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Gorecki AM, Anyaegbu CC, Fitzgerald M, Fuller KA, Anderton RS. Imaging flow cytometry reveals LPS-induced changes to intracellular intensity and distribution of α-synuclein in a TLR4-dependent manner in STC-1 cells. Methods 2025; 234:93-111. [PMID: 39486562 DOI: 10.1016/j.ymeth.2024.10.009] [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: 10/03/2023] [Revised: 10/15/2024] [Accepted: 10/18/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Parkinson's disease is a chronic neurodegenerative disorder, where pathological protein aggregates largely composed of phosphorylated α-synuclein are implicated in disease pathogenesis and progression. Emerging evidence suggests that the interaction between pro-inflammatory microbial factors and the gut epithelium contributes to α-synuclein aggregation in the enteric nervous system. However, the cellular sources and mechanisms for α-synuclein pathology in the gut are still unclear. METHODS The STC-1 cell line, which models an enteroendocrine population capable of communicating with the gut microbiota, immune and nervous systems, was treated with a TLR4 inhibitor (TAK-242) prior to microbial lipopolysaccharide (LPS) exposure to investigate the role of TLR4 signalling in α-synuclein alterations. Antibodies targeting the full-length protein (α-synuclein) and the Serine-129 phosphorylated form (pS129) were used. Complex, multi-parametric image analysis was conducted through confocal microscopy (with Zen 3.8 analysis) and imaging flow cytometry (with IDEAS® analysis). RESULTS Confocal microscopy revealed heterogenous distribution of α-synuclein and pS129 in STC-1 cells, with prominent pS129 staining along cytoplasmic processes. Imaging flow cytometry further quantified the relationship between various α-synuclein morphometric features. Thereafter, imaging flow cytometry demonstrated a dose-specific effect of LPS, where the low (8 μg/mL), but not high dose (32 μg/mL), significantly altered measures related to α-synuclein intensity, distribution, and localisation. Pre-treatment with a TLR4 inhibitor TAK-242 alleviated some of these significant alterations. CONCLUSION This study demonstrates that LPS-TLR4 signalling alters the intracellular localisation of α-synuclein in enteroendocrine cells in vitro and showcases the utility of combining imaging flow cytometry to investigate subtle protein changes that may not be apparent through confocal microscopy alone. Further investigation is required to understand the apparent dose-dependent effects of LPS on α-synuclein in the gut epithelium in healthy states as well as conditions such as Parkinson's disease.
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Affiliation(s)
- Anastazja M Gorecki
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA, Australia; Curtin Health Innovation Research Institute, Curtin University, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia; Perron Institute for Neurological and Translational Science, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia; School of Biological Sciences, University of Western Australia, Crawley, WA, Australia.
| | - Chidozie C Anyaegbu
- Curtin Health Innovation Research Institute, Curtin University, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia; Perron Institute for Neurological and Translational Science, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia
| | - Melinda Fitzgerald
- Curtin Health Innovation Research Institute, Curtin University, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia; Perron Institute for Neurological and Translational Science, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia
| | - Kathryn A Fuller
- Translational Cancer Pathology Laboratory, School of Biomedical Sciences (M504), The University of Western Australia, Crawley, WA, Australia
| | - Ryan S Anderton
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA, Australia
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Raya Tonetti F, Eguileor A, Llorente C. Goblet cells: guardians of gut immunity and their role in gastrointestinal diseases. EGASTROENTEROLOGY 2024; 2:e100098. [PMID: 39524932 PMCID: PMC11542612 DOI: 10.1136/egastro-2024-100098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 08/08/2024] [Indexed: 11/16/2024]
Abstract
Goblet cells (GCs) are specialised guardians lining the intestine. They play a critical role in gut defence and immune regulation. GCs continuously secrete mucus creating a physical barrier to protect from pathogens while harbouring symbiotic gut bacteria adapted to live within the mucus. GCs also form specialised GC-associated passages in a dynamic and regulated manner to deliver luminal antigens to immune cells, promoting gut tolerance and preventing inflammation. The composition of gut bacteria directly influences GC function, highlighting the intricate interplay between these components of a healthy gut. Indeed, imbalances in the gut microbiome can disrupt GC function, contributing to various gastrointestinal diseases like colorectal cancer, inflammatory bowel disease, cystic fibrosis, pathogen infections and liver diseases. This review explores the interplay between GCs and the immune system. We delve into the underlying mechanisms by which GC dysfunction contributes to the development and progression of gastrointestinal diseases. Finally, we examine current and potential treatments that target GCs and represent promising avenues for further investigation.
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Affiliation(s)
- Fernanda Raya Tonetti
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, California, USA
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Llorente C. The Imperative for Innovative Enteric Nervous System-Intestinal Organoid Co-Culture Models: Transforming GI Disease Modeling and Treatment. Cells 2024; 13:820. [PMID: 38786042 PMCID: PMC11119846 DOI: 10.3390/cells13100820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/29/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024] Open
Abstract
This review addresses the need for innovative co-culture systems integrating the enteric nervous system (ENS) with intestinal organoids. The breakthroughs achieved through these techniques will pave the way for a transformative era in gastrointestinal (GI) disease modeling and treatment strategies. This review serves as an introduction to the companion protocol paper featured in this journal. The protocol outlines the isolation and co-culture of myenteric and submucosal neurons with small intestinal organoids. This review provides an overview of the intestinal organoid culture field to establish a solid foundation for effective protocol application. Remarkably, the ENS surpasses the number of neurons in the spinal cord. Referred to as the "second brain", the ENS orchestrates pivotal roles in GI functions, including motility, blood flow, and secretion. The ENS is organized into myenteric and submucosal plexuses. These plexuses house diverse subtypes of neurons. Due to its proximity to the gut musculature and its cell type complexity, there are methodological intricacies in studying the ENS. Diverse approaches such as primary cell cultures, three-dimensional (3D) neurospheres, and induced ENS cells offer diverse insights into the multifaceted functionality of the ENS. The ENS exhibits dynamic interactions with the intestinal epithelium, the muscle layer, and the immune system, influencing epithelial physiology, motility, immune responses, and the microbiome. Neurotransmitters, including acetylcholine (ACh), serotonin (5-HT), and vasoactive intestinal peptide (VIP), play pivotal roles in these intricate interactions. Understanding these dynamics is imperative, as the ENS is implicated in various diseases, ranging from neuropathies to GI disorders and neurodegenerative diseases. The emergence of organoid technology presents an unprecedented opportunity to study ENS interactions within the complex milieu of the small and large intestines. This manuscript underscores the urgent need for standardized protocols and advanced techniques to unravel the complexities of the ENS and its dynamic relationship with the gut ecosystem. The insights gleaned from such endeavors hold the potential to revolutionize GI disease modeling and treatment paradigms.
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Affiliation(s)
- Cristina Llorente
- Department of Medicine, University of California San Diego, MC0063, 9500 Gilman Drive, La Jolla, CA 92093, USA
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El Mahdy RN, Nader MA, Helal MG, Abu-Risha SE, Abdelmageed ME. Tiron ameliorates acetic acid-induced colitis in rats: Role of TGF-β/EGFR/PI3K/NF-κB signaling pathway. Int Immunopharmacol 2024; 128:111587. [PMID: 38286073 DOI: 10.1016/j.intimp.2024.111587] [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: 12/02/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 01/31/2024]
Abstract
BACKGROUND Ulcerative colitis (UC), an ongoing inflammatory disorder of the colon, is marked by persistent mucosal surface irritation extending from the rectum to the near-proximal colon. Tiron is a synthetic analogue of vitamin E which is known to have antioxidant and anti-inflammatory effects in various animal models, so the goal of this study was to find out whether Tiron had any preventive impacts on UC inflicted by acetic acid (A.A) exposure in rats. METHOD Tiron (235 and 470 mg/kg) was administered intra-peritoneally for 2 weeks, and A.A (2 ml, 3 % v/v) was injected intra-rectally to cause colitis. Colon tissues and blood samples were then collected for measurement of various inflammatory and oxidative stress biomarkers. RESULTS Tiron administration significantly diminished lactate dehydrogenase (LDH), C-reactive protein (CRP), colon weight, and the weight/length ratio of the colon as compared to A.A-injected rats. Additionally, Tiron attenuated oxidative stress biomarkers. Tiron also enforced the levels of Glucagon-like peptide-1 (GLP-1) and trefoil factor-3 (TFF-3), while it greatly lowered the expression of nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interferon-γ (IFN-γ), and transforming growth factor-1(TGF-β1), phosphorylated epidermal growth factor receptor (P-EGFR), phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) expression in colonic cellular structures. Furthermore, colonichistopathologic damages, revealed by hematoxylin and eosin (H&E) and Alcian Blue stain, were significantly decreased upon Tiron administration. CONCLUSION Tiron prevented A.A-induced colitis in rats via modulating inflammatory pathway TGF-β1/P-EGFR/PI3K/AKT/NF-κB, alongside managing the oxidant/antioxidant equilibrium, and boosting the reliability of the intestinal barrier.
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Affiliation(s)
- Raghda N El Mahdy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Manar A Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Manar G Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Sally E Abu-Risha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Marwa E Abdelmageed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
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Engin ED. Microbiota and Lipotoxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:357-372. [PMID: 39287858 DOI: 10.1007/978-3-031-63657-8_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Gut microbiota is an indispensable commensal partner of human superorganism. The wealth of genetic repertoire provided by these microorganisms extends host's substrate processing capability. Energy and nutrient harvesting machinery primarily depends on the proper function of these organisms. However, the dynamic composition of microbiota changes with age, lifestyle, stress factors, infections, medications, and host pathophysiological conditions. Host immune system is primarily responsible for shaping up the microbial community and sustaining the symbiotic state. This involves controlling the delicate balance between agility toward pathobionts and tolerance toward symbionts. When things go wrong with this crosstalk, dysbiosis may arise.Metabolic syndrome is a multisystemic, low-grade chronic inflammatory disease that involves dyslipidemia, glucose intolerance, insulin resistance, and central obesity. Excess caloric intake with high-sugar and high-fat diet promote high energy harvesting and lipogenesis. The secretion of adipokines accompanies lipid spillover from fat cells, which contribute to insulin resistance and the expansion of adipose tissue in ectopic sites. Proinflammatory cytokines from adipose tissue macrophages increase the extent of adipose dysfunction.The inflammatory nature of obesity and metabolic syndrome recall the connection between dysbiosis and immune dysfunction. A remarkable association exits between obesity, inflammatory bowel disease, gluten-sensitive enteropathy, and dysbiosis. These conditions compromise the gut mucosa barrier and allow lipopolysaccharide to enter circulation. Unresolved chronic inflammation caused by one condition may overlap or trigger the other(s). Experimental studies and therapeutic trials of fecal microbiota transplantation promise limited improvement in some of these conditions.Typically, metabolic syndrome is considered as a consequence of overnutrition and the vicious cycle of lipogenesis, lipid accumulation, and chronic low-level inflammation. Because of the complex nature of this disorder, it remains inconclusive whether dysbiosis is a cause or consequence of obesity and metabolic syndrome.
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Affiliation(s)
- Evren Doruk Engin
- Biotechnology Institute, Ankara University, Gumusdere, Ankara, Turkey.
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Dicks LMT. Our Mental Health Is Determined by an Intrinsic Interplay between the Central Nervous System, Enteric Nerves, and Gut Microbiota. Int J Mol Sci 2023; 25:38. [PMID: 38203207 PMCID: PMC10778721 DOI: 10.3390/ijms25010038] [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: 11/22/2023] [Revised: 12/13/2023] [Accepted: 12/16/2023] [Indexed: 01/12/2024] Open
Abstract
Bacteria in the gut microbiome play an intrinsic part in immune activation, intestinal permeability, enteric reflex, and entero-endocrine signaling. The gut microbiota communicates with the central nervous system (CNS) through the production of bile acids, short-chain fatty acids (SCFAs), glutamate (Glu), γ-aminobutyric acid (GABA), dopamine (DA), norepinephrine (NE), serotonin (5-HT), and histamine. A vast number of signals generated in the gastrointestinal tract (GIT) reach the brain via afferent fibers of the vagus nerve (VN). Signals from the CNS are returned to entero-epithelial cells (EES) via efferent VN fibers and communicate with 100 to 500 million neurons in the submucosa and myenteric plexus of the gut wall, which is referred to as the enteric nervous system (ENS). Intercommunications between the gut and CNS regulate mood, cognitive behavior, and neuropsychiatric disorders such as autism, depression, and schizophrenia. The modulation, development, and renewal of nerves in the ENS and changes in the gut microbiome alter the synthesis and degradation of neurotransmitters, ultimately influencing our mental health. The more we decipher the gut microbiome and understand its effect on neurotransmission, the closer we may get to developing novel therapeutic and psychobiotic compounds to improve cognitive functions and prevent mental disorders. In this review, the intricate control of entero-endocrine signaling and immune responses that keep the gut microbiome in a balanced state, and the influence that changing gut bacteria have on neuropsychiatric disorders, are discussed.
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Affiliation(s)
- Leon M T Dicks
- Department of Microbiology, Stellenbosch University, Private Bag X1, Matieland, Stellenbosch 7602, South Africa
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Gorecki AM, Spencer H, Meloni BP, Anderton RS. The Poly-Arginine Peptide R18D Interferes with the Internalisation of α-Synuclein Pre-Formed Fibrils in STC-1 Enteroendocrine Cells. Biomedicines 2023; 11:2089. [PMID: 37626586 PMCID: PMC10452853 DOI: 10.3390/biomedicines11082089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
In Parkinson's disease (PD), gut inflammation is hypothesised to contribute to α-synuclein aggregation, but gastrointestinal α-synuclein expression is poorly characterised. Cationic arginine-rich peptides (CARPs) are an emerging therapeutic option that exerts various neuroprotective effects and may target the transmission of protein aggregates. This study aimed to investigate endogenous α-synuclein expression in enteroendocrine STC-1 cells and the potential of the CARP, R18D (18-mer of D-arginine), to prevent internalisation of pre-formed α-synuclein fibrils (PFFs) in enteroendocrine cells in vitro. Through confocal microscopy, the immunoreactivity of full-length α-synuclein and the serine-129 phosphorylated form (pS129) was investigated in STC-1 (mouse enteroendocrine) cells. Thereafter, STC-1 cells were exposed to PFFs tagged with Alexa-Fluor 488 (PFF-488) for 2 and 24 h and R18D-FITC for 10 min. After confirming the uptake of both PFFs and R18D-FITC through fluorescent microscopy, STC-1 cells were pre-treated with R18D (5 or 10 μM) for 10 min prior to 2 h of PFF-488 exposure. Immunoreactivity for endogenous α-synuclein and pS129 was evident in STC-1 cells, with prominent pS129 staining along cytoplasmic processes and in perinuclear areas. STC-1 cells internalised PFFs, confirmed through co-localisation of PFF-488 and human-specific α-synuclein immunoreactivity. R18D-FITC entered STC-1 cells within 10 min and pre-treatment of STC-1 cells with R18D interfered with PFF uptake. The endogenous presence of α-synuclein in enteroendocrine cells, coupled with their rapid uptake of PFFs, demonstrates a potential for pathogenic spread of α-synuclein aggregates in the gut. R18D is a novel therapeutic approach to reduce the intercellular transmission of α-synuclein pathology.
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Affiliation(s)
- Anastazja M. Gorecki
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA 6160, Australia; (H.S.)
- School of Biological Sciences, University of Western Australia, Crawley, WA 6009, Australia
- Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Holly Spencer
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA 6160, Australia; (H.S.)
| | - Bruno P. Meloni
- Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA 6009, Australia
- Department of Neurosurgery, Sir Charles Gairdner Hospital, First Floor, G-Block, QEII Medical Centre, Nedlands, WA 6008, Australia
| | - Ryan S. Anderton
- School of Health Sciences, University of Notre Dame Australia, Fremantle, WA 6160, Australia; (H.S.)
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Arvanitakis K, Koufakis T, Popovic D, Maltese G, Mustafa O, Doumas M, Giouleme O, Kotsa K, Germanidis G. GLP-1 Receptor Agonists in Obese Patients with Inflammatory Bowel Disease: from Molecular Mechanisms to Clinical Considerations and Practical Recommendations for Safe and Effective Use. Curr Obes Rep 2023; 12:61-74. [PMID: 37081371 DOI: 10.1007/s13679-023-00506-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/09/2023] [Indexed: 04/22/2023]
Abstract
PURPOSE OF REVIEW To discuss current literature and provide practical recommendations for the safe and effective use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in people with inflammatory bowel disease (IBD) and type 2 diabetes (T2D) and/or obesity. The molecular mechanisms that justify the potential benefits of GLP-1 RA in IBD and the links between IBD, obesity, and cardiovascular disease are also discussed. RECENT FINDINGS Preliminary data suggest that GLP-1 RA can modulate crucial pathways in the pathogenesis of IBD, such as chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, setting the stage for human trials to investigate the role of these agents in the treatment of IBD among people with or without diabetes and obesity. However, gastrointestinal side effects related to GLP-1 RA need appropriate clinical management to mitigate risks and maximize the benefits of therapy in people with IBD. GLP-1 RA originally emerged as drugs for the treatment of hyperglycemia and are currently licensed for the management of T2D and/or overweight/obesity. However, their wealth of pleiotropic actions soon raised expectations that they might confer benefits on non-metabolic disorders. Future studies are expected to clarify whether GLP-1 RA deserve an adjunct place in the arsenal of drugs against IBD.
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Affiliation(s)
- Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Djordje Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Giuseppe Maltese
- Department of Diabetes and Endocrinology, Epsom & St Helier University Hospitals, Surrey, SM5 1AA, UK
- Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences & Medicine, King's College, London, UK
| | - Omar Mustafa
- Department of Diabetes, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
- King's College London, London, UK
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Olga Giouleme
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece.
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece.
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Dar SH, Maniya MT, Merza N, Musheer A, Zahid M, Ahmed F, Shurjeel Q, Qazi S, Ahmed A, Shah H, Zafar A, Iqbal AZ, Khan SF, Rizwan T, Ligresti R. The Association of Antibiotic Exposure with New-Onset Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Clin Res Hepatol Gastroenterol 2023; 47:102129. [PMID: 37116651 DOI: 10.1016/j.clinre.2023.102129] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 04/16/2023] [Accepted: 04/19/2023] [Indexed: 04/30/2023]
Abstract
INTRODUCTION The role of antibiotics in the development of inflammatory bowel disease (IBD) remains controversial, primarily due to conflicting data from individual studies. We conduct a systematic review and meta-analysis to study the effect of antibiotic exposure on IBD development. METHODOLOGY The MEDLINE and Cochrane CENTRAL databases were queried from their inception to April 2021 for published articles studying the association between antibiotic exposure and new-onset IBD. Our analysis was stratified by timing of antibiotic exposure - exposure in childhood and any lifetime exposure. Adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) from each study were pooled using a random-effects model. RESULTS 10 case-control studies and 2 cohort studies (N=29,880 IBD patients and N=715,548 controls) were included. Patients with Crohn's Disease (CD), compared with controls, were associated significantly with antibiotic exposure in childhood and any lifetime exposure to antibiotics (OR 1.52 [1.23-1.87]; p<0.00001). Patients with Ulcerative Colitis (UC), compared with controls, reported non-significant association with antibiotic exposure in childhood and any lifetime exposure. (OR 1.11 [0.93-1.33]; p=0.25) CONCLUSION: This meta-analysis suggests that exposure to antibiotics significantly increases the odds of developing CD and IBD in general. These findings re-emphasize the importance of cautious and judicious use of antibiotics.
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Affiliation(s)
- Sophia Haroon Dar
- Department of Medicine, Long Island Jewish Medical Center, Queens, New York, USA.
| | | | - Nooraldin Merza
- Department of Internal Medicine, University of Toledo, Ohio, USA
| | - Adeena Musheer
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Mariyam Zahid
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Furqan Ahmed
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Qazi Shurjeel
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Sana Qazi
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Aymen Ahmed
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Hamza Shah
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Adnan Zafar
- Department of Medicine, CMH Lahore Medical College, Lahore, Pakistan
| | - Arsalan Zafar Iqbal
- Department of Medicine, FMH of College of Medicine and Dentistry, Lahore, Pakistan
| | - Shah Fahad Khan
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Tehlil Rizwan
- Department of Medicine, AMITA Health Saint Joseph Hospital, Chicago, Illinois, USA
| | - Rosario Ligresti
- Hackensack University School of Medicine, Medical Director, National Pancreas Foundation, Hackensack University Medical Center, Hackensack, NJ
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Babu G, Mohanty B. Neurotensin modulation of lipopolysaccharide induced inflammation of gut-liver axis: Evaluation using neurotensin receptor agonist and antagonist. Neuropeptides 2023; 97:102297. [PMID: 36368076 DOI: 10.1016/j.npep.2022.102297] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 10/13/2022] [Accepted: 10/16/2022] [Indexed: 11/07/2022]
Abstract
Lipopolysaccharide (LPS), a toxic component of the cell wall of Gram-negative bacteria, is a potent immune stressor. LPS-induced inflammation of the gut-liver axis is well demonstrated. Neurotensin (NTS), a tri-decapeptide present in the gastrointestinal tract, has anti-inflammatory, anti-oxidative, and growth-promoting properties. This study elucidated the efficacy of PD149163, the type I NTS receptor agonist (NTS1) in the modulation of LPS-induced inflammation of the gut-liver axis of mice. Young-adult female mice (Age: 8 weeks; BW: 25 ± 2.5 g) were maintained in six groups (6/group); Group I as control and Group II, III & IV were exposed to LPS (1 mg/kg BW/Day; i.p.) for five days. LPS pre-exposed Group III and Group IV mice were treated with NTS1 agonist PD149163 (100 μg/kg BW i.p.) and antagonist SR48692 (0.5 mg/kg BW i.p.) respectively for 28 days. Group V and Group VI mice were exposed to only PD149163 and only SR48692 respectively with the doses as mentioned above for 28 days. Group I and LPS-exposed Group II mice were also maintained four weeks without further treatment. Histopathology revealed LPS-induced inflammation of the gut and liver. Significant elevation of plasma TNF-α and IL-6 and serum ALT and AST reflected as biomarkers of inflammation. Oxidative stress on both organs was distinct from decreased glutathione reductase and increased lipid peroxidation. PD149163 but not SR48692 ameliorated LPS-induced inflammation in both gut and liver counteracting inflammatory responses and oxidative stress. The use of NTS agonists including PD149163 could be exploited for therapeutic intervention of inflammatory diseases including that of the gut-liver axis.
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Affiliation(s)
- Gyan Babu
- Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh 211002, India
| | - Banalata Mohanty
- Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh 211002, India.
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Elsasser TH, Ma B, Ravel J, Kahl S, Gajer P, Cross A. Short-term feeding of defatted bovine colostrum mitigates inflammation in the gut via changes in metabolites and microbiota in a chicken animal model. Anim Microbiome 2023; 5:6. [PMID: 36703224 PMCID: PMC9878500 DOI: 10.1186/s42523-023-00225-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 01/10/2023] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Nondrug supplement strategies to improve gut health have largely focused on the effects of individual compounds to improve one aspect of gut homeostasis. However, there is no comprehensive assessment of the reproducible effects of oral, short-term, low-level colostrum supplementation on gut inflammation status that are specific to the ileum. Herein, a chicken animal model highly responsive to even mild gut inflammatory stimuli was employed to compare the outcomes of feeding a standard diet (CON) to those of CON supplemented with a centrifuge-defatted bovine colostrum (BC) or a nonfat dried milk (NFDM) control on the efficiency of nutrient use, ileal morphology, gut nitro-oxidative inflammation status, metabolites, and the composition of the microbiota. RESULTS A repeated design, iterative multiple regression model was developed to analyze how BC affected ileal digesta-associated anti-inflammatory metabolite abundance coincident with observed changes in the ileal microbiome, mitigation of epithelial inflammation, and ileal surface morphology. An improved whole body nutrient use efficiency in the BC group (v CON and NFDM) coincided with the observed increased ileum absorptive surface and reduced epithelial cell content of tyrosine-nitrated protein (NT, biomarker of nitro-oxidative inflammatory stress). Metabolome analysis revealed that anti-inflammatory metabolites were significantly greater in abundance in BC-fed animals. BC also had a beneficial BC impact on microbiota, particularly in promoting the presence of the bacterial types associated with eubiosis and the segmented filamentous bacteria, Candidatus Arthromitus. CONCLUSION The data suggest that an anti-inflammatory environment in the ileum was more evident in BC than in the other feeding groups and associated with an increased content of statistically definable groups of anti-inflammatory metabolites that appear to functionally link the observed interactions between the host's improved gut health with an observed increase in whole body nutrient use efficiency, beneficial changes in the microbiome and immunometabolism.
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Affiliation(s)
- Ted H. Elsasser
- grid.463419.d0000 0001 0946 3608Animal Biosciences and Biotechnology Laboratory, USA Department of Agriculture (USDA), Agricultural Research Service (ARS), Beltsville, MD 20705 USA
| | - Bing Ma
- grid.411024.20000 0001 2175 4264Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201 USA
| | - Jacques Ravel
- grid.411024.20000 0001 2175 4264Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201 USA
| | - Stanislaw Kahl
- grid.463419.d0000 0001 0946 3608Animal Biosciences and Biotechnology Laboratory, USA Department of Agriculture (USDA), Agricultural Research Service (ARS), Beltsville, MD 20705 USA
| | - Pawel Gajer
- grid.411024.20000 0001 2175 4264Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201 USA
| | - Alan Cross
- grid.411024.20000 0001 2175 4264Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201 USA
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12
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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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13
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Xiong Y, Xu G, Chen M, Ma H. Intestinal Uptake and Tolerance to Food Antigens. Front Immunol 2022; 13:906122. [PMID: 35757706 PMCID: PMC9226482 DOI: 10.3389/fimmu.2022.906122] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/16/2022] [Indexed: 11/24/2022] Open
Abstract
Food allergy is a growing concern due to its increasing world-wide incidence. Strict avoidance of allergens is a passive treatment strategy. Since the mechanisms responsible for the occurrence and development of food allergy have not yet been fully elucidated, effective individualized treatment options are lacking. In this review, we summarize the pathways through which food antigens enter the intestine and review the proposed mechanisms describing how the intestine acquires and tolerates food antigens. When oral tolerance is not established, food allergy occurs. In addition, we also discuss the contribution of commensal bacteria of the gut in shaping tolerance to food antigens in the intestinal tract. Finally, we propose that elucidating the mechanisms of intestinal uptake and tolerance of food antigens will provide additional clues for potential treatment options for food allergy.
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Affiliation(s)
- Yuhong Xiong
- Department of Pediatrics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Institute of Immunology, The Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Guifeng Xu
- Department of Pediatrics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mingwu Chen
- Department of Pediatrics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Hongdi Ma
- Department of Pediatrics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Institute of Immunology, The Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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14
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Morales-Magaña J, Arciniega-Martínez IM, Drago-Serrano ME, Reséndiz-Albor AA, Jarillo-Luna RA, Cruz-Baquero A, Gómez-López M, Guzmán-Mejía F, Pacheco-Yépez J. Cholecystokinin Outcome on Markers of Intestinal IgA Antibody Response. Curr Issues Mol Biol 2022; 44:2542-2553. [PMID: 35735614 PMCID: PMC9221551 DOI: 10.3390/cimb44060173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/23/2022] [Accepted: 05/26/2022] [Indexed: 11/17/2022] Open
Abstract
Cholecystokinin 8 (CCK8) is an entero-octapeptide that participates in crosstalk with components of intestinal immunity via the CCK receptor (CCKR), but its role in modulation of the IgA response is not fully known under physiological conditions. Male eight-week-old BALB/c mice each were intraperitoneally injected once during 7 days with CCK8, devazapide (CCKR1 antagonist), L365,260 (CCKR2 antagonist) or vehicle (sham group). In intestinal lavages, total and secretory IgA (SIgA) were determined by ELISA; in lamina propria, IgA+ B lymphocytes and IgA+ plasma cells were analyzed by flow cytometry; mRNA levels of polymeric immunoglobulin receptor (pIgR) in epithelial cells and α chain, interleukins (ILs) in lamina propria cells were assessed by qRTPCR. Regarding the sham conditions, IgA+ plasma-cell percentage and IL-2, IL-5, IL-10 and transforming growth factor-β (TGF-β) mRNA levels were either increased by CCK8 or decreased by both CCKR antagonists. For IgA/SIgA responses, IL-4/IL-6 mRNA levels were decreased by all drugs and pIgR mRNA was increased by CCK8 and reduced by L365,260. IgA+ B cell percentage and α chain mRNA levels were elicited by CCK8 and L365,260. Data suggested a presumable differential role of CCK/CCKR on the IgA-response; outcome of L365,260 on the elicitation of IgA+ B cells and α chain mRNA needs further examination.
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Affiliation(s)
- Juan Morales-Magaña
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis esq. Salvador Díaz Mirón s/n, Mexico City 11340, Mexico; (J.M.-M.); (R.A.J.-L.); (M.G.-L.)
| | - Ivonne Maciel Arciniega-Martínez
- Laboratorio de Inmunidad de Mucosas, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis esq. Salvador Díaz Mirón s/n, Mexico City 11340, Mexico; (I.M.A.-M.); (A.A.R.-A.)
| | - Maria Elisa Drago-Serrano
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Calzada del Hueso No. 1100, Mexico City 04960, Mexico; (M.E.D.-S.); (F.G.-M.)
| | - Aldo Arturo Reséndiz-Albor
- Laboratorio de Inmunidad de Mucosas, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis esq. Salvador Díaz Mirón s/n, Mexico City 11340, Mexico; (I.M.A.-M.); (A.A.R.-A.)
| | - Rosa Adriana Jarillo-Luna
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis esq. Salvador Díaz Mirón s/n, Mexico City 11340, Mexico; (J.M.-M.); (R.A.J.-L.); (M.G.-L.)
- Departamento de Formación Básica Disciplinaria, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis esq. Salvador Díaz Mirón s/n, Mexico City 11340, Mexico
| | - Andrea Cruz-Baquero
- Bacteriología, Facultad de Ciencias de la Salud, Universidad Colegio Mayor de Cundinamarca, Bogotá 111311, Colombia;
| | - Modesto Gómez-López
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis esq. Salvador Díaz Mirón s/n, Mexico City 11340, Mexico; (J.M.-M.); (R.A.J.-L.); (M.G.-L.)
| | - Fabiola Guzmán-Mejía
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Calzada del Hueso No. 1100, Mexico City 04960, Mexico; (M.E.D.-S.); (F.G.-M.)
| | - Judith Pacheco-Yépez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis esq. Salvador Díaz Mirón s/n, Mexico City 11340, Mexico; (J.M.-M.); (R.A.J.-L.); (M.G.-L.)
- Correspondence: ; Tel.: +52-5557296000 (ext. 62817)
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15
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Taleb Z, Carmona-Alcocer V, Stokes K, Haireek M, Wang H, Collins SM, Khan WI, Karpowicz P. BMAL1 Regulates the Daily Timing of Colitis. Front Cell Infect Microbiol 2022; 12:773413. [PMID: 35223537 PMCID: PMC8863668 DOI: 10.3389/fcimb.2022.773413] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Many physiological functions exhibit circadian rhythms: oscillations in biological processes that occur in a 24-hour period. These daily rhythms are maintained through a highly conserved molecular pacemaker known as the circadian clock. Circadian disruption has been proposed to cause increased risk of Inflammatory Bowel Disease (IBD) but the underlying mechanisms remain unclear. Patients with IBD experience chronic inflammation and impaired regeneration of intestinal epithelial cells. Previous animal-based studies have revealed that colitis models of IBD are more severe in mice without a circadian clock but the timing of colitis, and whether its inflammatory and regenerative processes have daily rhythms, remains poorly characterized. We tested circadian disruption using Bmal1-/- mutant mice that have a non-functional circadian clock and thus no circadian rhythms. Dextran Sulfate Sodium (DSS) was used to induce colitis. The disease activity of colitis was found to exhibit time-dependent variation in Bmal1+/+ control mice but is constant and elevated in Bmal1-/- mutants, who exhibit poor recovery. Histological analyses indicate worsened colitis severity in Bmal1-/- mutant colon, and colon infiltration of immune system cells shows a daily rhythm that is lost in the Bmal1-/- mutant. Similarly, epithelial proliferation in the colon has a daily rhythm in Bmal1+/+ controls but not in Bmal1-/- mutants. Our results support a critical role of a functional circadian clock in the colon which drives 24-hour rhythms in inflammation and healing, and whose disruption impairs colitis recovery. This indicates that weakening circadian rhythms not only worsens colitis, but delays healing and should be taken into account in the management of IBD. Recognition of this is important in the management of IBD patients required to do shift work.
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Affiliation(s)
- Zainab Taleb
- Department of Biomedical Sciences, University of Windsor, Windsor, ON, Canada
| | | | - Kyle Stokes
- Department of Biomedical Sciences, University of Windsor, Windsor, ON, Canada
| | - Marta Haireek
- Department of Biomedical Sciences, University of Windsor, Windsor, ON, Canada
| | - Huaqing Wang
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Stephen M. Collins
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Waliul I. Khan
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Phillip Karpowicz
- Department of Biomedical Sciences, University of Windsor, Windsor, ON, Canada
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16
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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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17
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Zatorski H, Salaga M, Zielińska M, Mokrowiecka A, Jacenik D, Krajewska WM, Małecka-Panas E, Fichna J. Colonic inflammation induces changes in glucose levels through modulation of incretin system. Pharmacol Rep 2021; 73:1670-1679. [PMID: 34535873 PMCID: PMC8599322 DOI: 10.1007/s43440-021-00327-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 11/30/2022]
Abstract
Background The role of the incretin hormone, glucagon-like peptide (GLP-1), in Crohn’s disease (CD), is still poorly understood. The aim of this study was to investigate whether colitis is associated with changes in blood glucose levels and the possible involvement of the incretin system as an underlaying factor. Methods We used a murine model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Macroscopic and microscopic score and expression of inflammatory cytokines were measured. The effect of colitis on glucose level was studied by measurement of fasting glucose and GLP-1, dipeptidyl peptidase IV (DPP IV) levels, prohormone convertase 1/3 (PC 1/3) and GLP-1 receptor (GLP-1R) expression in mice. We also measured the level of GLP-1, DPP IV and expression of glucagon (GCG) and PC 1/3 mRNA in serum and colon samples from healthy controls and CD patients. Results Fasting glucose levels were increased in animals with colitis compared to controls. GLP-1 was decreased in both serum and colon of mice with colitis in comparison to the control group. DPP IV levels were significantly increased in serum, but not in the colon of mice with colitis as compared to healthy animals. Furthermore, PC 1/3 and GLP-1R expression levels were increased in mice with colitis as compared to controls. In humans, no differences were observed in fasting glucose level between healthy subjects and CD patients. GLP-1 levels were significantly decreased in the serum. Interestingly, GLP-1 level was significantly increased in colon samples of CD patients compared to healthy subjects. No significant differences in DPP IV levels in serum and colon samples were observed between groups. Conclusions Changes in the incretin system during colitis seem to contribute to the impaired glucose levels. Differences in incretin levels seem to be modulated by degrading enzyme DPP-IV and PC 1/3. Obtained results suggest that the incretin system may become a novel therapeutic approach in the treatment of CD.
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Affiliation(s)
- Hubert Zatorski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.,Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - Maciej Salaga
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Marta Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Anna Mokrowiecka
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Wanda Małgorzata Krajewska
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Ewa Małecka-Panas
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
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18
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Yoshinari Y, Kosakamoto H, Kamiyama T, Hoshino R, Matsuoka R, Kondo S, Tanimoto H, Nakamura A, Obata F, Niwa R. The sugar-responsive enteroendocrine neuropeptide F regulates lipid metabolism through glucagon-like and insulin-like hormones in Drosophila melanogaster. Nat Commun 2021; 12:4818. [PMID: 34376687 PMCID: PMC8355161 DOI: 10.1038/s41467-021-25146-w] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 07/24/2021] [Indexed: 02/08/2023] Open
Abstract
The enteroendocrine cell (EEC)-derived incretins play a pivotal role in regulating the secretion of glucagon and insulins in mammals. Although glucagon-like and insulin-like hormones have been found across animal phyla, incretin-like EEC-derived hormones have not yet been characterised in invertebrates. Here, we show that the midgut-derived hormone, neuropeptide F (NPF), acts as the sugar-responsive, incretin-like hormone in the fruit fly, Drosophila melanogaster. Secreted NPF is received by NPF receptor in the corpora cardiaca and in insulin-producing cells. NPF-NPFR signalling resulted in the suppression of the glucagon-like hormone production and the enhancement of the insulin-like peptide secretion, eventually promoting lipid anabolism. Similar to the loss of incretin function in mammals, loss of midgut NPF led to significant metabolic dysfunction, accompanied by lipodystrophy, hyperphagia, and hypoglycaemia. These results suggest that enteroendocrine hormones regulate sugar-dependent metabolism through glucagon-like and insulin-like hormones not only in mammals but also in insects.
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Affiliation(s)
- Yuto Yoshinari
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Hina Kosakamoto
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Laboratory for Nutritional Biology, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan
| | - Takumi Kamiyama
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Ryo Hoshino
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Rena Matsuoka
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Shu Kondo
- Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka, Japan
| | - Hiromu Tanimoto
- Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Akira Nakamura
- Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- Laboratory of Germline Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Fumiaki Obata
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Laboratory for Nutritional Biology, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan
- Laboratory of Molecular Cell Biology and Development, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- AMED-PRIME, Japan Agency for Medical Research and Development Chiyoda-ku, Tokyo, Japan
| | - Ryusuke Niwa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan.
- AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan.
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19
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Fazilaty H, Brügger MD, Valenta T, Szczerba BM, Berkova L, Doumpas N, Hausmann G, Scharl M, Basler K. Tracing colonic embryonic transcriptional profiles and their reactivation upon intestinal damage. Cell Rep 2021; 36:109484. [PMID: 34348153 DOI: 10.1016/j.celrep.2021.109484] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/25/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
We lack a holistic understanding of the genetic programs orchestrating embryonic colon morphogenesis and governing damage response in the adult. A window into these programs is the transcriptomes of the epithelial and mesenchymal cell populations in the colon. Performing unbiased single-cell transcriptomic analyses of the developing mouse colon at different embryonic stages (embryonic day 14.5 [E14.5], E15.5, and E18.5), we capture cellular and molecular profiles of the stages before, during, and after the appearance of crypt structures, as well as in a model of adult colitis. The data suggest most adult lineages are established by E18.5. We find embryonic-specific gene expression profiles and cell populations that reappear in response to tissue damage. Comparison of the datasets from mice and human colitis suggests the processes are conserved. In this study, we provide a comprehensive single-cell atlas of the developing mouse colon and evidence for the reactivation of embryonic genes in disease.
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Affiliation(s)
- Hassan Fazilaty
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - Michael David Brügger
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - Tomas Valenta
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Institute of Molecular Genetics of the ASCR, v. v. i., Vídeňská 1083, 142 20 Prague 4, Czech Republic.
| | - Barbara M Szczerba
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
| | - Linda Berkova
- Institute of Molecular Genetics of the ASCR, v. v. i., Vídeňská 1083, 142 20 Prague 4, Czech Republic
| | - Nikolaos Doumpas
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - George Hausmann
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
| | - Konrad Basler
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
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20
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Mishra A, Singh KP. Protective effect of neurotensin receptor-1 agonist PD 149163 against lipopolysaccharide-induced gut toxicity in mice. Drug Chem Toxicol 2021; 45:2399-2410. [PMID: 34334065 DOI: 10.1080/01480545.2021.1954698] [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: 10/20/2022]
Abstract
The interaction between neuroendocrine and immune components of the gut maintains the organism's physical and psychological health. Its disruption may reflect in disease conditions such as inflammatory bowel disease (IBD) and mental illness. The lipopolysaccharide (LPS) disrupts the endocrine-immune homeostasis resulting in gut toxicity. The Neurotensin receptor-1 (NTR-1) agonist PD 149163 (PD) acts as an atypical antipsychotic drug in psychiatric illness, but its role in modulating gut pathophysiology remains unknown. Therefore, the aim of the present study was to evaluate the protective effect of PD against LPS-induced gut toxicity. Swiss albino female mice (12 weeks) were divided into six groups (n = 6/group): (I) Control, (II) LPS (1 mg/kg, for 5 days), (III) LPS (1 mg/kg, for 5 days)+PD low (100 µg/kg, for 21 days), (IV) LPS (1 mg/kg, for 5 days)+PD high (300 µg/kg, for 21 days), (V) PD low (100 µg/kg, for 21 days), and (VI) PD high (300 µg/kg, for 21 days). Drugs were given intraperitoneal in the morning. PD administration prevented the LPS-induced gut inflammation observed in damage of epithelial barrier, disruption of goblet cells, and condensation of lamina propria (LP). The LPS-induced oxidative stress characterized by decreased superoxide dismutase (SOD) activity and increased lipid hydroperoxide (LOOH) (p < 0.001 for both), and enhanced interleukine-6 (IL-6) & tumor necrosis factor-α (TNF-α) (p < 0.001 for both) as well as immunointensity of NT (p < 0.01) and NTR-1 (p < 0.05) were reversed and normalized to control after PD treatment. Thus, the anti-inflammatory, anti-oxidative, and cell proliferation properties of PD modulate the gut toxicity in LPS-challenged mice.
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Affiliation(s)
- Ankit Mishra
- Neurobiology Lab, Department of Zoology, University of Allahabad, Prayagraj, India
| | - K P Singh
- Neurobiology Lab, Department of Zoology, University of Allahabad, Prayagraj, India
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21
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Lucotti P, Lovati E, Lenti MV, Valvo B, Sprio E, Aronico N, Giuffrida P, Dell'Aera D, Pasini A, Ubezio C, Delliponti M, Tinelli C, Corazza GR, Di Sabatino A. Abnormal post-prandial glucagon-like peptide release in patients with Crohn's disease. Clin Res Hepatol Gastroenterol 2021; 45:101533. [PMID: 33036955 DOI: 10.1016/j.clinre.2020.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/31/2020] [Accepted: 08/26/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Glucagon-like peptide GLP-1 and -2 have been shown to regulate immune responses in immune-mediated disorders, including Crohn's disease (CD). Our aim was to investigate post-prandial GLP release and its potential link to chronic inflammation, insulin secretion/sensitivity and body composition changes in CD patients. METHODS Fifteen patients with CD, 15 healthy controls (HC) and 15 patients with metabolic syndrome (MS) were recruited. All patients underwent assessment of body composition by means of bio-impedance followed by a meal tolerance test (MTT). Only one CD patient did not tolerate the MTT and was excluded. RESULTS Basal GLP-1 levels were up-regulated in CD, however, as compared to HC, stimulated GLP-1 secretion was significantly reduced in CD (-31 %, p < 0.05) as in MS (-52 %, p < 0.003). Similarly, basal GLP-2 levels were comparable to that of HC, while response to MTT in CD was virtually absent (p < 0.05). Similar fasting insulin sensitivity, estimated 1st and 2nd phase insulin secretion and insulinogenic index were found in CD and in HC. Post-prandial GLP secretion was positively correlated to insulin secretion indices, both in CD and MS. In CD, high-sensitive C reactive protein levels (hsCRP) and extra-cellular to intra-cellular water ratio (ECW/ICW), an index of cellular inflammation, were inversely correlated with stimulated GLP-1 (p < 0.05 and p < 0.01, respectively) levels. CONCLUSION CD is characterized by abnormal fasting and post-prandial GLP levels. Circulating GLP influences subclinical inflammation and glucose metabolism in CD patients, but not their body composition parameters.
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Affiliation(s)
- Pietro Lucotti
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Elisabetta Lovati
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Marco Vincenzo Lenti
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Beatrice Valvo
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Elisa Sprio
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Nicola Aronico
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Paolo Giuffrida
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Dominica Dell'Aera
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Alessandra Pasini
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Cristina Ubezio
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Mariangela Delliponti
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Carmine Tinelli
- Clinical Epidemiology and Biometric Unit, San Matteo Hospital Foundation, Pavia, Italy
| | - Gino Roberto Corazza
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
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22
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Jugder BE, Kamareddine L, Watnick PI. Microbiota-derived acetate activates intestinal innate immunity via the Tip60 histone acetyltransferase complex. Immunity 2021; 54:1683-1697.e3. [PMID: 34107298 DOI: 10.1016/j.immuni.2021.05.017] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/05/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023]
Abstract
Microbe-derived acetate activates the Drosophila immunodeficiency (IMD) pathway in a subset of enteroendocrine cells (EECs) of the anterior midgut. In these cells, the IMD pathway co-regulates expression of antimicrobial and enteroendocrine peptides including tachykinin, a repressor of intestinal lipid synthesis. To determine whether acetate acts on a cell surface pattern recognition receptor or an intracellular target, we asked whether acetate import was essential for IMD signaling. Mutagenesis and RNA interference revealed that the putative monocarboxylic acid transporter Tarag was essential for enhancement of IMD signaling by dietary acetate. Interference with histone deacetylation in EECs augmented transcription of genes regulated by the steroid hormone ecdysone including IMD targets. Reduced expression of the histone acetyltransferase Tip60 decreased IMD signaling and blocked rescue by dietary acetate and other sources of intracellular acetyl-CoA. Thus, microbe-derived acetate induces chromatin remodeling within enteroendocrine cells, co-regulating host metabolism and intestinal innate immunity via a Tip60-steroid hormone axis that is conserved in mammals.
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Affiliation(s)
- Bat-Erdene Jugder
- Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Layla Kamareddine
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar; Biomedical Research Center, Qatar University, Doha, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
| | - Paula I Watnick
- Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
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23
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Suslov AV, Chairkina E, Shepetovskaya MD, Suslova IS, Khotina VA, Kirichenko TV, Postnov AY. The Neuroimmune Role of Intestinal Microbiota in the Pathogenesis of Cardiovascular Disease. J Clin Med 2021; 10:1995. [PMID: 34066528 PMCID: PMC8124579 DOI: 10.3390/jcm10091995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/19/2021] [Accepted: 05/03/2021] [Indexed: 02/07/2023] Open
Abstract
Currently, a bidirectional relationship between the gut microbiota and the nervous system, which is considered as microbiota-gut-brain axis, is being actively studied. This axis is believed to be a key mechanism in the formation of somatovisceral functions in the human body. The gut microbiota determines the level of activation of the hypothalamic-pituitary system. In particular, the intestinal microbiota is an important source of neuroimmune mediators in the pathogenesis of cardiovascular disease. This review reflects the current state of publications in PubMed and Scopus databases until December 2020 on the mechanisms of formation and participation of neuroimmune mediators associated with gut microbiota in the development of cardiovascular disease.
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Affiliation(s)
- Andrey V. Suslov
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, 8-2 Trubetskaya Str., 119992 Moscow, Russia; (A.V.S.); (E.C.); (M.D.S.)
| | - Elizaveta Chairkina
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, 8-2 Trubetskaya Str., 119992 Moscow, Russia; (A.V.S.); (E.C.); (M.D.S.)
| | - Maria D. Shepetovskaya
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, 8-2 Trubetskaya Str., 119992 Moscow, Russia; (A.V.S.); (E.C.); (M.D.S.)
| | - Irina S. Suslova
- Central State Medical Academy of the Administrative Department of the President of the Russian Federation, 19-1A Marshal Timoshenko Str., 121359 Moscow, Russia;
| | - Victoria A. Khotina
- Research Institute of Human Morphology, 3 Tsyurupy Str., 117418 Moscow, Russia; (V.A.K.); (A.Y.P.)
- Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Str., 125315 Moscow, Russia
| | - Tatiana V. Kirichenko
- Research Institute of Human Morphology, 3 Tsyurupy Str., 117418 Moscow, Russia; (V.A.K.); (A.Y.P.)
- National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Str., 121552 Moscow, Russia
| | - Anton Y. Postnov
- Research Institute of Human Morphology, 3 Tsyurupy Str., 117418 Moscow, Russia; (V.A.K.); (A.Y.P.)
- National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Str., 121552 Moscow, Russia
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24
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Lerner A. The intestinal luminal sources of α-synuclein: a gastroenterologist perspective. Nutr Rev 2021; 80:282-293. [PMID: 33942062 DOI: 10.1093/nutrit/nuab024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease is characterized by nonmotor/motor dysfunction, midbrain dopaminergic neuronal death, and α-synuclein (aSN) deposits. The current hypothesis is that aSN accumulates in the enteric nervous system to reach the brain. However, invertebrate, vertebrate, and nutritional sources of aSN reach the luminal compartment. Submitted to local amyloidogenic forces, the oligomerized proteins' cargo can be sensed and sampled by a specialized mucosal cell to be transmitted to the adjacent enteric nervous system, starting their upward journey to the brain. The present narrative review extends the current mucosal origin of Parkinson's disease, presenting the possibility that the disease starts in the intestinal lumen. If substantiated, eliminating the nutritional sources of aSN (eg, applying a vegetarian diet) might revolutionize the currently used dopaminergic pharmacologic therapy.
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Affiliation(s)
- Aaron Lerner
- A. Lerner is with the Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, Israel
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25
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Melis M, Haehner A, Mastinu M, Hummel T, Tomassini Barbarossa I. Molecular and Genetic Factors Involved in Olfactory and Gustatory Deficits and Associations with Microbiota in Parkinson's Disease. Int J Mol Sci 2021; 22:ijms22084286. [PMID: 33924222 PMCID: PMC8074606 DOI: 10.3390/ijms22084286] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/14/2021] [Accepted: 04/17/2021] [Indexed: 12/11/2022] Open
Abstract
Deficits in olfaction and taste are among the most frequent non-motor manifestations in Parkinson’s disease (PD) that start very early and frequently precede the PD motor symptoms. The limited data available suggest that the basis of the olfactory and gustatory dysfunction related to PD are likely multifactorial and may include the same determinants responsible for other non-motor symptoms of PD. This review describes the most relevant molecular and genetic factors involved in the PD-related smell and taste impairments, and their associations with the microbiota, which also may represent risk factors associated with the disease.
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Affiliation(s)
- Melania Melis
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.)
| | - Antje Haehner
- Smell and Taste Clinic, Department of Otorhinolaryngology, Technical University of Dresden, 01307 Dresden, Germany; (A.H.); (T.H.)
| | - Mariano Mastinu
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.)
| | - Thomas Hummel
- Smell and Taste Clinic, Department of Otorhinolaryngology, Technical University of Dresden, 01307 Dresden, Germany; (A.H.); (T.H.)
| | - Iole Tomassini Barbarossa
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.)
- Correspondence: ; Tel.: +39-070-675-4144
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26
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The Intestinal Fatty Acid-Enteroendocrine Interplay, Emerging Roles for Olfactory Signaling and Serotonin Conjugates. Molecules 2021; 26:molecules26051416. [PMID: 33807994 PMCID: PMC7961910 DOI: 10.3390/molecules26051416] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/19/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022] Open
Abstract
Intestinal enteroendocrine cells (EECs) respond to fatty acids from dietary and microbial origin by releasing neurotransmitters and hormones with various paracrine and endocrine functions. Much has become known about the underlying signaling mechanisms, including the involvement of G-protein coupled receptors (GPCRs), like free fatty acids receptors (FFARs). This review focusses on two more recently emerging research lines: the roles of odorant receptors (ORs), and those of fatty acid conjugates in gut. Odorant receptors belong to a large family of GPCRs with functional roles that only lately have shown to reach beyond the nasal-oral cavity. In the intestinal tract, ORs are expressed on serotonin (5-HT) and glucagon-like-peptide-1 (GLP-1) producing enterochromaffin and enteroendocrine L cells, respectively. There, they appear to function as chemosensors of microbiologically produced short-, and branched-chain fatty acids. Another mechanism of fatty acid signaling in the intestine occurs via their conjugates. Among them, conjugates of unsaturated long chain fatty acids and acetate with 5-HT, N-acyl serotonins have recently emerged as mediators with immune-modulatory effects. In this review, novel findings in mechanisms and molecular players involved in intestinal fatty acid biology are highlighted and their potential relevance for EEC-mediated signaling to the pancreas, immune system, and brain is discussed.
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27
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Pereira JNB, Murata GM, Sato FT, Marosti AR, Carvalho CRDO, Curi R. Small intestine remodeling in male Goto-Kakizaki rats. Physiol Rep 2021; 9:e14755. [PMID: 33580916 PMCID: PMC7881800 DOI: 10.14814/phy2.14755] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Obesity is associated with the development of insulin resistance (IR) and type-2 diabetes mellitus (T2DM); however, not all patients with T2DM are obese. The Goto-Kakizaki (GK) rat is an experimental model of spontaneous and non-obese T2DM. There is evidence that the intestine contributes to IR development in GK animals. This information prompted us to investigate small intestine remodeling in this animal model. METHODS Four-month-old male Wistar (control) and GK rats were utilized for the present study. After removing the small intestine, the duodenum, proximal jejunum, and distal ileum were separated. We then measured villi and muscular and mucosa layer histomorphometry, goblet cells abundance, total myenteric and submucosal neuron populations, and inflammatory marker expression in the small intestinal segments and intestinal transit of both groups of animals. KEY RESULTS We found that the GK rats exhibited decreased intestinal area (p < 0.0001), decreased crypt depth in the duodenum (p = 0.01) and ileum (p < 0.0001), increased crypt depth in the jejunum (p < 0.0001), longer villi in the jejunum and ileum (p < 0.0001), thicker villi in the duodenum (p < 0.01) and ileum (p < 0.0001), thicker muscular layers in the duodenum, jejunum, and ileum (p < 0.0001), increased IL-1β concentrations in the duodenum and jejunum (p < 0.05), and increased concentrations of NF-κB p65 in the duodenum (p < 0.01), jejunum and ileum (p < 0.05). We observed high IL-1β reactivity in the muscle layer, myenteric neurons, and glial cells of the experimental group. GK rats also exhibited a significant reduction in submucosal neuron density in the jejunum and ileum, ganglionic hypertrophy in all intestinal segments studied (p < 0.0001), and a slower intestinal transit (about 25%) compared to controls. CONCLUSIONS The development of IR and T2DM in GK rats is associated with small intestine remodeling that includes marked alterations in small intestine morphology, local inflammation, and reduced intestinal transit.
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Affiliation(s)
| | | | - Fabio Takeo Sato
- Department of GeneticsEvolution, Microbiology and ImmunologyInstitute of BiologyState University of CampinasCampinasBrazil
| | | | | | - Rui Curi
- Interdisciplinary Post‐Graduate Program in Health SciencesCruzeiro do Sul UniversitySão PauloBrazil
- Department of Physiology and BiophysicsInstitute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
- Butantan InstituteSão PauloBrazil
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28
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McCullough RW. Barrier therapies supporting the biology of the mucosal barrier-medical devices for common clinical mucosal disorders. Transl Gastroenterol Hepatol 2021; 6:15. [PMID: 33409409 PMCID: PMC7724181 DOI: 10.21037/tgh.2020.02.02] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 01/18/2020] [Indexed: 12/12/2022] Open
Abstract
Recently mucosal barrier therapies have been either CE marked or licensed by Food and Drug Administration (FDA) as medical devices. A barrier therapy (BT) uses a physical non-drug mode of action as its sole mechanism to manage a clinical syndrome. A BT is verified as technically or biologically safe having efficacy that has been proven by valid clinical trials. However, it remains unclear what anatomical portions of the mucosa are physically engaged by any given BT. Therefore, this article clarifies the physical basis for clinical efficacy of any given mucosal BT's. Current regulatory classification of medical devices is defined. More importantly, the biology of mucosal barrier is detailed by structure, compartmental elements and function. A live-function or cross-sectional anatomical perspective of the mucosa is provided. A cross-sectional anatomical perspective of the mucosa is provided in order to highlight the physical point of contact for any given mucosal BT's. Five traits of an effective mucosal BT are proposed to assess traits of fitness for any given BT. A BT is either classical, possessing four to five traits, or non-classical, possessing three or fewer traits. Among 16 commercially available mucosal BT's which share nine distinct formulations, most are non-classical BT while two (alginate and polymeric sucralfate) are classical mucosal BT's.
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Affiliation(s)
- Ricky W McCullough
- Translational Medicine Clinic and Research Center at Storrs, Storrs, CT, USA
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29
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Beaurivage C, Kanapeckaite A, Loomans C, Erdmann KS, Stallen J, Janssen RAJ. Development of a human primary gut-on-a-chip to model inflammatory processes. Sci Rep 2020; 10:21475. [PMID: 33293676 PMCID: PMC7722760 DOI: 10.1038/s41598-020-78359-2] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a complex multi-factorial disease for which physiologically relevant in vitro models are lacking. Existing models are often a compromise between biological relevance and scalability. Here, we integrated intestinal epithelial cells (IEC) derived from human intestinal organoids with monocyte-derived macrophages, in a gut-on-a-chip platform to model the human intestine and key aspects of IBD. The microfluidic culture of IEC lead to an increased polarization and differentiation state that closely resembled the expression profile of human colon in vivo. Activation of the model resulted in the polarized secretion of CXCL10, IL-8 and CCL-20 by IEC and could efficiently be prevented by TPCA-1 exposure. Importantly, upregulated gene expression by the inflammatory trigger correlated with dysregulated pathways in IBD patients. Finally, integration of activated macrophages offers a first-step towards a multi-factorial amenable IBD platform that could be scaled up to assess compound efficacy at early stages of drug development or in personalized medicine.
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Affiliation(s)
- Claudia Beaurivage
- Galapagos BV, Leiden, South Holland, 2333CL, The Netherlands
- Department of Biomedical Science, Faculty of Science, University of Sheffield, Sheffield, S10 2TN, South Yorkshire, UK
| | | | - Cindy Loomans
- Galapagos BV, Leiden, South Holland, 2333CL, The Netherlands
| | - Kai S Erdmann
- Department of Biomedical Science, Faculty of Science, University of Sheffield, Sheffield, S10 2TN, South Yorkshire, UK
| | - Jan Stallen
- Galapagos BV, Leiden, South Holland, 2333CL, The Netherlands
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30
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Walrath T, Dyamenahalli KU, Hulsebus HJ, McCullough RL, Idrovo JP, Boe DM, McMahan RH, Kovacs EJ. Age-related changes in intestinal immunity and the microbiome. J Leukoc Biol 2020; 109:1045-1061. [PMID: 33020981 DOI: 10.1002/jlb.3ri0620-405rr] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 09/11/2020] [Accepted: 09/13/2020] [Indexed: 12/19/2022] Open
Abstract
The gastrointestinal (GI) tract is a vitally important site for the adsorption of nutrients as well as the education of immune cells. Homeostasis of the gut is maintained by the interplay of the intestinal epithelium, immune cells, luminal Ags, and the intestinal microbiota. The well-being of the gut is intrinsically linked to the overall health of the host, and perturbations to this homeostasis can have severe impacts on local and systemic health. One factor that causes disruptions in gut homeostasis is age, and recent research has elucidated how critical systems within the gut are altered during the aging process. Intestinal stem cell proliferation, epithelial barrier function, the gut microbiota, and the composition of innate and adaptive immune responses are all altered in advanced age. The aging population continues to expand worldwide, a phenomenon referred to as the "Silver Tsunami," and every effort must be made to understand how best to prevent and treat age-related maladies. Here, recent research about changes observed in the intestinal epithelium, the intestinal immune system, the microbiota, and how the aging gut interacts with and influences other organs such as the liver, lung, and brain are reviewed. Better understanding of these age-related changes and their impact on multi-organ interactions will aid the development of therapies to increase the quality of life for all aged individuals.
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Affiliation(s)
- Travis Walrath
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Kiran U Dyamenahalli
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Holly J Hulsebus
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA.,Immunology Graduate Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Rebecca L McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.,GI and Liver Innate Immune Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Juan-Pablo Idrovo
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Devin M Boe
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA.,Immunology Graduate Program, University of Colorado Denver, Aurora, Colorado, USA.,Medical Scientist Training Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Rachel H McMahan
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA
| | - Elizabeth J Kovacs
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Aurora, Colorado, USA.,Immunology Graduate Program, University of Colorado Denver, Aurora, Colorado, USA.,Medical Scientist Training Program, University of Colorado Denver, Aurora, Colorado, USA.,GI and Liver Innate Immune Program, University of Colorado Denver, Aurora, Colorado, USA
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31
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Genetic variants of TAS2R38 bitter taste receptor associate with distinct gut microbiota traits in Parkinson's disease: A pilot study. Int J Biol Macromol 2020; 165:665-674. [PMID: 32946938 DOI: 10.1016/j.ijbiomac.2020.09.056] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/06/2020] [Accepted: 09/09/2020] [Indexed: 12/21/2022]
Abstract
The non-tasting form of the bitter taste receptor, TAS2R38, has been shown as a genetic risk factor associated with the development of Parkinson's disease (PD). Specific taste receptors that are expressed in the lower gastrointestinal tract may respond to alteration in gut microbiota composition, detecting bacterial molecules, and regulate immune responses. Given the importance of brain-gut-microbiota axis and gene-environment interactions in PD, we investigate the associations between the genetic variants of TAS2R38 and gut microbiota composition in 39 PD patients. The results confirm that the majority of PD patients have reduced sensitivity to 6-n-propylthiouracil (PROP) and are carriers of at least one non-functional TAS2R38 AVI haplotype. Moreover, we found this correlation to be associated with a reduction in bacteria alpha-diversity with a predominant reduction of Clostridium genus. We hypothesised that the high frequency of the non-taster form of TAS2R38 associated with a diminuition of Clostridium bacteria in PD might determine a reduction in the activation of protective signalling-molecules useful in preserving gut homeostasis. This pilot study, by identifying a decrease in specific bacteria associated with a reduced sensitivity to PROP, adds essential information that opens new avenues of research into the association of PD microbiota composition and sensory modification.
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32
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Faniyi AA, Wijanarko KJ, Tollitt J, Worthington JJ. Helminth Sensing at the Intestinal Epithelial Barrier-A Taste of Things to Come. Front Immunol 2020; 11:1489. [PMID: 32849506 PMCID: PMC7409516 DOI: 10.3389/fimmu.2020.01489] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/08/2020] [Indexed: 11/13/2022] Open
Abstract
Human intestinal helminth infection affects more than 1 billion people often in the world's most deprived communities. These parasites are one of the most prevalent neglected tropical diseases worldwide bringing huge morbidities to the host population. Effective treatments and vaccines for helminths are currently limited, and therefore, it is essential to understand the molecular sensors that the intestinal epithelium utilizes in detecting helminths and how the responding factors produced act as modulators of immunity. Defining the cellular and molecular mechanisms that enable helminth detection and expulsion will be critical in identifying potential therapeutic targets to alleviate disease. However, despite decades of research, we have only recently been able to identify the tuft cell as a key helminth sensor at the epithelial barrier. In this review, we will highlight the key intestinal epithelial chemosensory roles associated with the detection of intestinal helminths, summarizing the recent advances in tuft cell initiation of protective type 2 immunity. We will discuss other potential sensory roles of epithelial subsets and introduce enteroendocrine cells as potential key sensors of the microbial alterations that a helminth infection produces, which, given their direct communication to the nervous system via the recently described neuropod, have the potential to transfer the epithelial immune interface systemically.
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Affiliation(s)
- Aduragbemi A Faniyi
- Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom.,Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Kevin J Wijanarko
- Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom.,Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong
| | - James Tollitt
- Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom
| | - John J Worthington
- Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom
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Skowron K, Kurnik-Łucka M, Dadański E, Bętkowska-Korpała B, Gil K. Backstage of Eating Disorder-About the Biological Mechanisms behind the Symptoms of Anorexia Nervosa. Nutrients 2020; 12:E2604. [PMID: 32867089 PMCID: PMC7551451 DOI: 10.3390/nu12092604] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022] Open
Abstract
Anorexia nervosa (AN) represents a disorder with the highest mortality rate among all psychiatric diseases, yet our understanding of its pathophysiological components continues to be fragmentary. This article reviews the current concepts regarding AN pathomechanisms that focus on the main biological aspects involving central and peripheral neurohormonal pathways, endocrine function, as well as the microbiome-gut-brain axis. It emerged from the unique complexity of constantly accumulating new discoveries, which hamper the ability to look at the disease in a more comprehensive way. The emphasis is placed on the mechanisms underlying the main symptoms and potential new directions that require further investigation in clinical settings.
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Affiliation(s)
- Kamil Skowron
- Department of Pathophysiology, Jagiellonian University Medical College, Czysta St 18, 31-121 Krakow, Poland; (K.S.); (M.K.-Ł.); (E.D.)
| | - Magdalena Kurnik-Łucka
- Department of Pathophysiology, Jagiellonian University Medical College, Czysta St 18, 31-121 Krakow, Poland; (K.S.); (M.K.-Ł.); (E.D.)
| | - Emil Dadański
- Department of Pathophysiology, Jagiellonian University Medical College, Czysta St 18, 31-121 Krakow, Poland; (K.S.); (M.K.-Ł.); (E.D.)
| | - Barbara Bętkowska-Korpała
- Department of Psychiatry, Jagiellonian University Medical College, Institute of Medical Psychology, Jakubowskiego St 2, 30-688 Krakow, Poland;
| | - Krzysztof Gil
- Department of Pathophysiology, Jagiellonian University Medical College, Czysta St 18, 31-121 Krakow, Poland; (K.S.); (M.K.-Ł.); (E.D.)
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Iyer RV, Konda B, Fountzilas C, Mukherjee S, Owen D, Attwood K, Wang C, Maguire O, Minderman H, Suffren SA, Hicks K, Wilton J, Bies R, Casucci D, Reidy-Lagunes D, Shah M. Multicenter phase 2 trial of nintedanib in advanced nonpancreatic neuroendocrine tumors. Cancer 2020; 126:3689-3697. [PMID: 32525561 DOI: 10.1002/cncr.32994] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 05/02/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Antiangiogenic-targeting agents have low response rates in patients with nonpancreatic neuroendocrine tumors (NETs). Nintedanib is an oral antiangiogenic agent that has inhibitory effects on the fibroblast growth factor receptor, which is highly expressed in NETs. The authors hypothesized that nintedanib would be active in patients with nonpancreatic NETs. METHODS Patients with advanced, grade 1 or 2, nonpancreatic NETs who were receiving a stable dose of somatostatin analogue were enrolled. Nintedanib was administered at a dose of 200 mg twice daily in 28-day cycles. The primary endpoint was progression-free survival (PFS) at 16 weeks. RESULTS Thirty-two patients were enrolled, and 30 were evaluable for the primary outcome. Most had radiographic disease progression within 12 months before enrollment. The 16-week PFS rate was 83%, and the median PFS and overall survival were 11.0 months and 32.7 months, respectively. Nintedanib was well tolerated and delayed deterioration in quality of life. The baseline serotonin level had a strong, positive correlation with activated but exhausted T cells. CONCLUSIONS Nintedanib is active in nonpancreatic NETs. The immunosuppressive effect of serotonin should be targeted in future clinical trials.
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Affiliation(s)
- Renuka V Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Bhavana Konda
- Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Christos Fountzilas
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Sarbajit Mukherjee
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Dwight Owen
- Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Chong Wang
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Orla Maguire
- Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Hans Minderman
- Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Sheryl-Ann Suffren
- Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Karen Hicks
- Department of Clinical Research Services, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - John Wilton
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Robert Bies
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Danielle Casucci
- Department of Clinical Research Services, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Diane Reidy-Lagunes
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Manisha Shah
- Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
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von Frieling J, Faisal MN, Sporn F, Pfefferkorn R, Nolte SS, Sommer F, Rosenstiel P, Roeder T. A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine. PLoS Genet 2020; 16:e1008789. [PMID: 32453733 PMCID: PMC7274450 DOI: 10.1371/journal.pgen.1008789] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 06/05/2020] [Accepted: 04/22/2020] [Indexed: 12/25/2022] Open
Abstract
Over-consumption of high-fat diets (HFDs) is associated with several pathologies. Although the intestine is the organ that comes into direct contact with all diet components, the impact of HFD has mostly been studied in organs that are linked to obesity and obesity related disorders. We used Drosophila as a simple model to disentangle the effects of a HFD on the intestinal structure and physiology from the plethora of other effects caused by this nutritional intervention. Here, we show that a HFD, composed of triglycerides with saturated fatty acids, triggers activation of intestinal stem cells in the Drosophila midgut. This stem cell activation was transient and dependent on the presence of an intestinal microbiota, as it was completely absent in germ free animals. Moreover, major components of the signal transduction pathway have been elucidated. Here, JNK (basket) in enterocytes was necessary to trigger synthesis of the cytokine upd3 in these cells. This ligand in turn activated the JAK/STAT pathway in intestinal stem cells. Chronic subjection to a HFD markedly altered both the microbiota composition and the bacterial load. Although HFD-induced stem cell activity was transient, long-lasting changes to the cellular composition, including a substantial increase in the number of enteroendocrine cells, were observed. Taken together, a HFD enhances stem cell activity in the Drosophila gut and this effect is completely reliant on the indigenous microbiota and also dependent on JNK signaling within intestinal enterocytes. High-fat diets have been associated with a plethora of morbidities. The major research focus has been on its effects on obesity related disorders, mostly omitting the intestine, although it is the organ that makes the first contact with all diet components. Here, we aimed to understand the effects of HFD on the intestine itself. Using Drosophila as a model, we showed that a HFD and more specifically, trigylcerides with saturated fatty acids, induced a transient activation of intestinal stem cells. This response completely depended on the presence of an intestinal microbiota, as in germ free flies this reaction was completely abolished. Mechanistically, we found that HFD induces JNK signaling in enterocytes, which triggers production of the cytokine upd3. This ligand of the JAK/STAT pathway, in turn activates STAT signaling in intestinal stem cells, leading to their activation. All these components of the JNK- and JAK/STAT-pathways are necessary for a HFD to lead to increased stem cell production. Moreover, HFD changed both, composition and abundance of the microbiota. As fecal transfer experiments failed to recapitulate the HFD phenotype, we assume that the increased bacterial load is the major cause for the HFD triggered stem cell activation in the intestine.
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Affiliation(s)
- Jakob von Frieling
- Zoological Institute, Department of Molecular Physiology, Kiel University, Kiel, Germany
| | - Muhammed Naeem Faisal
- Zoological Institute, Department of Molecular Physiology, Kiel University, Kiel, Germany
| | - Femke Sporn
- Zoological Institute, Department of Molecular Physiology, Kiel University, Kiel, Germany
| | - Roxana Pfefferkorn
- Zoological Institute, Department of Molecular Physiology, Kiel University, Kiel, Germany
| | - Stella Solveig Nolte
- Zoological Institute, Department of Molecular Physiology, Kiel University, Kiel, Germany
| | | | | | - Thomas Roeder
- Zoological Institute, Department of Molecular Physiology, Kiel University, Kiel, Germany
- German Center for Lung Research, Airway Research Center North, Kiel, Germany
- * E-mail:
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Interactions between taste receptors and the gastrointestinal microbiome in inflammatory bowel disease. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2019. [DOI: 10.1016/j.jnim.2019.100106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Singh AP, Hung YH, Shanahan MT, Kanke M, Bonfini A, Dame MK, Biraud M, Peck BC, Oyesola OO, Freund JM, Cubitt RL, Curry EG, Gonzalez LM, Bewick GA, Tait-Wojno ED, Kurpios NA, Ding S, Spence JR, Dekaney CM, Buchon N, Sethupathy P. Enteroendocrine Progenitor Cell-Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner. Cell Mol Gastroenterol Hepatol 2019; 9:447-464. [PMID: 31756561 PMCID: PMC7021555 DOI: 10.1016/j.jcmgh.2019.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/29/2019] [Accepted: 11/07/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis. It was recently shown that EEC progenitors contribute to intestinal epithelial growth and renewal, but the underlying mechanisms remain poorly understood. MicroRNAs are under-explored along the entire EEC lineage trajectory, and comparatively little is known about their contributions to intestinal homeostasis. METHODS We leverage unbiased sequencing and eight different mouse models and sorting methods to identify microRNAs enriched along the EEC lineage trajectory. We further characterize the functional role of EEC progenitor-enriched miRNA, miR-7, by in vivo dietary study as well as ex vivo enteroid in mice. RESULTS First, we demonstrate that miR-7 is highly enriched across the entire EEC lineage trajectory and is the most enriched miRNA in EEC progenitors relative to Lgr5+ intestinal stem cells. Next, we show in vivo that in EEC progenitors miR-7 is dramatically suppressed under dietary conditions that favor crypt division and suppress EEC abundance. We then demonstrate by functional assays in mouse enteroids that miR-7 exerts robust control of growth, as determined by budding (proxy for crypt division), EdU and PH3 staining, and likely regulates EEC abundance also. Finally, we show by single-cell RNA sequencing analysis that miR-7 regulates Xiap in progenitor/stem cells and we demonstrate in enteroids that the effects of miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling. CONCLUSIONS This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling.
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Affiliation(s)
- Ajeet P. Singh
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Yu-Han Hung
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Michael T. Shanahan
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Matt Kanke
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Alessandro Bonfini
- Cornell Institute of Host-Microbe Interactions and Disease. Department of Entomology, Cornell University, New York
| | - Michael K. Dame
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Mandy Biraud
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina
| | - Bailey C.E. Peck
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Oyebola O. Oyesola
- Baker Institute of Animal Health and Department of Microbiology and Immunology, Cornell University, Ithaca, New York
| | - John M. Freund
- Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina
| | - Rebecca L. Cubitt
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Ennessa G. Curry
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Liara M. Gonzalez
- Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina
| | - Gavin A. Bewick
- Diabetes Research Group, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Elia D. Tait-Wojno
- Baker Institute of Animal Health and Department of Microbiology and Immunology, Cornell University, Ithaca, New York
| | - Natasza A. Kurpios
- Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Shengli Ding
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Jason R. Spence
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Christopher M. Dekaney
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina
| | - Nicolas Buchon
- Cornell Institute of Host-Microbe Interactions and Disease. Department of Entomology, Cornell University, New York
| | - Praveen Sethupathy
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York,Correspondence Address correspondence to: Praveen Sethupathy, PhD, Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, 618 Tower Road T7 006D, Veterinary Research Tower, Ithaca, New York 14850. fax: (607) 253–4447.
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Mogilevski T, Burgell R, Aziz Q, Gibson PR. Review article: the role of the autonomic nervous system in the pathogenesis and therapy of IBD. Aliment Pharmacol Ther 2019; 50:720-737. [PMID: 31418887 DOI: 10.1111/apt.15433] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/25/2019] [Accepted: 07/01/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND There is a growing body of evidence implicating a role for the brain-gut axis in the pathogenesis of inflammation in patients with IBD. AIMS To perform a narrative review of published literature regarding the association of the autonomic nervous system and intestinal inflammation and to describe the rationale for and emerging use of autonomic manipulation as a therapeutic agent METHODS: Current relevant literature was summarised and critically examined. RESULTS There is substantial pre-clinical and clinical evidence for a multifaceted anti-inflammatory effect of the vagus at both systemic and local intestinal levels. It acts via acetylcholine-mediated activation of α-7-acetylcholine receptors involving multiple cell types in innate and adaptive immunity and the enteric nervous system with subsequent protective influences on the intestinal barrier, inflammatory mechanisms and the microbiome. In patients with IBD, there is evidence for a sympatho-vagal imbalance, functional enteric neuronal depletion and hyporeactivity of the hypothalamic-pituitary-adrenal axis. Direct or transcutaneous vagal neuromodulation up-regulates the cholinergic anti-inflammatory pathway in pre-clinical and clinical models with down-regulation of systemic and local intestinal inflammation. This is supported by two small studies in Crohn's disease although remains to be investigated in ulcerative colitis. CONCLUSIONS Modulating the cholinergic anti-inflammatory pathway influences inflammation both systemically and at a local intestinal level. It represents a potentially underutilised anti-inflammatory therapeutic strategy. Given the likely pathogenic role of the autonomic nervous system in patients with IBD, vagal neuromodulation, an apparently safe and successful means of increasing vagal tone, warrants further clinical exploration.
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Affiliation(s)
- Tamara Mogilevski
- Centre for Neuroscience, Surgery and Trauma, Barts and the London School of Medicine and Dentistry, Blizard Institute, Wingate Institute of Neurogastroenterology, London, UK.,Barts Health NHS Trust, London, UK.,Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
| | - Rebecca Burgell
- Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
| | - Qasim Aziz
- Centre for Neuroscience, Surgery and Trauma, Barts and the London School of Medicine and Dentistry, Blizard Institute, Wingate Institute of Neurogastroenterology, London, UK.,Barts Health NHS Trust, London, UK
| | - Peter R Gibson
- Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
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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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40
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Brain signalling systems: A target for treating type I diabetes mellitus. Brain Res Bull 2019; 152:191-201. [PMID: 31325597 DOI: 10.1016/j.brainresbull.2019.07.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/08/2019] [Accepted: 07/15/2019] [Indexed: 01/26/2023]
Abstract
From early to later stages of Type I Diabetes Mellitus (TIDM), signalling molecules including brain indolamines and protein kinases are altered significantly, and that has been implicated in the Metabolic Disorders (MD) as well as impairment of retinal, renal, neuronal and cardiovascular systems. Considerable attention has been focused to the effects of diabetes on these signalling systems. However, the exact pathophysiological mechanisms of these signals are not completely understood in TIDM, but it is likely that hyperglycemia, acidosis, and insulin resistance play significant roles. Insulin maintains normal glycemic levels and it acts by binding to its receptor, so that it activates the receptor's tyrosine kinase activity, resulting in phosphorylation of several substrates. Those substrates provide binding/interaction sites for signalling molecules, including serine/threonine kinases and indolamines. For more than two decades, our research has been focused on the mechanisms of protein kinases, CaM Kinase and Serotonin transporter mediated alterations of indolamines in TIDM. In this review, we have also discussed how discrete areas of brain respond to insulin or some of the pharmacological agents that triggers or restores these signalling molecules, and it may be useful for the treatment of specific region wise changes/disorders of diabetic brain.
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Walsh KT, Zemper AE. The Enteric Nervous System for Epithelial Researchers: Basic Anatomy, Techniques, and Interactions With the Epithelium. Cell Mol Gastroenterol Hepatol 2019; 8:369-378. [PMID: 31108231 PMCID: PMC6718943 DOI: 10.1016/j.jcmgh.2019.05.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 05/02/2019] [Accepted: 05/03/2019] [Indexed: 02/08/2023]
Abstract
The intestinal epithelium does not function in isolation, but interacts with many components including the Enteric Nervous System (ENS). Understanding ENS and intestinal epithelium interactions requires multidisciplinary approaches to uncover cells involved, mechanisms used, and the ultimate influence on intestinal physiology. This review is intended to serve as a reference for epithelial biologists interested in studying these interactions. With this in mind, this review aims to summarize the basic anatomy of the epithelium and ENS, mechanisms by which they interact, and techniques used to study these interactions. We highlight in vitro, ex vivo and in vivo techniques. Additionally, ENS influence on epithelial proliferation and gene expression within stem and differentiated cells as well as gastrointestinal cancer are discussed.
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Key Words
- 5-ht, 5-hydroxytryptamine
- 5-ht3r, 5-hydroxytryptamine 3 receptor
- ach, acetylcholine
- aitc, allyl isothicyanate
- cpi, crypt proliferation index
- eec, enteroendocrine cell
- ens, enteric nervous system
- gi, gastrointestinal
- hio, human intestinal organoid
- isc, intestinal stem cell
- lgr5, leucine-rich repeat–containing g protein–coupled receptor
- ne, norepinephrine
- ngf, nerve growth factor
- si, small intestine
- ta, transit-amplifying
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Affiliation(s)
- Kathleen T. Walsh
- Institute of Molecular Biology, University of Oregon, Eugene, Oregon,Institute of Neuroscience, University of Oregon, Eugene, Oregon,Department of Biology, University of Oregon, Eugene, Oregon
| | - Anne E. Zemper
- Institute of Molecular Biology, University of Oregon, Eugene, Oregon,Department of Biology, University of Oregon, Eugene, Oregon,Correspondence Address correspondence to: Anne E. Zemper, PhD, University of Oregon, 218 Streisinger Hall, 1370 Franklin Boulevard, Eugene, Oregon 97401. fax: (541) 346–6056.
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Haq S, Grondin J, Banskota S, Khan WI. Autophagy: roles in intestinal mucosal homeostasis and inflammation. J Biomed Sci 2019; 26:19. [PMID: 30764829 PMCID: PMC6375151 DOI: 10.1186/s12929-019-0512-2] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/07/2019] [Indexed: 12/13/2022] Open
Abstract
The intestinal mucosa is a site of multiple stressors and forms the barrier between the internal and external environment. In the intestine, a complex interplay between the microbiota, epithelial barrier and the local immune system maintains homeostasis and promotes a healthy gut. One of the major cellular catabolic processes that regulate this homeostasis is autophagy. Autophagy is required to maintain anti-microbial defense, epithelial barrier integrity and mucosal immune response. Dysregulation of the autophagy process causes disruption of several aspects of the intestinal epithelium and the immune system that can lead to an inappropriate immune response and subsequent inflammation. Genome-wide association studies have found an association between several risk loci in autophagy genes and inflammatory bowel disease. The aim of the current review is to provide an update on the role of autophagy in intestinal mucosal physiology and in the control of inappropriate inflammation.
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Affiliation(s)
- Sabah Haq
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, L8N 3Z5, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Room 3N7, Hamilton, ON, L8N 3Z5, Canada
| | - Jensine Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, L8N 3Z5, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Room 3N7, Hamilton, ON, L8N 3Z5, Canada
| | - Suhrid Banskota
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, L8N 3Z5, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Room 3N7, Hamilton, ON, L8N 3Z5, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, L8N 3Z5, Canada. .,Department of Pathology and Molecular Medicine, McMaster University, Room 3N7, Hamilton, ON, L8N 3Z5, Canada.
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Pavelock N, Masood U, Minchenberg S, Heisig D. Effects of obesity on the course of inflammatory bowel disease. Proc (Bayl Univ Med Cent) 2019; 32:14-17. [PMID: 30956572 DOI: 10.1080/08998280.2018.1542887] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/24/2018] [Accepted: 10/25/2018] [Indexed: 12/18/2022] Open
Abstract
Obesity is increasingly common among patients with inflammatory bowel disease (IBD). The interplay between proinflammatory states of obesity and the course of IBD is yet to be elucidated. We conducted a retrospective study of 55 patients with IBD over the course of 5 years (2012 to 2017). We documented various clinical outcomes (mean number of clinic visits, hospitalizations/flares, procedures, and escalations in therapy) based on three initial weight groups: normal weight, overweight, and obese. There was an increasing trend in all clinical outcomes with increasing weight and a statistically significant difference in mean clinic visits (P = 0.048) and mean hospitalizations/flares (P = 0.004) when comparing normal-weight to obese individuals. Our study suggests that obesity influences burden of disease and treatment in IBD. This should encourage clinicians to treat obesity in IBD patients as an active problem because it may help improve clinical outcomes.
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Affiliation(s)
- Natalie Pavelock
- Department of Gastroenterology, State University of New York Upstate Medical UniversitySyracuseNew York
| | - Umair Masood
- Department of Gastroenterology, State University of New York Upstate Medical UniversitySyracuseNew York
| | - Scott Minchenberg
- College of Medicine, State University of New York Upstate Medical UniversitySyracuseNew York
| | - David Heisig
- Department of Gastroenterology, State University of New York Upstate Medical UniversitySyracuseNew York
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Stevenson MJ, Uyeda KS, Harder NHO, Heffern MC. Metal-dependent hormone function: the emerging interdisciplinary field of metalloendocrinology. Metallomics 2019; 11:85-110. [PMID: 30270362 PMCID: PMC10249669 DOI: 10.1039/c8mt00221e] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
For over 100 years, there has been an incredible amount of knowledge amassed concerning hormones in the endocrine system and their central role in human health. Hormones represent a diverse group of biomolecules that are released by glands, communicate signals to their target tissue, and are regulated by feedback loops to maintain organism health. Many disease states, such as diabetes and reproductive disorders, stem from misregulation or dysfunction of hormones. Increasing research is illuminating the intricate roles of metal ions in the endocrine system where they may act advantageously in concert with hormones or deleteriously catalyze hormone-associated disease states. As the critical role of metal ions in the endocrine system becomes more apparent, it is increasingly important to untangle the complex mechanisms underlying the connections between inorganic biochemistry and hormone function to understand and control endocrinological phenomena. This tutorial review harmonizes the interdisciplinary fields of endocrinology and inorganic chemistry in the newly-termed field of "metalloendocrinology". We describe examples linking metals to both normal and aberrant hormone function with a focus on highlighting insight to molecular mechanisms. Hormone activities related to both essential metal micronutrients, such as copper, iron, zinc, and calcium, and disruptive nonessential metals, such as lead and cadmium are discussed.
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Affiliation(s)
- Michael J Stevenson
- Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
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Jabari S, Schrödl F, Kaser-Eichberger A, Kofler B, Brehmer A. Alarin in different human intestinal epithelial cell types. Histochem Cell Biol 2019; 151:513-520. [PMID: 30612153 DOI: 10.1007/s00418-018-1763-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2018] [Indexed: 12/18/2022]
Abstract
Alarin (AL), a new member of the galanin family, has been localized in various CNS regions, mainly in rodents. Among other effects, it modulates food intake. Therefore, we analyzed the immunohistochemical distribution pattern of AL in human intestinal epithelia. Cryosections of 12 human bowel samples were immunohistochemically double-stained for AL and α-defensin 5 (αD; first set). Two further sets of sections were quadruple-stained either (second set) for AL, chromogranin (CG), synaptophysin (SY), and somatostatin (SO) or (third set) for AL, CG, Peptide Y (PY), and 5-hydroxytryptamine (5-HT). Slides were digitized and quantitative analysis of co-localization rates was undertaken. Small bowel: most of AL-positive cells (56%) were αD-positive Paneth cells located within the base of the crypts (first set). In the second set, about 27% of AL-labeled cells were co-reactive for SY and CG, likely representing entero-endocrine cells. In the third set, the largest subpopulation of AL-positive cells was not co-reactive for other markers applied (89%); most of them were likely Paneth cells. Large bowel: co-localization of AL with αD was not detected (first set). In the second set, AL was frequently co-localized with the other three markers applied (68%). In the third set, AL was frequently co-localized with 5-HT and CG (31%) as well as with PY and 5-HT (22%). Due to its presence in various enteroendocrine as well as Paneth cells, AL may be involved in different physiological and pathological processes.
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Affiliation(s)
- Samir Jabari
- Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
| | - Falk Schrödl
- Department of Ophthalmology/Optometry, Research Program Experimental Ophthalmology, Paracelsus Medical University, Salzburg, Austria.,Department of Anatomy, Paracelsus Medical University, Salzburg, Austria
| | - Alexandra Kaser-Eichberger
- Department of Ophthalmology/Optometry, Research Program Experimental Ophthalmology, Paracelsus Medical University, Salzburg, Austria.,Department of Anatomy, Paracelsus Medical University, Salzburg, Austria
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Axel Brehmer
- Institute of Anatomy and Cell Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
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46
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Sharkey KA, Beck PL, McKay DM. Neuroimmunophysiology of the gut: advances and emerging concepts focusing on the epithelium. Nat Rev Gastroenterol Hepatol 2018; 15:765-784. [PMID: 30069036 DOI: 10.1038/s41575-018-0051-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The epithelial lining of the gastrointestinal tract serves as the interface for digestion and absorption of nutrients and water and as a defensive barrier. The defensive functions of the intestinal epithelium are remarkable considering that the gut lumen is home to trillions of resident bacteria, fungi and protozoa (collectively, the intestinal microbiota) that must be prevented from translocation across the epithelial barrier. Imbalances in the relationship between the intestinal microbiota and the host lead to the manifestation of diseases that range from disorders of motility and sensation (IBS) and intestinal inflammation (IBD) to behavioural and metabolic disorders, including autism and obesity. The latest discoveries shed light on the sophisticated intracellular, intercellular and interkingdom signalling mechanisms of host defence that involve epithelial and enteroendocrine cells, the enteric nervous system and the immune system. Together, they maintain homeostasis by integrating luminal signals, including those derived from the microbiota, to regulate the physiology of the gastrointestinal tract in health and disease. Therapeutic strategies are being developed that target these signalling systems to improve the resilience of the gut and treat the symptoms of gastrointestinal disease.
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Affiliation(s)
- Keith A Sharkey
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. .,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada. .,Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada. .,Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.
| | - Paul L Beck
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada.,Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada.,Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada.,Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Derek M McKay
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
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Khatun A, Sakurai M, Okada K, Sakai Y, Morimoto M. Detection of α-defensin in eosinophils in helminth-infected mouse model. J Vet Med Sci 2018; 80:1887-1894. [PMID: 30393268 PMCID: PMC6305521 DOI: 10.1292/jvms.18-0601] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
α-defensin is a potent antimicrobial peptide secreted from intestinal mucosal epithelial
cells, such as Paneth cells, and affects not only bacteria but also parasites and fungi.
Recently, human eosinophils have also been shown to produce α-defensin, but no studies
have been done on other animals. In this study, we attempted to detect α-defensin protein
in mouse eosinophils infiltrating the intestinal mucosa during a helminth infection using
Zamboni fixation and immunohistochemistry. Most of the eosinophils infiltrating the
intestinal mucosa during helminth infection were positive for α-defensin. The expression
level of α-defensin mRNA was 50 fold that in the control. Meanwhile, the number of Paneth
cells was doubled, and their α-defensin fluorescence intensity was increased. These
results suggested that eosinophils are also important producers of α-defensin, such as
Paneth cells in mice, and that α-defensin produced from eosinophils might be involved in
defensive mechanisms against helminths. Moreover, the experimental system used in this
study is a good model to study the generation of α-defensin by eosinophils.
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Affiliation(s)
- Afia Khatun
- Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
| | - Masashi Sakurai
- Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
| | - Kazuki Okada
- North Lab, 8-35 Hondori, 2-chome kita, Shiroishi-ku, Sapporo, Hokkaido 003-0027, Japan
| | - Yusuke Sakai
- Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
| | - Masahiro Morimoto
- Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
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48
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Sei Y, Feng J, Samsel L, White A, Zhao X, Yun S, Citrin D, McCoy JP, Sundaresan S, Hayes MM, Merchant JL, Leiter A, Wank SA. Mature enteroendocrine cells contribute to basal and pathological stem cell dynamics in the small intestine. Am J Physiol Gastrointest Liver Physiol 2018; 315:G495-G510. [PMID: 29848020 PMCID: PMC6230697 DOI: 10.1152/ajpgi.00036.2018] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Lgr5-expressing intestinal stem cells (ISCs) maintain continuous and rapid generation of the intestinal epithelium. Here, we present evidence that dedifferentiation of committed enteroendocrine cells (EECs) contributes to maintenance of the epithelium under both basal conditions and in response to injury. Lineage-tracing studies identified a subset of EECs that reside at +4 position for more than 2 wk, most of which were BrdU-label-retaining cells. Under basal conditions, cells derived from these EECs grow from the bottom of the crypt to generate intestinal epithelium according to neutral drift kinetics that is consistent with dedifferentiation of mature EECs to ISCs. The lineage tracing of EECs demonstrated reserve stem cell properties in response to radiation-induced injury with the generation of reparative EEC-derived epithelial patches. Finally, the enterochromaffin (EC) cell was the predominant EEC type participating in these stem cell dynamics. These results provide novel insights into the +4 reserve ISC hypothesis, stem cell dynamics of the intestinal epithelium, and in the development of EC-derived small intestinal tumors. NEW & NOTEWORTHY The current manuscript demonstrating that a subset of mature enteroendocrine cells (EECs), predominantly enterochromaffin cells, dedifferentiates to fully functional intestinal stem cells (ISCs) is novel, timely, and important. These cells dedifferentiate to ISCs not only in response to injury but also under basal homeostatic conditions. These novel findings provide a mechanism in which a specified cell can dedifferentiate and contribute to normal tissue plasticity as well as the development of EEC-derived intestinal tumors under pathologic conditions.
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Affiliation(s)
- Yoshitatsu Sei
- 1Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Jianying Feng
- 1Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Leigh Samsel
- 2Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Ayla White
- 3Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Xilin Zhao
- 1Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Sajung Yun
- 1Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Deborah Citrin
- 3Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - J. Philip McCoy
- 2Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Sinju Sundaresan
- 4Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Michael M. Hayes
- 4Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Juanita L. Merchant
- 5Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Andrew Leiter
- 6Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Stephen A. Wank
- 1Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Terry NA, Ngaba LV, Wilkins BJ, Pi D, Gheewala N, Kaestner KH. Lipid malabsorption from altered hormonal signaling changes early gut microbial responses. Am J Physiol Gastrointest Liver Physiol 2018; 315:G580-G591. [PMID: 29953253 PMCID: PMC6230693 DOI: 10.1152/ajpgi.00135.2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/11/2018] [Accepted: 06/11/2018] [Indexed: 01/31/2023]
Abstract
Infants with congenital diarrheal disorders caused by enteroendocrine cell dysgenesis, or the loss of intestinal endocrine cells, causes severe malabsorptive diarrhea, though the mechanism is not fully understood. The transcription factor "aristaless-related homeobox" (Arx) is specifically expressed in intestinal endocrine cells. This study seeks to characterize the early malabsorptive phenotype of mice deficient for Arx using cell-type specific gene ablation in Villin-Cre; ArxloxP/Y ( Arxint) mice. In neonatal mice, the loss of intestinal Arx caused the loss of intestinal hormones, such as cholecystokinin, secretin, neurotensin, glucose-dependent insulinotropic peptide, glucagon-like peptide (GLP)-1 and GLP-2 but also upregulation of somatostatin. Arxint mice exhibited steatorrhea with the loss of lipid transport in duodenal enterocytes, upregulation of lysozyme-positive Paneth cells, and a secondary increase in antimicrobial peptides, specifically Reg3β. When the epithelium from Arxint mice was cultured ex vivo into enteroids, however, the Reg3β upregulation was lost under the sterile conditions. Thus, Arx is required for the appropriate lineage allocation of multiple enteroendocrine subtypes. We concluded that altered hormonal signaling caused by Arx deficiency results in lipid malabsorption, premature Paneth cell differentiation, and an inflammatory response, including neutrophilic infiltrates and a microbiota-triggered upregulation of Reg3β. NEW & NOTEWORTHY The enteroendocrine transcription factor aristaless-related homeobox (Arx) plays a key role in lineage specification. Changes in hormonal expression mediated by Arx lead to lipid malabsorption and premature Paneth cell development. Furthermore, global profiling of whole intestine from Arx-deficient mice revealed significant upregulation of antimicrobial peptides. This antimicrobial response in Arx-deficient animals is lost under sterile culture conditions of enteroids.
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Affiliation(s)
- Natalie A Terry
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania
- Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania
| | - Lucie V Ngaba
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania
| | - Benjamin J Wilkins
- Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania
- Department of Pathology, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania
| | - Danielle Pi
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania
| | - Nishi Gheewala
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania
| | - Klaus H Kaestner
- Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania
- Department of Genetics and Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania
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50
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Inclan-Rico JM, Siracusa MC. First Responders: Innate Immunity to Helminths. Trends Parasitol 2018; 34:861-880. [PMID: 30177466 PMCID: PMC6168350 DOI: 10.1016/j.pt.2018.08.007] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 08/11/2018] [Accepted: 08/12/2018] [Indexed: 02/07/2023]
Abstract
Helminth infections represent a significant public health concern resulting in devastating morbidity and economic consequences across the globe. Helminths migrate through mucosal sites causing tissue damage and the induction of type 2 immune responses. Antihelminth protection relies on the mobilization and activation of multiple immune cells, including type 2 innate lymphocytes (ILC2s), basophils, mast cells, macrophages, and hematopoietic stem/progenitor cells. Further, epithelial cells and neurons have been recognized as important regulators of type 2 immunity. Collectively, these pathways stimulate host-protective responses necessary for worm expulsion and the healing of affected tissues. In this review we focus on the innate immune pathways that regulate immunity to helminth parasites and describe how better understanding of these pathways may lead to the development of new therapeutic strategies.
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Affiliation(s)
- Juan M Inclan-Rico
- Center for Immunity and Inflammation, Department of Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Mark C Siracusa
- Center for Immunity and Inflammation, Department of Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
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