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dos Santos BLB, da Silva ACA, Severo JS, de Sousa Barbosa B, de Sousa MC, dos Santos Moreira FA, de Sousa LE, Soares HS, de Freitas AKL, Torres-Leal FL, Correia-de-Sá P, dos Santos AA, da Silva MTB. Physical Exercise Alleviates Oxidative Stress and Autonomic Dysregulation in a Rat Model of Inflammatory Bowel Disease. Antioxidants (Basel) 2025; 14:328. [PMID: 40227268 PMCID: PMC11939737 DOI: 10.3390/antiox14030328] [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: 01/23/2025] [Revised: 03/03/2025] [Accepted: 03/04/2025] [Indexed: 04/15/2025] Open
Abstract
Inflammatory bowel disease (IBD) induces immunological and autonomic imbalances. Exercise is a beneficial strategy for controlling IBD symptoms. We investigated the role of exercise on gastrointestinal (GI) motility changes and autonomic parameters in rats with ileitis. Rats were divided into control, ileitis, and exercise+ileitis groups. Ileitis was induced by TNBS (40 mM, intraileally). The exercise was swimming (1 h/day/4 weeks, 5%/bw). We assessed eating behaviour and oxidative stress. Body composition was assessed by bioimpedance. Autonomic balance and ECG parameters were measured by an electrocardiogram (ECG). Gastrointestinal motility was evaluated using the phenol red technique. In terms of body composition, total body water (TBW), body mass index (BMI), and fat-free mass (FFM) were higher in the ileitis group (216.80 ± 11.44 mL; 24.09 ± 2.15 g/cm2; 287.1 ± 14.66 g) (p < 0.05) vs. control rats (130.06 ± 28.23 mL; 16.38 ± 2.50 g/cm2; 193 ± 42.21 g) and exercise prevented (91.33 ± 12.33 mL; 11.73 ± 0.47 g/cm2; 133.8 ± 16.82 g) (p < 0.05) these changes. The exercise+ileitis group induces a reduction (p < 0.05) in gastric retention vs. ileitis and control (11.22 ± 1.91% vs. 35.17 ± 1.01% and 33.96 ± 1.77%). Ileitis increased intestinal retention in the duodenum (46.3 ± 2.56% vs. 24.98 ± 1.78%) and jejunum (34.22 ± 2.33% and 34.72 ± 2.83% vs. 47.32 ± 1.48%) (p < 0.05) and decreased intestinal retention in the ileum (p < 0.05) vs. the control group. Exercise+ileitis prevented (p < 0.05) changes in the duodenum (24.96 ± 1.66% vs. 46.3 ± 2.56%) and ileum (40.32 ± 3.75% vs. 14.08 ± 0.88%). Ileitis induces high MDA levels (p < 0.05) vs. control rats (4.43 ± 0.69 vs. 2.15 ± 0.12 nmol/mg of the tissue). This effect was prevented (p < 0.05) in the exercise+ileitis group (2.75 ± 0.21 vs. 4.43 ± 0.69 nmol/mg of the tissue). We observed a reduction in the LF component (p < 0.05) in the ileitis group vs. control group (31.32 ± 3.99 vs. 43.43 ± 3.86). The correlation indicated a stronger interrelationship between the autonomic parameter and intestinal retention in the ileum (r: 0.68; p: 0.04). The current study suggests intestinal ileitis alters GI motility and autonomic balance, and physical exercise can represent an essential non-pharmacological approach to IBD treatment.
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Affiliation(s)
- Brenda Lois Barros dos Santos
- Graduate Program in Pharmaceutical Sciences, Federal University of Piaui, Teresina 64049-550, PI, Brazil;
- Laboratory of Exercise and Gastrointestinal Tract—Department of Physical Education, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (A.C.A.d.S.); (J.S.S.); (L.E.d.S.); (H.S.S.)
| | - Alda Cássia Alves da Silva
- Laboratory of Exercise and Gastrointestinal Tract—Department of Physical Education, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (A.C.A.d.S.); (J.S.S.); (L.E.d.S.); (H.S.S.)
- Graduate Program in Pharmacology, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (B.d.S.B.); (F.A.d.S.M.); (F.L.T.-L.)
| | - Juliana Soares Severo
- Laboratory of Exercise and Gastrointestinal Tract—Department of Physical Education, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (A.C.A.d.S.); (J.S.S.); (L.E.d.S.); (H.S.S.)
- Metabolic Diseases, Exercise and Nutrition Research Group (DOMEN), Laboratory of Metabolic Diseases Glauto Tuquarre, Department of Biophysics and Physiology, Center for Health Sciences, Federal University of Piaui, Teresina 64049-550, PI, Brazil
| | - Bruno de Sousa Barbosa
- Graduate Program in Pharmacology, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (B.d.S.B.); (F.A.d.S.M.); (F.L.T.-L.)
| | - Maisa Campêlo de Sousa
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil; (M.C.d.S.); (A.K.L.d.F.); (A.A.d.S.)
| | | | - Lucas Estevão de Sousa
- Laboratory of Exercise and Gastrointestinal Tract—Department of Physical Education, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (A.C.A.d.S.); (J.S.S.); (L.E.d.S.); (H.S.S.)
| | - Heron Silva Soares
- Laboratory of Exercise and Gastrointestinal Tract—Department of Physical Education, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (A.C.A.d.S.); (J.S.S.); (L.E.d.S.); (H.S.S.)
| | - Antônio Klingem Leite de Freitas
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil; (M.C.d.S.); (A.K.L.d.F.); (A.A.d.S.)
| | - Francisco Leonardo Torres-Leal
- Graduate Program in Pharmacology, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (B.d.S.B.); (F.A.d.S.M.); (F.L.T.-L.)
- Metabolic Diseases, Exercise and Nutrition Research Group (DOMEN), Laboratory of Metabolic Diseases Glauto Tuquarre, Department of Biophysics and Physiology, Center for Health Sciences, Federal University of Piaui, Teresina 64049-550, PI, Brazil
| | - Paulo Correia-de-Sá
- Laboratory of Pharmacology and Neurobiology, (MedInUP/RISE-Health), Department of Immuno-Physiology and Pharmacology, School of Medicine and Biomedical Science—ICBAS, University of Porto, 4050-313 Porto, Portugal;
| | - Armênio Aguiar dos Santos
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil; (M.C.d.S.); (A.K.L.d.F.); (A.A.d.S.)
| | - Moisés Tolentino Bento da Silva
- Laboratory of Exercise and Gastrointestinal Tract—Department of Physical Education, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (A.C.A.d.S.); (J.S.S.); (L.E.d.S.); (H.S.S.)
- Graduate Program in Pharmacology, Federal University of Piaui, Teresina 64049-550, PI, Brazil; (B.d.S.B.); (F.A.d.S.M.); (F.L.T.-L.)
- Laboratory of Physiology, (MedInUP/RISE-Health), Department of Immuno-Physiology and Pharmacology, School of Medicine and Biomedical Science—ICBAS, University of Porto, 4050-313 Porto, Portugal
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Nakamori H, Niimi A, Mitsui R, Hashitani H. Lipopolysaccharide accelerates peristalsis by stimulating glucagon-like peptide-1 release from L cells in the rat proximal colon. J Physiol 2024; 602:4803-4820. [PMID: 39287487 DOI: 10.1113/jp286258] [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: 01/11/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
Upon epithelial barrier dysfunction, lipopolysaccharide (LPS) stimulates glucagon-like peptide-1 (GLP-1) secretion from enteroendocrine L cells by activating Toll-like receptor 4 (TLR4). Because GLP-1 accelerates peristalsis in the proximal colon, the present study aimed to explore whether LPS facilitates colonic peristalsis by stimulating L cell-derived GLP-1 release. In isolated segments of rat proximal colon that were serosally perfused with physiological salt solution and luminally perfused with 0.9% saline, peristaltic wall motion was video recorded and converted into spatio-temporal maps. Fluorescence immunohistochemistry was also carried out. Intraluminal administration of LPS (100 or 1 µg mL-1 but not 100 ng mL-1) increased the frequency of oro-aboral propagating peristaltic contractions. The LPS-induced acceleration of colonic peristalsis was blocked by TAK-242 (the TLR4 antagonist), exendin-3 (the GLP-1 receptor antagonist) or BIBN4096 (the calcitonin gene-related peptide receptor antagonist). GLP-1-positive epithelial cells co-expressed TLR4 immunoreactivity. In aspirin-pretreated preparations where epithelial barrier function had been impaired, a lower dose of LPS (100 ng mL-1) became capable of accelerating peristalsis. By contrast, luminally applied dimethyl sulphoxide, a reactive oxygen species scavenger that protects epithelial integrity, attenuated the prokinetic effects of a higher dose of LPS (100 µg mL-1). In colonic segments of a stress rat model leading to a leaky gut, LPS induced more pronounced prokinetic effects. Colonic L cells may well sense luminal LPS via TLR4 triggering the release of GLP-1 that stimulates calcitonin gene-related peptide-containing neurons. The resultant acceleration of peristalsis would facilitate excretion of Gram-negative bacteria from the intestine, and thus L cells may have a protective role against intestinal bacterial infections. KEY POINTS: Colonic epithelial cells form a barrier against bacterial invasion but also may contribute more actively to the exclusion of luminal pathogen by stimulating colonic motility. Luminal lipopolysaccharide (LPS) accelerated colonic peristalsis by stimulating calcitonin gene-related peptide-containing neurons. The prokinetic effect of LPS was mediated by the secretion of glucagon-like peptide-1 from enteroendocrine L cells in which Toll-like receptor 4 was expressed. The LPS-mediated acceleration of peristalsis depended on epithelial barrier integrity. L cells have a defensive role against Gram-negative bacterial infections by facilitating faecal excretion, and could be a potential therapeutic target for gastrointestinal infections.
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Affiliation(s)
- Hiroyuki Nakamori
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan
| | - Atsuko Niimi
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan
| | - Retsu Mitsui
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan
| | - Hikaru Hashitani
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan
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Vivacqua G, Mancinelli R, Leone S, Vaccaro R, Garro L, Carotti S, Ceci L, Onori P, Pannarale L, Franchitto A, Gaudio E, Casini A. Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders. Neurogastroenterol Motil 2024; 36:e14780. [PMID: 38462652 DOI: 10.1111/nmo.14780] [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: 07/04/2023] [Revised: 01/27/2024] [Accepted: 03/03/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND Different studies have shown the key role of endoplasmic reticulum (ER) stress in autoimmune and chronic inflammatory disorders, as well as in neurodegenerative diseases. ER stress leads to the formation of misfolded proteins which affect the secretion of different cell types that are crucial for the intestinal homeostasis. PURPOSE In this review, we discuss the role of ER stress and its involvement in the development of inflammatory bowel diseases, chronic conditions that can cause severe damage of the gastrointestinal tract, focusing on the alteration of Paneth cells and goblet cells (the principal secretory phenotypes of the intestinal epithelial cells). ER stress is also discussed in the context of neurodegenerative diseases, in which protein misfolding represents the signature mechanism. ER stress in the bowel and consequent accumulation of misfolded proteins might represent a bridge between bowel inflammation and neurodegeneration along the gut-to-brain axis, affecting intestinal epithelial homeostasis and the equilibrium of the commensal microbiota. Targeting intestinal ER stress could foster future studies for designing new biomarkers and new therapeutic approaches for neurodegenerative disorders.
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Affiliation(s)
- Giorgio Vivacqua
- Integrated Research Center (PRAAB), Campus Biomedico University of Roma, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Stefano Leone
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Rosa Vaccaro
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Ludovica Garro
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Simone Carotti
- Integrated Research Center (PRAAB), Campus Biomedico University of Roma, Rome, Italy
| | - Ludovica Ceci
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Luigi Pannarale
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome 'Foro Italico', Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Arianna Casini
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
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Lee J, Kim WK. Applications of Enteroendocrine Cells (EECs) Hormone: Applicability on Feed Intake and Nutrient Absorption in Chickens. Animals (Basel) 2023; 13:2975. [PMID: 37760373 PMCID: PMC10525316 DOI: 10.3390/ani13182975] [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: 08/14/2023] [Revised: 09/09/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
This review focuses on the role of hormones derived from enteroendocrine cells (EECs) on appetite and nutrient absorption in chickens. In response to nutrient intake, EECs release hormones that act on many organs and body systems, including the brain, gallbladder, and pancreas. Gut hormones released from EECs play a critical role in the regulation of feed intake and the absorption of nutrients such as glucose, protein, and fat following feed ingestion. We could hypothesize that EECs are essential for the regulation of appetite and nutrient absorption because the malfunction of EECs causes severe diarrhea and digestion problems. The importance of EEC hormones has been recognized, and many studies have been carried out to elucidate their mechanisms for many years in other species. However, there is a lack of research on the regulation of appetite and nutrient absorption by EEC hormones in chickens. This review suggests the potential significance of EEC hormones on growth and health in chickens under stress conditions induced by diseases and high temperature, etc., by providing in-depth knowledge of EEC hormones and mechanisms on how these hormones regulate appetite and nutrient absorption in other species.
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Affiliation(s)
| | - Woo Kyun Kim
- Department of Poultry Science, University of Georgia, Athens, GA 30602, USA;
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Hu C, Liao S, Lv L, Li C, Mei Z. Intestinal Immune Imbalance is an Alarm in the Development of IBD. Mediators Inflamm 2023; 2023:1073984. [PMID: 37554552 PMCID: PMC10406561 DOI: 10.1155/2023/1073984] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 08/10/2023] Open
Abstract
Immune regulation plays a crucial role in human health and disease. Inflammatory bowel disease (IBD) is a chronic relapse bowel disease with an increasing incidence worldwide. Clinical treatments for IBD are limited and inefficient. However, the pathogenesis of immune-mediated IBD remains unclear. This review describes the activation of innate and adaptive immune functions by intestinal immune cells to regulate intestinal immune balance and maintain intestinal mucosal integrity. Changes in susceptible genes, autophagy, energy metabolism, and other factors interact in a complex manner with the immune system, eventually leading to intestinal immune imbalance and the onset of IBD. These events indicate that intestinal immune imbalance is an alarm for IBD development, further opening new possibilities for the unprecedented development of immunotherapy for IBD.
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Affiliation(s)
- Chunli Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
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Richard N, Savoye G, Leboutte M, Amamou A, Ghosh S, Marion-Letellier R. Crohn’s disease: Why the ileum? World J Gastroenterol 2023; 29:3222-3240. [PMID: 37377591 PMCID: PMC10292140 DOI: 10.3748/wjg.v29.i21.3222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
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Affiliation(s)
- Nicolas Richard
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Guillaume Savoye
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Mathilde Leboutte
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Asma Amamou
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Subrata Ghosh
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Rachel Marion-Letellier
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
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Lebrun LJ, Dusuel A, Xolin M, Le Guern N, Grober J. Activation of TLRs Triggers GLP-1 Secretion in Mice. Int J Mol Sci 2023; 24:5333. [PMID: 36982420 PMCID: PMC10049702 DOI: 10.3390/ijms24065333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/03/2023] [Accepted: 03/05/2023] [Indexed: 03/14/2023] Open
Abstract
The gastrointestinal tract constitutes a large interface with the inner body and is a crucial barrier against gut microbiota and other pathogens. As soon as this barrier is damaged, pathogen-associated molecular patterns (PAMPs) are recognized by immune system receptors, including toll-like receptors (TLRs). Glucagon-like peptide 1 (GLP-1) is an incretin that was originally involved in glucose metabolism and recently shown to be rapidly and strongly induced by luminal lipopolysaccharides (LPS) through TLR4 activation. In order to investigate whether the activation of TLRs other than TLR4 also increases GLP-1 secretion, we used a polymicrobial infection model through cecal ligation puncture (CLP) in wild-type and TLR4-deficient mice. TLR pathways were assessed by intraperitoneal injection of specific TLR agonists in mice. Our results show that CLP induces GLP-1 secretion both in wild-type and TLR4-deficient mice. CLP and TLR agonists increase gut and systemic inflammation. Thus, the activation of different TLRs increases GLP-1 secretion. This study highlights for the first time that, in addition to an increased inflammatory status, CLP and TLR agonists also strongly induce total GLP-1 secretion. Microbial-induced GLP-1 secretion is therefore not only a TLR4/LPS-cascade.
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Affiliation(s)
- Lorène J. Lebrun
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
- Institut Agro Dijon, 21000 Dijon, France
| | - Alois Dusuel
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Marion Xolin
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Naig Le Guern
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
| | - Jacques Grober
- INSERM LNC UMR1231, Université de Bourgogne, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France
- Institut Agro Dijon, 21000 Dijon, France
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8
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Abdalqadir N, Adeli K. GLP-1 and GLP-2 Orchestrate Intestine Integrity, Gut Microbiota, and Immune System Crosstalk. Microorganisms 2022; 10:2061. [PMID: 36296337 PMCID: PMC9610230 DOI: 10.3390/microorganisms10102061] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 12/15/2022] Open
Abstract
The intestine represents the body's largest interface between internal organs and external environments except for its nutrient and fluid absorption functions. It has the ability to sense numerous endogenous and exogenous signals from both apical and basolateral surfaces and respond through endocrine and neuronal signaling to maintain metabolic homeostasis and energy expenditure. The intestine also harbours the largest population of microbes that interact with the host to maintain human health and diseases. Furthermore, the gut is known as the largest endocrine gland, secreting over 100 peptides and other molecules that act as signaling molecules to regulate human nutrition and physiology. Among these gut-derived hormones, glucagon-like peptide 1 (GLP-1) and -2 have received the most attention due to their critical role in intestinal function and food absorption as well as their application as key drug targets. In this review, we highlight the current state of the literature that has brought into light the importance of GLP-1 and GLP-2 in orchestrating intestine-microbiota-immune system crosstalk to maintain intestinal barrier integrity, inflammation, and metabolic homeostasis.
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Affiliation(s)
- Nyan Abdalqadir
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1H3, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biology, College of Science, University of Sulaimani, Sulaymaniyah 46001, Iraq
| | - Khosrow Adeli
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1H3, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
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9
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Malick A, Shen B. Endoscopic Treatment of Postoperative Bleeding, Bezoars, and Foreign Bodies. Gastrointest Endosc Clin N Am 2022; 32:829-843. [PMID: 36202519 DOI: 10.1016/j.giec.2022.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Altered gastrointestinal anatomy is common in patients with inflammatory bowel disease, particularly in those who underwent bowel surgery. Commonly performed surgeries are bowel resection and anastomosis and strictureplasty for Crohn's disease; and restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. The area of anastomosis and suture line is at the greatest risk for the development of postoperative bleeding. Altered bowel anatomy, especially the presence of strictures, strictureplasty, or structural or functional pouch outlet obstruction, puts these patients at risk for bezoar formation and foreign body retention, including video endoscopy capsule. This article will focus on postoperative bleeding, bezoar formation, and video capsule retention in patients with inflammatory bowel disease. Endoscopic management of these conditions is useful and is becoming an increasingly popular alternative to surgery.
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Affiliation(s)
- Alyyah Malick
- Department of Medicine, Columbia University Irving Medical Center-New York Presbyterian Hospital, 622 W 168th St, New York, NY 10032, USA.
| | - Bo Shen
- Center for Inflammatory Bowel Disease, Columbia University Irving Medical Center-NewYork Presbyterian Hospital, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032, USA
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Alrubia S, Mao J, Chen Y, Barber J, Rostami-Hodjegan A. Altered Bioavailability and Pharmacokinetics in Crohn's Disease: Capturing Systems Parameters for PBPK to Assist with Predicting the Fate of Orally Administered Drugs. Clin Pharmacokinet 2022; 61:1365-1392. [PMID: 36056298 PMCID: PMC9553790 DOI: 10.1007/s40262-022-01169-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2022] [Indexed: 12/12/2022]
Abstract
Backgrond and Objective Crohn’s disease (CD) is a chronic inflammatory bowel disease that affects a wide age range. Hence, CD patients receive a variety of drugs over their life beyond those used for CD itself. The changes to the integrity of the intestine and its drug metabolising enzymes and transporters (DMETs) can alter the oral bioavailability of drugs. However, there are other changes in systems parameters determining the fate of drugs in CD, and understanding these is essential for dose adjustment in patients with CD. Methods The current analysis gathered all the available clinical data on the kinetics of drugs in CD (by March 2021), focusing on orally administered small molecule drugs. A meta-analysis of the systems parameters affecting oral drug pharmacokinetics was conducted. The systems information gathered on intestine, liver and blood proteins and other physiological parameters was incorporated into a physiologically based pharmacokinetic (PBPK) platform to create a virtual population of CD patients, with a view for guiding dose adjustment in the absence of clinical data in CD. Results There were no uniform trends in the reported changes in reported oral bioavailability. The nature of the drug as well as the formulation affected the direction and magnitude of variation in kinetics in CD patients relative to healthy volunteers. Even for the same drug, the reported changes in exposure varied, possibly due to a lack of distinction between the activity states of CD. The highest alteration was seen with S-verapamil and midazolam, 8.7- and 5.3-fold greater exposure, respectively, in active CD patients relative to healthy volunteers. Only one report was available on liver DMETs in CD, and indicated reduced CYP3A4 activity. In a number of reports, mRNA expression of DMETs in the ileum and colon of CD patients was measured, focussing on P-glycoprotein (p-gp) transporter and CYP3A4 enzyme, and showed contradictory results. No data were available on protein expression in duodenum and jejunum despite their dominant role in oral drug absorption. Conclusion There are currently inadequate dedicated clinical or quantitative proteomic studies in CD to enable predictive PBPK models with high confidence and adequate verification. The PBPK models for CD with the available systems parameters were able to capture the major physiological influencers and the gaps to be filled by future research. Quantification of DMETs in the intestine and the liver in CD is warranted, alongside well-defined clinical drug disposition studies with a number of index drugs as biomarkers of changes in DMETs in these patients, to avoid large-scale dedicated studies for every drug to determine the effects of disease on the drug’s metabolism and disposition and the consequential safety and therapeutic concerns. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01169-4.
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Affiliation(s)
- Sarah Alrubia
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.,Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Jialin Mao
- Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Yuan Chen
- Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Jill Barber
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
| | - Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK. .,Certara UK Ltd, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, UK.
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11
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da Silva EM, Yariwake VY, Alves RW, de Araujo DR, Andrade-Oliveira V. Crosstalk between incretin hormones, Th17 and Treg cells in inflammatory diseases. Peptides 2022; 155:170834. [PMID: 35753504 DOI: 10.1016/j.peptides.2022.170834] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/20/2022] [Accepted: 06/20/2022] [Indexed: 02/07/2023]
Abstract
Intestinal epithelial cells constantly crosstalk with the gut microbiota and immune cells of the gut lamina propria. Enteroendocrine cells, secrete hormones, such as incretin hormones, which participate in host physiological events, such as stimulating insulin secretion, satiety, and glucose homeostasis. Interestingly, evidence suggests that the incretin pathway may influence immune cell activation. Consequently, drugs targeting the incretin hormone signaling pathway may ameliorate inflammatory diseases such as inflammatory bowel diseases, cancer, and autoimmune diseases. In this review, we discuss how these hormones may modulate two subsets of CD4 + T cells, the regulatory T cells (Treg)/Th17 axis important for gut homeostasis: thus, preventing the development and progression of inflammatory diseases. We also summarize the main experimental and clinical findings using drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) signaling pathways and their great impact on conditions in which the Treg/Th17 axis is disturbed such as inflammatory diseases and cancer. Understanding the role of incretin stimulation in immune cell activation and function, might contribute to new therapeutic designs for the treatment of inflammatory diseases, autoimmunity, and tumors.
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Affiliation(s)
| | - Victor Yuji Yariwake
- Department of Immunology - Institute of Biomedical Sciences, University of São Paulo (USP), Brazil
| | - Renan Willian Alves
- Center for Natural and Human Sciences, Federal University of ABC (UFABC), Brazil
| | | | - Vinicius Andrade-Oliveira
- Paulista School of Medicine, Federal University of São Paulo (UNIFESP), Brazil; Department of Immunology - Institute of Biomedical Sciences, University of São Paulo (USP), Brazil; Center for Natural and Human Sciences, Federal University of ABC (UFABC), Brazil.
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12
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Roberts A, Phuah P, Cheng S, Murphy KG. Targeting Enteroendocrine Cells to Treat Metabolic Disease. COMPREHENSIVE PHARMACOLOGY 2022:344-372. [DOI: 10.1016/b978-0-12-820472-6.00068-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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13
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Manka P, Sydor S, Wase N, Best J, Brandenburg M, Hellbeck A, Schänzer J, Vilchez-Vargas R, Link A, Figge A, Jähnert A, von Arnim U, Coombes JD, Cubero FJ, Kahraman A, Kim MS, Kälsch J, Kinner S, Faber KN, Moshage H, Gerken G, Syn WK, Friedman SL, Canbay A, Bechmann LP. Anti-TNFα treatment in Crohn's disease: Impact on hepatic steatosis, gut-derived hormones and metabolic status. Liver Int 2021; 41:2646-2658. [PMID: 34219348 DOI: 10.1111/liv.15003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/04/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor-Necrosis-Factor (TNF) activity, yet it is unclear why anti-TNFα agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti-TNF treatment and hepatic steatosis in CD, focusing on the gut-liver axis. METHODS This cross-sectional study evaluated patients with established CD, with and without anti-TNFα treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis. RESULTS Patients on anti-TNFα treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti-TNFα therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti-TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group-specific alterations with low levels in patients without anti-TNFα treatment. Low abundance of Firmicutes was associated with higher triglyceride levels. CONCLUSIONS Anti-TNFα treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR-signalling (eg FGF19) and microbiota composition in CD.
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Affiliation(s)
- Paul Manka
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Svenja Sydor
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Nishikant Wase
- Biomolecular Analysis Facility, University of Virginia, School of Medicine, Charlottesville, VA, USA
| | - Jan Best
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Malte Brandenburg
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Annika Hellbeck
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Julia Schänzer
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Ramiro Vilchez-Vargas
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke-University Hospital Magdeburg, Magdeburg, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke-University Hospital Magdeburg, Magdeburg, Germany
| | - Anja Figge
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Andreas Jähnert
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Ulrike von Arnim
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke-University Hospital Magdeburg, Magdeburg, Germany
| | - Jason D Coombes
- Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Francisco-Javier Cubero
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas 12), Madrid, Spain
| | - Alisan Kahraman
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Moon-Sung Kim
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany
| | - Julia Kälsch
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Sonja Kinner
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany
| | - Klaas-Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Wing-Kin Syn
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
- Section of Gastroenterology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA
- Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, Vizcaya, Spain
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Lars P Bechmann
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
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Radbakhsh S, Atkin SL, Simental-Mendia LE, Sahebkar A. The role of incretins and incretin-based drugs in autoimmune diseases. Int Immunopharmacol 2021; 98:107845. [PMID: 34126341 DOI: 10.1016/j.intimp.2021.107845] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/25/2021] [Accepted: 05/31/2021] [Indexed: 02/07/2023]
Abstract
Incretin hormones, including glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP), are gastrointestinal peptides secreted from enteroendocrine cells. These hormones play significant roles in many physiological processes via binding to G-protein coupled receptors (GPCRs) on different organs and tissues; one of them is the immunomodulatory effect on the immune system and its molecular components such as cytokines and chemokines. Anti-inflammatory effects of incretins and dependent molecules involving long-acting analogs and DPP4 inhibitors through regulation of T and B cell activation may attenuate autoimmune diseases caused by immune system disorders in mistakenly recognizing self as the foreign agent. In this review, we investigate incretin effects on the immune system response and the potential benefits of incretin-based therapy for treating autoimmune diseases.
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Affiliation(s)
- Shabnam Radbakhsh
- Department of Medical Biotechnology and Nanotechnology, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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15
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Keller J, Hammer HF, Hauser B. 13 C-gastric emptying breath tests: Clinical use in adults and children. Neurogastroenterol Motil 2021; 33:e14172. [PMID: 33998745 DOI: 10.1111/nmo.14172] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 12/28/2022]
Abstract
13 C-gastric emptying breath tests (13 C-GEBT) are validated, reliable, and non-invasive tools for measurement of gastric emptying (GE) velocity of solids and liquids without radiation exposure or risk of toxicity. They are recommended and routinely used for clinical purposes in adult as well as pediatric patients and can be readily performed onsite or even at the patient's home. However, the underlying methodology is rather complex and test results can be influenced by dietary factors, physical activity, concurrent diseases, and medication. Moreover, epidemiological factors can influence gastric emptying as well as production and exhalation of 13 CO2 , which is the ultimate metabolic product measured for all 13 C-breath tests. Accordingly, in this issue of Neurogastroenterology & Motility, Kovacic et al. report performance of the 13 C-Spirulina breath test in a large group of healthy children and show significant effects of gender, pubertal status, and body size on test results. The purpose of this mini-review is to evaluate the clinical use of 13 C-GEBT in adults and children, exploring available protocols, analytical methods, and essential prerequisites for test performance, as well as the role of GE measurements in the light of the current discussion on relevance of delayed GE for symptom generation.
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Affiliation(s)
- Jutta Keller
- Department of Internal Medicine, Israelitic Hospital, Academic Hospital University of Hamburg, Hamburg, Germany
| | - Heinz F Hammer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Graz, Austria
| | - Bruno Hauser
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, KidZ Health Castle UZ Brussel, Brussels, Belgium
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16
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Keller J, Hammer HF, Afolabi PR, Benninga M, Borrelli O, Dominguez‐Munoz E, Dumitrascu D, Goetze O, Haas SL, Hauser B, Pohl D, Salvatore S, Sonyi M, Thapar N, Verbeke K, Fox MR. European guideline on indications, performance and clinical impact of 13 C-breath tests in adult and pediatric patients: An EAGEN, ESNM, and ESPGHAN consensus, supported by EPC. United European Gastroenterol J 2021; 9:598-625. [PMID: 34128346 PMCID: PMC8259225 DOI: 10.1002/ueg2.12099] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/06/2021] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and <10% disagreed. RESULTS The guideline gives an overview over general methodology of 13 C-breath testing and provides recommendations for the use of 13 C-breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of 13 C-breath testing are summarized briefly. The recommendations specifically detail when and how individual 13 C-breath tests should be performed including examples for well-established test protocols, patient preparation, and reporting of test results. CONCLUSION This clinical practice guideline should improve pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of 13 C-breath tests.
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Affiliation(s)
- Jutta Keller
- Department of Internal MedicineIsraelitic HospitalAcademic Hospital University of HamburgHamburgGermany
| | - Heinz F. Hammer
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
| | - Paul R. Afolabi
- NIHR Southampton Biomedical Research CentreUniversity Hospital Southampton NHS Foundation Trust and University of SouthamptonSouthamptonUK
| | - Marc Benninga
- Department of Pediatric Gastroenterology, Hepatology and NutritionEmma Children's HospitalAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Osvaldo Borrelli
- UCL Great Ormond Street Institute of Child Health and Department of GastroenterologyNeurogastroenterology and MotilityGreat Ormond Street HospitalLondonUK
| | - Enrique Dominguez‐Munoz
- Department of Gastroenterology and HepatologyUniversity Hospital of Santiago de CompostelaSantiagoSpain
| | | | - Oliver Goetze
- Department of Medicine IIDivision of HepatologyUniversity Hospital WürzburgWürzburgGermany
| | - Stephan L. Haas
- Department of Upper GI DiseasesKarolinska University HospitalStockholmSweden
| | - Bruno Hauser
- Department of Paediatric Gastroenterology, Hepatology and NutritionKidZ Health Castle UZ BrusselsBrusselsBelgium
| | - Daniel Pohl
- Division of Gastroenterology and HepatologyUniversity Hospital ZürichZürichSwitzerland
| | - Silvia Salvatore
- Pediatric DepartmentHospital "F. Del Ponte"University of InsubriaVareseItaly
| | - Marc Sonyi
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
- Clinic for General Medicine, Gastroenterology, and Infectious DiseasesAugustinerinnen HospitalCologneGermany
| | - Nikhil Thapar
- UCL Great Ormond Street Institute of Child Health and Department of GastroenterologyNeurogastroenterology and MotilityGreat Ormond Street HospitalLondonUK
- Department of Gastroenterology, Hepatology and Liver TransplantationQueensland Children's HospitalBrisbaneAustralia
| | - Kristin Verbeke
- Translational Research Center for Gastrointestinal DisordersKU LeuvenLeuvenBelgium
| | - Mark R. Fox
- Division of Gastroenterology and HepatologyUniversity Hospital ZürichZürichSwitzerland
- Digestive Function: Basel, Laboratory and Clinic for Motility Disorders and Functional Gastrointestinal DiseasesCentre for Integrative GastroenterologyKlinik ArlesheimArlesheimSwitzerland
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Kato S, Sato T, Fujita H, Kawatani M, Yamada Y. Effects of GLP-1 receptor agonist on changes in the gut bacterium and the underlying mechanisms. Sci Rep 2021; 11:9167. [PMID: 33911125 PMCID: PMC8080802 DOI: 10.1038/s41598-021-88612-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 04/13/2021] [Indexed: 01/07/2023] Open
Abstract
There is a close relationship between the gut microbiota and metabolic disorders. In this study, acute administration of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide to mice increased the cecal levels of caseinolytic protease B, a component of Escherichia coli, and of norepinephrine. Chemical sympathectomy blocked these events. Norepinephrine was found to pass into the intestinal lumen in vitro. c-Fos staining of the intermediolateral nucleus was identified as indirect evidence of sympathetic nervous system activation of the intestinal tract by GLP-1RA. Under normal conditions, the increase in E. coli did not affect the host. However, in mice with colitis, bacterial translocation was observed with attenuation of tight junction gene expression. This is the first study to investigate the unique underlying mechanisms related the effects of GLP-1RA on changes in the gut bacterium.
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Affiliation(s)
- Shunsuke Kato
- Departments of Endocrinology, Diabetes, and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Takehiro Sato
- Departments of Endocrinology, Diabetes, and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Hiroki Fujita
- Departments of Endocrinology, Diabetes, and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Masahiro Kawatani
- Departments of Neurophysiology, Akita University Graduate School of Medicine, Akita, Japan
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Yuichiro Yamada
- Departments of Endocrinology, Diabetes, and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
- Kansai Electric Power Medical Research Institute, 2-1-7 Fukushima, Fukushima-ku, Osaka, Japan.
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Moran GW, Thapaliya G. The Gut-Brain Axis and Its Role in Controlling Eating Behavior in Intestinal Inflammation. Nutrients 2021; 13:nu13030981. [PMID: 33803651 PMCID: PMC8003054 DOI: 10.3390/nu13030981] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 12/12/2022] Open
Abstract
Malnutrition represents a major problem in the clinical management of the inflammatory bowel disease (IBD). Presently, our understanding of the cross-link between eating behavior and intestinal inflammation is still in its infancy. Crohn's disease patients with active disease exhibit strong hedonic desires for food and emotional eating patterns possibly to ameliorate feelings of low mood, anxiety, and depression. Impulsivity traits seen in IBD patients may predispose them to palatable food intake as an immediate reward rather than concerns for future health. The upregulation of enteroendocrine cells (EEC) peptide response to food intake has been described in ileal inflammation, which may lead to alterations in gut-brain signaling with implications for appetite and eating behavior. In summary, a complex interplay of gut peptides, psychological, cognitive factors, disease-related symptoms, and inflammatory burden may ultimately govern eating behavior in intestinal inflammation.
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Affiliation(s)
- Gordon William Moran
- National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham, and Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK
- Correspondence:
| | - Gita Thapaliya
- Division of Child & Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
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Beyaz Ş, Akbal E. Increased serum nesfatin-1 levels in patients with inflammatory bowel diseases. Postgrad Med J 2021; 98:446-449. [PMID: 33541923 DOI: 10.1136/postgradmedj-2020-139227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/19/2020] [Accepted: 01/11/2021] [Indexed: 12/31/2022]
Abstract
BACKGROUND Adipokines are adipose tissue-derived secreted molecules that can exert anti-inflammatory or proinflammatory activities. Altered expression of adipokines has been described in various inflammatory diseases, including inflammatory bowel diseases (IBDs) such as Crohn's disease (CD) and ulcerative colitis (UC). Little is known about nesfatin-1, a recently identified adipokine, in IBD. The aim of this study was to investigate serum nesfatin-1 levels in patients with IBD. METHODS This study included a total of 52 adult individuals (17 patients with CD, 18 patients with UC and 17 healthy volunteers) with similar age and body mass index. Serum nesfatin-1 levels were measured by ELISA in healthy individuals and patients with IBD in their active and remission periods. Blood inflammation markers including C reactive protein (CRP), erythrocyte sedimentation (ESR) and white cell count (WCC) were also measured in patients. RESULTS We found significantly elevated levels of serum nesfatin-1 in the active disease period in both patients with CD (p=0.00003) and patients with UC (p=0.00001), compared with healthy individuals. Serum nesfatin-1 levels moderately decreased in the remission period; however, they were still significantly higher than that of healthy individuals. Receiver operating characteristic curve analyses indicated serum nesfatin-1 with an excellent diagnostic value for IBD. Finally, patients had significantly high CRP, ESR and WCC in the active IBD; however, we found the nesfatin-1 strongly correlated only with ESR in the active CD. CONCLUSION This is the first study investigating the circulating levels of nesfatin-1 in patients with IBD. Serum nesfatin-1 may serve as an additional inflammatory marker for diagnosis of IBD in affected individuals.
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Affiliation(s)
- Şengül Beyaz
- Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Erdem Akbal
- Department of Gastroenterology Advanced Endoscopy Unit, Memorial Bahçelievler Hospital, Istanbul, Turkey
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Piras IS, Perdigones N, Zismann V, Briones N, Facista S, Rivera JL, Rozanski E, London CA, Hendricks WPD. Identification of Genetic Susceptibility Factors Associated with Canine Gastric Dilatation-Volvulus. Genes (Basel) 2020; 11:genes11111313. [PMID: 33167491 PMCID: PMC7694454 DOI: 10.3390/genes11111313] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/29/2020] [Accepted: 10/31/2020] [Indexed: 12/16/2022] Open
Abstract
Canine gastric dilatation-volvulus (GDV) is a common life-threatening condition occurring primarily in large and giant breeds with a 3.9% to 36.7% lifetime risk. The genetic correlates of GDV have not previously been systematically explored. We undertook an inter-breed genome-wide association analysis (GWAS) of 253 dogs from ten breeds including 106 healthy dogs and 147 dogs with at least one GDV episode. SNP array genotyping followed by imputation was conducted on 241 samples to identify GDV-associated single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs). A subset of 33 dogs (15 healthy dogs and 18 GDV patients from the three most represented breeds) was characterized by whole genome sequencing (WGS). After genome-wide Bonferroni correction, we identified a significant putatively protective intergenic SNP (rs851737064) across all breeds. The signal was most significant in Collies, German Shorthaired Pointers, and Great Danes. Subsequent focused analysis across these three breeds identified 12 significant additional putatively protective or deleterious SNPs. Notable significant SNPs included those occurring in genes involved in gastric tone and motility including VHL, NALCN, and PRKCZ. These data provide important new clues to canine GDV risk factors and facilitate generation of hypotheses regarding the genetic and molecular underpinnings this syndrome.
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Affiliation(s)
- Ignazio S. Piras
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA;
| | - Nieves Perdigones
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; (N.P.); (V.Z.); (N.B.); (S.F.); (J.L.R.)
| | - Victoria Zismann
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; (N.P.); (V.Z.); (N.B.); (S.F.); (J.L.R.)
| | - Natalia Briones
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; (N.P.); (V.Z.); (N.B.); (S.F.); (J.L.R.)
| | - Salvatore Facista
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; (N.P.); (V.Z.); (N.B.); (S.F.); (J.L.R.)
| | - José Luis Rivera
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; (N.P.); (V.Z.); (N.B.); (S.F.); (J.L.R.)
| | - Elizabeth Rozanski
- Cummings School of Veterinary Medicine, Tufts University, Grafton, MA 01536, USA; (E.R.); (C.A.L.)
| | - Cheryl A. London
- Cummings School of Veterinary Medicine, Tufts University, Grafton, MA 01536, USA; (E.R.); (C.A.L.)
| | - William P. D. Hendricks
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; (N.P.); (V.Z.); (N.B.); (S.F.); (J.L.R.)
- Correspondence:
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21
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de Oliveira Santos R, da Silva Cardoso G, da Costa Lima L, de Sousa Cavalcante ML, Silva MS, Cavalcante AKM, Severo JS, de Melo Sousa FB, Pacheco G, Alves EHP, Nobre LMS, Medeiros JVR, Lima-Junior RC, Dos Santos AA, Tolentino M. L-Glutamine and Physical Exercise Prevent Intestinal Inflammation and Oxidative Stress Without Improving Gastric Dysmotility in Rats with Ulcerative Colitis. Inflammation 2020; 44:617-632. [PMID: 33128666 DOI: 10.1007/s10753-020-01361-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/07/2020] [Accepted: 10/12/2020] [Indexed: 12/11/2022]
Abstract
The aim of this study was to evaluate the effects of glutamine supplementation or exercise on gastric emptying and intestinal inflammation in rats with ulcerative colitis (UC). Strength exercise consisted of jump training 4 × 10 repetitions/5 days a week/8 weeks with progressive overload. Endurance exercise consisted of swimming without overload for a period of 1 h a day/5 days a week/8 weeks. Another group (sedentary) of animals was supplemented with L-glutamine (1 g/kg of body weight) orally for 8 weeks before induction of UC. Colitis was induced by intra-colonic administration of 1 mL of 4% acetic acid. We assessed gastric emptying, macroscopic and microscopic scoring, oxidative stress markers, and IL-1β, IL-6, and (TNF-α) levels. The UC significantly increased (p < 0.05) the gastric emptying compared with the saline control group. We observed a significantly decrease (p < 0.05) in body weight gain in UC rats compared with the control groups. Both exercise interventions and L-glutamine supplementation significantly prevented (p < 0.05) weight loss compared with the UC group. Strength and endurance exercises significantly prevented (p < 0.05) the increase of microscopic scores and oxidative stress (p < 0.05). L-glutamine supplementation in UC rats prevented hemorrhagic damage and improved oxidative stress markers (p < 0.05). Strength and endurance exercises and glutamine decreased the concentrations of inflammatory cytokines IL-1β, IL-6, and TNF-α compared with the UC group (p < 0.05). Strength and endurance exercises and L-glutamine supplementation prevented intestinal inflammation and improved cytokines and oxidative stress levels without altering gastric dysmotility in rats with UC.
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Affiliation(s)
| | - Geovane da Silva Cardoso
- Laboratory of Exercise and Gastrointestinal Tract - Department of Physical Education, Center for Health Sciences, Federal University of Piauí, Teresina, PI, 64049-550, Brazil
| | - Lara da Costa Lima
- Laboratory of Exercise and Gastrointestinal Tract - Department of Physical Education, Center for Health Sciences, Federal University of Piauí, Teresina, PI, 64049-550, Brazil
| | | | - Mariana Sousa Silva
- Graduate Program in Pharmacology, Federal University of Piauí, Teresina, PI, Brazil
| | | | - Juliana Soares Severo
- Graduate Program in Food and Nutrition, Federal University of Piauí, Teresina, PI, Brazil
| | | | - Gabriella Pacheco
- Graduate Program in Biotechnology, Federal University of Piauí, Parnaiba, PI, Brazil
| | | | - Lívia Maria Soares Nobre
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | | | - Roberto Cesar Lima-Junior
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Armênio Aguiar Dos Santos
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Moisés Tolentino
- Graduate Program in Food and Nutrition, Federal University of Piauí, Teresina, PI, Brazil. .,Laboratory of Exercise and Gastrointestinal Tract - Department of Physical Education, Center for Health Sciences, Federal University of Piauí, Teresina, PI, 64049-550, Brazil. .,Graduate Program in Pharmacology, Federal University of Piauí, Teresina, PI, Brazil.
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22
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Bassotti G, Antonelli E, Villanacci V, Nascimbeni R, Dore MP, Pes GM, Maconi G. Abnormal gut motility in inflammatory bowel disease: an update. Tech Coloproctol 2020; 24:275-282. [PMID: 32062797 DOI: 10.1007/s10151-020-02168-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 02/07/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND There is substantial evidence linking disturbed gastrointestinal motility to inflammation. Thus, it is not surprising that abnormalities of gastrointestinal motility play a role in inflammatory bowel disease (IBD), affecting patient outcomes. We performed a review of the literature to investigate the relationship between abnormal gut motility and IBD. METHODS With an extensive literature search, we retrieved the pertinent articles linking disturbed gut motility to IBD in various anatomical districts. RESULTS The evidence in the literature suggests that abnormal gastrointestinal motility plays a role in the clinical setting of IBD and may confuse the clinical picture. CONCLUSIONS Abnormal gut motility may be important in the clinical setting of IBD. However, additional data obtained with modern techniques (e.g., magnetic resonance imaging) are needed to individuate in a more precise manner gastrointestinal motor dysfunctions, to understand the nature of clinical manifestations and properly tailor the treatment of patients.
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Affiliation(s)
- G Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy.
- Clinica Di Gastroenterologia Ed Epatologia, Ospedale Santa Maria della Misericordia, Piazzale Menghini, 1, San Sisto, 06156, Perugia, Italy.
| | - E Antonelli
- Gastroenterology Unit, Perugia General Hospital, Perugia, Italy
| | - V Villanacci
- Pathology Institute, Spedali Civili, Brescia, Italy
| | - R Nascimbeni
- Surgical Section Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - M P Dore
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy
| | - G M Pes
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy
| | - G Maconi
- Gastroenterology Unit, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Milan, Italy
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23
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Khalaf A, Hoad CL, Blackshaw E, Alyami J, Spiller RC, Gowland PA, Vinayaka-Moorthy V, Perkins AC, Moran GW, Marciani L. Simultaneous Measurement of Gastric Emptying of a Soup Test Meal Using MRI and Gamma Scintigraphy. Diagnostics (Basel) 2020; 10:diagnostics10030170. [PMID: 32235742 PMCID: PMC7151156 DOI: 10.3390/diagnostics10030170] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/13/2020] [Accepted: 03/17/2020] [Indexed: 12/02/2022] Open
Abstract
Measurement of gastric emptying is of clinical value for a range of conditions. Gamma scintigraphy (GS) has an established role, but the use of magnetic resonance imaging (MRI) has recently increased. Previous comparison studies between MRI and GS showed good correlation, but were performed on separate study days. In this study, the modalities were alternated rapidly allowing direct comparison with no intra-individual variability confounds. Twelve healthy participants consumed 400 g of Technetium-99m (99mTc)-labelled soup test meal (204 kcal) and were imaged at intervals for 150 min, alternating between MRI and GS. The time to empty half of the stomach contents (T1/2) and retention rate (RR) were calculated and data correlated. The average T1/2 was similar for MRI (44 ± 6 min) and GS (35 ± 4 min) with a moderate but significant difference between the two modalities (p < 0.004). The individual T1/2 values were measured, and MRI and GS showed a good positive correlation (r = 0.95, p < 0.0001), as well as all the RRs at each time point up to 120 min. Gastric emptying was measured for the first time by MRI and GS on the same day. This may help with translating the use of this simple meal, known to elicit reliable, physiological, and pathological gastrointestinal motor, peptide, and appetite responses.
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Affiliation(s)
- Asseel Khalaf
- Radiologic Sciences, Allied Health Sciences, Kuwait University, 90805 Sulaibekhat, Kuwait City, Kuwait;
| | - Caroline L. Hoad
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UH, UK; (C.L.H.); (R.C.S.); (P.A.G.); (G.W.M.)
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham NG7 2QX, UK
| | - Elaine Blackshaw
- Medical Physics and Clinical Engineering, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK; (E.B.); (V.V.-M.)
| | - Jaber Alyami
- Diagnostic Radiology, Faculty of Applied Medical Science, King Abdulaziz University, 21589 Jeddah, Saudi Arabia;
| | - Robin C. Spiller
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UH, UK; (C.L.H.); (R.C.S.); (P.A.G.); (G.W.M.)
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham NG7 2QX, UK
| | - Penny A. Gowland
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UH, UK; (C.L.H.); (R.C.S.); (P.A.G.); (G.W.M.)
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham NG7 2QX, UK
| | - Vidhiya Vinayaka-Moorthy
- Medical Physics and Clinical Engineering, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK; (E.B.); (V.V.-M.)
| | - Alan C. Perkins
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham NG7 2QX, UK
- Medical Physics and Clinical Engineering, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK; (E.B.); (V.V.-M.)
- Radiological Sciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Gordon W. Moran
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UH, UK; (C.L.H.); (R.C.S.); (P.A.G.); (G.W.M.)
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham NG7 2QX, UK
| | - Luca Marciani
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UH, UK; (C.L.H.); (R.C.S.); (P.A.G.); (G.W.M.)
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham NG7 2QX, UK
- Correspondence:
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24
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Rubio C, Puerto M, García-Rodríquez JJ, Lu VB, García-Martínez I, Alén R, Sanmartín-Salinas P, Toledo-Lobo MV, Saiz J, Ruperez J, Barbas C, Menchén L, Gribble FM, Reimann F, Guijarro LG, Carrascosa JM, Valverde ÁM. Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice. Mol Metab 2020; 35:100954. [PMID: 32244182 PMCID: PMC7082558 DOI: 10.1016/j.molmet.2020.01.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 01/23/2020] [Accepted: 01/28/2020] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Non-alcoholic steatohepatitis (NASH) is characterized by a robust pro-inflammatory component at both hepatic and systemic levels together with a disease-specific gut microbiome signature. Protein tyrosine phosphatase 1 B (PTP1B) plays distinct roles in non-immune and immune cells, in the latter inhibiting pro-inflammatory signaling cascades. In this study, we have explored the role of PTP1B in the composition of gut microbiota and gut barrier dynamics in methionine and choline-deficient (MCD) diet-induced NASH in mice. METHODS Gut features and barrier permeability were characterized in wild-type (PTP1B WT) and PTP1B-deficient knockout (PTP1B KO) mice fed a chow or methionine/choline-deficient (MCD) diet for 4 weeks. The impact of inflammation was studied in intestinal epithelial and enteroendocrine cells. The secretion of GLP-1 was evaluated in primary colonic cultures and plasma of mice. RESULTS We found that a shift in the gut microbiota shape, disruption of gut barrier function, higher levels of serum bile acids, and decreased circulating glucagon-like peptide (GLP)-1 are features during NASH. Surprisingly, despite the pro-inflammatory phenotype of global PTP1B-deficient mice, they were partly protected against the alterations in gut microbiota composition during NASH and presented better gut barrier integrity and less permeability under this pathological condition. These effects concurred with higher colonic mucosal inflammation, decreased serum bile acids, and protection against the decrease in circulating GLP-1 levels during NASH compared with their WT counterparts together with increased expression of GLP-2-sensitive genes in the gut. At the molecular level, stimulation of enteroendocrine STC-1 cells with a pro-inflammatory conditioned medium (CM) from lipopolysaccharide (LPS)-stimulated macrophages triggered pro-inflammatory signaling cascades that were further exacerbated by a PTP1B inhibitor. Likewise, the pro-inflammatory CM induced GLP-1 secretion in primary colonic cultures, an effect augmented by PTP1B inhibition. CONCLUSION Altogether our results have unraveled a potential role of PTP1B in the gut-liver axis during NASH, likely mediated by increased sensitivity to GLPs, with potential therapeutic value.
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Affiliation(s)
- Carmen Rubio
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain; Centro de Biología Molecular Severo Ochoa (CBMSO, CSIC-UAM), Madrid, Spain
| | - Marta Puerto
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; CIBER de Enfermedades Hepáticas y Digestivas (CIBERHED), ISCIII, Madrid, Spain
| | - Juan J García-Rodríquez
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
| | - Van B Lu
- Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Irma García-Martínez
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Rosa Alén
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | | | - M Val Toledo-Lobo
- Departamento de Biología de Sistemas, Universidad de Alcalá de Henares, Madrid, Spain
| | - Jorge Saiz
- CEMBIO, Universidad San Pablo-CEU, Madrid, Spain
| | | | - Coral Barbas
- CEMBIO, Universidad San Pablo-CEU, Madrid, Spain
| | - Luis Menchén
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; CIBER de Enfermedades Hepáticas y Digestivas (CIBERHED), ISCIII, Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Spain
| | - Fiona M Gribble
- Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Frank Reimann
- Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Luis G Guijarro
- Departamento de Biología de Sistemas, Universidad de Alcalá de Henares, Madrid, Spain
| | - Jose M Carrascosa
- Centro de Biología Molecular Severo Ochoa (CBMSO, CSIC-UAM), Madrid, Spain.
| | - Ángela M Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain.
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25
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Khalaf A, Hoad CL, Menys A, Nowak A, Radford S, Taylor SA, Latief K, Lingaya M, Falcone Y, Singh G, Spiller RC, Gowland PA, Marciani L, Moran GW. Gastrointestinal peptides and small-bowel hypomotility are possible causes for fasting and postprandial symptoms in active Crohn's disease. Am J Clin Nutr 2020; 111:131-140. [PMID: 31557279 DOI: 10.1093/ajcn/nqz240] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 08/29/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Crohn's disease (CD) patients suffer postprandial aversive symptoms, which can lead to anorexia and malnutrition. Changes in the regulation of gut hormones and gut dysmotility are believed to play a role. OBJECTIVES This study aimed to investigate small-bowel motility and gut peptide responses to a standard test meal in CD by using MRI. METHODS We studied 15 CD patients with active disease (age 36 ± 3 y; BMI 26 ± 1 kg/m 2) and 20 healthy volunteers (HVs; age 31 ± 3 years; BMI 24 ± 1 kg/m 2). They underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling following a 400-g soup meal (204 kcal). Small-bowel motility, other MRI parameters, and glucagon-like peptide-1 (GLP-1), polypeptide YY (PYY), and cholecystokinin peptides were measured. Data are presented as means ± SEMs. RESULTS HVs had significantly higher fasting motility indexes [106 ± 13 arbitrary units (a.u.)], compared with CD participants (70 ± 8 a.u.; P ≤ 0.05). Postprandial small-bowel water content showed a significant time by group interaction (P < 0.05), with CD participants showing higher levels from 210 min postprandially. Fasting concentrations of GLP-1 and PYY were significantly greater in CD participants, compared with HVs [GLP-1, CD 50 ± 8 µg/mL versus HV 13 ± 3 µg/mL (P ≤ 0.0001); PYY, CD 236 ± 16 pg/mL versus HV 118 ± 12 pg/mL (P ≤ 0.0001)]. The meal challenge induced a significant postprandial increase in aversive symptom scores (fullness, distention, bloating, abdominal pain, and sickness) in CD participants compared with HVs (P ≤ 0.05). CONCLUSIONS The decrease in fasting small-bowel motility noted in CD participants can be ascribed to the increased fasting gut peptides. A better understanding of the etiology of aversive symptoms in CD will facilitate identification of better therapeutic targets to improve nutritional status. This trial was registered at clinicaltrials.gov as NCT03052465.
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Affiliation(s)
- Asseel Khalaf
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Caroline L Hoad
- National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom.,Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
| | | | - Adam Nowak
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Shellie Radford
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Stuart A Taylor
- Centre for Medical Imaging, Division of Medicine, University College London, United Kingdom
| | - Khalid Latief
- Department of Radiology, Nottingham University Hospitals, Nottingham, United Kingdom
| | - Melanie Lingaya
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Yirga Falcone
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Gulzar Singh
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Robin C Spiller
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Penny A Gowland
- National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom.,Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
| | - Luca Marciani
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Gordon W Moran
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute of Health Research Nottingham Biomedical Research Centre at Nottingham University, Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
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26
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Role of glucagon-like peptides in inflammatory bowel diseases-current knowledge and future perspectives. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:1321-1330. [PMID: 31359088 DOI: 10.1007/s00210-019-01698-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 07/15/2019] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, intestinal inflammatory disorders with complex and yet unrevealed pathogenesis in which genetic, immunological, and environmental factors play a role. Nowadays, a higher proportion of elderly IBD patients with coexisting conditions, such as cardiovascular disease and/or diabetes is recorded, who require more complex treatment and became a great challenge for gastroenterologists. Furthermore, some patients do not respond to anti-IBD therapy. These facts, together with increasing comorbidities in patients with IBD, imply that urgent, more complex, novel therapeutic strategies in the treatment are needed. Glucagon-like peptides (GLPs) possess numerous functions in the human body such as lowering blood glucose level, controlling body weight, inhibiting gastric emptying, reducing food ingestion, increasing crypt cell proliferation, and improving intestinal growth and nutrient absorption. Thus, GLPs and dipeptidyl peptidase IV (DPP-IV) inhibitors have recently gained attention in IBD research. Several animal models showed that treatment with GLPs may lead to improvement of colitis. This review presents data on the multitude effects of GLPs in the inflammatory intestinal diseases and summarizes the current knowledge on GLPs, which have the potential to become a novel therapeutic option in IBD therapy.
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27
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Song G, Fiocchi C, Achkar JP. Acupuncture in Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:1129-1139. [PMID: 30535303 DOI: 10.1093/ibd/izy371] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Indexed: 02/06/2023]
Abstract
Scientific research into the effects and mechanisms of acupuncture for gastrointestinal diseases including inflammatory bowel disease has been rapidly growing in the past several decades. In this review, we discuss the history, theory, and methodology of acupuncture and review potentially beneficial mechanisms of action of acupuncture for managing inflammatory bowel disease. Acupuncture has been shown to decrease disease activity and inflammation via increase of vagal activity in inflammatory bowel disease. Acupuncture has demonstrated beneficial roles in the regulation of gut dysbiosis, intestinal barrier function, visceral hypersensitivity, gut motor dysfunction, depression/anxiety, and pain, all of which are factors that can significantly impact quality of life in patients with inflammatory bowel disease. A number of clinical trials have been performed to investigate the therapeutic effects of acupuncture in ulcerative colitis and Crohn's disease. Although the data from these trials are promising, more studies are needed given the heterogeneous and multifactorial aspects of inflammatory bowel disease. There is also an important need to standardize acupuncture methodology, study designs, and outcome measurements.
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Affiliation(s)
- Gengqing Song
- Department of Gastroenterology, Hepatology & Nutrition, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | - Claudio Fiocchi
- Department of Gastroenterology, Hepatology & Nutrition, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | - Jean-Paul Achkar
- Department of Gastroenterology, Hepatology & Nutrition, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
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28
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Anand U, Yiangou Y, Akbar A, Quick T, MacQuillan A, Fox M, Sinisi M, Korchev YE, Jones B, Bloom SR, Anand P. Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons. PLoS One 2018; 13:e0198024. [PMID: 29813107 PMCID: PMC5973579 DOI: 10.1371/journal.pone.0198024] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 05/11/2018] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Glucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD). OBJECTIVES The aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons. METHODS GLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells. The morphological effects of incretin hormones oxyntomodulin, exendin-4 and glucagon were studied on neurite extension in cultured DRG neurons, and their functional effects on capsaicin and ATP signalling, using calcium imaging. RESULTS Significantly increased numbers of colonic mucosal nerve fibres were observed in IBD biopsies expressing GLP-1R (p = 0.0013), the pan-neuronal marker PGP9.5 (p = 0.0008), and sensory neuropeptide CGRP (p = 0.0014). An increase of GLP-1R positive nerve fibres in IBD colon was confirmed with a different antibody to GLP-1R (p = 0.016). GLP-1R immunostaining was intensely positive in small and medium-sized neurons in human DRG, and in human and rat DRG cultured neurons. Co-localization of GLP-1R expression with neuronal markers in colon and DRG confirmed the neural expression of GLP-1R, and antibody specificity was confirmed in HEK293 cells transfected with the GLP-1R. Treatment with oxyntomodulin, exendin-4 and GLP-1 increased neurite length in cultured neurons compared with controls, but did not stimulate calcium influx directly, or affect capsaicin responses. However, exendin-4 significantly enhanced ATP responses in human DRG neurons. CONCLUSION Our results show that increased GLP-1R innervation in IBD bowel could mediate enhanced visceral afferent signalling, and provide a peripheral target for therapeutic intervention. The differential effect of GLP-1R agonists on capsaicin and ATP responses in neurons suggest they may not affect pain mechanisms mediated by the capsaicin receptor TRPV1, but may enhance the effects of purinergic agonists.
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Affiliation(s)
- Uma Anand
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
- Nanomedicine Research Laboratory, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Yiangos Yiangou
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Ayesha Akbar
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Tom Quick
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
- Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom
| | - Anthony MacQuillan
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
- Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom
| | - Mike Fox
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
- Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom
| | - Marco Sinisi
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
- Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom
| | - Yuri E. Korchev
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Ben Jones
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London
| | - Steve R. Bloom
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London
| | - Praveen Anand
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
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Keller J, Bassotti G, Clarke J, Dinning P, Fox M, Grover M, Hellström PM, Ke M, Layer P, Malagelada C, Parkman HP, Scott SM, Tack J, Simren M, Törnblom H, Camilleri M. Expert consensus document: Advances in the diagnosis and classification of gastric and intestinal motility disorders. Nat Rev Gastroenterol Hepatol 2018; 15:291-308. [PMID: 29622808 PMCID: PMC6646879 DOI: 10.1038/nrgastro.2018.7] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Disturbances of gastric, intestinal and colonic motor and sensory functions affect a large proportion of the population worldwide, impair quality of life and cause considerable health-care costs. Assessment of gastrointestinal motility in these patients can serve to establish diagnosis and to guide therapy. Major advances in diagnostic techniques during the past 5-10 years have led to this update about indications for and selection and performance of currently available tests. As symptoms have poor concordance with gastrointestinal motor dysfunction, clinical motility testing is indicated in patients in whom there is no evidence of causative mucosal or structural diseases such as inflammatory or malignant disease. Transit tests using radiopaque markers, scintigraphy, breath tests and wireless motility capsules are noninvasive. Other tests of gastrointestinal contractility or sensation usually require intubation, typically represent second-line investigations limited to patients with severe symptoms and are performed at only specialized centres. This Consensus Statement details recommended tests as well as useful clinical alternatives for investigation of gastric, small bowel and colonic motility. The article provides recommendations on how to classify gastrointestinal motor disorders on the basis of test results and describes how test results guide treatment decisions.
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Affiliation(s)
- Jutta Keller
- Israelitic Hospital, Academic Hospital University of Hamburg, Orchideenstieg 14, 22297 Hamburg, Germany
| | - Gabrio Bassotti
- University of Perugia, Piazza dell’Università, 1, 06121 Perugia, Italy
| | - John Clarke
- Stanford University, 900 Blake Wilbur Dr, Palo Alto, CA 94304, USA
| | - Phil Dinning
- Flinders Medical Centre, GPO Box 2100, Adelaide 5001, Australia
| | - Mark Fox
- University Hospital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland, and St. Claraspital, Kleinriehenstrasse 30, 4058 Basel, Switzerland
| | | | - Per M. Hellström
- Uppsala University Hospital, Building 40, SE‑75185, Uppsala, Sweden
| | - Meiyun Ke
- Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China
| | - Peter Layer
- Israelitic Hospital, Academic Hospital University of Hamburg, Orchideenstieg 14, 22297 Hamburg, Germany
| | - Carolina Malagelada
- University of Barcelona, Passeig de la Vall d’Hebron, 119–129, 08035 Barcelona, Spain
| | - Henry P. Parkman
- Temple University Hospital, 3401 N Broad St, Philadelphia, PA 19140, USA
| | - S. Mark Scott
- Queen Mary University of London, The Wingate Institute, 26 Ashfield Street, Whitechapel, London E1 2AJ, UK
| | - Jan Tack
- University Hospital Gasthuisberg, University of Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Magnus Simren
- Sahlgrenska Academy, University of Gothenburg, Blå stråket 5, 41345 Gothenburg, Sweden
| | - Hans Törnblom
- Sahlgrenska Academy, University of Gothenburg, Blå stråket 5, 41345 Gothenburg, Sweden
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Worthington JJ, Reimann F, Gribble FM. Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity. Mucosal Immunol 2018; 11:3-20. [PMID: 28853441 DOI: 10.1038/mi.2017.73] [Citation(s) in RCA: 162] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 07/14/2017] [Indexed: 02/06/2023]
Abstract
The intestinal epithelium must balance efficient absorption of nutrients with partitioning commensals and pathogens from the bodies' largest immune system. If this crucial barrier fails, inappropriate immune responses can result in inflammatory bowel disease or chronic infection. Enteroendocrine cells represent 1% of this epithelium and have classically been studied for their detection of nutrients and release of peptide hormones to mediate digestion. Intriguingly, enteroendocrine cells are the key sensors of microbial metabolites, can release cytokines in response to pathogen associated molecules and peptide hormone receptors are expressed on numerous intestinal immune cells; thus enteroendocrine cells are uniquely equipped to be crucial and novel orchestrators of intestinal inflammation. In this review, we introduce enteroendocrine chemosensory roles, summarize studies correlating enteroendocrine perturbations with intestinal inflammation and describe the mechanistic interactions by which enteroendocrine and mucosal immune cells interact during disease; highlighting this immunoendocrine axis as a key aspect of innate immunity.
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Affiliation(s)
- J J Worthington
- Lancaster University, Faculty of Health and Medicine, Division of Biomedical and Life Sciences, Lancaster, Lancashire, UK
| | - F Reimann
- University of Cambridge, Metabolic Research Laboratories, Wellcome Trust/MRC Institute of Metabolic Science & MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Cambridge, UK
| | - F M Gribble
- University of Cambridge, Metabolic Research Laboratories, Wellcome Trust/MRC Institute of Metabolic Science & MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Cambridge, UK
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31
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Duan L, Rao X, Braunstein Z, Toomey AC, Zhong J. Role of Incretin Axis in Inflammatory Bowel Disease. Front Immunol 2017; 8:1734. [PMID: 29270177 PMCID: PMC5723660 DOI: 10.3389/fimmu.2017.01734] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/23/2017] [Indexed: 12/25/2022] Open
Abstract
The inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract and involve a complicated reciprocity of environmental, genetic, and immunologic factors. Despite substantial advances in the foundational understanding of the immunological pathogenesis of IBD, the detailed mechanism of the pathological progression in IBD remains unknown. In addition to Th1/Th2 cells, whose role in IBD has been previously well defined, recent evidence indicates that Th17 cells and Tregs also play a crucial role in the development of IBD. Diets which contain excess sugars, salt, and fat may also be important actors in the pathogenesis of IBD, which may be the cause of high IBD incidence in western developed and industrialized countries. Up until now, the reason for the variance in prevalence of IBD between developed and developing countries has been unknown. This is partly due to the increasing popularity of western diets in developing countries, which makes the data harder to interpret. The enterocrinins glucagon-like peptides (GLPs), including GLP-1 and GLP-2, exhibit notable benefits on lipid metabolism, atherosclerosis formation, plasma glucose levels, and maintenance of gastric mucosa integrity. In addition to the regulation of nutrient metabolism, the emerging role of GLPs and their degrading enzyme dipeptidyl peptidase-4 (DPP-4) in gastrointestinal diseases has gained increasing attention. Therefore, here we review the function of the DPP-4/GLP axis in IBD.
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Affiliation(s)
- Lihua Duan
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Xiaoquan Rao
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, United States
| | - Zachary Braunstein
- Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
| | - Amelia C. Toomey
- Department of Health Sciences, University of Missouri, Columbia, MO, United States
| | - Jixin Zhong
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, United States
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32
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Uchida M, Kobayashi O, Shimizu K. Gastric emptying after artificial ulceration in rats: differences due to the site of the ulcer and the effects of prokinetic drugs. J Smooth Muscle Res 2017; 53:48-56. [PMID: 28652516 PMCID: PMC5487827 DOI: 10.1540/jsmr.53.48] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background This study aimed to evaluate the effects of the position of
an acetic acid-induced gastric ulcer and the effects of prokinetic drugs on gastric
emptying. Materials and Methods Male Sprague-Dawley rats were used in
this study. Acetic acid ulcers were induced either in the region between the fundus and
pylorus on the anterior wall of the stomach or in the glandular region on the greater
curvature of the stomach to determine whether there were regional differences in the
effect of the ulcers. Gastric emptying was evaluated with a breath test using
[1-13C] acetic acid. In addition, the effects of the prokinetic drugs,
metoclopramide and mosapride, on gastric emptying were also evaluated.
Results Acetic acid induced ulcers in the region between the fundus and
pylorus on the anterior wall of the stomach significantly delayed gastric emptying as
compared with control rats, but not the acetic acid induced ulcers in the glandular region
on the greater curvature of the stomach. Metoclopramide and mosapride did not improve the
delayed gastric emptying even at doses that enhanced gastric emptying in normal rats.
Conclusion These findings show that gastric emptying is influenced by
the position of the ulcer and the region between the fundus and pylorus on the anterior
wall plays an important role in gastric emptying. Moreover, it was found that
metoclopramide and mosapride do not improve the delayed gastric emptying caused by acetic
acid ulcers induced on the anterior wall in the region between the fundus and pylorus.
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Affiliation(s)
- Masayuki Uchida
- Food Science Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Japan
| | - Orie Kobayashi
- Food Science Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Japan
| | - Kimiko Shimizu
- Food Science Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Japan
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Camilleri M, Malhi H, Acosta A. Gastrointestinal Complications of Obesity. Gastroenterology 2017; 152:1656-1670. [PMID: 28192107 PMCID: PMC5609829 DOI: 10.1053/j.gastro.2016.12.052] [Citation(s) in RCA: 149] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 12/08/2016] [Accepted: 12/12/2016] [Indexed: 12/19/2022]
Abstract
Obesity usually is associated with morbidity related to diabetes mellitus and cardiovascular diseases. However, there are many gastrointestinal and hepatic diseases for which obesity is the direct cause (eg, nonalcoholic fatty liver disease) or is a significant risk factor, such as reflux esophagitis and gallstones. When obesity is a risk factor, it may interact with other mechanisms and result in earlier presentation or complicated diseases. There are increased odds ratios or relative risks of several gastrointestinal complications of obesity: gastroesophageal reflux disease, erosive esophagitis, Barrett's esophagus, esophageal adenocarcinoma, erosive gastritis, gastric cancer, diarrhea, colonic diverticular disease, polyps, cancer, liver disease including nonalcoholic fatty liver disease, cirrhosis, hepatocellular carcinoma, gallstones, acute pancreatitis, and pancreatic cancer. Gastroenterologists are uniquely poised to participate in the multidisciplinary management of obesity as physicians caring for people with obesity-related diseases, in addition to their expertise in nutrition and endoscopic interventions.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
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Abdalla SM, Kalra G, Moshiree B. Motility Evaluation in the Patient with Inflammatory Bowel Disease. Gastrointest Endosc Clin N Am 2016; 26:719-38. [PMID: 27633599 DOI: 10.1016/j.giec.2016.06.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Patients with inflammatory bowel disease (IBD) suffer frequently from functional bowel diseases (FBD) and motility disorders. Management of FBD and motility disorders in IBD combined with continued treatment of a patient's IBD symptoms will likely lead to better clinical outcomes and improve the patient's quality of life. The goals of this review were to summarize the most recent literature on motility disturbances in patients with IBD and to give a brief overview of the ranges of motility disturbances, from reflux disease to anorectal disorders, and discuss their diagnosis and specific management.
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Affiliation(s)
- Sherine M Abdalla
- Department of Medicine, Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1611 NW 12th Avenue, Central Building, 600D, Miami, FL 33136, USA
| | - Gorav Kalra
- Department of Medicine, Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1120 Northwest 14th Street, CRB, 11th Floor, Miami, FL 33136, USA
| | - Baha Moshiree
- Department of Medicine, University of Miami Miller School of Medicine, 1120 Northwest 14th Street, CRB Suite 971, Miami, FL 33136, USA.
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Zietek T, Rath E. Inflammation Meets Metabolic Disease: Gut Feeling Mediated by GLP-1. Front Immunol 2016; 7:154. [PMID: 27148273 PMCID: PMC4840214 DOI: 10.3389/fimmu.2016.00154] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/08/2016] [Indexed: 12/14/2022] Open
Abstract
Chronic diseases, such as obesity and diabetes, cardiovascular, and inflammatory bowel diseases (IBD) share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways, such as the unfolded protein response (UPR), alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular, the L-cell-derived incretin hormone glucagon-like peptide 1 (GLP-1) has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D). Yet, accumulating data indicate a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment, including the microbiota via receptors and transporters. Subsequently, mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling. This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity, and disease.
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Affiliation(s)
- Tamara Zietek
- Department of Nutritional Physiology, Technische Universität München , Freising , Germany
| | - Eva Rath
- Chair of Nutrition and Immunology, Technische Universität München , Freising , Germany
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