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Petracco G, Faimann I, Reichmann F. Inflammatory bowel disease and neuropsychiatric disorders: Mechanisms and emerging therapeutics targeting the microbiota-gut-brain axis. Pharmacol Ther 2025; 269:108831. [PMID: 40023320 DOI: 10.1016/j.pharmthera.2025.108831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 02/03/2025] [Accepted: 02/23/2025] [Indexed: 03/04/2025]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are the two major entities of inflammatory bowel disease (IBD). These disorders are known for their relapsing disease course and severe gastrointestinal symptoms including pain, diarrhoea and bloody stool. Accumulating evidence suggests that IBD is not only restricted to the gastrointestinal tract and that disease processes are able to reach distant organs including the brain. In fact, up to 35 % of IBD patients also suffer from neuropsychiatric disorders such as generalized anxiety disorder and major depressive disorder. Emerging research in this area indicates that in many cases these neuropsychiatric disorders are a secondary condition as a consequence of the disturbed communication between the gut and the brain via the microbiota-gut-brain axis. In this review, we summarise the current knowledge on IBD-associated neuropsychiatric disorders. We examine the role of different pathways of the microbiota-gut-brain axis in the development of CNS disorders highlighting altered neural, immunological, humoral and microbial communication. Finally, we discuss emerging therapies targeting the microbiota-gut-brain axis to alleviate IBD and neuropsychiatric symptoms including faecal microbiota transplantation, psychobiotics, microbial metabolites and vagus nerve stimulation.
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Affiliation(s)
- Giulia Petracco
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Isabella Faimann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Florian Reichmann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria; BiotechMed-Graz, Austria.
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2
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Sotelo‐Parrilla G, Ruiz‐Calero A, García‐Miranda P, Calonge ML, Vázquez‐Carretero MD, Peral MJ. Motor, mood, and memory impairments persist during remission periods in chronic colitis and are influenced by neuroinflammation and sex. FASEB J 2024; 38:e70133. [PMID: 39460563 PMCID: PMC11580723 DOI: 10.1096/fj.202400837r] [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: 04/12/2024] [Revised: 09/25/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024]
Abstract
Ulcerative colitis is a chronic pathology characterized by relapsing-remitting phases of intestinal inflammation. Additionally, some patients develop neuropsychiatric disorders, such as depression and anxiety, or cognitive deficits. We aimed to investigate whether the development of chronic colitis elicits memory, locomotion, and mood impairments. It further examined whether these impairments are influenced by the relapsing-remitting phases of the colitis or by sex. Here, we used a chronic colitis model in male and female rats, induced with sodium dextran sulfate, mirroring the phases of human ulcerative colitis. Our results revealed that the severity of colitis was slightly higher in males than females. Chronic colitis triggered motor and short-term memory deficits and induced anxiety- and depression-like behaviors that remained throughout the development of the disease. There are also sex differences under control or inflammatory conditions. Therefore, in both situations, females compared to males displayed: (i) slightly lower locomotion, (ii) increased anxiety-like behaviors, (iii) similar depression-like behaviors, and (iv) similar short-term memory deficit. Additionally, under control conditions, the mRNA levels of IL-1β, IL-6, and TNF-α were higher in the female hippocampus. In both sexes, when chronic colitis was established, the neuroinflammation was evidenced by increased mRNA levels of these three cytokines in the hippocampus and in the motor and prefrontal cortices. Interestingly, this neuroinflammation was slightly greater in males. In summary, we show that the development of chronic colitis caused persistent behavioral abnormalities, highlighting sex differences, and that could be a consequence, at least in part, of the increase in IL-1β, IL-6, and TNF-α in the brain.
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Affiliation(s)
- Gema Sotelo‐Parrilla
- Departamento de Fisiología, Facultad de FarmaciaUniversidad de SevillaSevillaSpain
| | | | - Pablo García‐Miranda
- Departamento de Fisiología, Facultad de FarmaciaUniversidad de SevillaSevillaSpain
| | - María L. Calonge
- Departamento de Fisiología, Facultad de FarmaciaUniversidad de SevillaSevillaSpain
| | | | - María J. Peral
- Departamento de Fisiología, Facultad de FarmaciaUniversidad de SevillaSevillaSpain
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3
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Liu M, Lu Y, Xue G, Han L, Jia H, Wang Z, Zhang J, Liu P, Yang C, Zhou Y. Role of short-chain fatty acids in host physiology. Animal Model Exp Med 2024; 7:641-652. [PMID: 38940192 PMCID: PMC11528394 DOI: 10.1002/ame2.12464] [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: 04/10/2024] [Accepted: 06/08/2024] [Indexed: 06/29/2024] Open
Abstract
Short-chain fatty acids (SCFAs) are major metabolites produced by the gut microbiota through the fermentation of dietary fiber, and they have garnered significant attention due to their close association with host health. As important mediators between the gut microbiota and the host, SCFAs serve as energy substrates for intestinal epithelial cells and maintain homeostasis in host immune and energy metabolism by influencing host epigenetics, activating G protein-coupled receptors, and inhibiting pathogenic microbial infections. This review provides a comprehensive summary of SCFAs synthesis and metabolism and offering an overview of the latest research progress on their roles in protecting gut health, enhancing energy metabolism, mitigating diseases such as cancer, obesity, and diabetes, modulating the gut-brain axis and gut-lung axis, and promoting bone health.
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Affiliation(s)
- Mingyue Liu
- Stem Cell Storage Center, Hebei Reproductive Health Hospital, Hebei Women and Children's Health HospitalHebei Research Institute For Reproductive HealthShijiazhuangChina
| | - Yubo Lu
- School of Electronic Information and Electrical EngineeringShanghai Jiao Tong UniversityShanghaiChina
| | - Guoyu Xue
- Stem Cell Storage Center, Hebei Reproductive Health Hospital, Hebei Women and Children's Health HospitalHebei Research Institute For Reproductive HealthShijiazhuangChina
| | - Le Han
- Prevention Health Section, Hebei Reproductive Health Hospital, Hebei Women and Children's Health HospitalHebei Research Institute For Reproductive HealthShijiazhuangChina
| | - Hanbing Jia
- Department of Medical Imaging, Hebei Reproductive Health Hospital, Hebei Women and Children's Health HospitalHebei Research Institute For Reproductive HealthShijiazhuangChina
| | - Zi Wang
- Department of Medical Imaging, Hebei Reproductive Health Hospital, Hebei Women and Children's Health HospitalHebei Research Institute For Reproductive HealthShijiazhuangChina
| | - Jia Zhang
- Department of Obstetrical, Hebei Reproductive Health Hospital, Hebei Women and Children's Health HospitalHebei Research Institute For Reproductive HealthShijiazhuangChina
| | - Peng Liu
- Department of Clinical Laboratory, Hebei Reproductive Health Hospital, Hebei Women and Children's Health HospitalHebei Research Institute For Reproductive HealthShijiazhuangChina
| | - Chaojuan Yang
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering MedicineBeihang UniversityBeijingChina
| | - Yingjie Zhou
- Department of Obstetrics and Gynecology, Hebei Reproductive Health Hospital, Hebei Women and Children's Health HospitalHebei Research Institute For Reproductive HealthShijiazhuangChina
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4
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Dumiaty Y, Underwood BM, Phy-Lim J, Chee MJ. Neurocircuitry underlying the actions of glucagon-like peptide 1 and peptide YY 3-36 in the suppression of food, drug-seeking, and anxiogenesis. Neuropeptides 2024; 105:102427. [PMID: 38579490 DOI: 10.1016/j.npep.2024.102427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/07/2024]
Abstract
Obesity is a critical health condition worldwide that increases the risks of comorbid chronic diseases, but it can be managed with weight loss. However, conventional interventions relying on diet and exercise are inadequate for achieving and maintaining weight loss, thus there is significant market interest for pharmaceutical anti-obesity agents. For decades, receptor agonists for the gut peptide glucagon-like peptide 1 (GLP-1) featured prominently in anti-obesity medications by suppressing appetite and food reward to elicit rapid weight loss. As the neurocircuitry underlying food motivation overlaps with that for drugs of abuse, GLP-1 receptor agonism has also been shown to decrease substance use and relapse, thus its therapeutic potential may extend beyond weight management to treat addictions. However, as prolonged use of anti-obesity drugs may increase the risk of mood-related disorders like anxiety and depression, and individuals taking GLP-1-based medication commonly report feeling demotivated, the long-term safety of such drugs is an ongoing concern. Interestingly, current research now focuses on dual agonist approaches that include GLP-1 receptor agonism to enable synergistic effects on weight loss or associated functions. GLP-1 is secreted from the same intestinal cells as the anorectic gut peptide, Peptide YY3-36 (PYY3-36), thus this review assessed the therapeutic potential and underlying neural circuits targeted by PYY3-36 when administered independently or in combination with GLP-1 to curb the appetite for food or drugs of abuse like opiates, alcohol, and nicotine. Additionally, we also reviewed animal and human studies to assess the impact, if any, for GLP-1 and/or PYY3-36 on mood-related behaviors in relation to anxiety and depression. As dual agonists targeting GLP-1 and PYY3-36 may produce synergistic effects, they can be effective at lower doses and offer an alternative approach for therapeutic benefits while mitigating undesirable side effects.
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Affiliation(s)
- Yasmina Dumiaty
- Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
| | - Brett M Underwood
- Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
| | - Jenny Phy-Lim
- Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
| | - Melissa J Chee
- Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
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Robinson SL, Bendrath SC, Yates EM, Thiele TE. Basolateral amygdala neuropeptide Y system modulates binge ethanol consumption. Neuropsychopharmacology 2024; 49:690-698. [PMID: 37758802 PMCID: PMC10876546 DOI: 10.1038/s41386-023-01742-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 08/22/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023]
Abstract
Neuropeptide Y (NPY) signaling regulation of corticolimbic communication is known to modulate binge-like ethanol consumption in rodents. In this work we sought to assess the impact of intra-BLA NPY system modulation on binge-like ethanol intake and to assess the role of the NPY1R+ projection from the BLA to the mPFC in this behavior. We used "drinking-in-the-dark" (DID) procedures in C57BL6J mice to address these questions. First, the impact of intra-BLA administration of NPY on binge-like ethanol intake was assessed. Next, the impact of repeated cycles of DID intake on NPY1R expression in the BLA was assessed with use of immunohistochemistry (IHC). Finally, chemogenetic inhibition of BLA→mPFC NPY1R+ projections was assessed to determine if limbic communication with the mPFC was specifically involved in binge-like ethanol intake. Importantly, as both the BLA and NPY system are sexually dimorphic, both sexes were assessed in these studies. Intra-BLA NPY dose-dependently decreased binge-like ethanol intake in males only. Repeated DID reduced NPY1R expression in the BLA of both sexes. Silencing of BLA→mPFC NPY1R+ neurons significantly reduced binge-like ethanol intake in both sexes in a dose-dependent manner. We provide novel evidence that (1) intra-BLA NPY reduces binge-like ethanol intake in males; (2) binge-like ethanol intake reduces NPY1R levels in the BLA; and (3) chemogenetic inhibition of BLA→mPFC NPY1R+ neurons blunts binge-like drinking in male and female mice. These observations provide the first direct evidence that NPY signaling in the BLA, and specifically BLA communication with the mPFC, modulates binge-like ethanol consumption.
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Affiliation(s)
- Stacey L Robinson
- Department of Psychology & Neuroscience, The University of North Carolina, Chapel Hill, NC, 27599-3270, USA
- Bowles Center for Alcohol Studies, The University of North Carolina, Chapel Hill, NC, 27599-7178, USA
| | - Sophie C Bendrath
- Department of Psychology & Neuroscience, The University of North Carolina, Chapel Hill, NC, 27599-3270, USA
- Bowles Center for Alcohol Studies, The University of North Carolina, Chapel Hill, NC, 27599-7178, USA
| | - Elizabeth M Yates
- Department of Psychology & Neuroscience, The University of North Carolina, Chapel Hill, NC, 27599-3270, USA
| | - Todd E Thiele
- Department of Psychology & Neuroscience, The University of North Carolina, Chapel Hill, NC, 27599-3270, USA.
- Bowles Center for Alcohol Studies, The University of North Carolina, Chapel Hill, NC, 27599-7178, USA.
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6
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Kloock S, Ziegler CG, Dischinger U. Obesity and its comorbidities, current treatment options and future perspectives: Challenging bariatric surgery? Pharmacol Ther 2023; 251:108549. [PMID: 37879540 DOI: 10.1016/j.pharmthera.2023.108549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/08/2023] [Accepted: 10/19/2023] [Indexed: 10/27/2023]
Abstract
Obesity and its comorbidities, including type 2 diabetes mellitus, cardiovascular disease, heart failure and non-alcoholic liver disease are a major health and economic burden with steadily increasing numbers worldwide. The need for effective pharmacological treatment options is strong, but, until recently, only few drugs have proven sufficient efficacy and safety. This article provides a comprehensive overview of obesity and its comorbidities, with a special focus on organ-specific pathomechanisms. Bariatric surgery as the so far most-effective therapeutic strategy, current pharmacological treatment options and future treatment strategies will be discussed. An increasing knowledge about the gut-brain axis and especially the identification and physiology of incretins unfolds a high number of potential drug candidates with impressive weight-reducing potential. Future multi-modal therapeutic concepts in obesity treatment may surpass the effectivity of bariatric surgery not only with regard to weight loss, but also to associated comorbidities.
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Affiliation(s)
- Simon Kloock
- Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
| | - Christian G Ziegler
- Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany; Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Ulrich Dischinger
- Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany; Comprehensive Heart Failure Center, Würzburg, Germany.
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7
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Abstract
The multifaceted microbiota characterizing our gut plays a crucial role in maintaining immune, metabolic and tissue homeostasis of the intestine as well as of distal organs, including the central nervous system. Microbial dysbiosis is reported in several inflammatory intestinal diseases characterized by the impairment of the gut epithelial and vascular barriers, defined as leaky gut, and it is reported as a potential danger condition associated with the development of metabolic, inflammatory and neurodegenerative diseases. Recently, we pointed out the strict connection between the gut and the brain via a novel vascular axis. Here we want to deepen our knowledge on the gut-brain axis, with particular emphasis on the connection between microbial dysbiosis, leaky gut, cerebral and gut vascular barriers, and neurodegenerative diseases. The firm association between microbial dysbiosis and impairment of the vascular gut-brain axis will be summarized in the context of protection, amelioration or boosting of Alzheimer, Parkinson, Major depressive and Anxiety disorders. Understanding the relationship between disease pathophysiology, mucosal barrier function and host-microbe interaction will foster the use of the microbiome as biomarker for health and disease as well as a target for therapeutic and nutritional advances.
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Affiliation(s)
- Sara Carloni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, 20072 Pieve Emanuele, MI, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, MI, Italy.
| | - Maria Rescigno
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, 20072 Pieve Emanuele, MI, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, MI, Italy.
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8
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Helman TJ, Headrick JP, Stapelberg NJC, Braidy N. The sex-dependent response to psychosocial stress and ischaemic heart disease. Front Cardiovasc Med 2023; 10:1072042. [PMID: 37153459 PMCID: PMC10160413 DOI: 10.3389/fcvm.2023.1072042] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 04/03/2023] [Indexed: 05/09/2023] Open
Abstract
Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome-a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.
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Affiliation(s)
- Tessa J. Helman
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW, Sydney, Australia
- Correspondence: Tessa J. Helman
| | - John P. Headrick
- Schoolof Pharmacy and Medical Sciences, Griffith University, Southport, QLD, Australia
| | | | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW, Sydney, Australia
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Acute gut inflammation reduces neural activity and spine maturity in hippocampus but not basolateral amygdala. Sci Rep 2022; 12:20169. [PMID: 36418891 PMCID: PMC9684565 DOI: 10.1038/s41598-022-24245-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 11/11/2022] [Indexed: 11/25/2022] Open
Abstract
Gastrointestinal tract (gut) inflammation increases stress and threat-coping behaviors, which are associated with altered activity in fear-related neural circuits, such as the basolateral amygdala and hippocampus. It remains to be determined whether inflammation from the gut affects neural activity by altering dendritic spines. We hypothesized that acute inflammation alters dendritic spines in a brain region-specific manner. Here we show that acute gut inflammation (colitis) evoked by dextran sodium sulfate (DSS) did not affect the overall spine density in the CA1 region of hippocampus, but increased the relative proportion of immature spines to mature spines on basal dendrites of pyramidal neurons. In contrast, in animals with colitis, no changes in spine density or composition on dendrites of pyramidal cells was observed in the basolateral amygdala. Rather, we observed decreased spine density on dendrites of stellate neurons, but not the relative proportions of mature vs immature spines. We used cFos expression evoked by the forced swim task as a measure of neural activity during stress and found no effect of DSS on the density of cFos immunoreactive neurons in basolateral amygdala. In contrast, fewer CA1 neurons expressed cFos in mice with colitis, relative to controls. Furthermore, CA1 cFos expression negatively correlated with active stress-coping in the swim task and was negatively correlated with gut inflammation. These data reveal that the effects of acute gut inflammation on synaptic remodeling depend on brain region, neuronal phenotype, and dendrite location. In the hippocampus, a shift to immature spines and hypoactivity are more strongly related to colitis-evoked behavioral changes than is remodeling in basolateral amygdala.
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Vicentini FA, Szamosi JC, Rossi L, Griffin L, Nieves K, Bihan D, Lewis IA, Pittman QJ, Swain MG, Surette MG, Hirota SA, Sharkey KA. Colitis-associated microbiota drives changes in behaviour in male mice in the absence of inflammation. Brain Behav Immun 2022; 102:266-278. [PMID: 35259427 DOI: 10.1016/j.bbi.2022.03.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 02/10/2022] [Accepted: 03/03/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract. IBD are associated with a high prevalence of cognitive, behavioural and emotional comorbidities, including anxiety and depression. The link between IBD and the development of behavioural comorbidities is poorly understood. As the intestinal microbiota profoundly influences host behaviour, we sought to determine whether the altered gut microbiota associated with intestinal inflammation contributes to the development of behavioural abnormalities. Using the dextran sulphate sodium (DSS) model of colitis, we characterized intestinal inflammation, behaviour (elevated plus maze and tail suspension test) and the composition of the microbiota in male mice. Cecal contents from colitic mice were transferred into germ-free (GF) or antibiotic (Abx)-treated mice, and behaviour was characterized in recipient mice. Gene expression was measured using qPCR. DSS colitis was characterized by a significant reduction in body weight and an increase in colonic inflammatory markers. These changes were accompanied by increased anxiety-like behaviour, an altered gut microbiota composition, and increased central Tnf expression. Transfer of the cecal matter from colitic mice induced similar behavioural changes in both GF and Abx-treated recipient mice, with no signs of colonic or neuroinflammation. Upon characterization of the microbiota in donor and recipient mice, specific taxa were found to be associated with behavioural changes, notably members of the Lachnospiraceae family. Behavioural abnormalities associated with intestinal inflammation are transmissible via transfer of cecal matter, suggesting that alterations in the composition of the gut microbiota play a key role in driving behavioural changes in colitis.
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Affiliation(s)
- Fernando A Vicentini
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Inflammation Research Network, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Jake C Szamosi
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Laura Rossi
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Lateece Griffin
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Kristoff Nieves
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Inflammation Research Network, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Dominique Bihan
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Ian A Lewis
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Quentin J Pittman
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mark G Swain
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Michael G Surette
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Simon A Hirota
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Inflammation Research Network, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Keith A Sharkey
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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11
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Cluny NL, Nyuyki KD, Almishri W, Griffin L, Lee BH, Hirota SA, Pittman QJ, Swain MG, Sharkey KA. Recruitment of α4β7 monocytes and neutrophils to the brain in experimental colitis is associated with elevated cytokines and anxiety-like behavior. J Neuroinflammation 2022; 19:73. [PMID: 35379260 PMCID: PMC8981853 DOI: 10.1186/s12974-022-02431-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 03/15/2022] [Indexed: 02/07/2023] Open
Abstract
Background Behavioral comorbidities, such as anxiety and depression, are a prominent feature of IBD. The signals from the inflamed gut that cause changes in the brain leading to these behavioral comorbidities remain to be fully elucidated. We tested the hypothesis that enhanced leukocyte–cerebral endothelial cell interactions occur in the brain in experimental colitis, mediated by α4β7 integrin, to initiate neuroimmune activation and anxiety-like behavior. Methods Female mice treated with dextran sodium sulfate were studied at the peak of acute colitis. Circulating leukocyte populations were determined using flow cytometry. Leukocyte–cerebral endothelial cell interactions were examined using intravital microscopy in mice treated with anti-integrin antibodies. Brain cytokine and chemokines were assessed using a multiplex assay in animals treated with anti-α4β7 integrin. Anxiety-like behavior was assessed using an elevated plus maze in animals after treatment with an intracerebroventricular injection of interleukin 1 receptor antagonist. Results The proportion of classical monocytes expressing α4β7 integrin was increased in peripheral blood of mice with colitis. An increase in the number of rolling and adherent leukocytes on cerebral endothelial cells was observed, the majority of which were neutrophils. Treatment with anti-α4β7 integrin significantly reduced the number of rolling leukocytes. After anti-Ly6C treatment to deplete monocytes, the number of rolling and adhering neutrophils was significantly reduced in mice with colitis. Interleukin-1β and CCL2 levels were elevated in the brain and treatment with anti-α4β7 significantly reduced them. Enhanced anxiety-like behavior in mice with colitis was reversed by treatment with interleukin 1 receptor antagonist. Conclusions In experimental colitis, α4β7 integrin-expressing monocytes direct the recruitment of neutrophils to the cerebral vasculature, leading to elevated cytokine levels. Increased interleukin-1β mediates anxiety-like behavior. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02431-z.
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Affiliation(s)
- Nina L Cluny
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Kewir D Nyuyki
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Wagdi Almishri
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Lateece Griffin
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Benjamin H Lee
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Simon A Hirota
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Quentin J Pittman
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mark G Swain
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Keith A Sharkey
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. .,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. .,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
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12
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Sari DK, Ichwan M, Masyithah D, Dharmajaya R, Khatib A. Sex Differences in Neuropeptide Y Serum, But Not in Fat Intake and Body Mass Index. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.9282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background:
One’s appetite has a role in controlling food intake and maintaining energy balance, but its effect on body metabolism related to obesity is still questionable. The purpose of this study was to determine the levels of neuropeptide Y in healthy people and to see differences in gender and anthropometric parameters. The hypothesis of this study was that there would be differences in neuropeptide Y levels in groups with gender and anthropometric parameter differences.
Methods:
This study was a cross-sectional study involving 62 study subjects, male and female, who did not have chronic diseases or metabolic disorders. This research was conducted from April to September 2020. The parameters examined in this study were neuropeptide Y levels and anthropometric parameters. The statistical analysis performed was the Mann–Whitney test to see the differences between groups.
Results:
The mean age of the research subjects was 40.48 ± 10.85 years, with the same ethnic distribution. The distribution of men and women was more women than men. Based on anthropometric examination, it was found that obesity nutritional status was more common in the female group than in the male group; however, serum neuropeptide Y levels were found to be significantly different between male and female groups (male group was higher) which were mean±standard deviation: 348.37±330.09 ng/L, p=0.036.
Conclusions: The study found significant differences in serum neuropeptide Y levels in male and female groups, with neuropeptide Y levels being higher in men than in women.
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13
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Matisz C, Gruber A. Neuroinflammatory remodeling of the anterior cingulate cortex as a key driver of mood disorders in gastrointestinal disease and disorders. Neurosci Biobehav Rev 2022; 133:104497. [DOI: 10.1016/j.neubiorev.2021.12.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 11/10/2021] [Accepted: 12/09/2021] [Indexed: 02/08/2023]
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14
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Nahvi RJ, Tanelian A, Nwokafor C, Hollander CM, Peacock L, Sabban EL. Intranasal Neuropeptide Y as a Potential Therapeutic for Depressive Behavior in the Rodent Single Prolonged Stress Model in Females. Front Behav Neurosci 2021; 15:705579. [PMID: 34566592 PMCID: PMC8456029 DOI: 10.3389/fnbeh.2021.705579] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/19/2021] [Indexed: 01/14/2023] Open
Abstract
The susceptibility to stress-elicited disorders is markedly influenced by sex. Women are twice as likely as men to develop posttraumatic stress disorder (PTSD), depression, anxiety disorders, and social impairments following exposure to traumatic stress. However, most of the studies in animal models examining putative therapeutics for stress-triggered impairments, including single prolonged stress (SPS), were performed predominantly with males. Previous studies in males demonstrated that intranasal neuropeptide Y (NPY) can provide therapeutic relief of many SPS-triggered behaviors, but is ineffective in females at the same dose. Thus, females may need a higher dose of exogenous NPY to attain a therapeutically significant concentration since the overwhelming majority of studies found that NPY levels in females in many brain regions are lower than in male rodents. Here, we examined SPS as an appropriate model to elicit many PTSD-associated symptoms in females and whether intranasal NPY at higher doses than with males is able to alter the development of SPS-triggered behavioral impairments. Sprague-Dawley female rats were exposed to SPS only, or in a separate cohort after SPS stressors were immediately infused intranasally with one of several doses of NPY, starting with 600 μg/rat—four times the dose effective in males. In the third cohort of animals, females were infused intranasally with either 600 μg NPY, omarigliptin [a dipeptidyl peptidase IV (DPP4) inhibitor], or both right after the SPS stressors. After 19 days they were tested on several behavioral tests. SPS elicited significant depressive/despair like behavior on the forced swim test (FST), anxiety behavior on the elevated plus maze (EPM), as well as impaired social interaction. On the FST, there was a dose-response effect of intranasal NPY, with 1,200 μg, but not 600 μg, preventing the development of the SPS-elicited depressive-like behavior. The omarigliptin and 600 μg NPY combined treatment, but neither alone, was also sufficient at preventing depressive-like behavior on the FST. The results demonstrate that: (1) SPS elicits several behavioral manifestations of PTSD in females; (2) early intervention with a high dose of intranasal NPY has therapeutic potential also for females; and (3) NPY cleavage by DPP4 may play a role in the higher dose requirement for females.
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Affiliation(s)
- Roxanna J Nahvi
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, United States
| | - Arax Tanelian
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, United States
| | - Chiso Nwokafor
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, United States
| | - Callie M Hollander
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, United States
| | - Lauren Peacock
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, United States
| | - Esther L Sabban
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, United States
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15
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Tyszkiewicz-Nwafor M, Jowik K, Dutkiewicz A, Krasinska A, Pytlinska N, Dmitrzak-Weglarz M, Suminska M, Pruciak A, Skowronska B, Slopien A. Neuropeptide Y and Peptide YY in Association with Depressive Symptoms and Eating Behaviours in Adolescents across the Weight Spectrum: From Anorexia Nervosa to Obesity. Nutrients 2021; 13:nu13020598. [PMID: 33670342 PMCID: PMC7917982 DOI: 10.3390/nu13020598] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 12/28/2022] Open
Abstract
Neuropeptide Y (NPY) and peptide YY (PYY) are involved in metabolic regulation. The purpose of the study was to assess the serum levels of NPY and PYY in adolescents with anorexia nervosa (AN) or obesity (OB), as well as in a healthy control group (CG). The effects of potential confounders on their concentrations were also analysed. Eighty-nine adolescents were included in this study (AN = 30, OB = 30, and CG = 29). Anthropometric measurements and psychometric assessment of depressive symptoms, eating behaviours, body attitudes, and fasting serum levels of NPY and PYY were analysed. The AN group presented severe depressive symptoms, while the OB group held different attitudes towards the body. The levels of NPY were lower in the AN and OB groups as compared with the CG. The PYY levels were higher in the OB group than in the AN group and the CG. The severity of eating disorder symptoms predicted fasting serum concentrations of NPY. Lower levels of NPY in AN, as well as in OB suggests the need to look for a common link in the mechanism of this effect. Higher level of PYY in OB may be important in explaining complex etiopathogenesis of the disease. The psychopathological symptoms may have an influence on the neurohormones regulating metabolism.
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Affiliation(s)
- Marta Tyszkiewicz-Nwafor
- Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (K.J.); (A.D.); (N.P.); (A.S.)
- Correspondence:
| | - Katarzyna Jowik
- Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (K.J.); (A.D.); (N.P.); (A.S.)
| | - Agata Dutkiewicz
- Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (K.J.); (A.D.); (N.P.); (A.S.)
| | - Agata Krasinska
- Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.K.); (M.S.); (B.S.)
| | - Natalia Pytlinska
- Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (K.J.); (A.D.); (N.P.); (A.S.)
| | - Monika Dmitrzak-Weglarz
- Psychiatric Genetics Unit, Department of Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
| | - Marta Suminska
- Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.K.); (M.S.); (B.S.)
| | - Agata Pruciak
- Institute of Plant Protection—National Research Institute, Research Centre of Quarantine, Invasive and Genetically Modified Organisms, 60-318 Poznan, Poland;
| | - Bogda Skowronska
- Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.K.); (M.S.); (B.S.)
| | - Agnieszka Slopien
- Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (K.J.); (A.D.); (N.P.); (A.S.)
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16
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Hanscom M, Loane DJ, Aubretch T, Leser J, Molesworth K, Hedgekar N, Ritzel RM, Abulwerdi G, Shea-Donohue T, Faden AI. Acute colitis during chronic experimental traumatic brain injury in mice induces dysautonomia and persistent extraintestinal, systemic, and CNS inflammation with exacerbated neurological deficits. J Neuroinflammation 2021; 18:24. [PMID: 33461596 PMCID: PMC7814749 DOI: 10.1186/s12974-020-02067-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Disruptions of brain-gut axis have been implicated in the progression of a variety of gastrointestinal (GI) disorders and central nervous system (CNS) diseases and injuries, including traumatic brain injury (TBI). TBI is a chronic disease process characterized by persistent secondary injury processes which can be exacerbated by subsequent challenges. Enteric pathogen infection during chronic TBI worsened cortical lesion volume; however, the pathophysiological mechanisms underlying the damaging effects of enteric challenge during chronic TBI remain unknown. This preclinical study examined the effect of intestinal inflammation during chronic TBI on associated neurobehavioral and neuropathological outcomes, systemic inflammation, and dysautonomia. METHODS Dextran sodium sulfate (DSS) was administered to adult male C57BL/6NCrl mice 28 days following craniotomy (Sham) or TBI for 7 days to induce intestinal inflammation, followed by a return to normal drinking water for an additional 7 to 28 days for recovery; uninjured animals (Naïve) served as an additional control group. Behavioral testing was carried out prior to, during, and following DSS administration to assess changes in motor and cognitive function, social behavior, and mood. Electrocardiography was performed to examine autonomic balance. Brains were collected for histological and molecular analyses of injury lesion, neurodegeneration, and neuroinflammation. Blood, colons, spleens, mesenteric lymph nodes (mLNs), and thymus were collected for morphometric analyses and/or immune characterization by flow cytometry. RESULTS Intestinal inflammation 28 days after craniotomy or TBI persistently induced, or exacerbated, respectively, deficits in fine motor coordination, cognition, social behavior, and anxiety-like behavior. Behavioral changes were associated with an induction, or exacerbation, of hippocampal neuronal cell loss and microglial activation in Sham and TBI mice administered DSS, respectively. Acute DSS administration resulted in a sustained systemic immune response with increases in myeloid cells in blood and spleen, as well as myeloid cells and lymphocytes in mesenteric lymph nodes. Dysautonomia was also induced in Sham and TBI mice administered DSS, with increased sympathetic tone beginning during DSS administration and persisting through the first recovery week. CONCLUSION Intestinal inflammation during chronic experimental TBI causes a sustained systemic immune response and altered autonomic balance that are associated with microglial activation, increased neurodegeneration, and persistent neurological deficits.
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Affiliation(s)
- Marie Hanscom
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA.
| | - David J Loane
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
| | - Taryn Aubretch
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Jenna Leser
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Kara Molesworth
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Nivedita Hedgekar
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Rodney M Ritzel
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Gelareh Abulwerdi
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Terez Shea-Donohue
- Division of Translational Radiation Sciences (DTRS), Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
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17
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Schaper SJ, Hofmann T, Wölk E, Weibert E, Rose M, Stengel A. Pancreatic Polypeptide but Not Other Members of the Neuropeptide Y Family Shows a Moderate Association With Perceived Anxiety in Obese Men. Front Hum Neurosci 2020; 14:578578. [PMID: 33192409 PMCID: PMC7604387 DOI: 10.3389/fnhum.2020.578578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/22/2020] [Indexed: 01/01/2023] Open
Abstract
Neuropeptide Y (NPY), peptide tyrosine tyrosine (PYY), and pancreatic polypeptide (PP) are important mediators in the bidirectional communication along the gut-brain-axis. Best known for their role in the regulation of appetite and food intake they are considered to play a crucial role in the development of obesity. Additionally, mounting evidence indicates a regulatory function in anxiety, mood and stress resilience with potential sex differences. In the present study, we examined the associations of NPY, PYY, and PP plasma levels with anxiety, depressiveness and perceived stress in obese patients. We analyzed 144 inpatients (90 female, 54 male, BMI mean: 49.4 kg/m2) in a naturalistic treatment setting for obesity and its somatic and mental comorbidities. Fasting blood samples were taken, and patients completed psychometric self-assessment questionnaires (GAD-7, PHQ-9, PSQ-20) within the first week after admission and before discharge. Plasma concentrations of the peptides were measured by ELISA. Women showed significant higher anxiety (GAD-7: 8.13 ± 5.67 vs. 5.93 ± 5.42, p = 0.04) and stress scores (PSQ-20: 52.62 ± 23.5 vs. 41.23 ± 22.53, p = 0.01) than men. In the longitudinal analysis women with a clinically relevant improvement of anxiety (≥ 5 points on GAD-7, p < 0.001) also showed significant improvements in depression (PHQ-9: 38%, p = 0.002) and PSQ-20 scores (23%, p = 0.005) while anxiety-improved male patients only improved in the subscale tension of the PSQ-20 (34%, p = 0.02). In men we observed a positive correlation of PP with anxiety scores (GAD-7: r = 0.41, p = 0.007) and with age (r = 0.49, p = 0.001) on admission while NPY negatively correlated with age (r = -0.38, p = 0.01). In contrast, there were no significant associations (p > 0.05) in female subjects in the cross-sectional as well as in the longitudinal analysis. In conclusion, women suffering from morbid obesity showed greater psychological comorbidity and considerable interactions among them. Despite that we solely observed associations of PP with anxiety and age with NPY and PP in men, suggesting a possible influence of sex hormones on the NPY system. However, improvement of anxiety scores did not lead to significant changes in NPY.
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Affiliation(s)
- Selina Johanna Schaper
- Department for Psychosomatic Medicine, Charité Center for Internal Medicine and Dermatology, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Tobias Hofmann
- Department for Psychosomatic Medicine, Charité Center for Internal Medicine and Dermatology, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ellen Wölk
- Department for Psychosomatic Medicine, Charité Center for Internal Medicine and Dermatology, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Elena Weibert
- Department for Psychosomatic Medicine, Charité Center for Internal Medicine and Dermatology, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Matthias Rose
- Department for Psychosomatic Medicine, Charité Center for Internal Medicine and Dermatology, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, United States
| | - Andreas Stengel
- Department for Psychosomatic Medicine, Charité Center for Internal Medicine and Dermatology, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany
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18
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Yu J, Min D, Bai Y, Qu L, Zou T, Wang S. Electroacupuncture alleviates Parkinson disease and regulates the expression of brain-gut peptides. Exp Anim 2020; 69:448-460. [PMID: 32669479 PMCID: PMC7677085 DOI: 10.1538/expanim.19-0153] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 06/15/2020] [Indexed: 12/25/2022] Open
Abstract
The non-motor symptoms (NMS) of Parkinson's disease (PD) are found in more than 90% of patients with PD. Here, we explored the effects of electroacupuncture (EA) stimulation at Zhong wan (CV-12), Qihai (RN-7), Zusanli (ST-36) and Taichong (LR-3) on NMS and brain-gut peptides of PD. We found that EA intervention alleviated the motor deficit induced by 6-OHDA in rats indicated by the decreased abnormal involuntary movements (AIMs) scores and the net number of rotations and increased cylinder test grade. It also improved the spatial memory and attenuated anxiety-like and depression of PD model rats. EA treatment significantly inhibited neuronal apoptosis in PD model animals, as demonstrated by the increased number of TH positive cells and reduced number of apoptotic cells in the substantia nigra. The expression of cleaved caspase-3 and cleaved PARP in PD model rats was markedly suppressed by EA stimulation. Moreover, EA remarkably inhibited the inflammatory response in PD model rats, as revealed by the decreased levels of TNF-α, IL-1β, and COX-2 mRNA expression. It also attenuated the oxidative stress in rats, as indicated by the increased levels of SOD and GSH and the decreased level of MDA. EA treatment contributed to alleviating PD by regulating brain-gut peptides in rats, such as NPY, CCK, SST, GAS, and PYY. In conclusion, EA stimulation at CV-12, RN-7, ST-36, and LR-3 effectively alleviates the NMS of PD partly through regulating the levels of brain-gut peptides.
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Affiliation(s)
- Jianjun Yu
- Department of Massage, Heilongjiang Academy of Chinese Medical Sciences, 72-78 Xiang'an Street, Harbin 150036, People's Republic of China
| | - Dongmei Min
- Department of Rehabilitation Medicine, Heilongjiang Provincial Hospital, No. 82 Zhongshan Road, Xiangfang District, Harbin 150036, People's Republic of China
| | - Yan Bai
- Department of Acupuncture, Heilongjiang Academy of Chinese Medical Sciences, 72-78 Xiang'an Street, Harbin 150036, People's Republic of China
| | - Long Qu
- Department of Massage, Heilongjiang Academy of Chinese Medical Sciences, 72-78 Xiang'an Street, Harbin 150036, People's Republic of China
| | - Tianyu Zou
- Department of Acupuncture, Heilongjiang Academy of Chinese Medical Sciences, 72-78 Xiang'an Street, Harbin 150036, People's Republic of China
| | - Shun Wang
- Department of Acupuncture, Heilongjiang Academy of Chinese Medical Sciences, 72-78 Xiang'an Street, Harbin 150036, People's Republic of China
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19
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Bistoletti M, Bosi A, Banfi D, Giaroni C, Baj A. The microbiota-gut-brain axis: Focus on the fundamental communication pathways. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 176:43-110. [PMID: 33814115 DOI: 10.1016/bs.pmbts.2020.08.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
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20
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Nahvi RJ, Sabban EL. Sex Differences in the Neuropeptide Y System and Implications for Stress Related Disorders. Biomolecules 2020; 10:biom10091248. [PMID: 32867327 PMCID: PMC7564266 DOI: 10.3390/biom10091248] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 12/16/2022] Open
Abstract
The neuropeptide Y (NPY) system is emerging as a promising therapeutic target for neuropsychiatric disorders by intranasal delivery to the brain. However, the vast majority of underlying research has been performed with males despite females being twice as susceptible to many stress-triggered disorders such as posttraumatic stress disorder, depression, anorexia nervosa, and anxiety disorders. Here, we review sex differences in the NPY system in basal and stressed conditions and how it relates to varied susceptibility to stress-related disorders. The majority of studies demonstrate that NPY expression in many brain areas under basal, unstressed conditions is lower in females than in males. This could put them at a disadvantage in dealing with stress. Knock out animals and Flinders genetic models show that NPY is important for attenuating depression in both sexes, while its effects on anxiety appear more pronounced in males. In females, NPY expression after exposure to stress may depend on age, timing, and nature and duration of the stressors and may be especially pronounced in the catecholaminergic systems. Furthermore, alterations in NPY receptor expression and affinity may contribute to the sex differences in the NPY system. Overall, the review highlights the important role of NPY and sex differences in manifestation of neuropsychiatric disorders.
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21
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Hassan AM, Mancano G, Kashofer K, Liebisch G, Farzi A, Zenz G, Claus SP, Holzer P. Anhedonia induced by high-fat diet in mice depends on gut microbiota and leptin. Nutr Neurosci 2020; 25:299-312. [PMID: 32290785 DOI: 10.1080/1028415x.2020.1751508] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Objectives: Imbalanced nutrition and obesity are risk factors for depression, a relationship that in rodents can be modeled by depression-like behavior in response to high-fat diet (HFD). In this work, we examined the role of the intestinal microbiota and the adipocytokine leptin as potential mediators of the effects of HFD to induce anhedonia-like behavior and reduce self-care in mice.Methods: Male mice were fed a control diet or HFD (60 kJ% from fat) for a period of 4 weeks, after which behavioral tests and molecular analyses (gut microbiome composition, intestinal metabolome, fecal fatty acids, plasma hormone levels) were performed. The role of the intestinal microbiota was addressed by selective depletion of gut bacteria with a combination of non-absorbable antibiotics, while the implication of leptin was examined by the use of leptin-deficient ob/ob mice.Results: Antibiotic treatment reduced the HFD-induced weight gain and adiposity and prevented HFD-induced anhedonia-like behavior and self-care reduction. These effects were associated with a decrease in fecal fatty acids and intestinal microbiota-related metabolites including short-chain fatty acids, glucose and amino acids. Gut microbiota depletion suppressed the HFD-induced rise of plasma leptin, and the circulating leptin levels correlated with the anhedonia-like behavior and reduced self-care caused by HFD. The anhedonic effect of HFD was absent in leptin-deficient ob/ob mice although these animals gained more weight and adiposity in response to HFD than wild-type mice.Discussion: The results indicate that anhedonia-like behavior induced by HFD in mice depends on the intestinal microbiome and involves leptin as a signaling hormone.
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Affiliation(s)
- Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Giulia Mancano
- Department of Food and Nutritional Sciences, University of Reading, Reading, UK
| | - Karl Kashofer
- Diagnostic & Research Institute of Pathology, Diagnostic & Research Center of Molecular Biomedicine, Medical University of Graz, Graz, Austria
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Geraldine Zenz
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Sandrine P Claus
- Department of Food and Nutritional Sciences, University of Reading, Reading, UK
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
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Cordaro M, Scuto M, Siracusa R, D'amico R, Filippo Peritore A, Gugliandolo E, Fusco R, Crupi R, Impellizzeri D, Pozzebon M, Alfonsi D, Mattei N, Marcolongo G, Evangelista M, Cuzzocrea S, Di Paola R. Effect of N-palmitoylethanolamine-oxazoline on comorbid neuropsychiatric disturbance associated with inflammatory bowel disease. FASEB J 2020; 34:4085-4106. [PMID: 31950563 DOI: 10.1096/fj.201901584rr] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 12/19/2019] [Accepted: 12/31/2019] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation of the gastrointestinal (GI) tract, and it is associated with different neurological disorders. Recent evidence has demonstrated that the gut-brain-axis has a central function in the perpetuation of IBS, and for this reason, it can be considered a possible therapeutic target. N-Palmitoylethanolamine-oxazoline (PEA-OXA) possesses anti-inflammatory and potent neuroprotective effects. Although recent studies have explained the neuroprotective properties of PEA-OXA, nothing is known about its effects on the gut-brain axis during colitis. The aim of this study is to explore the mechanism and the effect of PEA-OXA on the gut-brain axis in rats subjected to experimental colitis induced by oral administration of dextran sulfate sodium (DSS). Daily oral administration of PEA-OXA (10 mg/kg daily o.s.) was able to decrease the body weight loss, macroscopic damage, colon length, histological alteration, and inflammation after DSS induction. Additionally, PEA-OXA administration enhanced neurotrophic growth factor release and decreased the astroglial and microglial activation induced by DSS. Moreover, PEA-OXA restored intestinal permeability and tight junctions (TJs) as well as reduced apoptosis in the colon and brain. In our work, we demonstrated, for the first time, the action of PEA-OXA on the gut-brain axis in a model of DSS-induced colitis and its implication on the "secondary" effects associated with colonic disturbance.
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Affiliation(s)
- Marika Cordaro
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Maria Scuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Ramona D'amico
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Alessio Filippo Peritore
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Enrico Gugliandolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Roberta Fusco
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Rosalia Crupi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | | | | | | | | | - Maurizio Evangelista
- Institute of Anaesthesiology and Reanimation, Catholic University of the Sacred Heart, Rome, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Rosanna Di Paola
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
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23
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Matisz CE, Vicentini FA, Hirota SA, Sharkey KA, Gruber AJ. Behavioral adaptations in a relapsing mouse model of colitis. Physiol Behav 2020; 216:112802. [PMID: 31931038 DOI: 10.1016/j.physbeh.2020.112802] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/09/2020] [Accepted: 01/09/2020] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by relapsing periods of gut inflammation, and is comorbid with depression, anxiety, and cognitive deficits. Animal models of IBD that explore the behavioral consequences almost exclusively use acute models of gut inflammation, which fails to recapitulate the cyclic, chronic nature of IBD. This study sought to identify behavioral differences in digging, memory, and stress-coping strategies in mice exposed to one (acute) or three (chronic) cycles of gut inflammation, using the dextran sodium sulfate (DSS) model of colitis. Similar levels of gut pathology were observed between acute and chronically exposed mice, although mice in the chronic treatment had significantly shorter colons, suggesting more severe disease. Behavioral measures revealed an unexpected pattern in which chronic treatment evoked fewer deficits than acute treatment. Specifically, acutely-treated mice showed alterations in measures of object burying, novel object recognition, object location memory, and stress-coping (forced swim task). Chronically-treated animals, however, showed similar alterations in object burying, but not the other measures. These data suggest an adaptive or tolerizing effect of repeated cycles of peripheral gut inflammation on mnemonic function and stress-coping, whereas some other behaviors continue to be affected by gut inflammation. We speculate that the normalization of some functions may involve the reversion to the baseline state of the hypothalamic-pituitary-adrenal axis and/or levels of neuroinflammation, which are both activated by the first exposure to the colitic agent.
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Affiliation(s)
- Chelsea E Matisz
- Canadian Center for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, 4401 University Drive West, Lethbridge T1K 3M4, AB, Canada.
| | - Fernando A Vicentini
- Hotchkiss Brain Institute, Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Inflammation Research Network, Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Simon A Hirota
- Inflammation Research Network, Snyder Institute for Chronic Diseases, Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keith A Sharkey
- Hotchkiss Brain Institute, Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Aaron J Gruber
- Canadian Center for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, 4401 University Drive West, Lethbridge T1K 3M4, AB, Canada
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24
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Sroor HM, Hassan AM, Zenz G, Valadez-Cosmes P, Farzi A, Holzer P, El-Sharif A, Gomaa FAZM, Kargl J, Reichmann F. Experimental colitis reduces microglial cell activation in the mouse brain without affecting microglial cell numbers. Sci Rep 2019; 9:20217. [PMID: 31882991 PMCID: PMC6934553 DOI: 10.1038/s41598-019-56859-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 12/16/2019] [Indexed: 12/25/2022] Open
Abstract
Inflammatory bowel disease (IBD) patients frequently suffer from anxiety disorders and depression, indicating that altered gut-brain axis signalling during gastrointestinal inflammation is a risk factor for psychiatric disease. Microglia, immune cells of the brain, is thought to be involved in a number of mental disorders, but their role in IBD is largely unknown. In the current work, we investigated whether colitis induced by dextran sulphate sodium (DSS), a murine model of IBD, alters microglial phenotypes in the brain. We found that colitis caused a reduction of Iba-1 and CD68 immunoreactivity, microglial activation markers, in specific brain regions of the limbic system such as the medial prefrontal cortex (mPFC), while other areas remained unaffected. Flow cytometry showed an increase of monocyte-derived macrophages during colitis and gene expression analysis in the mPFC showed pronounced changes of microglial markers including cluster of differentiation 86 (CD86), tumour necrosis factor-α, nitric oxide synthase 2, CD206 and chitinase-like protein 3 consistent with both M1 and M2 activation. Taken together, these findings suggest that experimental colitis-induced inflammation is propagated to the brain altering microglial function.
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Affiliation(s)
- Hoda M Sroor
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
- Microbiology and Immunology Department, Faculty of Pharmacy-Girls, Al-Azar University, Cairo, Egypt
| | - Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Geraldine Zenz
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Paulina Valadez-Cosmes
- Division of Pharmacology, Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Amany El-Sharif
- Microbiology and Immunology Department, Faculty of Pharmacy-Girls, Al-Azar University, Cairo, Egypt
| | - Fatma Al-Zahraa M Gomaa
- Microbiology and Immunology Department, Faculty of Pharmacy-Girls, Al-Azar University, Cairo, Egypt
- Pharmacognosy and Medicinal Herbs Department, Faculty of Clinical Pharmacy, Al-Baha University, Al-Baha, Saudi Arabia
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Florian Reichmann
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria.
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25
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Ilie IR. Neurotransmitter, neuropeptide and gut peptide profile in PCOS-pathways contributing to the pathophysiology, food intake and psychiatric manifestations of PCOS. Adv Clin Chem 2019; 96:85-135. [PMID: 32362321 DOI: 10.1016/bs.acc.2019.11.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Polycystic ovary syndrome (PCOS) is a major health problem with a heterogeneous hormone-imbalance and clinical presentation across the lifespan of women. Increased androgen production and abnormal gonadotropin-releasing hormone (GnRH) release and gonadotropin secretion, resulting in chronic anovulation are well-known features of the PCOS. The brain is both at the top of the neuroendocrine axis regulating ovarian function and a sensitive target of peripheral gonadal hormones and peptides. Current literature illustrates that neurotransmitters regulate various functions of the body, including reproduction, mood and body weight. Neurotransmitter alteration could be one of the reasons for disturbed GnRH release, consequently directing the ovarian dysfunction in PCOS, since there is plenty evidence for altered catecholamine metabolism and brain serotonin or opioid activity described in PCOS. Further, the dysregulated neurotransmitter and neuropeptide profile in PCOS could also be the reason for low self-esteem, anxiety, mood swings and depression or obesity, features closely associated with PCOS women. Can these altered central brain circuits, or the disrupted gut-brain axis be the tie that would both explain and link the pathogenesis of this disorder, the occurrence of depression, anxiety and other mood disorders as well as of obesity, insulin resistance and abnormal appetite in PCOS? This review intends to provide the reader with a comprehensive overview of what is known about the relatively understudied, but very complex role that neurotransmitters, neuropeptides and gut peptides play in PCOS. The answer to the above question may help the development of drugs to specifically target these central and peripheral circuits, thereby providing a valuable treatment for PCOS patients that present to the clinic with GnRH/LH hypersecretion, obesity or psychiatric manifestations.
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Affiliation(s)
- Ioana R Ilie
- Department of Endocrinology, University of Medicine and Pharmacy 'Iuliu-Hatieganu', Cluj-Napoca, Romania.
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26
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Abstract
Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota-gut-brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota-gut-brain interactions. The effects of SCFAs on cellular systems and their interaction with gut-brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined.
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27
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Dempsey E, Abautret-Daly Á, Docherty NG, Medina C, Harkin A. Persistent central inflammation and region specific cellular activation accompany depression- and anxiety-like behaviours during the resolution phase of experimental colitis. Brain Behav Immun 2019; 80:616-632. [PMID: 31063848 DOI: 10.1016/j.bbi.2019.05.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/18/2019] [Accepted: 05/03/2019] [Indexed: 02/08/2023] Open
Abstract
Depression and anxiety-related psychological symptoms are increasingly recognised as important co-morbidities in patients with inflammatory bowel disease (IBD). Dextran sulfate sodium (DSS) -induced colitis is an animal model of IBD in which afferent activation of the gut-brain axis can be assessed and explored as a source of behavioural change. Exposure of adult male Wistar rats to DSS (5%) in drinking water induced distal colitis. In parallel to local inflammatory responses in the gut wall, increased expression of IL-6 and iNOS was found in the cerebral cortex and an increase in ventricular volume. Immunoreactivity of immediate early gene FosB/ΔFosB activation was measured as an index of cellular activation and was increased in the nucleus accumbens and dorsal raphe nucleus in acutely colitic animals. Following resolution of the acute colitic response, sustained anhedonia in the saccharin preference test, immobility in the forced swim test, reduced burying behaviour in the marble burying test, and mild signs of anxiety in the elevated plus maze and light/dark box were observed. Central increases in iNOS expression persisted during the recovery phase and mapped to reactive microglia, particularly those found in the parenchyma surrounding circumventricular regions. Evidence of associated nitration was also found. Sustained increases in ventricular volume and reduced T2 magnetic resonance relaxometry time in cortical regions were observed during the recovery period. FosB/ΔFosB activation was evident in the dorsal raphe during recovery. Persistent central inflammation and cellular activation may underpin the emergence of symptoms of depression and anxiety in experimental colitis.
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Affiliation(s)
- Elaine Dempsey
- Neuropsychopharmacology Research Group, Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland; School of Pharmacy & Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland
| | - Áine Abautret-Daly
- Neuropsychopharmacology Research Group, Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland; School of Pharmacy & Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland
| | - Neil G Docherty
- Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland; Department of Physiology, School of Medicine, Trinity College, Dublin 2, Ireland
| | - Carlos Medina
- School of Pharmacy & Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland; Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Andrew Harkin
- Neuropsychopharmacology Research Group, Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland; School of Pharmacy & Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
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28
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Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity. Cells 2019; 8:cells8070670. [PMID: 31269754 PMCID: PMC6679154 DOI: 10.3390/cells8070670] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/24/2019] [Accepted: 06/28/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, modulate the intestinal immune system, and thereby regulate the intestinal inflammatory processes. Although the autonomic nervous system is classically divided in a sympathetic and parasympathetic branch, both play a pivotal role in the crosstalk with the immune system, with the enteric nervous system acting as a potential interface. Pilot clinical trials that employ vagus nerve stimulation to reduce inflammation are met with promising results. In this paper, we review current knowledge on the innervation of the gut, the potential of cholinergic and adrenergic systems to modulate intestinal immunity, and comment on ongoing developments in clinical trials.
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Electroacupuncture and Moxibustion Improved Anxiety Behavior in DSS-Induced Colitis Mice. Gastroenterol Res Pract 2019; 2019:2345890. [PMID: 30881446 PMCID: PMC6383400 DOI: 10.1155/2019/2345890] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/18/2018] [Accepted: 10/31/2018] [Indexed: 12/19/2022] Open
Abstract
Background and Aims Psychological disorders are prevalent in patients with inflammatory bowel disease, but the underlying mechanisms remain unknown. The aim of this study was to study whether electroacupuncture (EA) and moxibustion (MB) can improve anxiety behavior in DSS-induced colitis mice and to investigate whether this effect is related to hypothalamic-pituitary-adrenocortical (HPA) axis. Methods The colitis model was established by drinking 2.5% dextran sodium sulfate (DSS). DSS-induced colitis mice were treated by EA or MB. Disease activity index (DAI) was scored; intestinal morphological and pathological structure was observed; anxiety behavior was tested by the elevated plus maze and open field. The concentration of corticotropin-releasing hormone (CRH) and cortisol (CORT) in serum was measured by enzyme-linked immunosorbent assay (ELISA). The protein expression of CRH in the colon and hypothalamus was detected by Western blot (WB). Results Both EA and MB treatments can improvethe morphology of their distal colonic mucosal epithelia, as well as the disease activity index. Meanwhile, anxiety behavior in colitis mice was improved slightly after EA and MB treatment. In addition, the levels of CRH and CORT in the serum were slightly improved after EA and MB treatment. These effects are further supported by WB results. The expression of CRH in the colon and hypothalamus was increased significantly after treatment, compared with the model group. Conclusion EA and MB were able to regulate the concentration of CRH in serum and protein expression in the peripheral and central at different levels and promote the recovery of the HPA axis that may be the basis for EA and MB to improve colonic pathology and alleviate anxiety behavior in DSS-induced colitis.
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30
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Sandberg JC, Björck IME, Nilsson AC. Impact of rye-based evening meals on cognitive functions, mood and cardiometabolic risk factors: a randomized controlled study in healthy middle-aged subjects. Nutr J 2018; 17:102. [PMID: 30400947 PMCID: PMC6220522 DOI: 10.1186/s12937-018-0412-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 10/28/2018] [Indexed: 12/25/2022] Open
Abstract
Background Whole grain (WG) intake is associated with reduced risk of obesity, type 2 diabetes and cardiovascular disease, whereas type 2 diabetes increases the risk of cognitive decline and dementia. The purpose of this study was to investigate the effects of short-term intervention with WG rye on cognitive functions, mood and cardiometabolic risk markers in middle-aged test subjects. Method Rye-based breads were provided to 38 healthy test subjects (aged 52-70y) during three consecutive days in a crossover study design, using white wheat flour bread (WWB) as a reference. The rye-based bread consisted of a WG rye kernel/flour mixture (1:1 ratio) supplemented with resistant starch type 2 (RS2) (RB + RS2). The last bread portion was ingested at 2100 h, and cognitive function, mood and cardiometabolic risk markers were determined the following morning, 11 − 14 h post intake. Results In comparison to WWB, the RB + RS2 product increased ratings of mood parameters (valance, P < 0.001; activation P < 0.05). No differences were seen in the cognitive tests depending on intervention (P > 0.05). RB + RS2 increased insulin sensitivity (P < 0.05), fasting levels of gut hormones (PYY, P < 0.05; GLP-2, P < 0.01) and fasting concentrations of plasma acetate, butyrate and total SCFA (P < 0.001). In contrast, fasting levels of IL − 1β were decreased (P < 0.05). Insulin sensitivity was positively correlated with working memory test performance (P < 0.05). Conclusions This study display novel findings regarding effects of WG rye products on mood, and glucose and appetite regulation in middle-aged subjects, indicating anti-diabetic properties of WG rye. The beneficial effects are suggested to be mediated through gut fermentation of dietary fiber in the RB + RS2 product. Trial registration The study was retrospectively registered at ClinicalTrials.gov, register number NCT03275948. Registered September 8 2017.
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Affiliation(s)
- Jonna C Sandberg
- Department of Food Technology, Engineering and Nutrition, Lund University, P.O. Box 124, SE-221 00, Lund, Sweden.,Food for Health Science Centre, Lund University, P.O. Box 124, SE-221 00, Lund, Sweden
| | - Inger M E Björck
- Food for Health Science Centre, Lund University, P.O. Box 124, SE-221 00, Lund, Sweden
| | - Anne C Nilsson
- Department of Food Technology, Engineering and Nutrition, Lund University, P.O. Box 124, SE-221 00, Lund, Sweden. .,Food for Health Science Centre, Lund University, P.O. Box 124, SE-221 00, Lund, Sweden.
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31
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Gut-brain actions underlying comorbid anxiety and depression associated with inflammatory bowel disease. Acta Neuropsychiatr 2018; 30:275-296. [PMID: 28270247 DOI: 10.1017/neu.2017.3] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED IntroductionInflammatory bowel disease (IBD) is a chronic relapsing and remitting disorder characterised by inflammation of the gastrointestinal tract. There is a growing consensus that IBD is associated with anxiety- and depression-related symptoms. Psychological symptoms appear to be more prevalent during active disease states with no difference in prevalence between Crohn's disease and ulcerative colitis. Behavioural disturbances including anxiety- and depression-like symptoms have also been observed in animal models of IBD. RESULTS The likely mechanisms underlying the association are discussed with particular reference to communication between the gut and brain. The close bidirectional relationship known as the gut-brain axis includes neural, hormonal and immune communication links. Evidence is provided for a number of interacting factors including activation of the inflammatory response system in the brain, the hypothalamic-pituitary-adrenal axis, and brain areas implicated in altered behaviours, changes in blood brain barrier integrity, and an emerging role for gut microbiota and response to probiotics in IBD.DiscussionThe impact of psychological stress in models of IBD remains somewhat conflicted, however, it is weighted in favour of stress or early stressful life events as risk factors in the development of IBD, stress-induced exacerbation of inflammation and relapse. CONCLUSION It is recommended that patients with IBD be screened for psychological disturbance and treated accordingly as intervention can improve quality of life and may reduce relapse rates.
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32
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Schaefer AS. Genetics of periodontitis: Discovery, biology, and clinical impact. Periodontol 2000 2018; 78:162-173. [DOI: 10.1111/prd.12232] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Arne S Schaefer
- Department of Periodontology and Synoptic Dentistry; Institute for Dental and Craniofacial Sciences; Research Centre ImmunoSciences; Charité - University Medicine Berlin; Berlin Germany
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Winter G, Hart RA, Charlesworth RP, Sharpley CF. Gut microbiome and depression: what we know and what we need to know. Rev Neurosci 2018; 29:629-643. [DOI: 10.1515/revneuro-2017-0072] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 12/08/2017] [Indexed: 02/07/2023]
Abstract
Abstract
Gut microbiome diversity has been strongly associated with mood-relating behaviours, including major depressive disorder (MDD). This association stems from the recently characterised bi-directional communication system between the gut and the brain, mediated by neuroimmune, neuroendocrine and sensory neural pathways. While the link between gut microbiome and depression is well supported by research, a major question needing to be addressed is the causality in the connection between the two, which will support the understanding of the role that the gut microbiota play in depression. In this article, we address this question by examining a theoretical ‘chronology’, reviewing the evidence supporting two possible sequences of events. First, we discuss that alterations in the gut microbiota populations of specific species might contribute to depression, and secondly, that depressive states might induce modification of specific gut microbiota species and eventually contribute to more severe depression. The feasibility of both sequences is supported by pre-clinical trials. For instance, research in rodents has shown an onset of depressive behaviour following faecal transplantations from patients with MDD. On the other hand, mental induction of stress and depressive behaviour in rodents resulted in reduced gut microbiota richness and diversity. Synthesis of these chronology dynamics raises important research directions to further understand the role that gut microbiota play in mood-relating behaviours, which holds substantial potential clinical outcomes for persons who experience MDD or related depressive disorders.
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Sanz Y, Romaní-Perez M, Benítez-Páez A, Portune KJ, Brigidi P, Rampelli S, Dinan T, Stanton C, Delzenne N, Blachier F, Neyrinck AM, Beaumont M, Olivares M, Holzer P, Günther K, Wolters M, Ahrens W, Claus SP, Campoy C, Murphy R, Sadler C, Fernández L, Kamp JWVD. Towards microbiome-informed dietary recommendations for promoting metabolic and mental health: Opinion papers of the MyNewGut project. Clin Nutr 2018; 37:2191-2197. [PMID: 30033172 DOI: 10.1016/j.clnu.2018.07.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/02/2018] [Accepted: 07/03/2018] [Indexed: 12/18/2022]
Abstract
The gut microbiota coexists in partnership with the human host through adaptations to environmental and physiological changes that help maintain dynamic homeostatic healthy states. Break-down of this delicate balance under sustained exposure to stressors (e.g. unhealthy diets) can, however, contribute to the onset of disease. Diet is a key modifiable environmental factor that modulates the gut microbiota and its metabolic capacities that, in turn, could impact human physiology. On this basis, the diet and the gut microbiota could act as synergistic forces that provide resilience against disease or that speed the progress from health to disease states. Associations between unhealthy dietary patterns, non-communicable diseases and intestinal dysbiosis can be explained by this hypothesis. Translational studies showing that dietary-induced alterations in microbial communities recapitulate some of the pathological features of the original host further support this notion. In this introductory paper by the European project MyNewGut, we briefly summarize the investigations conducted to better understand the role of dietary patterns and food components in metabolic and mental health and the specificities of the microbiome-mediating mechanisms. We also discuss how advances in the understanding of the microbiome's role in dietary health effects can help to provide acceptable scientific grounds on which to base dietary advice for promoting healthy living.
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Affiliation(s)
- Yolanda Sanz
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain.
| | - Marina Romaní-Perez
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain.
| | - Alfonso Benítez-Páez
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Kevin J Portune
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Patrizia Brigidi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Simone Rampelli
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Ted Dinan
- APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | | | - Nathalie Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - François Blachier
- UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Martin Beaumont
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Marta Olivares
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Pharmacology Section, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Kathrin Günther
- Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany
| | - Maike Wolters
- Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany
| | - Wolfgang Ahrens
- Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany; Institute of Statistics, University of Bremen, Bremen, Germany
| | - Sandrine P Claus
- Department of Food and Nutritional Sciences, University of Reading, Reading, United Kingdom
| | - Cristina Campoy
- Department of Paediatrics, School of Medicine, University of Granada, Granada, Spain; EURISTIKOS Excellence Centre for Paediatric Research, Biomedical Research Centre, University of Granada, Granada, Spain; Spanish Network of Biomedical Research in Epidemiology and Public Health (CIBERESP), Carlos III Institute, Granada node, Spain
| | - Rinki Murphy
- Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | | | - Laura Fernández
- European Food Information Council (EUFIC), Brussels, Belgium
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Nyuyki KD, Cluny NL, Swain MG, Sharkey KA, Pittman QJ. Altered Brain Excitability and Increased Anxiety in Mice With Experimental Colitis: Consideration of Hyperalgesia and Sex Differences. Front Behav Neurosci 2018; 12:58. [PMID: 29670513 PMCID: PMC5893896 DOI: 10.3389/fnbeh.2018.00058] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 03/13/2018] [Indexed: 12/28/2022] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are incurable lifelong inflammatory bowel diseases (IBD) with a rising worldwide incidence. IBD is characterized by diarrhea, rectal bleeding, severe cramping and weight loss. However, there is a growing evidence that IBD is also associated with anxiety- and depression-related disorders, which further increase the societal burden of these diseases. Given the limited knowledge of central nervous system (CNS) changes in IBD, we investigated CNS-related comorbidities in a mouse model of experimental colitis induced by dextran sulfate sodium (DSS) administration in drinking water for 5 days. In male and female C57BL6J mice, DSS treatment caused increased brain excitability, revealed by a decrease in seizure onset times after intraperitoneal administration of kainic acid. Moreover, both sexes showed increased anxiety-related behavior in the elevated plus-maze (EPM) and open field (OF) paradigms. We assessed somatic pain levels, because they may influence behavioral responses. Only male mice were hyperalgesic when tested with calibrated von Frey hairs and on the hotplate for mechanical and thermal pain sensitivity respectively. Administration of diazepam (DZP; ip, 1 mg/kg) 30 min before EPM rescued the anxious phenotype and improved locomotion, even though it significantly increased thermal sensitivity in both sexes. This indicates that the altered behavioral response is unlikely attributable to an interference with movement due to somatic pain in females. We show that experimental colitis increases CNS excitability in response to administration of kainic acid, and increases anxiety-related behavior as revealed using the EPM and OF tests.
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Affiliation(s)
- Kewir D Nyuyki
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Nina L Cluny
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mark G Swain
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calgary Liver Unit, Division of Gastroenterology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Keith A Sharkey
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Quentin J Pittman
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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36
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Lach G, Schellekens H, Dinan TG, Cryan JF. Anxiety, Depression, and the Microbiome: A Role for Gut Peptides. Neurotherapeutics 2018; 15:36-59. [PMID: 29134359 PMCID: PMC5794698 DOI: 10.1007/s13311-017-0585-0] [Citation(s) in RCA: 347] [Impact Index Per Article: 49.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.
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Affiliation(s)
- Gilliard Lach
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Harriet Schellekens
- APC Microbiome Institute, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- Food for Health Ireland, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Institute, University College Cork, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Institute, University College Cork, Cork, Ireland.
- Food for Health Ireland, University College Cork, Cork, Ireland.
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Holzer P, Farzi A, Hassan AM, Zenz G, Jačan A, Reichmann F. Visceral Inflammation and Immune Activation Stress the Brain. Front Immunol 2017; 8:1613. [PMID: 29213271 PMCID: PMC5702648 DOI: 10.3389/fimmu.2017.01613] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 11/07/2017] [Indexed: 12/20/2022] Open
Abstract
Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut-brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut-brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention.
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Affiliation(s)
- Peter Holzer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Geraldine Zenz
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Angela Jačan
- CBmed GmbH-Center for Biomarker Research in Medicine, Graz, Austria
| | - Florian Reichmann
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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38
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Bouhlal S, Ellefsen KN, Sheskier MB, Singley E, Pirard S, Gorelick DA, Huestis MA, Leggio L. Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses. Drug Alcohol Depend 2017; 180:68-75. [PMID: 28881319 PMCID: PMC5654385 DOI: 10.1016/j.drugalcdep.2017.07.033] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 07/27/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Food intake and use of drugs of abuse like cocaine share common central and peripheral physiological pathways. Appetitive hormones play a major role in regulating food intake; however, little is known about the effects of acute cocaine administration on the blood concentrations of these hormones in cocaine users. METHODS We evaluated serum concentrations of six appetitive hormones: ghrelin (total and acyl-ghrelin), amylin, glucagon-like peptide-1 (GLP-1), insulin, leptin and peptide YY (PYY), as well as acute cardiorespiratory and subjective responses of 8 experienced cocaine users who received 25mg intravenous (IV) cocaine. RESULTS Serum concentrations of GLP-1 (p=0.014) and PYY (p=0.036) were significantly decreased one hour following IV cocaine administration; there was a trend towards a decrease for insulin (p=0.055) and amylin (p=0.063) concentrations, while no significant IV cocaine effect was observed for ghrelin (total or acyl-ghrelin) or leptin concentrations (p's≫>0.5). We also observed associations between hormone concentrations acutely affected by IV cocaine (GLP-1, PYY, insulin, amylin) and some cocaine-related cardiorespiratory and subjective responses (e.g., increased heart and respiratory rates; feeling high and anxious). DISCUSSION These findings show a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses. Additional research is needed to further investigate the potential mechanisms underlining these associations.
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Affiliation(s)
- Sofia Bouhlal
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, 10 Center Drive (10CRC/15330), Bethesda, MD 20892, United States
| | - Kayla N. Ellefsen
- Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States
| | - Mikela B. Sheskier
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, 10 Center Drive (10CRC/15330), Bethesda, MD 20892, United States
| | - Erick Singley
- Clinical Core Laboratory, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, United States
| | - Sandrine Pirard
- Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States
| | - David A. Gorelick
- Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States
| | - Marilyn A. Huestis
- Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States
| | - Lorenzo Leggio
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, 10 Center Drive (10CRC/15330), Bethesda, MD 20892, United States; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI 02906, United States.
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Langgartner D, Peterlik D, Foertsch S, Füchsl AM, Brokmann P, Flor PJ, Shen Z, Fox JG, Uschold-Schmidt N, Lowry CA, Reber SO. Individual differences in stress vulnerability: The role of gut pathobionts in stress-induced colitis. Brain Behav Immun 2017; 64:23-32. [PMID: 28012830 DOI: 10.1016/j.bbi.2016.12.019] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 12/15/2016] [Accepted: 12/16/2016] [Indexed: 12/21/2022] Open
Abstract
Chronic subordinate colony housing (CSC), an established mouse model for chronic psychosocial stress, promotes a microbial signature of gut inflammation, characterized by expansion of Proteobacteria, specifically Helicobacter spp., in association with colitis development. However, whether the presence of Helicobacter spp. during CSC is critically required for colitis development is unknown. Notably, during previous CSC studies performed at Regensburg University (University 1), male specific-pathogen-free (SPF) CSC mice lived in continuous subordination to a physically present and Helicobacter spp.-positive resident. Therefore, it is likely that CSC mice were colonized, during the CSC procedure, with Helicobacter spp. originating from the dominant resident. In the present study we show that employing SPF CSC mice and Helicobacter spp.-free SPF residents at Ulm University (University 2), results in physiological responses that are typical of chronic psychosocial stress, including increased adrenal and decreased thymus weights, decreased adrenal in vitro adrenocorticotropic hormone (ACTH) responsiveness, and increased anxiety-related behavior. However, in contrast to previous studies that used Helicobacter spp.-positive resident mice, use of Helicobacter spp.-negative resident mice failed to induce spontaneous colitis in SPF CSC mice. Consistent with the hypothesis that the latter is due to a lack of Helicobacter spp. transmission from dominant residents to subordinate mice during the CSC procedure, colonization of SPF residents with Helicobacter typhlonius at University 2, prior to the start of the CSC model, rescued the colitis-inducing potential of CSC exposure. Furthermore, using SPF CSC mice and H. typhlonius-free SPF residents at University 1 prevented CSC-induced colitis. In summary, our data support the hypothesis that the presence or absence of exposure to certain pathobionts contributes to individual variability in susceptibility to stress-/trauma-associated pathologies and to reproducibility of stress-related outcomes between laboratories.
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Affiliation(s)
- Dominik Langgartner
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany
| | - Daniel Peterlik
- Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany
| | - Sandra Foertsch
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany
| | - Andrea M Füchsl
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany
| | - Petra Brokmann
- Animal Research Facility, University of Ulm, 89081 Ulm, Germany
| | - Peter J Flor
- Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany
| | - Zeli Shen
- Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - James G Fox
- Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Nicole Uschold-Schmidt
- Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany
| | - Christopher A Lowry
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Department of Physical Medicine & Rehabilitation and Center for Neuroscience, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Rocky Mountain Mental Illness Research Education and Clinical Center, Denver, CO 80220, USA; Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE), Aurora, CO 80045, USA
| | - Stefan O Reber
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany.
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El-Salhy M, Solomon T, Hausken T, Gilja OH, Hatlebakk JG. Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease. World J Gastroenterol 2017; 23:5068-5085. [PMID: 28811704 PMCID: PMC5537176 DOI: 10.3748/wjg.v23.i28.5068] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/15/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn’s disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients’ quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease.
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Mitani T, Yoshioka Y, Furuyashiki T, Yamashita Y, Shirai Y, Ashida H. Enzymatically synthesized glycogen inhibits colitis through decreasing oxidative stress. Free Radic Biol Med 2017; 106:355-367. [PMID: 28257879 DOI: 10.1016/j.freeradbiomed.2017.02.048] [Citation(s) in RCA: 32] [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] [Received: 08/17/2016] [Revised: 02/17/2017] [Accepted: 02/27/2017] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases are a group of chronic inflammation conditions of the gastrointestinal tract. Disruption of the mucosal immune response causes accumulation of oxidative stress, resulting in the induction of inflammatory bowel disease. In this study, we investigated the effect of enzymatically synthesized glycogen (ESG), which is produced from starch, on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in C57BL/6 mice. Oral administration of ESG suppressed DSS- and TNBS-induced shortening of large intestine in female mice and significant decreased DSS-induced oxidative stress and TNBS-induced pro-inflammatory cytokine expression in the large intestine. ESG increase in the expression levels of heme oxygenase-1 (HO-1) and NF-E2-related factor-2 (Nrf2), a transcription factor for HO-1 expressed in the large intestine. Furthermore, ESG-induced HO-1 and Nrf2 were expressed mainly in intestinal macrophages. ESG is considered to be metabolized to resistant glycogen (RG) during digestion with α-amylase in vivo. In mouse macrophage RAW264.7 cells, RG, but not ESG decreased 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced reactive oxygen species (ROS). Knockdown of Nrf2 inhibited RG-induced HO-1 expression and negated the decrease in AAPH-induced ROS brought about by RG. RG up-regulated the protein stability of Nrf2 to decrease the formation of Nrf2-Keap1 complexes. RG-induced phosphorylation of Nrf2 at Ser40 was suppressed by ERK1/2 and JNK inhibitors. Our data indicate that ESG, digested with α-amylase to RG, suppresses DSS- and TNBS-induced colitis by increasing the expression of HO-1 in the large intestine of mice. Furthermore, we demonstrate that RG induces HO-1 expression by promoting phosphorylation of Nrf2 at Ser40 through activation of the ERK1/2 and JNK cascade in macrophages.
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Affiliation(s)
- Takakazu Mitani
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan; Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 6578501, Japan
| | - Yasukiyo Yoshioka
- Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 6578501, Japan
| | | | - Yoko Yamashita
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan
| | - Yasuhito Shirai
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan
| | - Hitoshi Ashida
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan.
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Lemieux AM, al'Absi M. Changes in circulating peptide YY and ghrelin are associated with early smoking relapse. Biol Psychol 2017; 131:43-48. [PMID: 28300626 DOI: 10.1016/j.biopsycho.2017.03.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 01/18/2017] [Accepted: 03/10/2017] [Indexed: 12/29/2022]
Abstract
Ghrelin and peptide YY (PYY) during ad libitum smoking have been associated with decreased reported craving (ghrelin) and increased positive affect (PYY), and higher baseline ghrelin levels predicted subsequent increased risk of smoking relapse. The current study assessed PYY and ghrelin during ad libitum smoking and again after the initial 48h of a smoking cessation attempt. The data compared smokers who abstained for 28days (n=37), smokers who relapsed (n=54), and nonsmokers (n=37). Plasma samples and subjective measures assessing craving and mood were collected at the beginning of each session. Results showed that relapsers experienced greater levels of distress (ps <0.01). While nonsmokers and abstainers showed no change in ghrelin across the initial 48h, relapsers declined (p <0.01). With PYY, relapsers increased (p <0.05) across the early abstinent phase. PYY and ghrelin may be useful predictors of relapse, specifically in reference to early withdrawal.
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Affiliation(s)
- Andrine M Lemieux
- Duluth Medical Research Institute, University of Minnesota Medical School, Duluth, MN, USA.
| | - Mustafa al'Absi
- Duluth Medical Research Institute, University of Minnesota Medical School, Duluth, MN, USA; Department of Biobehavioral Health and Population Sciences, University of Minnesota Medical School, Duluth, MN, USA.
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Aoki K, Kondo M, Okuda M, Saneyasu T, Honda K, Kamisoyama H. Identification, expression analysis, and functional characterization of peptide YY in chickens (Gallus gallus domesticus). Gen Comp Endocrinol 2017; 242:11-17. [PMID: 27118705 DOI: 10.1016/j.ygcen.2016.04.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 04/05/2016] [Accepted: 04/22/2016] [Indexed: 01/04/2023]
Abstract
Peptide YY (PYY) functions as a postprandial satiety signal in mammals. However, the genomic information and physiological roles of chicken PYY have not yet been clarified, although PYY peptide was isolated from chicken intestines in 1992. In this study, we identified a full-length complementary DNA (cDNA) sequence encoding the chicken PYY precursor. The deduced amino acid sequence of chicken PYY was completely consistent with the previously identified peptide sequence. PYY mRNA was abundantly expressed in the small intestine compared with the large intestine. PYY mRNA levels in the jejunum were significantly higher during ad libitum feeding compared with fasting, suggesting that intestinal PYY expression is altered in response to nutritional status in chicks. Intravenous administration of PYY significantly suppressed food intake in chicks. Furthermore, neuropeptide Y receptor Y2, a possible target of PYY, was expressed in various brain regions including the appetite-regulating centers in chicks. This is the first evidence that the intestinal hormone PYY may function as an anorexigenic hormone in chicks.
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Affiliation(s)
- Koji Aoki
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Makoto Kondo
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Mika Okuda
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Takaoki Saneyasu
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Kazuhisa Honda
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
| | - Hiroshi Kamisoyama
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
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44
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El-Salhy M, Hausken T, Gilja OH, Hatlebakk JG. The possible role of gastrointestinal endocrine cells in the pathophysiology of irritable bowel syndrome. Expert Rev Gastroenterol Hepatol 2017; 11:139-148. [PMID: 27927062 DOI: 10.1080/17474124.2017.1269601] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The etiology of irritable bowel syndrome (IBS) is unknown, but several factors appear to play a role in its pathophysiology, including abnormalities of the gastrointestinal endocrine cells. The present review illuminates the possible role of gastrointestinal hormones in the pathophysiology of IBS and the possibility of utilizing the current knowledge in treating the disease. Areas covered: Research into the intestinal endocrine cells and their possible role in the pathophysiology of IBS is discussed. Furthermore, the mechanisms underlying the abnormalities in the gastrointestinal endocrine cells in IBS patients are revealed. Expert commentary: The abnormalities observed in the gastrointestinal endocrine cells in IBS patients explains their visceral hypersensitivity, gastrointestinal dysmotility, and abnormal intestinal secretion, as well as the interchangeability of symptoms over time. Clarifying the role of the intestinal stem cells in the pathophysiology of IBS may lead to new treatment methods for IBS.
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Affiliation(s)
- Magdy El-Salhy
- a Division of Gastroenterology, Department of Medicine , Stord Hospital , Stord , Norway.,b Division of Gastroenterology, Department of Clinical Medicine , University of Bergen , Bergen , Norway.,c National Centre for Functional Gastrointestinal Disorders, Department of Medicine , Haukeland University Hospital , Bergen , Norway
| | - Trygve Hausken
- b Division of Gastroenterology, Department of Clinical Medicine , University of Bergen , Bergen , Norway.,c National Centre for Functional Gastrointestinal Disorders, Department of Medicine , Haukeland University Hospital , Bergen , Norway
| | - Odd Helge Gilja
- b Division of Gastroenterology, Department of Clinical Medicine , University of Bergen , Bergen , Norway.,c National Centre for Functional Gastrointestinal Disorders, Department of Medicine , Haukeland University Hospital , Bergen , Norway.,d National Centre for Ultrasound in Gastroenterology, Department of Medicine , Haukeland University Hospital , Bergen , Norway
| | - Jan Gunnar Hatlebakk
- b Division of Gastroenterology, Department of Clinical Medicine , University of Bergen , Bergen , Norway.,c National Centre for Functional Gastrointestinal Disorders, Department of Medicine , Haukeland University Hospital , Bergen , Norway
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Abstract
The gut microbiota and the brain interact with each other through multiple bidirectional signaling pathways in which neuropeptides and neuroactive peptide messengers play potentially important mediator roles. Currently, six particular modes of a neuropeptide link are emerging. (i) Neuropeptides and neurotransmitters contribute to the mutual microbiota-host interaction. (ii) The synthesis of neuroactive peptides is influenced by microbial control of the availability of amino acids. (iii) The activity of neuropeptides is tempered by microbiota-dependent autoantibodies. (iv) Peptide signaling between periphery and brain is modified by a regulatory action of the gut microbiota on the blood-brain barrier. (v) Within the brain, gut hormones released under the influence of the gut microbiota turn into neuropeptides that regulate multiple aspects of brain activity. (vi) Cerebral neuropeptides participate in the molecular, behavioral, and autonomic alterations which the brain undergoes in response to signals from the gut microbiota.
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Affiliation(s)
- P Holzer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria.
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Massironi S, Zilli A, Cavalcoli F, Conte D, Peracchi M. Chromogranin A and other enteroendocrine markers in inflammatory bowel disease. Neuropeptides 2016; 58:127-34. [PMID: 26804239 DOI: 10.1016/j.npep.2016.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 01/10/2016] [Accepted: 01/10/2016] [Indexed: 02/08/2023]
Abstract
Changes in the distribution and products of enteroendocrine cells may play a role in immune activation and regulation of gut inflammation. This review aims at critically evaluating the main enteroendocrine markers in inflammatory bowel diseases (IBD). A narrative review was performed by searching inflammatory bowel diseases and enteroendocrine biomarkers in PubMed. Relevant modifications of some enteroendocrine markers, such as Chromogranin A, and their correlation with disease activity have been reported in patients with inflammatory bowel diseases. Even if data about neuroendocrine markers are sometimes contrasting, they may be potentially useful for the diagnosis and clinical management of these patients.
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Affiliation(s)
- Sara Massironi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
| | - Alessandra Zilli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; Postgraduate School of Gastroenterology, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy.
| | - Federica Cavalcoli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; Postgraduate School of Gastroenterology, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy.
| | - Dario Conte
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; Postgraduate School of Gastroenterology, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy.
| | - Maddalena Peracchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; Postgraduate School of Gastroenterology, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy.
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Reichmann F, Wegerer V, Jain P, Mayerhofer R, Hassan AM, Fröhlich EE, Bock E, Pritz E, Herzog H, Holzer P, Leitinger G. Environmental enrichment induces behavioural disturbances in neuropeptide Y knockout mice. Sci Rep 2016; 6:28182. [PMID: 27305846 PMCID: PMC4910086 DOI: 10.1038/srep28182] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 05/31/2016] [Indexed: 12/28/2022] Open
Abstract
Environmental enrichment (EE) refers to the provision of a complex and stimulating housing condition which improves well-being, behaviour and brain function of laboratory animals. The mechanisms behind these beneficial effects of EE are only partially understood. In the current report, we describe a link between EE and neuropeptide Y (NPY), based on findings from NPY knockout (KO) mice exposed to EE. Relative to EE-housed wildtype (WT) animals, NPY KO mice displayed altered behaviour as well as molecular and morphological changes in amygdala and hippocampus. Exposure of WT mice to EE reduced anxiety and decreased central glucocorticoid receptor expression, effects which were absent in NPY KO mice. In addition, NPY deletion altered the preference of EE items, and EE-housed NPY KO mice responded to stress with exaggerated hyperthermia, displayed impaired spatial memory, had higher hippocampal brain-derived neurotrophic factor mRNA levels and altered hippocampal synaptic plasticity, effects which were not seen in WT mice. Accordingly, these findings suggest that NPY contributes to the anxiolytic effect of EE and that NPY deletion reverses the beneficial effects of EE into a negative experience. The NPY system could thus be a target for "enviromimetics", therapeutics which reproduce the beneficial effects of enhanced environmental stimulation.
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Affiliation(s)
- Florian Reichmann
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Vanessa Wegerer
- Research Unit Electron Microscopic Techniques, Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria
| | - Piyush Jain
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Raphaela Mayerhofer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Ahmed M. Hassan
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Esther E. Fröhlich
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Elisabeth Bock
- Research Unit Electron Microscopic Techniques, Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria
| | - Elisabeth Pritz
- Research Unit Electron Microscopic Techniques, Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria
| | - Herbert Herzog
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Gerd Leitinger
- Research Unit Electron Microscopic Techniques, Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria
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Lu Y, Ho RCM. An association between neuropeptide Y levels and leukocyte subsets in stress-exacerbated asthmatic mice. Neuropeptides 2016; 57:53-8. [PMID: 26673939 DOI: 10.1016/j.npep.2015.11.091] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 11/22/2015] [Accepted: 11/22/2015] [Indexed: 02/07/2023]
Abstract
Neuropeptide Y (NPY) was recently proposed to be associated with stress and airway inflammation; however, this has rarely been studied in animal models of asthma. Twenty-four C57BL/6 mice were randomly divided into 3 groups of 8 each: naive control group, asthma group (with an established asthma model), and stressed asthma group (with established asthma and stress models). Bronchoalveolar lavage (BAL) fluid was collected for total cell counts using a hemocytometer and for cytological examinations by Wright stain. Differential inflammatory cell counts were performed to identify eosinophils, macrophages, neutrophils, and lymphocytes. NPY and corticosterone serum levels were determined with enzyme immunoassay kits. Stress was associated with increased airway inflammatory response, which was manifested by the accumulation of total leukocytes and eosinophils in the BAL fluid in comparison with the asthma and the control groups. The levels of NPY (p<0.05) and corticosterone (p<0.01) were elevated in the stressed asthma group in comparison with the control and asthma groups. The concentration of NPY and corticosterone positively correlated with the total leukocyte count (r=0.892, p<0.05 and r=0.937, p<0.01 respectively) and eosinophil numbers (r=0.806, p=0.053 and r=0.885, p<0.01 respectively). Stress may be associated with elevated peripheral NPY level, which was observed to be associated with exacerbated airway inflammation in asthmatic mice.
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Affiliation(s)
- Yanxia Lu
- Department of Clinical Psychology and Psychiatry/School of Public Health, Zhejiang University College of Medicine, Hangzhou, China
| | - Roger Chun-Man Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore.
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Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc Natl Acad Sci U S A 2016; 113:E3130-9. [PMID: 27185913 DOI: 10.1073/pnas.1600324113] [Citation(s) in RCA: 159] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1-2 wk following the final immunization. Furthermore, immunization with M. vaccae prevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies.
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El-Salhy M, Mazzawi T, Hausken T, Hatlebakk JG. Interaction between diet and gastrointestinal endocrine cells. Biomed Rep 2016; 4:651-656. [PMID: 27284402 PMCID: PMC4887949 DOI: 10.3892/br.2016.649] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 03/01/2016] [Indexed: 02/07/2023] Open
Abstract
The gastrointestinal endocrine cells are essential for life. They regulate the gastrointestinal motility, secretion, visceral sensitivity, absorption, local immune defense, cell proliferation and appetite. These cells act as sensory cells with specialized microvilli that project into the lumen that sense the gut contents (mostly nutrients and/or bacteria byproducts), and respond to luminal stimuli by releasing hormones into the lamina propria. These released hormones exert their actions by entering the circulating blood and reaching distant targets (endocrine mode), nearby structures (paracrine mode) or via afferent and efferent synaptic transmission. The mature intestinal endocrine cells are capable of expressing several hormones. A change in diet not only affects the release of gastrointestinal hormones, but also alters the densities of the gut endocrine cells. The interaction between ingested foodstuffs and the gastrointestinal endocrine cells can be utilized for the clinical management of gastrointestinal and metabolic diseases, such as irritable bowel syndrome, obesity and diabetes.
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Affiliation(s)
- Magdy El-Salhy
- Section for Gastroenterology, Department of Medicine, Stord Helse-Fonna Hospital, 5409 Stord, Norway; Section for Gastroenterology, Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway; Department of Medicine, National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital, 5021 Bergen, Norway
| | - Tarek Mazzawi
- Section for Gastroenterology, Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway; Department of Medicine, National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital, 5021 Bergen, Norway
| | - Trygve Hausken
- Section for Gastroenterology, Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway; Department of Medicine, National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital, 5021 Bergen, Norway
| | - Jan Gunnar Hatlebakk
- Section for Gastroenterology, Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway; Department of Medicine, National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital, 5021 Bergen, Norway
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