR and Platform of expertise for rare diseases Paris-Saclay, Paris-Saclay University Hospital, Le Kremlin-Bicêtre, France
- University Paris Saclay, INSERM, Endocrinologie et physiopathologie endocrinienne, Bicêtre Paris Saclay University Hospital, Le Kremlin-Bicêtre, France
| | - Béatrice Dubern
- Pediatric Nutrition and Gastroenterology Department, Reference Center for Rare Disorders, PRADORT (Syndrome de PRADer-Willi et autres Obésités Rares avec Troubles du comportement alimentaire), Trousseau Hospital, AP-HP, Sorbonne University, Paris, France
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14
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Palatini Jackson KM, Mhawish R, Komarnytsky S. Bitter Phytochemicals Acutely Lower Blood Glucose Levels by Inhibition of Glucose Absorption in the Gut. ENDOCRINES 2024; 5:304-322. [DOI: 10.3390/endocrines5030022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
For early hominids, frequent encounters with plant foods necessitated the ability to discern bitter poisons and adjust the activity of the gastrointestinal system in anticipation of carbohydrate-rich meals. Plants bitters were also used historically to manage a variety of metabolic and digestive disorders despite an immense structural diversity of bitter phytochemicals without a common molecular target. Our study confirms these observations in a standardized C57BL/6J prediabetic mouse model using 24 model compounds by demonstrating acute lower peak blood glucose values and improved glucose tolerance following intragastric, but not intraperitoneal, treatment. The administration of the synthetic bitter compound denatonium benzoate yielded similar results that were attenuated by co-application of the allosteric inhibitor of the bitter TAS2R receptors. We also show that these effects occur dose-dependently; associate with reduced glucose uptake, increased intracellular [Ca2+] fluxes, and enhanced GLP-1 expression; and are attenuated by the TAS2R inhibitor in the neuroendocrine STC-1 intestinal cells. These findings support the view that inhibition of glucose transport from the intestinal lumen to the blood by TAS2R bitter receptor signaling in the gut may represent a common mechanism in the acute response to oral ingestion of bitter phytochemicals.
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Affiliation(s)
| | - Reham Mhawish
- Plants for Human Health Institute, North Carolina State University, 600 Laureate Way, Kannapolis, NC 28081, USA
| | - Slavko Komarnytsky
- Plants for Human Health Institute, North Carolina State University, 600 Laureate Way, Kannapolis, NC 28081, USA
- Department of Food, Bioprocessing, and Nutrition Sciences, North Carolina State University, 400 Dan Allen Drive, Raleigh, NC 27695, USA
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15
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Gao J, Zhang S, Deng P, Wu Z, Lemaitre B, Zhai Z, Guo Z. Dietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion. Nat Commun 2024; 15:3514. [PMID: 38664401 PMCID: PMC11045819 DOI: 10.1038/s41467-024-47465-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Amino acid availability is monitored by animals to adapt to their nutritional environment. Beyond gustatory receptors and systemic amino acid sensors, enteroendocrine cells (EECs) are believed to directly percept dietary amino acids and secrete regulatory peptides. However, the cellular machinery underlying amino acid-sensing by EECs and how EEC-derived hormones modulate feeding behavior remain elusive. Here, by developing tools to specifically manipulate EECs, we find that Drosophila neuropeptide F (NPF) from mated female EECs inhibits feeding, similar to human PYY. Mechanistically, dietary L-Glutamate acts through the metabotropic glutamate receptor mGluR to decelerate calcium oscillations in EECs, thereby causing reduced NPF secretion via dense-core vesicles. Furthermore, two dopaminergic enteric neurons expressing NPFR perceive EEC-derived NPF and relay an anorexigenic signal to the brain. Thus, our findings provide mechanistic insights into how EECs assess food quality and identify a conserved mode of action that explains how gut NPF/PYY modulates food intake.
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Affiliation(s)
- Junjun Gao
- Department of Medical Genetics, School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Zhang
- Department of Medical Genetics, School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pan Deng
- State Key Laboratory of Digital Manufacturing Equipment and Technology, Huazhong University of Science and Technology, Wuhan, PR China
- Department of Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada
| | - Zhigang Wu
- State Key Laboratory of Digital Manufacturing Equipment and Technology, Huazhong University of Science and Technology, Wuhan, PR China
| | - Bruno Lemaitre
- Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Zongzhao Zhai
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan, PR China.
| | - Zheng Guo
- Department of Medical Genetics, School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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16
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Walmsley R, Chong L, Hii MW, Brown RM, Sumithran P. The effect of bariatric surgery on the expression of gastrointestinal taste receptors: A systematic review. Rev Endocr Metab Disord 2024; 25:421-446. [PMID: 38206483 PMCID: PMC10942945 DOI: 10.1007/s11154-023-09865-7] [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] [Accepted: 12/11/2023] [Indexed: 01/12/2024]
Abstract
Gastrointestinal nutrient sensing via taste receptors may contribute to weight loss, metabolic improvements, and a reduced preference for sweet and fatty foods following bariatric surgery. This review aimed to investigate the effect of bariatric surgery on the expression of oral and post-oral gastrointestinal taste receptors and associations between taste receptor alterations and clinical outcomes of bariatric surgery. A systematic review was conducted to capture data from both human and animal studies on changes in the expression of taste receptors in oral or post-oral gastrointestinal tissue following any type of bariatric surgery. Databases searched included Medline, Embase, Emcare, APA PsychInfo, Cochrane Library, and CINAHL. Two human and 21 animal studies were included. Bariatric surgery alters the quantity of many sweet, umami, and fatty acid taste receptors in the gastrointestinal tract. Changes to the expression of sweet and amino acid receptors occur most often in intestinal segments surgically repositioned more proximally, such as the alimentary limb after gastric bypass. Conversely, changes to fatty acid receptors were observed more frequently in the colon than in the small intestine. Significant heterogeneity in the methodology of included studies limited conclusions regarding the direction of change in taste receptor expression induced by bariatric surgeries. Few studies have investigated associations between taste receptor expression and clinical outcomes of bariatric surgery. As such, future studies should look to investigate the relationship between bariatric surgery-induced changes to gut taste receptor expression and function and the impact of surgery on taste preferences, food palatability, and eating behaviour.Registration code in PROSPERO: CRD42022313992.
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Affiliation(s)
- Rosalind Walmsley
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Parkville, VIC, 3052, Australia
- Department of Surgery, St Vincent's Hospital Melbourne, University of Melbourne, Victoria, Australia
| | - Lynn Chong
- Department of Surgery, St Vincent's Hospital Melbourne, University of Melbourne, Victoria, Australia
| | - Michael W Hii
- Department of Surgery, St Vincent's Hospital Melbourne, University of Melbourne, Victoria, Australia
| | - Robyn M Brown
- Department of Pharmacology and Biochemistry, University of Melbourne, Victoria, Australia
| | - Priya Sumithran
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Parkville, VIC, 3052, Australia.
- Department of Surgery, Central Clinical School, Monash University, Victoria, Australia.
- Department of Endocrinology and Diabetes, Alfred Health, Victoria, Australia.
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17
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Seong H, Song JW, Lee KH, Jang G, Shin DM, Shon WJ. Taste receptor type 1 member 3 regulates Western diet-induced male infertility. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159433. [PMID: 38007088 DOI: 10.1016/j.bbalip.2023.159433] [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: 06/20/2023] [Revised: 11/05/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023]
Abstract
Western diet (WD), characterized by a high intake of fats and sugary drinks, is a risk factor for male reproductive impairment. However, the molecular mechanisms underlying this remain unclear. Taste receptor type 1 member 3 (TAS1R3), activated by ligands of WD, is highly expressed in extra-oral tissues, particularly in the testes. Here, we investigated to determine the effects of WD intake on male reproduction and whether TAS1R3 mediates WD-induced impairment in male reproduction. Male C57BL/6 J wild-type (WT) and Tas1r3 knockout (KO) mice were fed either a normal diet and plain water (ND) or a 60 % high-fat-diet and 30 % (w/v) sucrose water (WD) for 18 weeks (n = 7-9/group). Long-term WD consumption significantly impaired sperm count, motility and testicular morphology in WT mice with marked Tas1r3 overexpression, whereas Tas1r3 KO mice were protected from WD-induced reproductive impairment. Testicular transcriptome analysis revealed downregulated AMP-activated protein kinase (AMPK) signaling and significantly elevated AMPK-targeted nuclear receptor 4A1 (Nr4a1) expression in WD-fed Tas1r3 KO mice. In vitro studies further validated that Tas1r3 knockdown in Leydig cells prevented the suppression of Nr4a1 and downstream steroidogenic genes (Star, Cyp11a1, Cyp17a1, and Hsd3b1) caused by high glucose, fructose, and palmitic acid levels, and maintained the levels of testosterone. Additionally, we analyzed the public human dataset to assess the clinical implications of our findings and confirmed a significant association between TAS1R3 and male-infertility-related diseases. Our findings suggest that TAS1R3 regulates WD-induced male reproductive impairment via the AMPK/NR4A1 signaling and can be a novel therapeutic target for male infertility.
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Affiliation(s)
- Hobin Seong
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul 08826, Republic of Korea
| | - Jae Won Song
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul 08826, Republic of Korea
| | - Keon-Hee Lee
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul 08826, Republic of Korea
| | - Goo Jang
- Department of Veterinary Clinical Science, College of Veterinary Medicine and the Research Institute of Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea; Comparative Medicine Disease Research Center, Seoul National University, Seoul 08826, Republic of Korea
| | - Dong-Mi Shin
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Human Ecology, Seoul National University, Seoul 08826, Republic of Korea.
| | - Woo-Jeong Shon
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Human Ecology, Seoul National University, Seoul 08826, Republic of Korea.
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18
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Raouf Z, Steinway SN, Scheese D, Lopez CM, Duess JW, Tsuboi K, Sampah M, Klerk D, El Baassiri M, Moore H, Tragesser C, Prindle T, Wang S, Wang M, Jang HS, Fulton WB, Sodhi CP, Hackam DJ. Colitis-Induced Small Intestinal Hypomotility Is Dependent on Enteroendocrine Cell Loss in Mice. Cell Mol Gastroenterol Hepatol 2024; 18:53-70. [PMID: 38438014 PMCID: PMC11127033 DOI: 10.1016/j.jcmgh.2024.02.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/06/2024]
Abstract
BACKGROUND & AIMS The abdominal discomfort experienced by patients with colitis may be attributable in part to the presence of small intestinal dysmotility, yet mechanisms linking colonic inflammation with small-bowel motility remain largely unexplored. We hypothesize that colitis results in small intestinal hypomotility owing to a loss of enteroendocrine cells (EECs) within the small intestine that can be rescued using serotonergic-modulating agents. METHODS Male C57BL/6J mice, as well as mice that overexpress (EECOVER) or lack (EECDEL) NeuroD1+ enteroendocrine cells, were exposed to dextran sulfate sodium (DSS) colitis (2.5% or 5% for 7 days) and small intestinal motility was assessed by 70-kilodalton fluorescein isothiocyanate-dextran fluorescence transit. EEC number and differentiation were evaluated by immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and quantitative reverse-transcriptase polymerase chain reaction. Mice were treated with the 5-hydroxytryptamine receptor 4 agonist prucalopride (5 mg/kg orally, daily) to restore serotonin signaling. RESULTS DSS-induced colitis was associated with a significant small-bowel hypomotility that developed in the absence of significant inflammation in the small intestine and was associated with a significant reduction in EEC density. EEC loss occurred in conjunction with alterations in the expression of key serotonin synthesis and transporter genes, including Tph1, Ddc, and Slc6a4. Importantly, mice overexpressing EECs revealed improved small intestinal motility, whereas mice lacking EECs had worse intestinal motility when exposed to DSS. Finally, treatment of DSS-exposed mice with the 5-hydroxytryptamine receptor 4 agonist prucalopride restored small intestinal motility and attenuated colitis. CONCLUSIONS Experimental DSS colitis induces significant small-bowel dysmotility in mice owing to enteroendocrine loss that can be reversed by genetic modulation of EEC or administering serotonin analogs, suggesting novel therapeutic approaches for patients with symptomatic colitis.
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Affiliation(s)
- Zachariah Raouf
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Steve N Steinway
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Daniel Scheese
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Carla M Lopez
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Johannes W Duess
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Koichi Tsuboi
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Maame Sampah
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Daphne Klerk
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mahmoud El Baassiri
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hannah Moore
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Cody Tragesser
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Thomas Prindle
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sanxia Wang
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Menghan Wang
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hee-Seong Jang
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - William B Fulton
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Chhinder P Sodhi
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - David J Hackam
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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19
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Rodríguez-Viso P, Domene A, Vélez D, Devesa V, Zúñiga M, Monedero V. Protective effects of oral administration of lactic acid bacteria strains against methylmercury-induced intestinal toxicity in a murine model. Food Chem Toxicol 2024; 185:114461. [PMID: 38253281 DOI: 10.1016/j.fct.2024.114461] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 01/08/2024] [Accepted: 01/14/2024] [Indexed: 01/24/2024]
Abstract
The utilization of lactic acid bacteria has been proposed to mitigate the burden of heavy metal exposure through processes probably involving chelation and reduced metal bioaccessibility. We evaluated the effects of daily intake of two strains of lactobacilli (Lactobacillus intestinalis LE1 or Lactobacillus johnsonii LE2) on intestinal toxicity during methylmercury (MeHg) exposure through drinking water (5 mg/L) for two months in mice. MeHg exposure resulted in inflammation and oxidative stress at the colon, as well as an increase in intestinal permeability accompanied by decreased fecal short-chain fatty acids (SCFA). The administration of the strains resulted in a differential protective effect that, based on their chelation capacity, supported the existence of additional mechanisms of action besides chelation. Both strains reduced IL-1β levels and oxidative stress, while LE1 lowered TNF-α, diminished MeHg-induced mucus over-secretion triggered by the IL-4/IL-13/STAT6 pathway, reduced intestinal permeability, and ameliorated inflammation and oxidative stress, probably by acting on the Keap1/Nrf2/ARE pathway. Administration of LE1 partially restored SCFA contents, which could be partly responsible for the positive effects of this strain in alleviating MeHg toxicity. These results demonstrate that lactobacilli strains can be useful tools in reducing the intestinal toxicity of MeHg, the main mercurial form conveyed by food.
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Affiliation(s)
- Pilar Rodríguez-Viso
- Instituto de Agroquímica y Tecnología de Alimentos (IATA-CSIC), Agustín Escardino 7, 46980, Paterna, (Valencia), Spain
| | - Adrián Domene
- Instituto de Agroquímica y Tecnología de Alimentos (IATA-CSIC), Agustín Escardino 7, 46980, Paterna, (Valencia), Spain
| | - Dinoraz Vélez
- Instituto de Agroquímica y Tecnología de Alimentos (IATA-CSIC), Agustín Escardino 7, 46980, Paterna, (Valencia), Spain
| | - Vicenta Devesa
- Instituto de Agroquímica y Tecnología de Alimentos (IATA-CSIC), Agustín Escardino 7, 46980, Paterna, (Valencia), Spain
| | - Manuel Zúñiga
- Instituto de Agroquímica y Tecnología de Alimentos (IATA-CSIC), Agustín Escardino 7, 46980, Paterna, (Valencia), Spain
| | - Vicente Monedero
- Instituto de Agroquímica y Tecnología de Alimentos (IATA-CSIC), Agustín Escardino 7, 46980, Paterna, (Valencia), Spain.
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Patil M, Casari I, Warne LN, Falasca M. G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype? Biomed Pharmacother 2024; 172:116245. [PMID: 38340396 DOI: 10.1016/j.biopha.2024.116245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/23/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
'Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable 'unimolecular poly-incretin-agonist' therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity.
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Affiliation(s)
- Mohan Patil
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Ilaria Casari
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Leon N Warne
- Little Green Pharma, West Perth, Western Australia 6872, Australia
| | - Marco Falasca
- University of Parma, Department of Medicine and Surgery, Via Volturno 39, 43125 Parma, Italy.
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21
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Clarke GS, Li H, Ladyman SR, Young RL, Gatford KL, Page AJ. Effect of pregnancy on the expression of nutrient-sensors and satiety hormones in mice. Peptides 2024; 172:171114. [PMID: 37926186 DOI: 10.1016/j.peptides.2023.171114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/31/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
Small intestinal satiation pathways involve nutrient-induced stimulation of chemoreceptors leading to release of satiety hormones from intestinal enteroendocrine cells (ECCs). Whether adaptations in these pathways contribute to increased maternal food intake during pregnancy is unknown. To determine the expression of intestinal nutrient-sensors and satiety hormone transcripts and proteins across pregnancy in mice. Female C57BL/6J mice (10-12 weeks old) were randomized to mating and then tissue collection at early- (6.5 d), mid- (12.5 d) or late-pregnancy (17.5 d), or to an unmated age matched control group. Relative transcript expression of intestinal fatty acid, peptide and amino acid and carbohydrate chemoreceptors, as well as gut hormones was determined across pregnancy. The density of G-protein coupled receptor 93 (GPR93), free fatty acid receptor (FFAR) 4, cholecystokinin (CCK) and glucagon-like peptide1 (GLP-1) immunopositive cells was then compared between non-pregnant and late-pregnant mice. Duodenal GPR93 expression was lower in late pregnant than non-pregnant mice (P < 0.05). Ileal FFAR1 expression was higher at mid- than at early- or late-pregnancy. Ileal FFAR2 expression was higher at mid-pregnancy than in early pregnancy. Although FFAR4 expression was consistently lower in late-pregnant than non-pregnant mice (P < 0.001), the density of FFAR4 immunopositive cells was higher in the jejunum of late-pregnant than non-pregnant mice. A subset of protein and fatty acid chemoreceptor transcripts undergo region-specific change during murine pregnancy, which could augment hormone release and contribute to increased food intake. Further investigations are needed to determine the functional relevance of these changes.
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Affiliation(s)
- Georgia S Clarke
- School of Biomedicine, The University of Adelaide, Adelaide, SA 5005, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, SAHMRI, Adelaide, SA 5000, Australia
| | - Hui Li
- School of Biomedicine, The University of Adelaide, Adelaide, SA 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, SAHMRI, Adelaide, SA 5000, Australia
| | - Sharon R Ladyman
- Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Richard L Young
- Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, SAHMRI, Adelaide, SA 5000, Australia
| | - Kathryn L Gatford
- School of Biomedicine, The University of Adelaide, Adelaide, SA 5005, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, SAHMRI, Adelaide, SA 5000, Australia
| | - Amanda J Page
- School of Biomedicine, The University of Adelaide, Adelaide, SA 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, SAHMRI, Adelaide, SA 5000, Australia.
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22
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Martemucci G, Fracchiolla G, Muraglia M, Tardugno R, Dibenedetto RS, D’Alessandro AG. Metabolic Syndrome: A Narrative Review from the Oxidative Stress to the Management of Related Diseases. Antioxidants (Basel) 2023; 12:2091. [PMID: 38136211 PMCID: PMC10740837 DOI: 10.3390/antiox12122091] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/15/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
Metabolic syndrome (MS) is a growing disorder affecting thousands of people worldwide, especially in industrialised countries, increasing mortality. Oxidative stress, hyperglycaemia, insulin resistance, inflammation, dysbiosis, abdominal obesity, atherogenic dyslipidaemia and hypertension are important factors linked to MS clusters of different pathologies, such as diabesity, cardiovascular diseases and neurological disorders. All biochemical changes observed in MS, such as dysregulation in the glucose and lipid metabolism, immune response, endothelial cell function and intestinal microbiota, promote pathological bridges between metabolic syndrome, diabesity and cardiovascular and neurodegenerative disorders. This review aims to summarise metabolic syndrome's involvement in diabesity and highlight the link between MS and cardiovascular and neurological diseases. A better understanding of MS could promote a novel strategic approach to reduce MS comorbidities.
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Affiliation(s)
- Giovanni Martemucci
- Department of Agricultural and Environmental Sciences, University of Bari Aldo Moro, 70126 Bari, Italy;
| | - Giuseppe Fracchiolla
- Department of Pharmacy–Drug Sciences, University of Bari Aldo Moro, 70126 Bari, Italy; (M.M.); (R.T.); (R.S.D.)
| | - Marilena Muraglia
- Department of Pharmacy–Drug Sciences, University of Bari Aldo Moro, 70126 Bari, Italy; (M.M.); (R.T.); (R.S.D.)
| | - Roberta Tardugno
- Department of Pharmacy–Drug Sciences, University of Bari Aldo Moro, 70126 Bari, Italy; (M.M.); (R.T.); (R.S.D.)
| | - Roberta Savina Dibenedetto
- Department of Pharmacy–Drug Sciences, University of Bari Aldo Moro, 70126 Bari, Italy; (M.M.); (R.T.); (R.S.D.)
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23
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Bany Bakar R, Reimann F, Gribble FM. The intestine as an endocrine organ and the role of gut hormones in metabolic regulation. Nat Rev Gastroenterol Hepatol 2023; 20:784-796. [PMID: 37626258 DOI: 10.1038/s41575-023-00830-y] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2023] [Indexed: 08/27/2023]
Abstract
Gut hormones orchestrate pivotal physiological processes in multiple metabolically active tissues, including the pancreas, liver, adipose tissue, gut and central nervous system, making them attractive therapeutic targets in the treatment of obesity and type 2 diabetes mellitus. Most gut hormones are derived from enteroendocrine cells, but bioactive peptides that are derived from other intestinal epithelial cell types have also been implicated in metabolic regulation and can be considered gut hormones. A deeper understanding of the complex inter-organ crosstalk mediated by the intestinal endocrine system is a prerequisite for designing more effective drugs that are based on or target gut hormones and their receptors, and extending their therapeutic potential beyond obesity and diabetes mellitus. In this Review, we present an overview of gut hormones that are involved in the regulation of metabolism and discuss their action in the gastrointestinal system and beyond.
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Affiliation(s)
- Rula Bany Bakar
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Frank Reimann
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Fiona M Gribble
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
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24
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Qi Y, Zheng T, Yang S, Zhang Q, Li B, Zeng X, Zhong Y, Chen F, Guan W, Zhang S. Maternal sodium acetate supplementation promotes lactation performance of sows and their offspring growth performance. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2023; 14:213-224. [PMID: 37484994 PMCID: PMC10362078 DOI: 10.1016/j.aninu.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 07/25/2023]
Abstract
Milk yield and composition are critical determining factors for the early growth and development of neonates. The objective of this experiment was to comprehensively evaluate the effects of dietary sodium acetate (SA) supplementation on the milk yield and composition of sows and the growth performance of their offspring. A total of 80 sows (Landrace × Yorkshire, 3 to 6 parity) were randomly assigned to 2 groups (with or without 0.1% SA) from d 85 of gestation to d 21 of lactation. The result shows that maternal 0.1% SA supplementation significantly increased sows milk yield, milk fat, immunoglobulin A (IgA) and IgG content in milk (P < 0.05), with the up-regulation of short-chain fatty acids receptors (GPR41 and GPR43) expression and the activation of mammalian target of rapamycin complex C1 (mTORC1) signaling pathway. Consistently, in our in vitro experiment, SA also activated mTORC1 signaling in porcine mammary epithelial cells (P < 0.05). Furthermore, the improvement of milk quality and quantity caused by maternal SA supplementation led to the increase in body weight (BW) and average daily weight gain (ADG) of weaning piglets, with the improvement of gut health and colonization of the beneficial bacteria (P < 0.05). In conclusion, maternal supplementation of 0.1% SA improved the lactation performance (milk yield and milk fat) of sows, possibly with the activation of GPR41/GPR43-mTORC1 signaling. Furthermore, enhanced milk quality improved growth performance, gut health and the colonization of beneficial microbial flora of their piglets.
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Affiliation(s)
- Yingao Qi
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Tenghui Zheng
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Siwang Yang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Qianzi Zhang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Baofeng Li
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
| | - Yongxing Zhong
- Chia Tai Conti Agri-Husbandry Group Co., Ltd, Shenzhen, China
| | - Fang Chen
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Wutai Guan
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Shihai Zhang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
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Besa E, Tembo MJ, Mulenga C, Mweetwa M, Choudhry N, Chandwe K, Storer C, Head R, Amadi B, Haritunians T, McGovern D, Kwenda G, Peiris M, Kelly P. Potential determinants of low circulating glucagon-like peptide 2 concentrations in Zambian children with non-responsive stunting. Exp Physiol 2023; 108:568-580. [PMID: 36744850 PMCID: PMC10103869 DOI: 10.1113/ep090492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 01/19/2023] [Indexed: 02/07/2023]
Abstract
NEW FINDINGS What is the central question of this study? Non-responsive stunting is characterised by a progressive decline of circulating glucagon-like peptide 2: what are the possible causes of this decline? What is the main finding and its importance? In contrast with the established loss of Paneth and goblet cells in environmental enteropathy, there was no evidence of a parallel loss of enteroendocrine cells as seen by positive tissue staining for chromogranin A. Transcriptomic and genomic analyses showed evidence of genetic transcripts that could account for some of the variability seen in circulating glucagon-like peptide 2 values. ABSTRACT Nutrient sensing determines digestive and hormonal responses following nutrient ingestion. We have previously reported decreased levels of glucagon-like peptide 2 (GLP-2) in children with stunting. Here we demonstrate the presence of enteroendocrine cells in stunted children and explore potential pathways that may be involved in reduced circulating levels of GLP-2. At the time of performing diagnostic endoscopies for non-responsive stunted children, intestinal biopsies were collected for immunofluorescence staining of enteroendocrine cells and transcriptomic analysis. Circulating levels of GLP-2 were also measured and correlated with transcriptomic data. An exploratory genome-wide association study (GWAS) was conducted on DNA samples (n = 158) to assess genetic contribution to GLP-2 variability. Intestinal tissue sections collected from non-responsive stunted children stained positive for chromogranin A (88/89), alongside G-protein-coupled receptors G-protein receptor 119 (75/87), free fatty acid receptor 3 (76/89) and taste 1 receptor 1 (39/45). Transcriptomic analysis found three pathways correlated with circulating GLP-2: sugar metabolism, epithelial transport, and barrier function, which likely reflect downstream events following receptor-ligand interaction. GWAS analysis revealed potential genetic contributions to GLP-2 half-life and receptor binding. Enteroendocrine cell loss was not identified in stunted Zambian children as has been observed for goblet and Paneth cells. Transcriptomic analysis suggests that GLP-2 has pleiotrophic actions on the intestinal mucosa in malnutrition, but further work is needed to dissect pathways leading to perturbations in nutrient sensing.
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Affiliation(s)
- Ellen Besa
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Mizinga Jacqueline Tembo
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Chola Mulenga
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Monica Mweetwa
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Naheed Choudhry
- Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Kanta Chandwe
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Chad Storer
- Genome Technology Access Center at McDonnell Genome InstituteWashington University in St LouisSt LouisMOUSA
| | - Richard Head
- Genome Technology Access Center at McDonnell Genome InstituteWashington University in St LouisSt LouisMOUSA
| | - Beatrice Amadi
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Talin Haritunians
- Cedars‐Sinai Medical CenterInflammatory Bowel and Immunobiology Research InstituteLos AngelesCAUSA
| | - Dermot McGovern
- Cedars‐Sinai Medical CenterInflammatory Bowel and Immunobiology Research InstituteLos AngelesCAUSA
| | - Geoffrey Kwenda
- Department of Biomedical Sciences, School of Health SciencesUniversity of ZambiaLusakaZambia
| | - Madusha Peiris
- Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Paul Kelly
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
- Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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26
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Hayashi M, Kaye JA, Douglas ER, Joshi NR, Gribble FM, Reimann F, Liberles SD. Enteroendocrine cell lineages that differentially control feeding and gut motility. eLife 2023; 12:78512. [PMID: 36810133 PMCID: PMC10032656 DOI: 10.7554/elife.78512] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Enteroendocrine cells are specialized sensory cells of the gut-brain axis that are sparsely distributed along the intestinal epithelium. The functions of enteroendocrine cells have classically been inferred by the gut hormones they release. However, individual enteroendocrine cells typically produce multiple, sometimes apparently opposing, gut hormones in combination, and some gut hormones are also produced elsewhere in the body. Here, we developed approaches involving intersectional genetics to enable selective access to enteroendocrine cells in vivo in mice. We targeted FlpO expression to the endogenous Villin1 locus (in Vil1-p2a-FlpO knock-in mice) to restrict reporter expression to intestinal epithelium. Combined use of Cre and Flp alleles effectively targeted major transcriptome-defined enteroendocrine cell lineages that produce serotonin, glucagon-like peptide 1, cholecystokinin, somatostatin, or glucose-dependent insulinotropic polypeptide. Chemogenetic activation of different enteroendocrine cell types variably impacted feeding behavior and gut motility. Defining the physiological roles of different enteroendocrine cell types provides an essential framework for understanding sensory biology of the intestine.
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Affiliation(s)
- Marito Hayashi
- Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
| | - Judith A Kaye
- Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
| | - Ella R Douglas
- Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
| | - Narendra R Joshi
- Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
| | - Fiona M Gribble
- Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Frank Reimann
- Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Stephen D Liberles
- Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
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27
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Qi Y, Zheng T, Liu X, Yang S, Li Q, Shao J, Zeng X, Guan W, Zhang S. Sodium acetate regulates milk fat synthesis through the activation of GPR41/GPR43 signaling pathway. Front Nutr 2023; 10:1098715. [PMID: 36969813 PMCID: PMC10035050 DOI: 10.3389/fnut.2023.1098715] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/26/2023] [Indexed: 02/22/2023] Open
Abstract
BackgroundFat is a critical component in milk, which provided energy for the early growth and development of mammals. Milk fat is positively related to the concentration of acetate in the blood, while the underlying mechanism is still unclear.ObjectiveThis study is to investigate the effects of sodium acetate (NaAc) on milk fat synthesis in the mammary gland, and explored the underlying mechanism.MethodsIn vitro experiments were carried out in mouse mammary epithelial cell line (HC11) cells cultured with NaAc to explore the potential pathway of NaAc on milk fat synthesis. Furthermore, 24 pregnant mice (from d 18.5 of gestation to d 7 of lactation, exposed to 200 mM NaAc drinking water) were used as an in vivo model to verify the results.ResultsIn this study, we found that NaAc promoted milk fat synthesis and the expression of related genes and proteins in HC11 mammary epithelial cells with the activation of GPCR and mTORC1 signaling pathways (p < 0.05). Pretreatment with the mTORC1 inhibitors and G protein inhibitors attenuated the NaAc-induced milk fat synthesis in HC11 mammary epithelial cells (p < 0.05). Importantly, the effect of NaAc on milk synthesis was attenuated in GPR41 and GPR43 knockdown HC11 mammary epithelial cells (p < 0.05). This evidence indicates that NaAc might regulate milk fat synthesis through the GPR41/GPR43-mTORC1 pathway. Consistently, in in vivo experiment, dietary supplementation with NaAc significantly increased milk fat content and fat synthesis-related proteins in mice mammary glands with the activation of mTORC1 and GPCR signaling pathways at peak lactation (p < 0.05).ConclusionThe addition of NaAc promoted the increase of milk fat synthesis in HC11 mammary epithelial cells and mice mammary glands at peak lactation. Mechanistically, NaAc activates GPR41 and GPR43 receptors, leading to the activation of the mTORC1 signaling pathway to promote the synthesis of milk fat.
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Affiliation(s)
- Yingao Qi
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Tenghui Zheng
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xinghong Liu
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Siwang Yang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qihui Li
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jiayuan Shao
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
| | - Wutai Guan
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Shihai Zhang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
- *Correspondence: Shihai Zhang,
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Miao ZH, Wang JN, Shen X, Zhou QQ, Luo YT, Liang HJ, Wang SJ, Qi SH, Cheng RY, He F. Long-term use of Lacticaseibacillus paracasei N1115 from early life alleviates high-fat-diet-induced obesity and dysmetabolism in mice. Benef Microbes 2022; 13:407-416. [PMID: 36239668 DOI: 10.3920/bm2021.0171] [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] [Indexed: 11/19/2022]
Abstract
Obesity has become one of the most serious public health problems worldwide, and an increasing number of studies indicate that the gut microbiota can affect host metabolism. Therefore, the present study was conducted to evaluate whether long-term use of probiotics can alleviate host obesity and metabolism by altering gut microbiota. The high-fat diet (HFD) starting from weaned period led to higher levels of visceral fat and a significantly heavier liver in male mice. Moreover, HFD resulted in disorders of glucose and lipid metabolism, changes in insulin-resistance indices (IR), and an increase in serum insulin and leptin in mice. Of note, 15 weeks use of Lacticaseibacillus paracasei N1115 decreased visceral fat, liver weight, serum levels of insulin and leptin, and IR and alleviated lipid dysmetabolism. HFD resulted in a significant increase in the relative abundance of Bilophila, Lachnoclostridium, and Blautia and may decrease the faecal short-chain fatty acid (SCFA) levels in mice; in turn, treatment with the potential probiotic strain L. paracasei N1115 protected mice from these negative effects. HFD significant impaired the physiology of the host especially in male mice and dramatically changed the composition of host gut microbiota. However, the use of potential probiotic strain, such as L. paracasei N1115, may prevent these impairments due to HFD via effecting the host gut microbiota and SCFA.
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Affiliation(s)
- Z H Miao
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, 3section, South Renmin Road, 610041 Chengdu, Sichuan, China P.R
| | - J N Wang
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, 3section, South Renmin Road, 610041 Chengdu, Sichuan, China P.R
| | - X Shen
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, 3section, South Renmin Road, 610041 Chengdu, Sichuan, China P.R
| | - Q Q Zhou
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, 3section, South Renmin Road, 610041 Chengdu, Sichuan, China P.R
| | - Y T Luo
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, 3section, South Renmin Road, 610041 Chengdu, Sichuan, China P.R
| | - H J Liang
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, 3section, South Renmin Road, 610041 Chengdu, Sichuan, China P.R
| | - S J Wang
- College of Food and Biology Hebei University of Science and Technology, 36Shitong Road, 050221 Shijiazhuang, Hebei, China P.R
| | - S H Qi
- Basic Research and Development Center, Hebei Inatrual Bio-tech Co. Ltd., Shijiazhuang, Hebei, China P.R
| | - R Y Cheng
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, 3section, South Renmin Road, 610041 Chengdu, Sichuan, China P.R
| | - F He
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, 3section, South Renmin Road, 610041 Chengdu, Sichuan, China P.R
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He Y, Su J, Gao H, Li J, Feng Z, Yin Y. Untargeted Metabolomics Reveals the Function of GPRC6A in Amino Acid and Lipid Metabolism in Mice. Metabolites 2022; 12:metabo12090776. [PMID: 36144181 PMCID: PMC9502419 DOI: 10.3390/metabo12090776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 08/22/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
GPRC6A is an amino acid sensor in the cytomembrane. Despite substantial evidence for the role of GPRC6A in metabolism, the specific effects and mechanism by which this gene acts on metabolic processes are still unresolved. In this study, serum biochemical parameters related to liver and kidney function and serum amino acid levels were determined in GPRC6A wild-type (WT) and knockout (KO) mice. An untargeted serum metabolomics analysis was also conducted for the first time, to the best of our knowledge, to decipher the function of GPRC6A in metabolic processes. GPRC6A was involved in lipid and amino acid metabolism, mainly by affecting liver function. A loss of GPRC6A function may perturb bile acid metabolism, thus leading to abnormal unsaturated fatty acid metabolism. GPRC6A KO may lead to excessive protein breakdown under starvation, and the loss of GPRC6A had a significant effect on phenylalanine metabolism-related pathways. Our metabolomics data provide a novel basis for further functional studies of GPRC6A.
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Affiliation(s)
- Yumin He
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Canter for Healthy Livestock and Poultry Production, Scientific Observational and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China(
- Animal Nutrition and Human Health Laboratory, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Jingyun Su
- Animal Nutrition and Human Health Laboratory, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Hongrui Gao
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Canter for Healthy Livestock and Poultry Production, Scientific Observational and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China(
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Jianzhong Li
- Animal Nutrition and Human Health Laboratory, College of Life Sciences, Hunan Normal University, Changsha 410081, China
- Correspondence: (J.L.); (Z.F.)
| | - Zemeng Feng
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Canter for Healthy Livestock and Poultry Production, Scientific Observational and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China(
- Correspondence: (J.L.); (Z.F.)
| | - Yulong Yin
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Canter for Healthy Livestock and Poultry Production, Scientific Observational and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China(
- Animal Nutrition and Human Health Laboratory, College of Life Sciences, Hunan Normal University, Changsha 410081, China
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Qin Z, Zhang H, Wu Q, Wei B, Wu R, Guo X, Xiao H, Wu W. Glucose-Dependent Insulinotropic Polypeptide and Substance P Mediate Emetic Response Induction by Masked Trichothecene Deoxynivalenol-3-Glucoside through Ca2+ Signaling. Toxins (Basel) 2022; 14:toxins14060371. [PMID: 35737032 PMCID: PMC9230016 DOI: 10.3390/toxins14060371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/06/2022] [Accepted: 05/07/2022] [Indexed: 02/04/2023] Open
Abstract
Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G’s emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend® restrained the induction of emesis by SP and D3G. Importantly, CaSR antagonist NPS-2143 or TRP channel antagonist ruthenium red dose-dependently inhibited both D3G-induced emesis and brain-gut peptides GIP and SP release; cotreatment with both antagonists additively suppressed both emetic and brain-gut peptide responses to D3G. To summarize, our findings demonstrate that activation of CaSR and TRP channels contributes to D3G-induced emesis by mediating brain-gut peptide exocytosis in mink.
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Affiliation(s)
- Zihui Qin
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (Z.Q.); (B.W.); (R.W.); (X.G.); (H.X.)
| | - Hua Zhang
- School of Animal Husbandry and Veterinary Medicine, Jiangsu Vocational College of Agriculture and Forestry, Jurong 212400, China;
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou 434025, China;
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Ben Wei
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (Z.Q.); (B.W.); (R.W.); (X.G.); (H.X.)
| | - Ran Wu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (Z.Q.); (B.W.); (R.W.); (X.G.); (H.X.)
| | - Xinyi Guo
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (Z.Q.); (B.W.); (R.W.); (X.G.); (H.X.)
| | - Huiping Xiao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (Z.Q.); (B.W.); (R.W.); (X.G.); (H.X.)
| | - Wenda Wu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (Z.Q.); (B.W.); (R.W.); (X.G.); (H.X.)
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003 Hradec Kralove, Czech Republic
- Correspondence:
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Zhao X, Hui Q, Azevedo P, Nyachoti CM, O K, Yang C. Calcium-sensing receptor is not expressed in the absorptive enterocytes of weaned piglets. J Anim Sci 2022; 100:6549683. [PMID: 35294536 PMCID: PMC9030235 DOI: 10.1093/jas/skac085] [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: 02/06/2022] [Accepted: 03/12/2022] [Indexed: 11/14/2022] Open
Abstract
The calcium-sensing receptor (CaSR) is a kokumi receptor that plays an essential role in nutrient sensing and animal physiology, growth, and development. Pig CaSR (pCaSR) was identified and characterized in the intestine. However, further research is still needed to confirm the expression of CaSR in the epithelial cells isolated from weaned piglets. In this study, primary enterocytes were isolated and characterized from the ileum of weaned piglets by the Weiser distended intestinal sac technique and fluorescence-activated cell sorting (FACS) based on sucrase-isomaltase (SI) as an enterocyte-specific marker. The expression of CaSR was investigated in both primary enterocytes and the intestinal porcine enterocyte cell line-j2 (IPEC-J2) by droplet digital polymerase chain reaction (ddPCR), immunofluorescence staining, and Western blotting. Results demonstrated that porcine enterocytes could be obtained using FACS with the SI as the enterocyte-specific marker and that pCaSR is not expressed in both porcine ileal enterocytes and IPEC-J2 cells, which specifically identified the expression of pCaSR in ileal enterocytes with sensitive and specific approaches.
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Affiliation(s)
- Xiaoya Zhao
- Department of Animal Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Qianru Hui
- Department of Animal Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Paula Azevedo
- Department of Animal Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | | | - Karmin O
- Department of Animal Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.,CCARM, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Chengbo Yang
- Department of Animal Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
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Mamieva Z, Poluektova E, Svistushkin V, Sobolev V, Shifrin O, Guarner F, Ivashkin V. Antibiotics, gut microbiota, and irritable bowel syndrome: What are the relations? World J Gastroenterol 2022; 28:1204-1219. [PMID: 35431513 PMCID: PMC8968486 DOI: 10.3748/wjg.v28.i12.1204] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/01/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder in which recurrent abdominal pain is associated with defecation or a change in bowel habits (constipation, diarrhea, or both), and it is often accompanied by symptoms of abdominal bloating and distension. IBS is an important health care issue because it negatively affects the quality of life of patients and places a considerable financial burden on health care systems. Despite extensive research, the etiology and underlying pathophysiology of IBS remain incompletely understood. Proposed mechanisms involved in its pathogenesis include increased intestinal permeability, changes in the immune system, visceral hypersensitivity, impaired gut motility, and emotional disorders. Recently, accumulating evidence has highlighted the important role of the gut microbiota in the development of IBS. Microbial dysbiosis within the gut is thought to contribute to all aspects of its multifactorial pathogenesis. The last few decades have also seen an increasing interest in the impact of antibiotics on the gut microbiota. Moreover, antibiotics have been suggested to play a role in the development of IBS. Extensive research has established that antibacterial therapy induces remarkable shifts in the bacterial community composition that are quite similar to those observed in IBS. This suggestion is further supported by data from cohort and case-control studies, indicating that antibiotic treatment is associated with an increased risk of IBS. This paper summarizes the main findings on this issue and contributes to a deeper understanding of the link between antibiotic use and the development of IBS.
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Affiliation(s)
- Zarina Mamieva
- Department of Internal Disease Propaedeutics, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Elena Poluektova
- Department of Internal Disease Propaedeutics, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Valery Svistushkin
- Department of Ear, Throat and Nose Diseases, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Vasily Sobolev
- Department of Ear, Throat and Nose Diseases, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Oleg Shifrin
- Department of Internal Disease Propaedeutics, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Francisco Guarner
- Digestive System Research Unit, Vall d’Hebron Research Institute, Barcelona 08035, Spain
| | - Vladimir Ivashkin
- Department of Internal Disease Propaedeutics, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
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Walker EG, Lo KR, Pahl MC, Shin HS, Lang C, Wohlers MW, Poppitt SD, Sutton KH, Ingram JR. An extract of hops (Humulus lupulus L.) modulates gut peptide hormone secretion and reduces energy intake in healthy-weight men: a randomized, crossover clinical trial. Am J Clin Nutr 2022; 115:925-940. [PMID: 35102364 DOI: 10.1093/ajcn/nqab418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 12/20/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Gastrointestinal enteroendocrine cells express chemosensory bitter taste receptors that may play an important role in regulating energy intake (EI) and gut function. OBJECTIVES To determine the effect of a bitter hop extract (Humulus lupulus L.) on acute EI, appetite, and hormonal responses. METHODS Nineteen healthy-weight men completed a randomized 3-treatment, double-blind, crossover study with a 1-wk washout between treatments. Treatments comprised either placebo or 500 mg of hop extract administered in delayed-release capsules (duodenal) at 11:00 h or quick-release capsules (gastric) at 11:30 h. Ad libitum EI was recorded at the lunch (12:00 h) and afternoon snack (14:00 h), with blood samples taken and subjective ratings of appetite, gastrointestinal (GI) discomfort, vitality, meal palatability, and mood assessed throughout the day. RESULTS Total ad libitum EI was reduced following both the gastric (4473 kJ; 95% CI: 3811, 5134; P = 0.006) and duodenal (4439 kJ; 95% CI: 3777, 5102; P = 0.004) hop treatments compared with the placebo (5383 kJ; 95% CI: 4722, 6045). Gastric and duodenal treatments stimulated prelunch ghrelin secretion and postprandial cholecystokinin, glucagon-like peptide 1, and peptide YY responses compared with placebo. In contrast, postprandial insulin, glucose-dependent insulinotropic peptide, and pancreatic polypeptide responses were reduced in gastric and duodenal treatments without affecting glycemia. In addition, gastric and duodenal treatments produced small but significant increases in subjective measures of GI discomfort (e.g., nausea, bloating, abdominal discomfort) with mild to severe adverse GI symptoms reported in the gastric treatment only. However, no significant treatment effects were observed for any subjective measures of appetite or meal palatability. CONCLUSIONS Both gastric and duodenal delivery of a hop extract modulates the release of hormones involved in appetite and glycemic regulation, providing a potential "bitter brake" on EI in healthy-weight men.
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Affiliation(s)
- Edward G Walker
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Kim R Lo
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Malcolm C Pahl
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Hyun S Shin
- Human Nutrition Unit; School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Claudia Lang
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Mark W Wohlers
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Sally D Poppitt
- Human Nutrition Unit; School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Kevin H Sutton
- The New Zealand Institute for Plant and Food Research Limited, Lincoln, New Zealand
| | - John R Ingram
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
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Petersen N, Greiner TU, Torz L, Bookout A, Gerstenberg MK, Castorena CM, Kuhre RE. Targeting the Gut in Obesity: Signals from the Inner Surface. Metabolites 2022; 12:metabo12010039. [PMID: 35050161 PMCID: PMC8778595 DOI: 10.3390/metabo12010039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/26/2021] [Accepted: 12/31/2021] [Indexed: 12/17/2022] Open
Abstract
Obesity is caused by prolonged energy surplus. Current anti-obesity medications are mostly centralized around the energy input part of the energy balance equation by increasing satiety and reducing appetite. Our gastrointestinal tract is a key organ for regulation of food intake and supplies a tremendous number of circulating signals that modulate the activity of appetite-regulating areas of the brain by either direct interaction or through the vagus nerve. Intestinally derived messengers are manifold and include absorbed nutrients, microbial metabolites, gut hormones and other enterokines, collectively comprising a fine-tuned signalling system to the brain. After a meal, nutrients directly interact with appetite-inhibiting areas of the brain and induce satiety. However, overall feeding behaviour also depends on secretion of gut hormones produced by highly specialized and sensitive enteroendocrine cells. Moreover, circulating microbial metabolites and their interactions with enteroendocrine cells further contribute to the regulation of feeding patterns. Current therapies exploiting the appetite-regulating properties of the gut are based on chemically modified versions of the gut hormone, glucagon-like peptide-1 (GLP-1) or on inhibitors of the primary GLP-1 inactivating enzyme, dipeptidyl peptidase-4 (DPP-4). The effectiveness of these approaches shows that that the gut is a promising target for therapeutic interventions to achieve significant weigh loss. We believe that increasing understanding of the functionality of the intestinal epithelium and new delivery systems will help develop selective and safe gut-based therapeutic strategies for improved obesity treatment in the future. Here, we provide an overview of the major homeostatic appetite-regulating signals generated by the intestinal epithelial cells and how these signals may be harnessed to treat obesity by pharmacological means.
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Affiliation(s)
- Natalia Petersen
- Global Obesity and Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Novo Park 1, 2670 Måløv, Denmark; (L.T.); (M.K.G.); (R.E.K.)
- Correspondence:
| | - Thomas U. Greiner
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden;
| | - Lola Torz
- Global Obesity and Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Novo Park 1, 2670 Måløv, Denmark; (L.T.); (M.K.G.); (R.E.K.)
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Angie Bookout
- Global Obesity and Liver Disease Research, Global Drug Discovery, Novo Nordisk Research Center, Seattle, WA 98109, USA; (A.B.); (C.M.C.)
| | - Marina Kjærgaard Gerstenberg
- Global Obesity and Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Novo Park 1, 2670 Måløv, Denmark; (L.T.); (M.K.G.); (R.E.K.)
| | - Carlos M. Castorena
- Global Obesity and Liver Disease Research, Global Drug Discovery, Novo Nordisk Research Center, Seattle, WA 98109, USA; (A.B.); (C.M.C.)
| | - Rune Ehrenreich Kuhre
- Global Obesity and Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Novo Park 1, 2670 Måløv, Denmark; (L.T.); (M.K.G.); (R.E.K.)
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
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Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion. Cell Rep 2022; 38:110179. [PMID: 34986353 PMCID: PMC8972502 DOI: 10.1016/j.celrep.2021.110179] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 10/01/2021] [Accepted: 12/06/2021] [Indexed: 12/20/2022] Open
Abstract
G protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention. Yan et al. locate GPR17 expression in the enteroendocrine cells of human and rodent intestinal epithelium. They find that GPR17 signaling inhibits intracellular rise of cAMP and calcium and that loss of intestinal Gpr17 in rodents leads to better glucose tolerance via increased hormone secretion in response to nutrient ingestion.
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Raybould HE, Zumpano DL. Microbial metabolites and the vagal afferent pathway in the control of food intake. Physiol Behav 2021; 240:113555. [PMID: 34375620 DOI: 10.1016/j.physbeh.2021.113555] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 07/06/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023]
Abstract
The gut microbiota is able to influence overall energy balance via effects on both energy intake and expenditure, and is a peripheral target for potential obesity therapies. However, the precise mechanism by which the gut microbiota influences energy intake and body weight regulation is not clear. Microbes use small molecules to communicate with each other; some of these molecules are ligands at mammalian receptors and this may be a mechanism by which microbes communicate with the host. Here we briefly review the literature showing beneficial effects of microbial metabolites on food intake regulation and examine the potential role for vagal afferent neurons, the gut-brain axis.
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Affiliation(s)
- Helen E Raybould
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, UC Davis, Davis, CA 95616, USA.
| | - Danielle L Zumpano
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, UC Davis, Davis, CA 95616, USA
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37
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Mazloom R. Evidence of the Physiologic Functions of the Gastrointestinal Tract as a Complex System. FOUNDATIONS OF SCIENCE 2021; 26:257-274. [DOI: 10.1007/s10699-020-09656-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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The Microbiota and the Gut-Brain Axis in Controlling Food Intake and Energy Homeostasis. Int J Mol Sci 2021; 22:ijms22115830. [PMID: 34072450 PMCID: PMC8198395 DOI: 10.3390/ijms22115830] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity currently represents a major societal and health challenge worldwide. Its prevalence has reached epidemic proportions and trends continue to rise, reflecting the need for more effective preventive measures. Hypothalamic circuits that control energy homeostasis in response to food intake are interesting targets for body-weight management, for example, through interventions that reinforce the gut-to-brain nutrient signalling, whose malfunction contributes to obesity. Gut microbiota-diet interactions might interfere in nutrient sensing and signalling from the gut to the brain, where the information is processed to control energy homeostasis. This gut microbiota-brain crosstalk is mediated by metabolites, mainly short chain fatty acids, secondary bile acids or amino acids-derived metabolites and subcellular bacterial components. These activate gut-endocrine and/or neural-mediated pathways or pass to systemic circulation and then reach the brain. Feeding time and dietary composition are the main drivers of the gut microbiota structure and function. Therefore, aberrant feeding patterns or unhealthy diets might alter gut microbiota-diet interactions and modify nutrient availability and/or microbial ligands transmitting information from the gut to the brain in response to food intake, thus impairing energy homeostasis. Herein, we update the scientific evidence supporting that gut microbiota is a source of novel dietary and non-dietary biological products that may beneficially regulate gut-to-brain communication and, thus, improve metabolic health. Additionally, we evaluate how the feeding time and dietary composition modulate the gut microbiota and, thereby, the intraluminal availability of these biological products with potential effects on energy homeostasis. The review also identifies knowledge gaps and the advances required to clinically apply microbiome-based strategies to improve the gut-brain axis function and, thus, combat obesity.
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Therapeutic potential of targeting intestinal bitter taste receptors in diabetes associated with dyslipidemia. Pharmacol Res 2021; 170:105693. [PMID: 34048925 DOI: 10.1016/j.phrs.2021.105693] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 05/23/2021] [Accepted: 05/23/2021] [Indexed: 12/19/2022]
Abstract
Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis. The impaired incretin effects observed in the pathophysiologic abnormality of type 2 diabetes have triggered the pharmacological development of incretin-based therapy through the activation of glucagon-like peptide-1 (GLP-1) receptor, including GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP4) inhibitors. In the light of the mechanisms involved in the stimulation of GLP-1 secretion, it is a fundamental question to explore whether glucose and lipid homeostasis can be manipulated by the digestive system in response to nutrient ingestion and taste perception along the gastrointestinal tract. While glucose is a potent stimulant of GLP-1 secretion, emerging evidence highlights the importance of bitter tastants in the enteroendocrine secretion of gut hormones through activation of bitter taste receptors. This review summarizes bitter chemosensation in the intestines for GLP-1 secretion and metabolic regulation based on recent advances in biological research of bitter taste receptors and preclinical and clinical investigation of bitter medicinal plants, including bitter melon, hops strobile, and berberine-containing herbs (e.g. coptis rhizome and barberry root). Multiple mechanisms of action of relevant bitter phytochemicals are discussed with the consideration of pharmacokinetic studies. Current evidence suggests that specific agonists targeting bitter taste receptors, such as human TAS2R1 and TAS2R38, may provide both metabolic benefits and anti-inflammatory effects with the modulation of the enteroendocrine hormone secretion and bile acid turnover in metabolic syndrome individuals or diabetic patients with dyslipidemia-related comorbidities.
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Tian M, Wu Z, Heng J, Chen F, Guan W, Zhang S. Novel advances in understanding fatty acid-binding G protein-coupled receptors and their roles in controlling energy balance. Nutr Rev 2021; 80:187-199. [PMID: 34027989 DOI: 10.1093/nutrit/nuab021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 01/10/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetes, obesity, and other metabolic diseases have been recognized as the main factors that endanger human health worldwide. Most of these metabolic syndromes develop when the energy balance in the body is disrupted. Energy balance depends upon the systemic regulation of food intake, glucose homeostasis, and lipid metabolism. Fatty acid-binding G protein-coupled receptors (GPCRs) are widely expressed in various types of tissues and cells involved in energy homeostasis regulation. In this review, the distribution and biological functions of fatty acid-binding GPCRs are summarized, particularly with respect to the gut, pancreas, and adipose tissue. A systematic understanding of the physiological functions of the fatty acid-binding GPCRs involved in energy homeostasis regulation will help in identifying novel pharmacological targets for metabolic diseases.
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Affiliation(s)
- Min Tian
- M. Tian, Z. Wu, J. Heng, F. Chen, W. Guan, and S. Zhang are with the Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China. F. Chen, W. Guan, and S. Zhang are with the College of Animal Science and National Engineering Research Center for Breeding Swine Industry, and the Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Zhihui Wu
- M. Tian, Z. Wu, J. Heng, F. Chen, W. Guan, and S. Zhang are with the Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China. F. Chen, W. Guan, and S. Zhang are with the College of Animal Science and National Engineering Research Center for Breeding Swine Industry, and the Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Jinghui Heng
- M. Tian, Z. Wu, J. Heng, F. Chen, W. Guan, and S. Zhang are with the Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China. F. Chen, W. Guan, and S. Zhang are with the College of Animal Science and National Engineering Research Center for Breeding Swine Industry, and the Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Fang Chen
- M. Tian, Z. Wu, J. Heng, F. Chen, W. Guan, and S. Zhang are with the Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China. F. Chen, W. Guan, and S. Zhang are with the College of Animal Science and National Engineering Research Center for Breeding Swine Industry, and the Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Wutai Guan
- M. Tian, Z. Wu, J. Heng, F. Chen, W. Guan, and S. Zhang are with the Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China. F. Chen, W. Guan, and S. Zhang are with the College of Animal Science and National Engineering Research Center for Breeding Swine Industry, and the Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
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Effect of Obesity on the Expression of Nutrient Receptors and Satiety Hormones in the Human Colon. Nutrients 2021; 13:nu13041271. [PMID: 33924402 PMCID: PMC8070384 DOI: 10.3390/nu13041271] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/07/2021] [Accepted: 04/09/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Receptors located on enteroendocrine cells (EECs) of the colon can detect nutrients in the lumen. These receptors regulate appetite through a variety of mechanisms, including hormonal and neuronal signals. We assessed the effect of obesity on the expression of these G-protein coupled receptors (GPCRs) and hormones at both mRNA and protein level. Methods: qPCR and immunohistochemistry were used to examine colonic tissue from cohorts of patients from the Netherlands (proximal and sigmoid tissue) and the United Kingdom (tissue from across the colon) and patients were grouped by body mass index (BMI) value (BMI < 25 and BMI ≥ 25). Results: The mRNA expression of the hormones/signaling molecules serotonin, glucagon, peptide YY (PYY), CCK and somatostatin were not significantly different between BMI groups. GPR40 mRNA expression was significantly increased in sigmoid colon samples in the BMI ≥ 25 group, but not proximal colon. GPR41, GPR109a, GPR43, GPR120, GPRC6A, and CaSR mRNA expression were unaltered between low and high BMI. At the protein level, serotonin and PYY containing cell numbers were similar in high and low BMI groups. Enterochromaffin cells (EC) showed high degree of co-expression with amino acid sensing receptor, CaSR while co-expression with PYY containing L-cells was limited, regardless of BMI. Conclusions: While expression of medium/long chain fatty acid receptor GPR40 was increased in the sigmoid colon of the high BMI group, expression of other nutrient sensing GPCRs, and expression profiles of EECs involved in peripheral mechanisms of appetite regulation were unchanged. Collectively, these data suggest that in human colonic tissue, EEC and nutrient-sensing receptor expression profiles are not affected despite changes to BMI.
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Yang M, Reimann F, Gribble FM. Chemosensing in enteroendocrine cells: mechanisms and therapeutic opportunities. Curr Opin Endocrinol Diabetes Obes 2021; 28:222-231. [PMID: 33449572 DOI: 10.1097/med.0000000000000614] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Enteroendocrine cells (EECs) are scattered chemosensory cells in the intestinal epithelium that release hormones with a wide range of actions on intestinal function, food intake and glucose homeostasis. The mechanisms by which gut hormones are secreted postprandially, or altered by antidiabetic agents and surgical interventions are of considerable interest for future therapeutic development. RECENT FINDINGS EECs are electrically excitable and express a repertoire of G-protein coupled receptors that sense nutrient and nonnutrient stimuli, coupled to intracellular Ca2+ and cyclic adenosine monophosphate. Our knowledge of EEC function, previously developed using mouse models, has recently been extended to human cells. Gut hormone release in humans is enhanced by bariatric surgery, as well as by some antidiabetic agents including sodium-coupled glucose transporter inhibitors and metformin. SUMMARY EECs are important potential therapeutic targets. A better understanding of their chemosensory mechanisms will enhance the development of new therapeutic strategies to treat metabolic and gastrointestinal diseases.
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Affiliation(s)
- Ming Yang
- University of Cambridge, Institute of Metabolic Science and MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Cambridge, UK
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Weber HC. Editorial: Gastrointestinal regulatory peptides. Curr Opin Endocrinol Diabetes Obes 2021; 28:196-197. [PMID: 33428343 DOI: 10.1097/med.0000000000000613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- H Christian Weber
- Section of Gastroenterology, Boston University School of Medicine
- Section of Gastroenterology and Hepatology, VA Boston Healthcare System, Boston, Massachusetts, USA
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Devaux CA, Lagier JC, Raoult D. New Insights Into the Physiopathology of COVID-19: SARS-CoV-2-Associated Gastrointestinal Illness. Front Med (Lausanne) 2021; 8:640073. [PMID: 33681266 PMCID: PMC7930624 DOI: 10.3389/fmed.2021.640073] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 01/20/2021] [Indexed: 12/17/2022] Open
Abstract
Although SARS-CoV-2 is considered a lung-tropic virus that infects the respiratory tract through binding to the ACE2 cell-surface molecules present on alveolar lungs epithelial cells, gastrointestinal symptoms have been frequently reported in COVID-19 patients. What can be considered an apparent paradox is that these symptoms (e.g., diarrhea), sometimes precede the development of respiratory tract illness as if the breathing apparatus was not its first target during viral dissemination. Recently, evidence was reported that the gut is an active site of replication for SARS-CoV-2. This replication mainly occurs in mature enterocytes expressing the ACE2 viral receptor and TMPRSS4 protease. In this review we question how SARS-CoV-2 can cause intestinal disturbances, whether there are pneumocyte-tropic, enterocyte-tropic and/or dual tropic strains of SARS-CoV-2. We examine two major models: first, that of a virus directly causing damage locally (e.g., by inducing apoptosis of infected enterocytes); secondly, that of indirect effect of the virus (e.g., by inducing changes in the composition of the gut microbiota followed by the induction of an inflammatory process), and suggest that both situations probably occur simultaneously in COVID-19 patients. We eventually discuss the consequences of the virus replication in brush border of intestine on long-distance damages affecting other tissues/organs, particularly lungs.
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Affiliation(s)
- Christian A. Devaux
- Aix-Marseille University, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
- CNRS, Marseille, France
| | - Jean-Christophe Lagier
- Aix-Marseille University, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Didier Raoult
- Aix-Marseille University, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
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Abstract
Glucagon like peptide-1 (GLP-1), a peptide hormone from the intestinal tract, plays a central role in the coordination of postprandial glucose homeostasis through actions on insulin secretion, food intake and gut motility. GLP-1 forms the basis for a variety of current drugs for the treatment of type 2 diabetes and obesity, as well as new agents currently being developed. Here, we provide a concise overview of the core physiology of GLP-1 secretion and action, and the role of the peptide in human health, disease and therapeutics.
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Affiliation(s)
- Fiona M Gribble
- Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
| | - Frank Reimann
- Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
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Wang Y, Alkhalidy H, Liu D. The Emerging Role of Polyphenols in the Management of Type 2 Diabetes. Molecules 2021; 26:molecules26030703. [PMID: 33572808 PMCID: PMC7866283 DOI: 10.3390/molecules26030703] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic β-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.
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Affiliation(s)
- Yao Wang
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA;
| | - Hana Alkhalidy
- Department of Nutrition and Food Technology, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Dongmin Liu
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA;
- Correspondence: ; Tel.: +1-540-231-3402; Fax: +1-540-231-3916
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Masetti R, Zama D, Leardini D, Muratore E, Turroni S, Brigidi P, Pession A. Microbiome-Derived Metabolites in Allogeneic Hematopoietic Stem Cell Transplantation. Int J Mol Sci 2021; 22:1197. [PMID: 33530464 PMCID: PMC7865777 DOI: 10.3390/ijms22031197] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
The gut microbiome has emerged as a major character in the context of hematopoietic stem cell transplantation. The biology underpinning this relationship is still to be defined. Recently, mounting evidence has suggested a role for microbiome-derived metabolites in mediating crosstalk between intestinal microbial communities and the host. Some of these metabolites, such as fiber-derived short-chain fatty acids or amino acid-derived compounds, were found to have a role also in the transplant setting. New interesting data have been published on this topic, posing a new intriguing perspective on comprehension and treatment. This review provides an updated comprehensive overview of the available evidence in the field of gut microbiome-derived metabolites and hematopoietic stem cell transplantation.
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Affiliation(s)
- Riccardo Masetti
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (R.M.); (D.Z.); (E.M.); (A.P.)
| | - Daniele Zama
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (R.M.); (D.Z.); (E.M.); (A.P.)
| | - Davide Leardini
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (R.M.); (D.Z.); (E.M.); (A.P.)
| | - Edoardo Muratore
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (R.M.); (D.Z.); (E.M.); (A.P.)
| | - Silvia Turroni
- Unit of Microbial Ecology of Health, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy;
| | - Patrizia Brigidi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy;
| | - Andrea Pession
- Pediatric Oncology and Hematology “Lalla Seràgnoli”, Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (R.M.); (D.Z.); (E.M.); (A.P.)
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Organ-specific, multimodal, wireless optoelectronics for high-throughput phenotyping of peripheral neural pathways. Nat Commun 2021; 12:157. [PMID: 33420038 PMCID: PMC7794361 DOI: 10.1038/s41467-020-20421-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 11/12/2020] [Indexed: 11/17/2022] Open
Abstract
The vagus nerve supports diverse autonomic functions and behaviors important for health and survival. To understand how specific components of the vagus contribute to behaviors and long-term physiological effects, it is critical to modulate their activity with anatomical specificity in awake, freely behaving conditions using reliable methods. Here, we introduce an organ-specific scalable, multimodal, wireless optoelectronic device for precise and chronic optogenetic manipulations in vivo. When combined with an advanced, coil-antenna system and a multiplexing strategy for powering 8 individual homecages using a single RF transmitter, the proposed wireless telemetry enables low cost, high-throughput, and precise functional mapping of peripheral neural circuits, including long-term behavioral and physiological measurements. Deployment of these technologies reveals an unexpected role for stomach, non-stretch vagal sensory fibers in suppressing appetite and demonstrates the durability of the miniature wireless device inside harsh gastric conditions. Advances in wireless technologies have enabled internalisation of light sources, but organ specific illumination is challenging. Here, the authors present a durable, multimodal, wireless system enabling optogenetic stimulation of peripheral neurons within organs.
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Hosseinkhani F, Heinken A, Thiele I, Lindenburg PW, Harms AC, Hankemeier T. The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases. Gut Microbes 2021; 13:1-22. [PMID: 33590776 PMCID: PMC7899087 DOI: 10.1080/19490976.2021.1882927] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 01/07/2021] [Accepted: 01/14/2021] [Indexed: 02/04/2023] Open
Abstract
The interaction disorder between gut microbiota and its host has been documented in different non-communicable diseases (NCDs) such as metabolic syndrome, neurodegenerative disease, and autoimmune disease. The majority of these altered interactions arise through metabolic cross-talk between gut microbiota and host immune system, inducing a low-grade chronic inflammation that characterizes all NCDs. In this review, we discuss the contribution of bacterial metabolites to immune signaling pathways involved in NCDs. We then review recent advances that aid to rationally design microbial therapeutics. A deeper understanding of these intersections between host and gut microbiota metabolism using metabolomics-based system biology platform promises to reveal the fundamental mechanisms that drive metabolic predispositions to disease and suggest new avenues to use microbial therapeutic opportunities for NCDs treatment and prevention. Abbreviations: NCDs: non-communicable disease, IBD: inflammatory bowel disease, IL: interleukin, T2D: type 2 diabetes, SCFAs: short-chain fatty acids, HDAC: histone deacetylases, GPCR: G-protein coupled receptors, 5-HT: 5-hydroxytryptamine receptor signaling, DCs: dendritic cells, IECs: intestinal epithelial cells, T-reg: T regulatory cell, NF-κB: nuclear factor κB, TNF-α: tumor necrosis factor alpha, Th: T helper cell, CNS: central nervous system, ECs: enterochromaffin cells, NSAIDs: non-steroidal anti-inflammatory drugs, AhR: aryl hydrocarbon receptor, IDO: indoleamine 2,3-dioxygenase, QUIN: quinolinic acid, PC: phosphatidylcholine, TMA: trimethylamine, TMAO: trimethylamine N-oxide, CVD: cardiovascular disease, NASH: nonalcoholic steatohepatitis, BAs: bile acids, FXR: farnesoid X receptor, CDCA: chenodeoxycholic acid, DCA: deoxycholic acid, LCA: lithocholic acid, UDCA: ursodeoxycholic acid, CB: cannabinoid receptor, COBRA: constraint-based reconstruction and analysis.
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Affiliation(s)
- F. Hosseinkhani
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - A. Heinken
- Division of System Biomedicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - I. Thiele
- Division of System Biomedicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - P. W. Lindenburg
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
- Research Group Metabolomics, Faculty Science & Technology, Leiden Centre for Applied Bioscience, University of Applied Sciences, Leiden, Netherlands
| | - A. C. Harms
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - T. Hankemeier
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
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Sun J, Li H, Jin Y, Yu J, Mao S, Su KP, Ling Z, Liu J. Probiotic Clostridium butyricum ameliorated motor deficits in a mouse model of Parkinson's disease via gut microbiota-GLP-1 pathway. Brain Behav Immun 2021; 91:703-715. [PMID: 33148438 DOI: 10.1016/j.bbi.2020.10.014] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 10/07/2020] [Accepted: 10/10/2020] [Indexed: 12/16/2022] Open
Abstract
A connection between gut microbiota and Parkinson's disease (PD) indicates that dysbiosis of the gut microbiota might represent a risk factor for PD. Microbiota-targeted interventions, including probiotic Clostridium butyricum (Cb), have been recently shown to have favorable effects in PD by regulating microbiota-gut-brain axis. However, the potential beneficial roles and its mechanisms of Cb on PD were still unknown. Male C57BL/6 mice were subjected to a PD model-induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and were treated intragastrically with Cb for 4 weeks. The motor functions were assessed by a series of behavioral tests including pole test, beam walking teat, forced swimming test and open field test. The dopaminergic neuron loss, synaptic plasticity and microglia activation, as well as the levels of colonic glucagon-like peptide-1 (GLP-1), colonic G protein-coupled receptors GPR41/43 and cerebral GLP-1 receptors were assessed. Gut microbial composition was assessed by 16S rRNA sequencing analysis. Our results showed that oral administration of Cb could improve motor deficits, dopaminergic neuron loss, synaptic dysfunction and microglia activation in the MPTP-induced mice. Meanwhile, Cb treatment could reverse the dysbiosis of gut microbiota and the decreased levels of colonic GLP-1, colonic GPR41/43 and cerebral GLP-1 receptor in the MPTP-induced mice. These findings indicated that the neuroprotective mechanism of Cb on PD might be related to the improvement of abnormal gut microbiota-gut-brain axis.
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Affiliation(s)
- Jing Sun
- Department of Neurology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Haijun Li
- Department of Neurology, Taizhou Second People's Hospital, Taizhou, Zhejiang 317000, China
| | - Yangjie Jin
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jiaheng Yu
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shiyin Mao
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Kuan-Pin Su
- Department of Psychiatry and Mind-Body Interface Laboratory, China Medical University Hospital, Taichung, Taiwan
| | - Zongxin Ling
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
| | - Jiaming Liu
- Department of Neurology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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