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1
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Liang C, Wei S, Ji Y, Lin J, Jiao W, Li Z, Yan F, Jing X. The role of enteric nervous system and GDNF in depression: Conversation between the brain and the gut. Neurosci Biobehav Rev 2024; 167:105931. [PMID: 39447778 DOI: 10.1016/j.neubiorev.2024.105931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 10/14/2024] [Accepted: 10/20/2024] [Indexed: 10/26/2024]
Abstract
Depression is a debilitating mental disorder that causes a persistent feeling of sadness and loss of interest. Approximately 280 million individuals worldwide suffer from depression by 2023. Despite the heavy medical and social burden imposed by depression, pathophysiology remains incompletely understood. Emerging evidence indicates various bidirectional interplay enable communication between the gut and brain. These interplays provide a link between intestinal and central nervous system as well as feedback from cortical and sensory centers to enteric activities, which also influences physiology and behavior in depression. This review aims to overview the significant role of the enteric nervous system (ENS) in the pathophysiology of depression and gut-brain axis's contribution to depressive disorders. Additionally, we explore the alterations in enteric glia cells (EGCs) and glial cell line-derived neurotrophic factor (GDNF) in depression and their involvement in neuronal support, intestinal homeostasis maintains and immune response activation. Modulating ENS function, EGCs and GDNF level could serve as novel strategies for future antidepressant therapy.
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Affiliation(s)
- Chuoyi Liang
- School of Nursing, Jinan University, Guangzhou, China
| | - Sijia Wei
- School of Nursing, Jinan University, Guangzhou, China
| | - Yelin Ji
- School of Nursing, Jinan University, Guangzhou, China
| | - Jiayi Lin
- School of Nursing, Jinan University, Guangzhou, China
| | - Wenli Jiao
- School of Nursing, Jinan University, Guangzhou, China
| | - Zhiying Li
- School of Nursing, Jinan University, Guangzhou, China
| | - Fengxia Yan
- School of Nursing, Jinan University, Guangzhou, China.
| | - Xi Jing
- School of Nursing, Jinan University, Guangzhou, China; Guangdong-Hong Kong-Macau Great Bay Area Geoscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, China.
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2
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Thomann AK, Schmitgen MM, Stephan JC, Ebert MP, Thomann PA, Szabo K, Reindl W, Wolf RC. Associations Between Brain Morphology, Inflammatory Markers, and Symptoms of Fatigue, Depression, or Anxiety in Active and Remitted Crohn's Disease. J Crohns Colitis 2024; 18:1767-1779. [PMID: 38757201 DOI: 10.1093/ecco-jcc/jjae078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 04/17/2024] [Accepted: 05/15/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND Fatigue and psychosocial impairments are highly prevalent in IBD, particularly during active disease. Disturbed brain-gut interactions may contribute to these symptoms. This study examined associations between brain structure, faecal calprotectin, and symptoms of fatigue, depression, and anxiety in persons with Crohn's disease [CD] in different disease states. METHODS In this prospective observational study, n = 109 participants [n = 67 persons with CD, n = 42 healthy controls] underwent cranial magnetic resonance imaging, provided stool samples for analysis of faecal calprotectin, and completed questionnaires to assess symptoms of fatigue, depression, and anxiety. We analysed differences in grey matter volume [GMV] between patients and controls, and associations between regional GMV alterations, neuropsychiatric symptoms, and faecal calprotectin. RESULTS Symptoms of fatigue, depression, and anxiety were increased in patients with CD compared with controls, with highest scores in active CD. Patients exhibited regionally reduced GMV in cortical and subcortical sensorimotor regions, occipitotemporal and medial frontal areas. Regional GMV differences showed a significant negative association with fatigue, but not with depression or anxiety. Subgroup analyses revealed symptom-GMV associations for fatigue in remitted but not in active CD, whereas fatigue was positively associated with faecal calprotectin in active but not in remitted disease. CONCLUSION Our findings support disturbed brain-gut interactions in CD which may be particularly relevant for fatigue during remitted disease. Reduced GMV in the precentral gyrus and other sensorimotor areas could reflect key contributions to fatigue pathophysiology in CD. A sensorimotor model of fatigue in CD could also pave the way for novel treatment approaches.
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Affiliation(s)
- Anne K Thomann
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Mike M Schmitgen
- Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
| | - Jule C Stephan
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philipp A Thomann
- Department of Psychiatry and Psychotherapy, SRH Clinic Karlsbad-Langensteinbach, Karlsbad, Germany
| | - Kristina Szabo
- Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Wolfgang Reindl
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - R Christian Wolf
- Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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3
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Feng L, Cai X, Zou Q, Peng Y, Xu L, Wang L, Liu Q, Lou T. Exploring the management and treatment of IBD from the perspective of psychological comorbidities. Therap Adv Gastroenterol 2024; 17:17562848241290685. [PMID: 39421001 PMCID: PMC11483836 DOI: 10.1177/17562848241290685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 09/25/2024] [Indexed: 10/19/2024] Open
Abstract
The prevalence of anxiety, depression, and other psychological comorbidities among patients with inflammatory bowel disease (IBD) significantly exceeds that of the general population. Moreover, a bidirectional relationship exists between psychological comorbidities and IBD. This intricate interplay has substantial clinical implications, impacting treatment adherence, therapeutic efficacy, and disease recurrence rates. In this review, we explore the multifaceted mechanisms through which psychological factors influence IBD progression, treatment response, and prognosis. Specifically, we delve into the involvement of the hypothalamic-pituitary-adrenal axis, autonomic nervous system, enteric nervous system, microbiota-gut-brain axis, systemic inflammatory cytokines, and immune cell function. Additionally, we discuss the potential benefits of antidepressant therapy in mitigating IBD risk and the role of psychotropic drugs in reducing peripheral inflammation. Recognizing and addressing psychological comorbidity is pivotal in comprehensive IBD management. We advocate for the integration of biopsychosocial approaches into IBD treatment strategies, emphasizing the need for innovative psychological interventions as adjuncts to conventional therapies. Rigorous research investigating the impact of antidepressants and behavioral interventions on IBD-specific outcomes may herald a paradigm shift in IBD management.
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Affiliation(s)
- Lijuan Feng
- Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
| | - Xunchao Cai
- Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
| | - Qian Zou
- Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
| | - Yao Peng
- Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
| | - Long Xu
- Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
| | - Linlin Wang
- Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
| | - Qing Liu
- Department of Gastroenterology, Futian District Second People’s Hospital, Shenzhen 518049, China
| | - Ting Lou
- Health Management Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen 518055, China
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4
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Liu R, Luo Y, Ma J, Zhang Q, Sheng Y, Li J, Li H, Zhao T. Traditional Chinese medicine for functional gastrointestinal disorders and inflammatory bowel disease: narrative review of the evidence and potential mechanisms involving the brain-gut axis. Front Pharmacol 2024; 15:1444922. [PMID: 39355776 PMCID: PMC11443704 DOI: 10.3389/fphar.2024.1444922] [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: 06/06/2024] [Accepted: 08/23/2024] [Indexed: 10/03/2024] Open
Abstract
Functional gastrointestinal disorders (FGIDs) and inflammatory bowel disease (IBD) are common clinical disorders characterized by recurrent diarrhea and abdominal pain. Although their pathogenesis has not been fully clarified, disruptions in intestinal motility and immune function are widely accepted as contributing factors to both conditions, and the brain-gut axis plays a key role in these processes. Traditional Chinese Medicine (TCM) employs a holistic approach to treatment, considers spleen and stomach impairments and liver abnormality the main pathogenesis of these two diseases, and offers a unique therapeutic strategy that targets these interconnected pathways. Clinical evidence shows the great potential of TCM in treating FGIDs and IBD. This study presents a systematic description of the pathological mechanisms of FGIDs and IBD in the context of the brain-gut axis, discusses clinical and preclinical studies on TCM and acupuncture for the treatment of these diseases, and summarizes TCM targets and pathways for the treatment of FGIDs and IBD, integrating ancient wisdom with contemporary biomedical insights. The alleviating effects of TCM on FGID and IBD symptoms are mainly mediated through the modulation of intestinal immunity and inflammation, sensory transmission, neuroendocrine-immune network, and microbiota and their metabolism through brain-gut axis mechanisms. TCM may be a promising treatment option in controlling FGIDs and IBD; however, further high-quality research is required. This review provides a reference for an in-depth exploration of the interventional effects and mechanisms of TCM in FGIDs and IBD, underscoring TCM's potential to recalibrate the dysregulated brain-gut axis in FGIDs and IBD.
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Affiliation(s)
- RuiXuan Liu
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - YunTian Luo
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - JinYing Ma
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qi Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yudong Sheng
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiashan Li
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hongjiao Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - TianYi Zhao
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Li S, Qian Q, Xie Y, Wu Z, Yang H, Yin Y, Cui Y, Li X. Ameliorated Effects of Fucoidan on Dextran Sulfate Sodium-Induced Ulcerative Colitis and Accompanying Anxiety and Depressive Behaviors in Aged C57BL/6 Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:14199-14215. [PMID: 38871671 DOI: 10.1021/acs.jafc.4c03039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Fucoidan has shown better effects on the improvement of acute ulcerative colitis (UC). However, the specific mechanisms by which fucoidan improves UC-related behavioral disorders in aged mice, especially its effect on the gut-brain axis, remain to be further explored. C57BL/6 male mice aged 8 months were gavaged with 400 or 100 mg/kg bw day fucoidan for five consecutive weeks, with UC being induced by ad libitum to dextran sulfate sodium (DSS) solution in the fifth week. The results showed that fucoidan ameliorated UC and accompanying anxiety- and depressive-like behaviors with downregulated expressions of (NOD)-like receptor family and pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteine aspartate-specific protease-1 (Caspase-1) and interlekin-1β (IL-1β), and elevated mRNA levels of brain-derived neurotrophic factor (Bdnf) and postsynaptic-density protein 95 (Psd-95) in cortex and hippocampus. Furthermore, fucoidan improved the permeability of intestinal barrier and blood-brain barrier and restored the abnormal structure of the gut microbiota with a significantly decreased ratio of Firmicutes to Bacteroidota (F/B) and obviously increased abundance of Akkermansia. As a diet-derived bioactive ingredient, fucoidan might be a better alternative for the prevention of UC and accompanying anxiety- and depressive-like behaviors.
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Affiliation(s)
- Shilan Li
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Qingfan Qian
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yisha Xie
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Zhengli Wu
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Hao Yang
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yan Yin
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yuan Cui
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Xinli Li
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
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Ahmed M, Pu A, Jencks K, Bishu S, Higgins P, Chey WD, Rao K, Lee A. Predictors of irritable bowel syndrome-like symptoms in quiescent inflammatory bowel disease. Neurogastroenterol Motil 2024; 36:e14809. [PMID: 38651743 PMCID: PMC11806413 DOI: 10.1111/nmo.14809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 04/04/2024] [Accepted: 04/14/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Many patients with quiescent inflammatory bowel disease (IBD) suffer from irritable bowel syndrome (IBS)-like symptoms. Although these symptoms cause significant reductions in quality of life, evidence-based treatments are lacking as risk factors and pathophysiology of these symptoms are not clearly defined. We aimed to identify risk factors for development of IBS-like symptoms in IBD patients with quiescent disease. METHODS We performed a single-center retrospective cohort study of adults with IBD from 2015 to 2021. Quiescent IBD was defined by a fecal calprotectin level <250 μg/g of stool or endoscopic evidence of quiescent disease. Cox regression was performed to identify variables that were independently associated with the incident development of IBS-like symptoms in IBD patients. KEY RESULTS A total of 368 IBD patients were included for analysis, including 278 patients with UC and 88 with Crohn's disease. 15.5% of quiescent IBD patients developed IBS symptoms, with an incidence rate of (95% CI 48.0-82.0) 63.3 per 1000 person-years. In the multivariate model, mood disorders (including anxiety and depression) and Crohn's disease were associated with increased risk for developing IBS symptoms. Male sex and higher iron levels conferred lower risk for developing IBS symptoms. Results from the multivariable model were similar in sensitivity analysis with quiescent IBD defined by fecal calprotectin level <150 mcg/g. CONCLUSIONS & INFERENCES Mood disorder and Crohn's disease were positively associated with IBS-like symptoms in quiescent IBD, whereas male sex and iron levels were protective. Our results were robust to different fecal calprotectin levels, arguing against inflammation as a mechanism for IBS-like symptoms. This data suggests noninflammatory mechanisms may be important in the pathogenesis of IBS-like symptoms in quiescent IBD. Future work may address whether modifying these risk factors may alter disease course.
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Affiliation(s)
- Mehwish Ahmed
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Autumn Pu
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Kara Jencks
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Shrinivas Bishu
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Peter Higgins
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - William D. Chey
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Krishna Rao
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | - Allen Lee
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Ananthakrishnan AN, Gerasimidis K, Ho SM, Mayer E, Pollock J, Soni S, Wu GD, Benyacoub J, Ali B, Favreau A, Smith DE, Oh JE, Heller C, Hurtado-Lorenzo A, Moss A, Croitoru K. Challenges in IBD Research 2024: Environmental Triggers. Inflamm Bowel Dis 2024; 30:S19-S29. [PMID: 38778624 DOI: 10.1093/ibd/izae085] [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: 03/15/2024] [Indexed: 05/25/2024]
Abstract
Environmental factors play an important role in inflammatory bowel diseases (IBD; Crohn's disease, [CD], ulcerative colitis [UC]). As part of the Crohn's & Colitis Challenges 2024 agenda, the Environmental Triggers workgroup summarized the progress made in the field of environmental impact on IBD since the last Challenges cycle in this document. The workgroup identified 4 unmet gaps in this content area pertaining to 4 broad categories: (1) Epidemiology; (2) Exposomics and environmental measurement; (3) Biologic mechanisms; and (4) Interventions and Implementation. Within epidemiology, the biggest unmet gaps were in the study of environmental factors in understudied populations including racial and ethnic minority groups and in populations witnessing rapid rise in disease incidence globally. The workgroup also identified a lack of robust knowledge of how environmental factors may impact difference stages of the disease and for different disease-related end points. Leveraging existing cohorts and targeted new prospective studies were felt to be an important need for the field. The workgroup identified the limitations of traditional questionnaire-based assessment of environmental exposure and placed high priority on the identification of measurable biomarkers that can quantify cross-sectional and longitudinal environmental exposure. This would, in turn, allow for identifying the biologic mechanisms of influence of environmental factors on IBD and understand the heterogeneity in effect of such influences. Finally, the working group emphasized the importance of generating high-quality data on effective environmental modification on an individual and societal level, and the importance of scalable and sustainable methods to deliver such changes.
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Affiliation(s)
- Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kostantinos Gerasimidis
- Human Nutrition, School of Medicine, University of Glasgow, New Lister Building, Glasgow Royal Infirmary, G31 2ER, Glasgow, UK
| | - Shuk-Mei Ho
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Emeran Mayer
- G. Oppenheimer Center for Neurobiology of Stress and Resilience; Goodman-Luskin Microbiome Center; The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jennifer Pollock
- Cardio-Renal Physiology and Medicine Section, Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Shefali Soni
- Crohn's Disease Program, The Leona M. and Harry B. Helmsley Charitable Trust, New York, NY, USA
| | - Gary D Wu
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Basmah Ali
- Crohn's & Colitis Foundation, IBD Patient Representative, USA
| | - Alex Favreau
- Crohn's & Colitis Foundation, IBD Patient Representative, USA
| | | | - Ji-Eun Oh
- Research Department, Crohn's & Colitis Foundation, New York, NY, USA
| | - Caren Heller
- Research Department, Crohn's & Colitis Foundation, New York, NY, USA
| | | | - Alan Moss
- Research Department, Crohn's & Colitis Foundation, New York, NY, USA
| | - Ken Croitoru
- Division of Gastroenterology, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada
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Piovani D, Armuzzi A, Bonovas S. Association of Depression With Incident Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Inflamm Bowel Dis 2024; 30:573-584. [PMID: 37300511 PMCID: PMC10988103 DOI: 10.1093/ibd/izad109] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Indexed: 06/12/2023]
Abstract
BACKGROUND Individuals with a history of depression/depressive symptoms are suspected to be at increased risk of incident inflammatory bowel diseases (IBDs). METHODS We systematically searched MEDLINE/PubMed, Embase, and Scopus databases for longitudinal studies examining the association between depression/depressive symptoms and subsequent new-onset IBD (ie, Crohn's disease and ulcerative colitis). We included studies in which the exposure was a confirmed diagnosis of depression/depressive symptoms measured through a validated scale. To limit concerns of diagnostic bias and reverse causality, and support temporality between exposure and outcomes, we synthesized estimates corresponding to the longest time lag reported. Two authors extracted study data independently and assessed each study's risk of bias. Maximally adjusted relative risk (RR) estimates were synthesized using random- and fixed-effects models. RESULTS Of 5307 records, 13 studies (8 cohort and 5 nested case-control studies; 9 million individuals) fulfilled the eligibility criteria. Depression was significantly associated with incident Crohn's disease (RRrandom, 1.17; 95% confidence interval, 1.02-1.34; 7 studies, 17 676 cases) and ulcerative colitis (RRrandom, 1.21; 95% confidence interval, 1.10-1.33; 6 studies, 28 165 cases). The primary studies considered pertinent confounders. Several years, on average, separated exposure and outcomes. No evidence of important heterogeneity or publication bias was found. Summary estimates were at low risk of bias, and results were confirmed in multiple sensitivity analyses. No firm conclusions could be drawn regarding a dilution of the association over time. CONCLUSIONS Individuals with a history of depression may show small-to-moderate increased risk of IBD even when depression is diagnosed several years before new-onset IBD. Further epidemiological and mechanistic studies should clarify whether these associations are causal.
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Affiliation(s)
- Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Alessandro Armuzzi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Italy
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Teng S, Yang Y, Zhang W, Li X, Li W, Cui Z, Min L, Wu J. Antidepressant fluoxetine alleviates colitis by reshaping intestinal microenvironment. Cell Commun Signal 2024; 22:176. [PMID: 38475799 PMCID: PMC10935910 DOI: 10.1186/s12964-024-01538-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND The impact of antidepressants on Inflammatory bowel diseases (IBD) has been extensively studied. However, the biological effects and molecular mechanisms of antidepressants in alleviating colitis remain unclear. METHODS We systematically assessed how antidepressants (fluoxetine, fluvoxamine and venlafaxine) affected IBD and chose fluoxetine, the most effective one, for mechanism studies. We treated the C56BL/6 mice of the IBD model with fluoxetine and their controls. We initially assessed the severity of intestinal inflammation in mice by body weight loss, disease Activity Index scores and the length of the colon. The H&E staining and immunohistochemical staining of MUC2 of colon sections were performed to observe the pathological changes. RT-qPCR and western blot were conducted to assess the expression level of the barrier and inflammation-associated genes. Then, single-cell RNA sequencing was performed on mouse intestinal mucosa. Seurat was used to visualize the data. Uniform Manifold Approximation and Projection (UMAP) was used to perform the dimensionality reduction. Cell Chat package was used to perform cell-cell communication analysis. Monocle was used to conduct developmental pseudotime analysis. Last, RT-qPCR, western blot and immunofluorescence staining were conducted to test the phenomenon discovered by single-cell RNA sequencing in vitro. RESULTS We found that fluoxetine treatment significantly alleviated colon inflammation. Notably, single-cell RNA sequencing analysis revealed that fluoxetine affected the distribution of different cell clusters, cell-cell communication and KEGG pathway enrichment. Under the treatment of fluoxetine, enterocytes, Goblet cells and stem cells became the dominating cells. The pseudotime analysis showed that there was a trend for M1 macrophages to differentiate into M2 macrophages. Lastly, we tested this phenomenon in vitro, which exhibited anti-inflammatory effects on enterocytes. CONCLUSIONS Fluoxetine exhibited anti-inflammatory effects on intestinal mucosa via remodeling of the intestinal cells and macrophages, which reveals that fluoxetine is a promising therapeutic drug for the treatment of IBD and psychiatric comorbidities.
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Affiliation(s)
- Shuo Teng
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China
- Peking University Ninth School of Clinical Medicine, Beijing, 100038, China
| | - Yi Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China
| | - Wanru Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China
| | - Xiangji Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China
| | - Wenkun Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China
| | - Zilu Cui
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China.
| | - Jing Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China.
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Storan D, McDermott E, Moloney J, Keenan L, Stack R, Sheridan J, Doherty G, Cullen G, McHugh L, Mulcahy HE. Inflammatory Bowel Disease Disability Index is a valid and reliable measure of disability in an English-speaking hospital practice and predicts long-term requirement for treatment escalation. Frontline Gastroenterol 2024; 15:130-136. [PMID: 38486665 PMCID: PMC10935531 DOI: 10.1136/flgastro-2023-102428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 10/24/2023] [Indexed: 03/17/2024] Open
Abstract
Objective The Inflammatory Bowel Disease Disability Index (IBD-DI) was developed according to WHO standards and has been validated in population-based cohorts. However, there are limited data on its relationship to various psychosocial and economic variables or its relevance to hospital clinical practice. The study aims were to determine the validity and reliability of the IBD-DI in an English-speaking hospital out-patient population and to evaluate its association with short and long-term disease activity. Design/Methods 329 subjects were enrolled in a cross-sectional and longitudinal study assessing the IBD-DI and a range of quality of life, work impairment, depression, anxiety, body image, interpersonal, self-esteem, disease activity, symptom scoring scales in addition to long-term outcome. Results The IBD-DI had adequate structure, was internally consistent and demonstrated convergent and predictive validity and was reliable in test-retest study. Disability was related to female sex (p=0.002), antidepressant use (p<0.001), steroid use (p<0.001) and disease activity (p<0.001). Higher IBD-DI scores were associated with long-term disease activity and need for treatment escalation in univariate (p<0.001) and multivariate (p=0.002) analyses. Conclusion The IBD-DI is a valid and reliable measure of disability in English-speaking hospital populations and predicts long-term requirement for treatment escalation.
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Affiliation(s)
- Darragh Storan
- Department of Gastroenterology, Saint Vincent's University Hospital, Dublin, Ireland
| | - Edel McDermott
- Department of Gastroenterology, Saint Vincent's University Hospital, Dublin, Ireland
| | - Jenny Moloney
- Department of Gastroenterology, St Luke’s Hospital, Kilkenny, Ireland
| | - Lisa Keenan
- School of Psychology, University College Dublin, Dublin, Ireland
| | - Roisin Stack
- Department of Gastroenterology, Saint Vincent's University Hospital, Dublin, Ireland
- Department of Gastroenterology, St Luke’s Hospital, Kilkenny, Ireland
| | - Juliette Sheridan
- Department of Gastroenterology, Saint Vincent's University Hospital, Dublin, Ireland
| | - Glen Doherty
- Department of Gastroenterology, Saint Vincent's University Hospital, Dublin, Ireland
| | - Garret Cullen
- Department of Gastroenterology, Saint Vincent's University Hospital, Dublin, Ireland
| | - Louise McHugh
- School of Psychology, University College Dublin, Dublin, Ireland
| | - Hugh E Mulcahy
- Department of Gastroenterology, Saint Vincent's University Hospital, Dublin, Ireland
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11
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Liu X, Li Y, Gu M, Xu T, Wang C, Chang P. Radiation enteropathy-related depression: A neglectable course of disease by gut bacterial dysbiosis. Cancer Med 2024; 13:e6865. [PMID: 38457257 PMCID: PMC10923036 DOI: 10.1002/cam4.6865] [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: 07/10/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 03/10/2024] Open
Abstract
Radiation enteropathy (RE) is common in patients treated with radiotherapy for pelvic-abdominal cancers. Accumulating data indicate that gut commensal bacteria determine intestinal radiosensitivity. Radiotherapy can result in gut bacterial dysbiosis. Gut bacterial dysbiosis contributes to the pathogenesis of RE. Mild to moderate depressive symptoms can be observed in patients with RE in clinical settings; however, the rate of these symptoms has not been reported. Studies have demonstrated that gut bacterial dysbiosis induces depression. In the state of comorbidity, RE and depression may be understood as local and abscopal manifestations of gut bacterial disorders. The ability of comorbid depression to worsen inflammatory bowel disease (IBD) has long been demonstrated and is associated with dysfunction of cholinergic neural anti-inflammatory pathways. There is a lack of direct evidence for RE comorbid with depression. It is widely accepted that RE shares similar pathophysiologic mechanisms with IBD. Therefore, we may be able to draw on the findings of the relationship between IBD and depression. This review will explore the relationship between gut bacteria, RE, and depression in light of the available evidence and indicate a method for investigating the mechanisms of RE combined with depression. We will also describe new developments in the treatment of RE with probiotics, prebiotics, and fecal microbial transplantation.
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Affiliation(s)
- Xinliang Liu
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
| | - Ying Li
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
| | - Meichen Gu
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
| | - Tiankai Xu
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
| | - Chuanlei Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Pengyu Chang
- Department of Radiation Oncology and TherapyThe First Hospital of Jilin UniversityChangchunChina
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12
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Fakhfouri G, Mijailović NR, Rahimian R. Psychiatric Comorbidities of Inflammatory Bowel Disease: It Is a Matter of Microglia's Gut Feeling. Cells 2024; 13:177. [PMID: 38247868 PMCID: PMC10814793 DOI: 10.3390/cells13020177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/13/2024] [Accepted: 01/15/2024] [Indexed: 01/23/2024] Open
Abstract
Inflammatory bowel disease (IBD), a common term for Crohn's disease and ulcerative colitis, is a chronic, relapse-remitting condition of the gastrointestinal tract that is increasing worldwide. Psychiatric comorbidities, including depression and anxiety, are more prevalent in IBD patients than in healthy individuals. Evidence suggests that varying levels of neuroinflammation might underlie these states in IBD patients. Within this context, microglia are the crucial non-neural cells in the brain responsible for innate immune responses following inflammatory insults. Alterations in microglia's functions, such as secretory profile, phagocytic activity, and synaptic pruning, might play significant roles in mediating psychiatric manifestations of IBD. In this review, we discuss the role played by microglia in IBD-associated comorbidities.
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Affiliation(s)
- Gohar Fakhfouri
- Department of Psychiatry, Douglas Hospital, McGill University, Montreal, QC H4H 1R3, Canada;
| | - Nataša R. Mijailović
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia;
| | - Reza Rahimian
- McGill Group for Suicide Studies, Douglas Mental Health Institute, McGill University, 6875 Boulevard LaSalle, Montreal, QC H4H 1R3, Canada
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13
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Zhang X, Wang P, Yang Y, Gao X, Tang Y, Luo Y, Deng X, Yu Y, Zhang L, Zhang Y. Monocyte/macrophage mediates the impact of depression on Crohn's disease. Scand J Gastroenterol 2023; 58:1434-1444. [PMID: 37635462 DOI: 10.1080/00365521.2023.2245938] [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: 06/27/2023] [Revised: 07/28/2023] [Accepted: 08/03/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND Depression increases the risk of Crohn's disease (CD) and worsens its prognosis. Monocytes/macrophages, immune modulate cells, play vital roles in both depression and CD. OBJECTIVES We investigated whether monocyte/macrophage could mediate the impact of depression on CD through induction of CD4 + T lymphocyte differentiation and epithelial barrier dysfunction, in addition to the alteration of their own phagocytic ability and cytokines production. METHODS Circulating monocytes and intestinal macrophages were isolated from eligible CD patients, divided into depressed and non-depressed groups. Phagocytosis was determined using flow cytometry while in vitro cytokine production was quantified using Luminex assay and qPCR. CD4 + T cells were cocultured with monocytes, then Type 1 Helper T Lymphocytes Th1/Type 2 Helper T Lymphocytes (Th2) /Type 17 Helper T Lymphocytes (Th17)/Treg subsets were analyzed using flow cytometry and qPCR. Caco-2 monolayers simulating epithelial barrier were cocultured with macrophages, and integrity and proliferation were evaluated. Tight junction protein expression was detected using immunofluorescence and western blot. RESULTS Decreased monocyte/macrophage phagocytosis and enhanced production of pro-inflammatory cytokines including Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and Interleukin-1β (IL-1β) were revealed in the depressed versus non-depressed CD groups. Higher proportions of Th1 and Th17 cells with a lower proportion of Treg cell were observed after cocultured with monocytes from the depressed versus non-depressed CD patients. So were the expressions of their corresponding transcription factors T-bet, Retinoic Acid Related Orphan Nuclear Receptor gamma T (RORγt) and Forkhead box protein P3 (FoxP3). Caco-2 cells cocultured with macrophages from depressed CD displayed lower Transepithelial electric resistance (TEER), reduced proliferation activity, and decreased tight junction protein expressions compared with their counterpart cocultured with macrophages from non-depressed CD. CONCLUSIONS Monocyte/macrophage may underlie the impact of depression upon CD via decreased phagocytosis, increased pro-inflammatory cytokine production, inducing CD4 + T cell differentiation toward Th1/Th17 cells rather than Treg cell, and impairing macrophage-enhanced epithelial barrier.
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Affiliation(s)
- Xin Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Pengbo Wang
- School of Professional Studies, Columbia University, New York, NY, USA
| | - Yi Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Xin Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Yu Tang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Ying Luo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Xiangbing Deng
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, People's Republic of China
| | - Yongyang Yu
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, People's Republic of China
| | - Lanlan Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- State Key Laboratory of Respiratory Health and Multimorbidity, Chengdu, People's Republic of China
| | - Yan Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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14
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Lang BM, Ledergerber M, Jordi SBU, Krupka N, Biedermann L, Schreiner P, Juillerat P, Wyss J, Vavricka SR, Zeitz J, von Känel R, Rogler G, Beerenwinkel N, Misselwitz B. Because I'm happy - positive affect and its predictive value for future disease activity in patients with inflammatory bowel diseases: a retrospective cohort study. Therap Adv Gastroenterol 2023; 16:17562848231179335. [PMID: 37564129 PMCID: PMC10411285 DOI: 10.1177/17562848231179335] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 05/15/2023] [Indexed: 08/12/2023] Open
Abstract
Background While the detrimental impact of negative emotions on the clinical course of inflammatory bowel disease (IBD) and quality of life has been extensively investigated, evidence for a potential impact of positive emotions is scarce. Objectives We aim to analyse contributing factors of positive affect and their predictive value for disease course in IBD patients. Design In this retrospective cohort study, epidemiological, psychosocial and IBD disease characteristics of Swiss IBD cohort study patients were analysed longitudinally. Methods Epidemiological, psychosocial and disease characteristics were extracted from the database of the Swiss IBD cohort study. Participants' positive emotions were assessed cross-sectionally with the seven-item Marburg questionnaire (range 1-6) addressing positive affect in different aspects of daily life. Predictors of positive emotions were identified by linear regression. The quantitative longitudinal impact of positive emotions on the further disease course was analysed using a multivariable Cox proportional hazards model. Results Among 702 IBD patients, those reporting more positive emotions were found to have significantly less intense medical treatment, less pain and fewer depressive symptoms (p < 0.05). A higher percentage of variability in positive emotions was explained by pain (36%) and depressive symptoms (13%) than by epidemiological characteristics (0.3%), or characteristics of IBD and its treatment (2.4%). Patients with higher levels of positive emotions (score > 3.5) experienced longer flare-free survival, also after adjusting for confounders (adjusted hazard ratio: 0.39, p < 0.05). Conclusions The absence of pain and depressive symptoms were the strongest drivers for high positive affect. Higher scores of positive affect were associated with longer disease-free survival in IBD patients.
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Affiliation(s)
- Brian M. Lang
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
- SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Martina Ledergerber
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Sebastian Bruno Ulrich Jordi
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Niklas Krupka
- Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Philipp Schreiner
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Pascal Juillerat
- Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Jacqueline Wyss
- Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Stephan R. Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Jonas Zeitz
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Centre of Gastroenterology, Clinic Hirslanden, Zurich, Switzerland
| | - Roland von Känel
- Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Niko Beerenwinkel
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
- SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Benjamin Misselwitz
- Department of Visceral Surgery and Medicine, Inselspital Bern and University of Bern, Freiburgstr. 18, Bern 3010, Switzerland
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15
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Wang Y, Liu H, Zhang Z, Bian D, Shao K, Wang S, Ding Y. G-MDSC-derived exosomes mediate the differentiation of M-MDSC into M2 macrophages promoting colitis-to-cancer transition. J Immunother Cancer 2023; 11:e006166. [PMID: 37364932 PMCID: PMC10410840 DOI: 10.1136/jitc-2022-006166] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUNDS In inflammatory bowel disease microenvironment, transdifferentiation of myeloid-derived suppressor cells (MDSCs) and M2 macrophage accumulation are crucial for the transition of colitis-to-cancer. New insights into the cross-talk and the underling mechanism between MDSCs and M2 macrophage during colitis-to-cancer transition are opening new avenues for colitis-associated cancer (CAC) prevention and treatment. METHODS The role and underlying mechanism that granulocytic MDSCs (G-MDSCs) or exosomes (Exo) regulates the differentiation of monocytic MDSCs (M-MDSCs) into M2 macrophages were investigated using immunofluorescence, FACS, IB analysis, etc, and employing siRNA and antibodies. In vivo efficacy and mechanistic studies were conducted with dextran sulfate sodium-induced CAC mice, employed IL-6 Abs and STAT3 inhibitor. RESULTS G-MDSCs promote the differentiation of M-MDSC into M2 macrophages through exosomal miR-93-5 p which downregulating STAT3 activity in M-MDSC. IL-6 is responsible for miR-93-5 p enrichment in G-MDSC exosomes (GM-Exo). Mechanistically, chronic inflammation-driven IL-6 promote the synthesis of miR-93-5 p in G-MDSC via IL-6R/JAK/STAT3 pathway. Early use of IL-6 Abs enhances the effect of STAT3 inhibitor against CAC. CONCLUSIONS IL-6-driven secretion of G-MDSC exosomal miR-93-5 p promotes the differentiation of M-MDSC into M2 macrophages and involves a STAT3 signaling mechanism that promote colitis-to-cancer transition. Combining STAT3 inhibitors with strategies that inhibit IL-6-mediated G-MDSC exosomal miR-93-5 p production is beneficial for the prevention and treatment of CAC.
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Affiliation(s)
- Yungang Wang
- Department of Laboratory Medicine, Dermatology, and Endocrinology, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yangcheng, China
| | - Hongli Liu
- Department of Clinical Laboratory, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Zhe Zhang
- Department of Laboratory Medicine, Dermatology, and Endocrinology, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yangcheng, China
| | - Dezhi Bian
- Department of Laboratory Medicine, Dermatology, and Endocrinology, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yangcheng, China
| | - Keke Shao
- Department of Laboratory Medicine, Dermatology, and Endocrinology, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yangcheng, China
| | - Shengjun Wang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine Jiangsu University, Zhenjiang, China
| | - Yanxia Ding
- Department of Laboratory Medicine, Dermatology, and Endocrinology, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yangcheng, China
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16
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Yu R, Liu C, Zhang J, Li J, Tian S, Ding F, Liu Z, Wang T, Liu Z, Jiang C, Shi J, Wu K, Dong W. Correlation Analysis Between Disease Activity and Anxiety, Depression, Sleep Disturbance, and Quality of Life in Patients with Inflammatory Bowel Disease. Nat Sci Sleep 2023; 15:407-421. [PMID: 37261369 PMCID: PMC10228587 DOI: 10.2147/nss.s407388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 05/17/2023] [Indexed: 06/02/2023] Open
Abstract
Objective To explore the correlation between disease activity and anxiety, depression, sleep quality, and quality of life in patients with inflammatory bowel disease (IBD). Methods The disease activity of IBD patients was evaluated by 66 gastroenterologists from 42 hospitals in 22 provinces in China from September 2021 to May 2022. Anxiety, depression, sleep quality and quality of life of IBD patients were investigated and statistically analyzed by different scales, including Generalized Anxiety Disorder 7-item Scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), and Inflammatory Bowel Disease Quality-of-Life Questionnaire (IBD-Q). Results A total of 2478 IBD patients were included, of which 1532 (61.8%) were in active stage and 946 (38.2%) were in remission. The proportions of active IBD with anxiety, depression, sleep disturbance, and poor quality of life were 29.5%, 29.7%, 71.1%, and 50.1%, respectively, while the proportions of remission IBD with anxiety, depression, sleep disturbance, and poor quality of life were 19.1%, 24.4%, 69.3%, and 17.4%, respectively. IBD patients who also had anxiety, depression, sleep disturbances and poor quality of life had 80 cases (8.46%) in remission and 114 cases (7.44%) in active stage, with 54 cases (9.18%) in mild activity, 51 cases (6.95%) in moderate activity and 9 cases (4.49%) in severe activity. IBD patients with different disease activity levels differed in GAD-7 scores, PHQ-9 scores, PSQI scores, and IBD-Q scores (all P<0.001). In IBD patients, anxiety, depression, and sleep disturbance, which interact with each other, can further aggravate their disease activity (all P<0.001). Conclusion Anxiety, depression, sleep disturbances, and quality of life are strongly correlated with disease activity in IBD patients, and IBD patients with psychological disturbances are most often in the active stage and have a poor quality of life.
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Affiliation(s)
- Rong Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Chuan Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Jiao Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Shan Tian
- Department of Infectious Diseases, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China
| | - Fugui Ding
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Zhengru Liu
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China
| | - Ting Wang
- Department of Gastroenterology, First Affiliated Hospital of Hainan Medical College, Haikou, 570102, People’s Republic of China
| | - Zhongchun Liu
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Changqing Jiang
- Department of Clinical Psychology, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, People’s Republic of China
| | - Jie Shi
- Department of Medical Psychology, Chinese People’s Liberation Army Rocket Army Characteristic Medical Center, Beijing, 100088, People’s Republic of China
| | - Kaichun Wu
- Department of Gastroenterology, Xijing Hospital, Air Force Medical University, Xi’an, 710032, People’s Republic of China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
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17
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Liang C, Tang Y, Gao X, Lei N, Luo Y, Chen P, Duan S, Cao Y, Yang Y, Zhang Y. Depression Exacerbates Dextran Sulfate Sodium-Induced Colitis via IRF5-Mediated Macrophage Polarization. Dig Dis Sci 2023; 68:1269-1279. [PMID: 36088512 DOI: 10.1007/s10620-022-07679-2] [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: 09/25/2021] [Accepted: 08/18/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS Patients with inflammatory bowel disease (IBD) and concurrent depression are predisposed to severer disease activity and a worse prognosis. Macrophage polarization toward the M1 phenotype may contribute to the exacerbation of IBD with comorbid depression. Moreover, interferon regulatory factor 5 (IRF5) is involved in the pathogenesis of IBD. The aim of this study was to explore the role of IRF5 in macrophage polarization in the impact of depression upon colitis. METHODS Depressive-like behavior was induced by repeated forced swim stress. Colon length, disease activity index (DAI), colon morphology, histology, ultrastructure of epithelial barrier, lamina propria macrophage polarization, and expression of IRF5 were compared between DSS colitis rats with and without depressive-like behavior. IRF5 shRNA was constructed to affect the rat peritoneal macrophages polarization in vitro. After IRF5 shRNA lentivirus was introduced into colon by enema, the colitis severity, lamina propria macrophage polarization, and TNF-α, IL-1β, and IL-10 of colon tissues were measured. RESULTS The study found severer colonic inflammation in depressed versus non-depressed DSS-colitis rats. Depressed DSS-colitis rats exhibited smaller subepithelial macrophages size and reduced intracellular granule diversity compared with nondepressed DSS-colitis rats. Increased polarization toward the M1 phenotype, elevated expression of IRF5, and co-expression of IRF5 with CD86 were found in depressed versus nondepressed DSS-colitis rats. Lentivirus-mediated shRNA interference with IRF5 expression switched rat peritoneal macrophage polarization from the M1 to the M2 phenotype, downregulated TNF-α, IL-1β expression to a greater extent in depressed versus nondepressed colitis rats. CONCLUSIONS IRF5-mediated macrophage polarization may likely underlie the deterioration of DSS-induced colitis caused by depression.
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Affiliation(s)
- Chang Liang
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Yu Tang
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Xin Gao
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Na Lei
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Ying Luo
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Pingrun Chen
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Shihao Duan
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Yubin Cao
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Yi Yang
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China
| | - Yan Zhang
- Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China.
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18
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Kim S, Lee S, Han K, Koh SJ, Im JP, Kim JS, Lee HJ. Depression and anxiety are associated with poor outcomes in patients with inflammatory bowel disease: A nationwide population-based cohort study in South Korea. Gen Hosp Psychiatry 2023; 81:68-75. [PMID: 36827815 DOI: 10.1016/j.genhosppsych.2023.01.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/25/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND Prevalence of depression and anxiety are known to be increased in patients with inflammatory bowel disease (IBD), but it is unclear whether such elevations adversely affect IBD outcomes. OBJECTIVE We aimed to investigate the association between depression or anxiety and clinical outcomes of IBD. METHOD Using claims data from the South Korean National Health Insurance Service (NHIS), patients with IBD were identified by codes of the International Classification of Disease, 10th Revision (ICD-10) and the Rare/Intractable Disease (RID) registration program for years 2010 to 2017. ICD-10 codes were also used to identify depression and anxiety in this population. Primary study endpoints were IBD-related outcomes, including emergency room (ER) visits, hospitalizations, and surgeries during the follow-up period. RESULTS Our cohort included 32,867 patients with IBD, of whom 3794 (11.5%) experienced depression and anxiety during the 6-year median follow-up period. In multivariate analysis, comorbid depression and anxiety were associated with increased risks of ER visits (hazard ratio [HR] = 1.34, 95% confidence interval [CI]: 1.19-1.51) and hospitalizations (HR = 1.24, 95% CI: 1.12-1.37), whereas surgical risk was not different for IBD patients with and without depression and anxiety. There was no differential effect of depression and anxiety on outcomes in IBD patients, but depression was more closely associated with outcomes in CD patients and anxiety in UC patients. CONCLUSION In patients with IBD, comorbid depression and anxiety are associated with increased risks of ER visits and hospitalizations, but not surgery. These associations are more pronounced for depression in CD patients and for anxiety in UC patients.
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Affiliation(s)
- Seulji Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seungwoo Lee
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Seong-Joon Koh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyun Jung Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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19
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Tomita T, Fukui H, Morishita D, Maeda A, Makizaki Y, Tanaka Y, Ohno H, Oshima T, Miwa H. Diarrhea-predominant Irritable Bowel Syndrome-like Symptoms in Patients With Quiescent Crohn's Disease: Comprehensive Analysis of Clinical Features and Intestinal Environment Including the Gut Microbiome, Organic Acids, and Intestinal Permeability. J Neurogastroenterol Motil 2023; 29:102-112. [PMID: 36606441 PMCID: PMC9837540 DOI: 10.5056/jnm22027] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 07/06/2022] [Accepted: 08/06/2022] [Indexed: 01/07/2023] Open
Abstract
Background/Aims Diarrhea-predominant irritable bowel syndrome (IBS-D)-like symptoms frequently occur in patients with quiescent Crohn's disease (CD). To investigate the factors underlying IBS-D-like symptoms in patients with quiescent CD, we performed a comprehensive analysis of the clinical features and intestinal environment in those patients. Methods We performed a prospective observational study of 27 patients with quiescent CD (CD activity index [CDAI] ≤ 150; C-reactive protein ≤ 0.3 mg/dL). The presence and severity of IBS-D-like symptoms, health-related quality of life, disease-specific quality of life, and status of depression and anxiety were evaluated. The level of intestinal permeability, fecal calprotectin and organic acids and the profiles of gut microbiome were analyzed. Results Twelve of the 27 patients with quiescent CD (44.4%) had IBS-like symptoms, and these patients showed a significantly higher CDAI, IBS severity index and anxiety score than those without. The inflammatory bowel disease questionnaire score was significantly lower in the patients with IBS-D-like symptoms. There were no significant differences in small intestinal/colonic permeability or the levels of organic acids between the patients with and without IBS-D-like symptoms. Fusicatenibacter was significantly less abundant in the patients with IBS-D-like symptoms whereas their fecal calprotectin level was significantly higher (384.8 ± 310.6 mg/kg) than in patients without (161.0 ± 251.0 mg/kg). The receiver operating characteristic curve constructed to predict IBS-D-like symptoms in patients with quiescent CD using the fecal calprotectin level (cutoff, 125 mg/kg) showed a sensitivity and specificity of 73.3% and 91.7%, respectively. Conclusion Minimal inflammation is closely associated with the development of IBS-D-like symptoms in patients with quiescent CD.
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Affiliation(s)
- Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan,Correspondence: Hirokazu Fukui, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya, 663-8501, Japan, Tel: +81-798-45-6662, Fax: +81-798-45-6661, E-mail:
| | - Daisuke Morishita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Ayako Maeda
- R&D Center, Biofermin Pharmaceutical Co, Ltd, Kobe, Japan
| | | | - Yoshiki Tanaka
- R&D Center, Biofermin Pharmaceutical Co, Ltd, Kobe, Japan
| | - Hiroshi Ohno
- R&D Center, Biofermin Pharmaceutical Co, Ltd, Kobe, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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20
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Wang Y, Wang Q, Duan L, Li X, Yang W, Huang T, Kong M, Guan F, Ma S. Fucoidan ameliorates LPS-induced neuronal cell damage and cognitive impairment in mice. Int J Biol Macromol 2022; 222:759-771. [PMID: 36174863 DOI: 10.1016/j.ijbiomac.2022.09.231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/22/2022] [Accepted: 09/25/2022] [Indexed: 11/21/2022]
Abstract
The incidence of cognitive impairment is rising globally, but there is no effective therapy. Recent studies showed that fucoidan (Fuc), a sulfated polysaccharide enriched in brown algae, is widely used due to its anti-inflammatory, antioxidant, and prebiotic effects. However, the effects and mechanisms of Fuc on lipopolysaccharide (LPS)-induced neuronal cell damage and cognitive impairment in mice need to be explored further. In the present study, we found that Fuc treatment protected HT22 cells from LPS-induced damage by inhibiting the activation of NLRP3 inflammasomes. Fuc exerted neuroprotective effects in mice with LPS-induced cognitive impairment by ameliorating neuroinflammation, promoting neurogenesis, and reducing blood-brain barrier and intestinal barrier permeability. Mechanistically, Fuc supplement significantly restructured the gut microbiota composition, which may be related to glucose and fructose metabolism. In conclusion, Fuc ameliorated LPS-induced neuronal cell damage and cognitive impairment in mice, suggesting that Fuc may be a medicinal and food homologous functional agent to improve cognitive function.
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Affiliation(s)
- Yingying Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Qianqian Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Linyan Duan
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Xingfan Li
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Wenzhi Yang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Tuanjie Huang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Mingyue Kong
- NHC Key Laboratory of Birth Defects Prevention, Henan Institute of Reproduction Health Science and Technology, Zhengzhou 450002, Henan, China
| | - Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China; NHC Key Laboratory of Birth Defects Prevention, Henan Institute of Reproduction Health Science and Technology, Zhengzhou 450002, Henan, China; Institute of Neuroscience, Zhengzhou University, Zhengzhou 450052, China.
| | - Shanshan Ma
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China; NHC Key Laboratory of Birth Defects Prevention, Henan Institute of Reproduction Health Science and Technology, Zhengzhou 450002, Henan, China; Institute of Neuroscience, Zhengzhou University, Zhengzhou 450052, China.
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21
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Bisgaard TH, Allin KH, Keefer L, Ananthakrishnan AN, Jess T. Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment. Nat Rev Gastroenterol Hepatol 2022; 19:717-726. [PMID: 35732730 DOI: 10.1038/s41575-022-00634-6] [Citation(s) in RCA: 239] [Impact Index Per Article: 79.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2022] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic, relapsing immune-mediated disease with a varying and sometimes severe disease course. IBD is often diagnosed in early adulthood and can lead to a substantial decline in quality of life. It has been suggested that patients with IBD are at increased risk of depression and anxiety, but it is still unclear to what extent these diseases co-occur and in what sequence they arise. This Review summarizes the literature on the degree of co-occurrence of IBD with depression and anxiety and the temporal relationship between these diseases. We also discuss the effect of psychological stress on the onset and course of IBD. In addition, we outline the possible mechanisms underlying the co-occurrence of IBD and depression and anxiety, which include changes in brain signalling and morphology, increases in peripheral and intracerebral pro-inflammatory cytokines, impairment of the nitric oxide pathway, changes in vagal nerve signalling, gut dysbiosis and genetics. Finally, we examine the possible effects of treatment of depression and anxiety on the risk and course of IBD, the influence of psychological interventions on IBD, and the effects of IBD treatment on psychiatric comorbidity.
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Affiliation(s)
- Tania H Bisgaard
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Kristine H Allin
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark.,Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Laurie Keefer
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Tine Jess
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark. .,Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark.
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22
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Fairbrass KM, Lovatt J, Barberio B, Yuan Y, Gracie DJ, Ford AC. Bidirectional brain-gut axis effects influence mood and prognosis in IBD: a systematic review and meta-analysis. Gut 2022; 71:1773-1780. [PMID: 34725197 DOI: 10.1136/gutjnl-2021-325985] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/20/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The role of the brain-gut axis is of increasing interest in IBD, as the link between common mental disorders and GI inflammation may be bidirectional. We performed a systematic review examining these issues. DESIGN We searched EMBASE Classic and EMBASE, Medline, and APA PsychInfo (to 11 July 2021) for longitudinal follow-up studies examining effect of symptoms of anxiety or depression on subsequent adverse outcomes in IBD, or effect of active IBD on subsequent development of symptoms of anxiety or depression. We pooled relative risks (RRs) and HRs with 95% CIs for adverse outcomes (flare, escalation of therapy, hospitalisation, emergency department attendance, surgery or a composite of any of these) according to presence of symptoms of anxiety or depression at baseline, or RRs and HRs with 95% CIs for new onset of symptoms of anxiety or depression according to presence of active IBD at baseline. RESULTS We included 12 separate studies, recruiting 9192 patients. All 12 studies examined brain-to-gut effects. Anxiety at baseline was associated with significantly higher risks of escalation of therapy (RR=1.68; 95% CI 1.18 to 2.40), hospitalisation (RR=1.72; 95% CI 1.01 to 2.95), emergency department attendance (RR=1.30; 95% CI 1.21 to 1.39), or a composite of any adverse outcome. Depression at baseline was associated with higher risks of flare (RR=1.60; 95% CI 1.21 to 2.12), escalation of therapy (RR=1.41; 95% CI 1.08 to 1.84), hospitalisation (RR=1.35; 95% CI 1.17 to 1.57), emergency department attendance (RR=1.38; 95% CI 1.22 to 1.56), surgery (RR=1.63; 95% CI 1.19 to 2.22) or a composite of any of these. Three studies examined gut-to-brain effects. Active disease at baseline was associated with future development of anxiety or depression (RR=2.24; 95% CI 1.25 to 4.01 and RR=1.49; 95% CI 1.11 to 1.98, respectively). CONCLUSION Bidirectional effects of the brain-gut axis are present in IBD and may influence both the natural history of the disease and psychological health.
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Affiliation(s)
- Keeley M Fairbrass
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK.,Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Jessica Lovatt
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK
| | - Brigida Barberio
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy
| | - Yuhong Yuan
- Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - David J Gracie
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK.,Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK .,Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
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23
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Hill E, Nguyen NH, Qian AS, Patel S, Chen PL, Tse CS, Singh S. Impact of Comorbid Psychiatric Disorders on Healthcare Utilization in Patients with Inflammatory Bowel Disease: A Nationally Representative Cohort Study. Dig Dis Sci 2022; 67:4373-4381. [PMID: 35503486 DOI: 10.1007/s10620-022-07505-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 02/07/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS Patients with inflammatory bowel disease (IBD) frequently experience comorbid psychiatric disorders, which negatively impact quality of life. We characterized the longitudinal burden of hospitalization-related healthcare utilization in adults with IBD with and without comorbid anxiety, depression, or bipolar disorder. METHODS In the 2017 Nationwide Readmissions Database (NRD), we identified 40,177 patients with IBD who were hospitalized between January 1, 2017 and June 30, 2017 and who were followed until December 31, 2017. In this cohort, we compared the annual burden (i.e., total days spent in hospital), costs, risk of readmission, inpatient mortality, and IBD-related surgery in patients with and without comorbid psychiatric disorders (anxiety, depression, or bipolar disorder). RESULTS Of the 40,177 adults who were hospitalized for IBD, 25.7% had comorbid psychiatric disorders. Over a 10 month-long period of follow-up, patients with comorbid psychiatric disorders spent more days in the hospital (median, 7 days vs. 5 days, p < 0.01), experienced higher 30-day (31.3 vs. 25.4%; p < 0.01) and 90-day (42.6 vs. 35.3%, p < 0.01) readmission rates, and had higher hospitalization-related costs (median, $41,418 vs. $39,242, p < 0.01). However, they were less likely to undergo IBD-related procedures or surgeries. There were no differences in risk of mortality. On Cox proportional hazard analysis, the presence of comorbid psychiatric disorders was associated with a 16% higher risk of readmission (HR, 1.16; 95% CI, 1.13-1.20) and a 13% higher risk of severe IBD-related hospitalization (HR, 1.13; 95% CI, 1.08-1.16). CONCLUSIONS In adults with IBD, comorbid psychiatric disorders were independently associated with a higher burden and cost of hospitalization, without an increase in the risk of IBD-related surgery or procedures. Population-based interventions aimed at treating psychiatric comorbidities may decrease the risk of unplanned healthcare utilization.
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Affiliation(s)
- Eddie Hill
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9452 Medical Center Dr., ACTRI 1W501, La Jolla, CA, 92093, USA
| | - Nghia H Nguyen
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9452 Medical Center Dr., ACTRI 1W501, La Jolla, CA, 92093, USA
| | - Alexander S Qian
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9452 Medical Center Dr., ACTRI 1W501, La Jolla, CA, 92093, USA
| | - Sagar Patel
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9452 Medical Center Dr., ACTRI 1W501, La Jolla, CA, 92093, USA
| | - Peter L Chen
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9452 Medical Center Dr., ACTRI 1W501, La Jolla, CA, 92093, USA
| | - Chung-Sang Tse
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9452 Medical Center Dr., ACTRI 1W501, La Jolla, CA, 92093, USA
| | - Siddharth Singh
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9452 Medical Center Dr., ACTRI 1W501, La Jolla, CA, 92093, USA.
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24
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Kelly MJ, Breathnach C, Tracey KJ, Donnelly SC. Manipulation of the inflammatory reflex as a therapeutic strategy. Cell Rep Med 2022; 3:100696. [PMID: 35858588 PMCID: PMC9381415 DOI: 10.1016/j.xcrm.2022.100696] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 06/20/2021] [Accepted: 06/23/2022] [Indexed: 02/07/2023]
Abstract
The cholinergic anti-inflammatory pathway is the efferent arm of the inflammatory reflex, a neural circuit through which the CNS can modulate peripheral immune responses. Signals communicated via the vagus and splenic nerves use acetylcholine, produced by Choline acetyltransferase (ChAT)+ T cells, to downregulate the inflammatory actions of macrophages expressing α7 nicotinic receptors. Pre-clinical studies using transgenic animals, cholinergic agonists, vagotomy, and vagus nerve stimulation have demonstrated this pathway's role and therapeutic potential in numerous inflammatory diseases. In this review, we summarize what is understood about the inflammatory reflex. We also demonstrate how pre-clinical findings are being translated into promising clinical trials, and we draw particular attention to innovative bioelectronic methods of harnessing the cholinergic anti-inflammatory pathway for clinical use.
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Affiliation(s)
- Mark J Kelly
- Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Tallaght University Hospital, Dublin, Ireland
| | | | - Kevin J Tracey
- Center for Biomedical Science and Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA
| | - Seamas C Donnelly
- Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Tallaght University Hospital, Dublin, Ireland.
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25
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Robbins JP, Solito E. Does Neuroinflammation Underlie the Cognitive Changes Observed With Dietary Interventions? Front Neurosci 2022; 16:854050. [PMID: 35620671 PMCID: PMC9127342 DOI: 10.3389/fnins.2022.854050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/24/2022] [Indexed: 11/13/2022] Open
Abstract
Dietary interventions, such as calorie restriction and ketogenic diet, have been extensively studied in ageing research, including in cognitive decline. Epidemiological studies indicate beneficial effects of certain dietary regimes on mental health, including mood disorders and dementia. However, randomised-controlled trials (the gold-standard of evidence-based medicine) on calorie restriction diets and the ketogenic diet have yet to show clinically convincing effects in neuropsychiatric disorders. This review will examine the quality of studies and evidence base for the ketogenic and calorie restriction diets in common neuropsychiatric conditions, collating findings from preclinical experiments, case reports or small clinical studies, and randomised controlled clinical trials. The major cellular mechanisms that mediate the effects of these dietary interventions on brain health include neuroinflammation, neuroprotection, and neuromodulation. We will discuss the studies that have investigated the roles of these pathways and their interactions. Popularity of the ketogenic and calorie restriction diets has grown both in the public domain and in psychiatry research, allowing for informed review of the efficacy, the limitations, and the side effects of these diets in specific patient populations. In this review we will summarise the clinical evidence for these diets in neuropsychiatry and make suggestions to improve clinical translation of future research studies.
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Affiliation(s)
- Jacqueline P. Robbins
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Egle Solito
- William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
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26
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Asscher VER, Waars SN, van der Meulen-de Jong AE, Stuyt RJL, Baven-Pronk AMC, van der Marel S, Jacobs RJ, Haans JJL, Meijer LJ, Klijnsma-Slagboom JD, Duin MH, Peters MER, Lee-Kong FVYL, Provoost NE, Tijdeman F, van Dijk KT, Wieland MWM, Verstegen MGM, van der Meijs ME, Maan ADI, van Deudekom FJ, Mooijaart SP, Maljaars PWJ. Deficits in Geriatric Assessment Associate With Disease Activity and Burden in Older Patients With Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2022; 20:e1006-e1021. [PMID: 34153476 DOI: 10.1016/j.cgh.2021.06.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 05/15/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We aimed to perform geriatric assessment in older patients with inflammatory bowel disease (IBD) to evaluate which IBD characteristics associate with deficits in geriatric assessment and the impact of deficits on disease burden (health-related quality of life). METHODS A prospective multicenter cohort study including 405 consecutive outpatient patients with IBD aged ≥65 years. Somatic domain (comorbidity, polypharmacy, malnutrition), impairments in (instrumental) activities of daily living, physical capacity (handgrip strength, gait speed), and mental (depressive symptoms, cognitive impairment) and social domain (life-partner) were assessed. Deficits in geriatric assessment were defined as ≥2 abnormal domains; 2-3 moderate deficits and 4-5 severe deficits. Clinical (Harvey Bradshaw Index >4/partial Mayo Score >2) and biochemical (C-reactive protein ≥10 mg/L and/or fecal calprotectin ≥250 μg/g) disease activity and disease burden (short Inflammatory Bowel Disease Questionnaire) were assessed. RESULTS Somatic domain (51.6%) and activities of daily living (43.0%) were most frequently impaired. A total of 160 (39.5%) patients had moderate deficits in their geriatric assessment; 32 (7.9%) severe. Clinical and biochemical disease activity associated with deficits (clinical: adjusted odds ratio, 2.191; 95% confidence interval, 1.284-3.743; P = .004; biochemical: adjusted odds ratio, 3.358; 95% confidence interval, 1.936-5.825; P < .001). Deficits in geriatric assessment independently associate with lower health-related quality of life. CONCLUSION Deficits in geriatric assessment are highly prevalent in older patients with IBD. Patients with active disease are more prone to deficits, and deficits associate with lower health-related quality of life, indicating higher disease burden. Prospective data validating impact of frailty and geriatric assessment on outcomes are warranted to further improve treatment strategies.
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Affiliation(s)
- Vera E R Asscher
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands.
| | - Sanne N Waars
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | | | - Rogier J L Stuyt
- Department of Gastroenterology and Hepatology, HagaZiekenhuis, The Hague, the Netherlands
| | - A Martine C Baven-Pronk
- Department of Gastroenterology and Hepatology, Groene Hart Ziekenhuis, Gouda, the Netherlands
| | - Sander van der Marel
- Department of Gastroenterology and Hepatology, Haaglanden Medical Centre, The Hague, the Netherlands
| | - Rutger J Jacobs
- Department of Gastroenterology and Hepatology, Alrijne Hospital, Leiden and Leiderdorp, the Netherlands
| | - Jeoffrey J L Haans
- Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Lennart J Meijer
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | | | - Marijn H Duin
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Milou E R Peters
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Felicia V Y L Lee-Kong
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Nanda E Provoost
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Femke Tijdeman
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Kenan T van Dijk
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Monse W M Wieland
- Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Mirre G M Verstegen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Melissa E van der Meijs
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Annemijn D I Maan
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Floor J van Deudekom
- Department of Gerontology and Geriatrics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Simon P Mooijaart
- Department of Gerontology and Geriatrics, Leiden University Medical Centre, Leiden, the Netherlands; Institute for Evidence-Based Medicine in Old Age (IEMO), Leiden, the Netherlands
| | - P W Jeroen Maljaars
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
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27
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Lin L, Wang T, Lu Y, Chen P, Zhang Y, Zu X, Chen B, Mao R, Feng R, Cui Y, Zhang S, He Y. Mucosal healing and quality of life in therapeutic goals of ulcerative colitis: occurrence and related factors of functional bowel disorder-like symptoms. Therap Adv Gastroenterol 2022; 15:17562848221092597. [PMID: 35509421 PMCID: PMC9058349 DOI: 10.1177/17562848221092597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/17/2022] [Indexed: 02/04/2023] Open
Abstract
Background Mucosal healing (MH) is considered the preferred therapeutic target for ulcerative colitis (UC). Impaired quality of life (QoL), irritable bowel syndrome (IBS)-like symptoms, and functional bowel symptoms have been reported in several inactive patients with UC. This study aims to assess the occurrence of functional bowel disorders (FBD)-like symptoms and QoL in UC patients with MH, and to explore the factors related to FBD-like symptoms. Methods UC patients with MH (Mayo endoscopic score, MES = 0 or 1) were required to complete the Rome IV diagnostic questionnaire, the 32-item version of Inflammatory Bowel Disease Questionnaire (IBDQ-32), the 36-item short form healthy survey questionnaire (SF-36), and the Hospital Anxiety and Depression Scale (HADS). UC patients who did not achieve MH (MES > 1) completed the IBDQ-32, the SF-36, and the HADS. Community-dwelling healthy controls (HCs) completed the SF-36 and the HADS. Results Among the 119 UC patients with MH recruited, 45.4% reported functional bowel symptoms; functional constipation-like symptom (13.4%) was the most prevalent, followed by IBS-like symptom (10.9%), and functional diarrhea-like symptom (10.0%). The IBDQ-32 and SF-36 scores were significantly lower in MH patients with FBD-like symptoms than in those without FBD-like symptoms. Disease duration [odds ratio (OR): 1.022; p < 0.001], body mass index (BMI; OR: 0.726; p < 0.001) were independent predictors of FBD-like symptoms in UC patients with MH. Combining these two factors could attain area under the curve [0.786; 95% confidence interval (CI): 0.701-0.856, p < 0.001] to predict FBD-like symptoms in MH patients. Conclusion A number of UC patients with MH had accompanying FBD-like symptoms and significantly impaired QoL. Disease duration, BMI could predict the occurrence of FBD-like symptoms.
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Affiliation(s)
- Lihui Lin
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Tianqi Wang
- Division of Science and Technology, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, P.R. China
| | - Yaming Lu
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Peng Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Yingfan Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Xiaoman Zu
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Baili Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Ren Mao
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Rui Feng
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Yi Cui
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, P.R. China
| | - Yao He
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, P.R. China
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Li ML, Fan YH. Common psychological issues and management in patients with inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2022; 30:370-374. [DOI: 10.11569/wcjd.v30.i8.370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) have a significantly higher incidence of psychological issues than the general population. Anxiety and depression are the most common psychological problems. These psychological problems have an adverse impact on the quality of life and prognosis of IBD patients. Low quality of life and complex course of disease also aggravate patients' anxiety and depression. The disorder of the brain-gut axis is the important mechanism in bi-directional interactions between IBD disease activity and psychological issues. More and more attention has been paid to the diagnostic approaches for psychological conditions and standardized management in IBD. This article reviews the common psychological issues in IBD patients, the interactions between psychological issues and IBD disease activity, and related management of psychological problems in patients with IBD.
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Affiliation(s)
- Meng-Lin Li
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Yi-Hong Fan
- Department of GI Medicine, Zhejiang Hospital of Traditional Chinese Medicine, Hangzhou 310053, Zhejiang Province, China
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29
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Wu S, Yuan W, Luo W, Nie K, Wu X, Meng X, Shen Z, Wang X. MiR-126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis-associated colorectal cancer. Mol Oncol 2022; 16:3465-3489. [PMID: 35363937 PMCID: PMC9533691 DOI: 10.1002/1878-0261.13218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/23/2022] [Accepted: 03/30/2022] [Indexed: 12/02/2022] Open
Abstract
Inflammatory bowel disease, characterised by chronic relapsing‐remitting colitis, is a significant risk factor for colorectal cancer (CRC). Previously, we showed that miR‐126 functions as a tumour suppressor in CRC and is inversely correlated with tumour proliferation, metastasis and patient prognosis. In the current study, we documented a protective role for miR‐126 in colitis‐associated CRC (CAC) and its underlying mechanism. We detected downregulated miR‐126 expression during colorectal tumorigenesis in the mouse CAC model and in specimens from patients with CRC. The deficiency of miR‐126 in intestinal epithelial cells (IECs) exacerbated tumorigenesis in mice. We identified CXCL12 as a direct target of miR‐126 in inhibiting the development of colitis and CAC. Moreover, miR‐126 regulated the recruitment of macrophages via CXCL12 and decreased the levels of proinflammatory cytokines (IL‐6, IL‐12 and IL‐23). In addition, IL‐6 secreted by macrophages, which were regulated by cocultured transfected CRC cells, altered the proliferation and migration of colon cells. Our data suggest that miR‐126 exerts an antitumour effect on CAC by regulating the crosstalk between IECs and macrophages via CXCL12‐IL‐6 signalling. Our study contributes to the understanding of cancer progression and suggests miR‐126 as a potential therapy for CRC.
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Affiliation(s)
- Shuai Wu
- Department of Gastroenterology, The Central South University, Changsha, Hunan, China.,Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, Hunan, China
| | - Wei Yuan
- Department of Gastroenterology, The Central South University, Changsha, Hunan, China.,Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, Hunan, China.,Department of Hepatology, The First Affiliated Hospital, The Hunan University of Chinese Medicine, Changsha, Hunan, P.R. China
| | - Weiwei Luo
- Department of Gastroenterology, The Central South University, Changsha, Hunan, China.,Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, Hunan, China
| | - Kai Nie
- Department of Gastroenterology, The Central South University, Changsha, Hunan, China.,Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, Hunan, China
| | - Xing Wu
- Department of Gastroenterology, The Central South University, Changsha, Hunan, China.,Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, Hunan, China
| | - Xiangrui Meng
- Department of Gastroenterology, The Central South University, Changsha, Hunan, China.,Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, Hunan, China
| | - Zhaohua Shen
- Department of Gastroenterology, The Central South University, Changsha, Hunan, China.,Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, Hunan, China
| | - Xiaoyan Wang
- Department of Gastroenterology, The Central South University, Changsha, Hunan, China.,Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, Hunan, China
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30
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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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31
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Ali H, Pamarthy R, Bolick NL, Lambert K, Naseer M. Relation between inflammatory bowel disease, depression, and inpatient outcomes in the United States. Proc AMIA Symp 2022; 35:278-283. [DOI: 10.1080/08998280.2022.2028344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Affiliation(s)
- Hassam Ali
- Department of Internal Medicine, East Carolina University/Vidant Medical Center, Greenville, North Carolina
| | - Rahul Pamarthy
- Department of Internal Medicine, East Carolina University/Vidant Medical Center, Greenville, North Carolina
| | | | - Karissa Lambert
- Department of Gastroenterology, East Carolina University/Vidant Medical Center, Greenville, North Carolina
| | - Maliha Naseer
- Department of Gastroenterology, Vanderbilt University, Nashville, Tennessee
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32
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Badarnee M, Weiss B, Shouval D, Kreitler S. Motivational disposition towards psychological characteristics of israeli children with inflammatory bowel diseases: A case-control study. J Pediatr Nurs 2022; 62:e131-e138. [PMID: 34465507 DOI: 10.1016/j.pedn.2021.08.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 08/20/2021] [Accepted: 08/21/2021] [Indexed: 01/20/2023]
Abstract
BACKGROUND Psychological stress is a general and non-specific factor associated with many health conditions, including Inflammatory Bowel Diseases (IBD). It is related not only to external stressors but also to internal characteristics which enhance patients' vulnerability to stress. PURPOSE To identify specific psychological characteristics of pediatric IBD related to stress. DESIGN AND METHODS A case-control-cohort study that compared the psychological characteristics of 49 patients and 56 comparisons. The psychological characteristics were defined by four belief types - beliefs about self, general beliefs, beliefs about norms, and goals - which refer to a set of specific themes. RESULTS The belief types differentiated between the two groups, and the patients were characterized by six themes: like routines, strive to get others' love, caring about the body and the health, doing things only at their own pace, expressing negative emotion without regulations, and feeling over-identification with others. Patients' likelihood of being characterized by the themes is 2.18 to 2.90 times higher than the comparisons. CONCLUSION Children with IBD are characterized by a set of specific psychological characteristics. These characteristics were discussed mainly concerning generating chronic stress (e.g., over-identification with others) and interpersonal conflicts (e.g., doing things only at their own pace) among the patients. IMPLICATIONS FOR PRACTICE It is suggested to healthcare workers to be aware of the specific psychological characteristics of children with IBD, and sensitive to these characteristics during interactions with them. Besides, the characteristics may pave the way for developing a targeted psychological intervention that corresponds specifically to the patients' needs.
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Affiliation(s)
- Muhammad Badarnee
- School of Psychological Sciences, Tel-Aviv University, Israel; The Psycho-Oncology Research Center, The Chaim Sheba Medical Center, Israel; The Latif Mental Health Clinics in Umm Al-Fahim and Shefa-Amr, Israel.
| | - Batia Weiss
- Sackler Faculty of Medicine, Tel-Aviv University, Israel; Pediatric Gastroenterology and Nutrition Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center, Israel.
| | - Dror Shouval
- Sackler Faculty of Medicine, Tel-Aviv University, Israel; Pediatric Gastroenterology and Nutrition Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center, Israel.
| | - Shulamith Kreitler
- School of Psychological Sciences, Tel-Aviv University, Israel; The Psycho-Oncology Research Center, The Chaim Sheba Medical Center, Israel.
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Ferrarese D, Spagnolo G, Vecchione M, Scaldaferri F, Armuzzi A, Chieffo D, Belella D, Petito C, Mirijello A, Gasbarrini A, Addolorato G. Signs of Dissociation and Symptoms of Post-Traumatic Stress Disorder in Inflammatory Bowel Disease: A Case-Control Study. Dig Dis 2021; 40:701-709. [PMID: 34923490 DOI: 10.1159/000521424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 12/09/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Several psychological disorders have been described in patients affected by inflammatory bowel disease (IBD). Few studies have focused on the relationship between IBD and post-traumatic stress disorder (PTSD) symptoms, and no data are available on the relationship between IBD and dissociative symptoms. The aim of the present study was to evaluate the prevalence of PTSD and dissociative symptoms in a sample of IBD patients compared to healthy controls. A possible relationship with disease activity was also investigated. METHODS A total of 112 IBD patients, 55 Crohn's disease (CD) and 57 ulcerative colitis (UC), and 114 healthy individuals were evaluated. IBD patients were divided into 3 subgroups according to disease activity (remission, mild, and moderate). The revised version of the Impact of Event Scale (IES-R) and the Dissociative Experience Scale (DES) were administered to patients and controls. RESULTS IBD patients showed significantly higher rates of PTSD and dissociative symptoms compared to healthy controls. No differences were found between CD and UC patients. PTSD and dissociative symptoms were higher among CD patients with mild to moderate-severe activity compared to the remission group. No differences were found among UC patients with different activity levels. CONCLUSION IBD patients show a high prevalence of dissociative and traumatic affective disorders. Future studies are needed to investigate the role of these disorders in the clinical course and management of IBD patients according to the different disease activity phase.
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Affiliation(s)
- Daniele Ferrarese
- Unit of Internal Medicine, Gastroenterology and Hepatology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,Unit of Clinical Psychology, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giorgia Spagnolo
- Unit of Clinical Psychology, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Michele Vecchione
- Department of Social and Developmental Psychology, Sapienza, University of Rome, Rome, Italy
| | - Franco Scaldaferri
- Unit of Internal Medicine, Gastroenterology and Hepatology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessandro Armuzzi
- Unit of Internal Medicine, Gastroenterology and Hepatology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Daniela Chieffo
- Unit of Clinical Psychology, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Daniela Belella
- Unit of Clinical Psychology, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Claudia Petito
- Unit of Clinical Psychology, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Antonio Mirijello
- Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza General Hospital, San Giovanni Rotondo, Italy
| | - Antonio Gasbarrini
- Unit of Internal Medicine, Gastroenterology and Hepatology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.,CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Addolorato
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.,Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy.,Internal Medicine Unit, Department of Internal Medicine and Gastroenterology, Columbus-Gemelli Hospital, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italy
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Chen J, Chen X, Sun Y, Xie Y, Wang X, Li R, Hesketh T. The physiological and psychological effects of cognitive behavior therapy on patients with inflammatory bowel disease before COVID-19: a systematic review. BMC Gastroenterol 2021; 21:469. [PMID: 34911469 PMCID: PMC8672154 DOI: 10.1186/s12876-021-02003-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 11/01/2021] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Cognitive behavioral therapy (CBT) is now included in the treatment of patients with inflammatory bowel disease (IBD) in many settings. However, different clinical trials report different outcomes without consensus. This study aims to evaluate the impact of CBT on the mental state, quality of life and disease activity of patients with IBD. DESIGN Systematic review. METHODS This systematic review searched eligible studies from 1946 to December 8, 2019, in MEDLINE, EMBASE, CINAHL, Cochrane library, ClinicalTrials.gov, PsycINFO, Web of Science for eligible randomized controlled trials (RCT). RESULTS Among the initial identified 1807 references, 11 studies met inclusion criteria. CBT was shown to improve patient's quality of life and reduce the level of depression and anxiety post-intervention but was not sustained. Evidence is not enough for the effect of CBT on disease activity, or C-reactive protein level. CONCLUSIONS CBT has shown short-term positive psychological effects on IBD patients, but there is insufficient evidence for sustained physical and psychological improvements of IBD patients. PROSPERO registration: CRD42019152330.
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Affiliation(s)
- Jie Chen
- Centre for Global Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China.,Department of Gastroenterology, Central South University, The Third Xiangya Hospital138 Tongzipo Road, Changsha, Hunan, 410013, People's Republic of China
| | - Xuejie Chen
- Department of Gastroenterology, Central South University, The Third Xiangya Hospital138 Tongzipo Road, Changsha, Hunan, 410013, People's Republic of China
| | - Yuhao Sun
- Centre for Global Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China
| | - Ying Xie
- Centre for Global Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China
| | - Xiaoyan Wang
- Department of Gastroenterology, Central South University, The Third Xiangya Hospital138 Tongzipo Road, Changsha, Hunan, 410013, People's Republic of China.
| | - Ran Li
- Centre for Global Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China.
| | - Therese Hesketh
- Centre for Global Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China. .,Institute for Global Health, University College London, 30 Guilford St, London, WC1N1EH, UK.
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Chen T, Wang R, Duan Z, Yuan X, Ding Y, Feng Z, Bu F, Liu L, Wang Q, Zhou J, Zhu L, Ni Q, Shi G, Chen Y. Akkermansia muciniphila Protects Against Psychological Disorder-Induced Gut Microbiota-Mediated Colonic Mucosal Barrier Damage and Aggravation of Colitis. Front Cell Infect Microbiol 2021; 11:723856. [PMID: 34722332 PMCID: PMC8551916 DOI: 10.3389/fcimb.2021.723856] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/20/2021] [Indexed: 12/22/2022] Open
Abstract
Psychological disorders are associated with increased risk of severe inflammatory bowel disease (IBD) by causing gut microbiota dysbiosis and colonic mucosal barrier damage. However, the interaction between chronic restraint stress (CRS), gut microbiota composition, and colonic mucus remains unclear. We demonstrated that mice under CRS conditions exhibited alterations in microbiota composition, disruption of colonic mucus, and aggravation of colitis. In addition, the abundance of Akkermansia muciniphila was significantly decreased in mice under CRS and UC patients with depression, and positively associated with the expression of MUC2. After antibiotic treatment, the recipient mice colonized with CRS microbiota showed barrier defects and severe colitis. Administration of Akkermansia muciniphila was found to restore colonic mucus and modify the gut microbiota. We confirm that CRS-mediated gut microbiota dysbiosis results in colonic mucosal barrier damage and aggravation of colitis. Our results suggest that A. muciniphila is expected to be a potential probiotic to protect and treat colonic mucus that is involved in IBD with psychological disorders.
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Affiliation(s)
- Tuo Chen
- Department of General Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, China
| | - Rong Wang
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhenglan Duan
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaomin Yuan
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Ding
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zeyu Feng
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fan Bu
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Li Liu
- Glycomics and Glycan Bioengineering Research Center, College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Qiong Wang
- Basic Pharmacology Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinyong Zhou
- Central Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Lei Zhu
- Collaborative Innovation Center for Cancer Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qing Ni
- Department of General Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, China
| | - Guoping Shi
- Collaborative Innovation Center for Cancer Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yugen Chen
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Duan H, Cai X, Luan Y, Yang S, Yang J, Dong H, Zeng H, Shao L. Regulation of the Autonomic Nervous System on Intestine. Front Physiol 2021; 12:700129. [PMID: 34335306 PMCID: PMC8317205 DOI: 10.3389/fphys.2021.700129] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Intestine is composed of various types of cells including absorptive epithelial cells, goblet cells, endocrine cells, Paneth cells, immunological cells, and so on, which play digestion, absorption, neuroendocrine, immunological function. Intestine is innervated with extrinsic autonomic nerves and intrinsic enteric nerves. The neurotransmitters and counterpart receptors are widely distributed in the different intestinal cells. Intestinal autonomic nerve system includes sympathetic and parasympathetic nervous systems, which regulate cellular proliferation and function in intestine under physiological and pathophysiological conditions. Presently, distribution and functional characteristics of autonomic nervous system in intestine were reviewed. How autonomic nervous system regulates intestinal cell proliferation was discussed. Function of autonomic nervous system on intestinal diseases was extensively reviewed. It might be helpful to properly manipulate autonomic nervous system during treating different intestinal diseases.
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Affiliation(s)
- Hongyi Duan
- Medical College of Nanchang University, Nanchang, China
| | - Xueqin Cai
- Medical College of Nanchang University, Nanchang, China
| | - Yingying Luan
- Medical College of Nanchang University, Nanchang, China
| | - Shuo Yang
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Juan Yang
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Hui Dong
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - Huihong Zeng
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - Lijian Shao
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
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Brenner EJ, Long MD, Mann CM, Lin L, Chen W, Reyes C, Bahnson KM, Reeve BB, Kappelman MD. Anxiety and Depressive Symptoms Are Not Associated With Future Pediatric Crohn's Disease Activity. Inflamm Bowel Dis 2021; 28:728-733. [PMID: 34245258 PMCID: PMC9071096 DOI: 10.1093/ibd/izab162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Studies of adults with Crohn's disease (CD) suggest that poor mental health precedes worsening disease activity. We evaluated whether depression and/or anxiety forecast worsening pediatric CD disease activity. METHODS Through the Inflammatory Bowel Disease Partners Kids & Teens internet-based cohort, children with CD age 9 to 17 completed Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric measures and the short Crohn's disease activity index (sCDAI). Using general linear models, we examined how baseline PROMIS Pediatric anxiety and depressive symptom scores independently associate with subsequent sCDAI scores (average survey interval 6.4 months). Models included baseline PROMIS Pediatric anxiety and depressive symptoms scores, baseline sCDAI, sex, age, parental education, race/ethnicity, and prior IBD-related surgery. We performed a post hoc subanalysis of children in baseline remission (sCDAI <150) with otherwise identical models. RESULTS We analyzed 159 children with CD (mean age 14 years, 45% female, 84% in baseline remission). We found no association between baseline PROMIS Pediatric anxiety score and subsequent sCDAI (change in sCDAI for 3-point change in PROMIS Pediatric -0.89; 95% CI -4.81 to 3.03). Baseline PROMIS Pediatric depressive symptoms score was not associated with future sCDAI (change in sCDAI for 3-point change in PROMIS Pediatric <0.01; 95% CI -4.54 to 4.53). In a subanalysis of patients in remission at baseline, the lack of association remained. CONCLUSION We found that neither anxiety nor depressive symptoms associate with subsequent disease activity in pediatric CD. These findings contrast with adult IBD studies, thus underschoring the unique pathophysiology, natural history, and outcomes of pediatric CD.
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Affiliation(s)
- Erica J Brenner
- Department of Pediatric Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America,Address correspondence to: Erica J. Brenner, MD, University of North Carolina Department of Pediatric Gastroenterology, 333 S. Columbia St. 247 MacNider Hall, CB# 7229, Chapel Hill, NC, 27599, United States of America.
| | - Millie D Long
- Department of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Courtney M Mann
- Department of Population Health Sciences, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Li Lin
- Department of Population Health Sciences, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Wenli Chen
- Department of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Camila Reyes
- Office of Clinical Research, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Kirsten M Bahnson
- Department of Population Health Sciences, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Bryce B Reeve
- Department of Population Health Sciences, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Michael D Kappelman
- Department of Pediatric Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
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Stakenborg N, Boeckxstaens GE. Bioelectronics in the brain-gut axis: focus on inflammatory bowel disease (IBD). Int Immunol 2021; 33:337-348. [PMID: 33788920 PMCID: PMC8183669 DOI: 10.1093/intimm/dxab014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/30/2021] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence shows that intestinal homeostasis is mediated by cross-talk between the nervous system, enteric neurons and immune cells, together forming specialized neuroimmune units at distinct anatomical locations within the gut. In this review, we will particularly discuss how the intrinsic and extrinsic neuronal circuitry regulates macrophage function and phenotype in the gut during homeostasis and aberrant inflammation, such as observed in inflammatory bowel disease (IBD). Furthermore, we will provide an overview of basic and translational IBD research using these neuronal circuits as a novel therapeutic tool. Finally, we will highlight the different challenges ahead to make bioelectronic neuromodulation a standard treatment for intestinal immune-mediated diseases.
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Affiliation(s)
- Nathalie Stakenborg
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium
| | - Guy E Boeckxstaens
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium
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39
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Moughnyeh MM, Brawner KM, Kennedy BA, Yeramilli VA, Udayakumar N, Graham JA, Martin CA. Stress and the Gut-Brain Axis: Implications for Cancer, Inflammation and Sepsis. J Surg Res 2021; 266:336-344. [PMID: 34062291 DOI: 10.1016/j.jss.2021.02.055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 01/28/2021] [Accepted: 02/27/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The gut-brain axis has been discussed, directly or indirectly, for centuries, with the ideas of the gut affecting anything from moods to overall physiology being discussed across the centuries. With a recent explosion in research that looks to the microbiota as a mechanistic link between the gut and the brain, one sees that the gut-brain axis has various means of communication, such as through the vagus nerve and the enteric nervous system and can use the metabolites in the gut to communicate to the brain. METHODS The purpose of this review is to view the gut-brain axis through the lens of stress and how stress, from the prenatal period all the way through adulthood can impact the physiology of a human being. Studies have shown multiple mechanisms of measurable change with disruption in the microbiota that lead to behavioral changes. There are also effects of gut inflammation on the brain and the corresponding systemic response observed. CONCLUSION The overall literature is encouraging that the more understanding of the gut-brain axis, the greater ability to wield that understanding for therapeutic benefits.
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Affiliation(s)
- Mohamad M Moughnyeh
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Kyle M Brawner
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Bethany A Kennedy
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Venkata A Yeramilli
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Neha Udayakumar
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jessica A Graham
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Colin A Martin
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL.
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40
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Blackwell J, Alexakis C, Saxena S, Creese H, Bottle A, Petersen I, Hotopf M, Pollok RCG. Association between antidepressant medication use and steroid dependency in patients with ulcerative colitis: a population-based study. BMJ Open Gastroenterol 2021; 8:bmjgast-2020-000588. [PMID: 34045238 PMCID: PMC8162076 DOI: 10.1136/bmjgast-2020-000588] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 12/17/2022] Open
Abstract
Background Animal studies indicate a potential protective role of antidepressant medication (ADM) in models of colitis but the effect of their use in humans with ulcerative colitis (UC) remains unclear. Objective To study the relationship between ADM use and corticosteroid dependency in UC. Design Using the Clinical Practice Research Datalink we identified patients diagnosed with UC between 2005 and 2016. We grouped patients according to serotonin selective reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) exposure in the 3 years following diagnosis: ‘continuous users’, ‘intermittent users’ and ‘non-users’. We used logistic regression to estimate the adjusted risk of corticosteroid dependency between ADM exposure groups. Results We identified 6373 patients with UC. Five thousand two hundred and thirty (82%) use no ADMs, 627 (10%) were intermittent SSRI users and 282 (4%) were continuous SSRI users, 246 (4%) were intermittent TCA users and 63 (1%) were continuous TCA users. Corticosteroid dependency was more frequent in continuous SSRI and TCA users compared with non-users (19% vs 24% vs 14%, respectively, χ2 p=0.002). Intermittent SSRI and TCA users had similar risks of developing corticosteroid dependency to non-users (SSRI: OR 1.19, 95% CI 0.95 to 1.50, TCA: OR 1.14, 95% CI 0.78 to 1.66). Continuous users of both SSRIs and TCAs had significantly higher risks of corticosteroid dependency compared with non-users (SSRI: OR 1.62, 95% CI 1.15 to 2.27, TCA: OR 2.02, 95% CI 1.07 to 3.81). Conclusions Continuous ADM exposure has no protective effect in routine clinical practice in UC and identifies a population of patients requiring more intensive medical therapy. ADM use is a flag for potentially worse clinical outcomes in UC.
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Affiliation(s)
- Jonathan Blackwell
- Imperial College London Department of Primary Care and Public Health, London, UK .,Department Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK.,The POP-IBD study group, London, UK
| | - Christopher Alexakis
- The POP-IBD study group, London, UK.,Gastroenterology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK
| | - Sonia Saxena
- Imperial College London Department of Primary Care and Public Health, London, UK.,The POP-IBD study group, London, UK
| | - Hanna Creese
- Imperial College London Department of Primary Care and Public Health, London, UK.,The POP-IBD study group, London, UK
| | - Alex Bottle
- The POP-IBD study group, London, UK.,Primary Care and Public Health, Imperial College, London, UK.,Dr Foster Unit, School of Public Health, Faculty of Medicine, Imperial College, London, UK
| | - Irene Petersen
- The POP-IBD study group, London, UK.,Department of Primary Care & Population Health, University College London, London, UK
| | - Matthew Hotopf
- The POP-IBD study group, London, UK.,Division of Academic Psychiatry, Institute of Psychiatry Psychology and Neuroscience, London, UK.,South London and Maudsley Mental Health NHS Trust, London, London, UK
| | - Richard C G Pollok
- Department Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK.,The POP-IBD study group, London, UK.,Institute for Infection and Immunity, St George's University of London, London, UK
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Aggarwal S, Ranjha R, Paul J. Neuroimmunomodulation by gut bacteria: Focus on inflammatory bowel diseases. World J Gastrointest Pathophysiol 2021; 12:25-39. [PMID: 34084590 PMCID: PMC8160600 DOI: 10.4291/wjgp.v12.i3.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/01/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Microbes colonize the gastrointestinal tract are considered as highest complex ecosystem because of having diverse bacterial species and 150 times more genes as compared to the human genome. Imbalance or dysbiosis in gut bacteria can cause dysregulation in gut homeostasis that subsequently activates the immune system, which leads to the development of inflammatory bowel disease (IBD). Neuromediators, including both neurotransmitters and neuropeptides, may contribute to the development of aberrant immune response. They are emerging as a regulator of inflammatory processes and play a key role in various autoimmune and inflammatory diseases. Neuromediators may influence immune cell’s function via the receptors present on these cells. The cytokines secreted by the immune cells, in turn, regulate the neuronal functions by binding with their receptors present on sensory neurons. This bidirectional communication of the enteric nervous system and the enteric immune system is involved in regulating the magnitude of inflammatory pathways. Alterations in gut bacteria influence the level of neuromediators in the colon, which may affect the gastrointestinal inflammation in a disease condition. Changed neuromediators concentration via dysbiosis in gut microbiota is one of the novel approaches to understand the pathogenesis of IBD. In this article, we reviewed the existing knowledge on the role of neuromediators governing the pathogenesis of IBD, focusing on the reciprocal relationship among the gut microbiota, neuromediators, and host immunity. Understanding the neuromediators and host-microbiota interactions would give a better insight in to the disease pathophysiology and help in developing the new therapeutic approaches for the disease.
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Affiliation(s)
- Surbhi Aggarwal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi 110016, India
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
| | - Raju Ranjha
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
- Field Unit Raipur, ICMR-National Institute of Malaria Research, Raipur 492015, Chhattisgarh, India
| | - Jaishree Paul
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
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Pu Y, Tan Y, Qu Y, Chang L, Wang S, Wei Y, Wang X, Hashimoto K. A role of the subdiaphragmatic vagus nerve in depression-like phenotypes in mice after fecal microbiota transplantation from Chrna7 knock-out mice with depression-like phenotypes. Brain Behav Immun 2021; 94:318-326. [PMID: 33422641 DOI: 10.1016/j.bbi.2020.12.032] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/23/2020] [Accepted: 12/31/2020] [Indexed: 02/08/2023] Open
Abstract
The α7 subtype of the nicotinic acetylcholine receptor (α7 nAChR: coded by Chrna7) regulates the cholinergic ascending anti-inflammatory pathway involved in depression. We previously reported that Chrna7 knock-out (KO) mice show depression-like phenotypes through systemic inflammation. In this study, we investigated whether fecal microbiota transplantation (FMT) from Chrna7 KO mice causes depression-like phenotypes in mice treated with an antibiotic cocktail (ABX). Chrna7 KO mice with depression-like phenotypes show an abnormal gut microbiota composition, although the alpha diversity and beta diversity were not altered. FMT from Chrna7 KO mice caused depression-like phenotypes, systemic inflammation, and downregulation of synaptic proteins in the prefrontal cortex (PFC) in the ABX-treated mice compared to FMT from the control mice. The Principal component analysis based on the OTU level showed that the FMT group from the KO mice were different from the FMT group from the control mice. We found differences in abundance for several bacteria in the FMT group from the KO mice at the taxonomic level when compared with the other group. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of depression-like phenotypes in the ABX-treated mice after FMT from Chrna7 KO mice. These data suggest that FMT from Chrna7 KO mice produce depression-like phenotypes in ABX-treated mice via the subdiaphragmatic vagus nerve. The brain-gut-microbiota axis association with the subdiaphragmatic vagus nerve plays an important role in the development of depression.
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Affiliation(s)
- Yaoyu Pu
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Yunfei Tan
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Youge Qu
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Lijia Chang
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Siming Wang
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Yan Wei
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Xingming Wang
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
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Sollai G, Melis M, Mastinu M, Paduano D, Chicco F, Magri S, Usai P, Hummel T, Barbarossa IT, Crnjar R. Olfactory Function in Patients with Inflammatory Bowel Disease (IBD) Is Associated with Their Body Mass Index and Polymorphism in the Odor Binding-Protein (OBPIIa) Gene. Nutrients 2021; 13:nu13020703. [PMID: 33671721 PMCID: PMC7926749 DOI: 10.3390/nu13020703] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/09/2021] [Accepted: 02/19/2021] [Indexed: 02/06/2023] Open
Abstract
Smell strongly contributes to food choice and intake, influencing energy balance and body weight; its reduction or loss has been related to malnutrition problems. Some patients with inflammatory bowel disease (IBD), mainly Crohn’s disease (CD) and ulcerative colitis (UC), are underweight, while others are overweight. Some studies suggest that changes in eating habits could be linked to specific disorders of the olfactory functions. We assessed the olfactory performance in 199 subjects (healthy control (HC) n = 99, IBD n = 100), based on the olfactory Threshold, Discrimination and Identification score (TDI score), measured with the “Sniffin’ Sticks” test. Subjects were genotyped for the rs2590498 polymorphism of the OBPIIa gene. IBD patients showed both a slightly, but significantly, lower olfactory function and a higher BMI compared to HC subjects. Threshold (in both population) and Discrimination (in IBD patients) olfactory score were affected by the OBPIIa genotype. BMI was influenced by both health status and OBPIIa genotype. A lower olfactory function may delay the satiety sensation and thus increase meal duration and body weight in IBD patients. However, the AA genotype of the OBPIIa seems to “protect” IBD patients from more severe olfactory dysfunction.
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Affiliation(s)
- Giorgia Sollai
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
- Correspondence: ; Tel.: +39-070-6754160
| | - Melania Melis
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
| | - Mariano Mastinu
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
| | - Danilo Paduano
- Department of Medical Sciences and Public Health, University of Cagliari, Presidio Policlinico of Monserrato, 09042 Cagliari, Italy; (D.P.); (F.C.); (S.M.); (P.U.)
| | - Fabio Chicco
- Department of Medical Sciences and Public Health, University of Cagliari, Presidio Policlinico of Monserrato, 09042 Cagliari, Italy; (D.P.); (F.C.); (S.M.); (P.U.)
| | - Salvatore Magri
- Department of Medical Sciences and Public Health, University of Cagliari, Presidio Policlinico of Monserrato, 09042 Cagliari, Italy; (D.P.); (F.C.); (S.M.); (P.U.)
| | - Paolo Usai
- Department of Medical Sciences and Public Health, University of Cagliari, Presidio Policlinico of Monserrato, 09042 Cagliari, Italy; (D.P.); (F.C.); (S.M.); (P.U.)
| | - Thomas Hummel
- Smell and Taste Clinic, Department of Otorhinolaryngology, TU Dresden, 01067 Dresden, Germany;
| | - Iole Tomassini Barbarossa
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
| | - Roberto Crnjar
- Department of Biomedical Sciences, University of Cagliari, Monserrato, 09042 Cagliari, Italy; (M.M.); (M.M.); (I.T.B.); (R.C.)
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Hon KL, Li JTS, Leung AKC, Lee VWY. Current and emerging pharmacotherapy for chronic spontaneous Urticaria: a focus on non-biological therapeutics. Expert Opin Pharmacother 2021; 22:497-509. [PMID: 32990110 DOI: 10.1080/14656566.2020.1829593] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
INTRODUCTION Chronic spontaneous urticaria (CSU) refers to urticaria (wheals) or angioedema, which occur for a period of six weeks or longer without an apparent cause. The condition may impair the patient's quality of life. AREAS COVERED Treatment for CSU is mainly symptomatic. Both AAAAI/ACAAI practice parameters and EAACI/GA2LEN/EDF/WAO guidelines suggest CSU management in a stepwise manner. First-line therapy is with second-generation H1-antihistamines. Treatment should be stepped up along the algorithm if symptoms are not adequately controlled. Increasing the dosage of second-generation H1-antihistamines, with the addition of first-generation H1-antihistamines, H2 antagonist, omalizumab, ciclosporin A, or short-term corticosteroid may be necessary. New medications are being developed to treat refractory CSU. They include spleen tyrosine kinase inhibitor, Bruton tyrosine kinase inhibitor, prostaglandin D2 receptor inhibitor, H4-antihistamine, and other agents. The authors discuss these treatments and provide expert perspectives on the management of CSU. EXPERT OPINION Second-generation H1-antihistamines remain the first-line therapeutic options for the management of CSU. For patients not responding to higher-dose H1-antihistamines, international guidelines recommend the addition of omalizumab. Efficacy and safety data for newer agents are still pending. Large-scale, well-designed, randomized, double-blind, placebo-controlled trials will further provide evidence on the safety profile and efficacy of these agents in patients with CSU.
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Affiliation(s)
- Kam Lun Hon
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong & Department of Paediatrics and adolescent Medicine, the Hong Kong Children's Hospital, Shatin, Hong Kong
| | - Joyce T S Li
- Centre for Learning Enhancement and Research, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Alexander K C Leung
- Department of Pediatrics, The University of Calgary and The Alberta Children's Hospital, Calgary, Alberta, Canada
| | - Vivian W Y Lee
- Centre for Learning Enhancement and Research, The Chinese University of Hong Kong, Shatin, Hong Kong
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Peppas S, Pansieri C, Piovani D, Danese S, Peyrin-Biroulet L, Tsantes AG, Brunetta E, Tsantes AE, Bonovas S. The Brain-Gut Axis: Psychological Functioning and Inflammatory Bowel Diseases. J Clin Med 2021; 10:377. [PMID: 33498197 PMCID: PMC7863941 DOI: 10.3390/jcm10030377] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/11/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
The brain-gut axis represents a complex bi-directional system comprising multiple interconnections between the neuroendocrine pathways, the autonomous nervous system and the gastrointestinal tract. Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a chronic, relapsing-remitting inflammatory disorder of the gastrointestinal tract with a multifactorial etiology. Depression and anxiety are prevalent among patients with chronic disorders characterized by a strong immune component, such as diabetes mellitus, cancer, multiple sclerosis, rheumatoid arthritis and IBD. Although psychological problems are an important aspect of morbidity and of impaired quality of life in patients with IBD, depression and anxiety continue to be under-diagnosed. There is lack of evidence regarding the exact mechanisms by which depression, anxiety and cognitive dysfunction may occur in these patients, and whether psychological disorders are the result of disease activity or determinants of the IBD occurrence. In this comprehensive review, we summarize the role of the brain-gut axis in the psychological functioning of patients with IBD, and discuss current preclinical and clinical data on the topic and therapeutic strategies potentially useful for the clinical management of these patients. Personalized pathways of psychological supports are needed to improve the quality of life in patients with IBD.
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Affiliation(s)
- Spyros Peppas
- Department of Gastroenterology, Athens Naval Hospital, 11521 Athens, Greece;
| | - Claudia Pansieri
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (C.P.); (S.D.); (E.B.)
- Humanitas Clinical and Research Center–IRCCS, 20089 Milan, Italy
| | - Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (C.P.); (S.D.); (E.B.)
- Humanitas Clinical and Research Center–IRCCS, 20089 Milan, Italy
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (C.P.); (S.D.); (E.B.)
- Humanitas Clinical and Research Center–IRCCS, 20089 Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Inserm U1256 NGERE, Nancy University Hospital, Lorraine University, 54500 Vandoeuvre-les-Nancy, France;
| | - Andreas G. Tsantes
- Attiko Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece; (A.G.T.); (A.E.T.)
| | - Enrico Brunetta
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (C.P.); (S.D.); (E.B.)
- Humanitas Clinical and Research Center–IRCCS, 20089 Milan, Italy
| | - Argirios E. Tsantes
- Attiko Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece; (A.G.T.); (A.E.T.)
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (C.P.); (S.D.); (E.B.)
- Humanitas Clinical and Research Center–IRCCS, 20089 Milan, Italy
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Sandes S, Figueiredo N, Pedroso S, Sant'Anna F, Acurcio L, Abatemarco Junior M, Barros P, Oliveira F, Cardoso V, Generoso S, Caliari M, Nicoli J, Neumann E, Nunes Á. Weissella paramesenteroides WpK4 plays an immunobiotic role in gut-brain axis, reducing gut permeability, anxiety-like and depressive-like behaviors in murine models of colitis and chronic stress. Food Res Int 2020; 137:109741. [PMID: 33233306 DOI: 10.1016/j.foodres.2020.109741] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 08/12/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
The relationship between inflammatory bowel disease (IBD) and mood disorders is complex and involves overlapping metabolic pathways, which may determine comorbidity. Several studies have been shown that this comorbidity could worsen IBD clinical course. The treatment of ulcerative colitis is complex, and involves traditional therapy to promote the function of epithelial barrier, reducing exacerbated inflammatory responses. Recently, it has been shown that some probiotic strains could modulate gut-brain axis, reducing depressive and anxiety scores in humans, including IBD patients. Accordingly, this study aimed to evaluate the role of Weissella paramesenteroides WpK4 in murine models of ulcerative colitis and chronic stress. It was observed that bacterium ingestion improved health of colitis mice, reducing intestinal permeability, besides improving colon histopathological appearance. In stressed mice, bacterial consumption was associated with a reduced anxiety-like and depressive-like behaviors. In both assays, the beneficial role of W. paramesenteroides WpK4 was related to its immunomodulatory feature. It is possible to state that W. paramesenteroides WpK4 exerted their beneficial roles in gut-brain axis through their immunomodulatory effects with consequences in several metabolic pathways related to intestinal permeability and hippocampal physiology.
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Affiliation(s)
- Sávio Sandes
- Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Brazil.
| | - Naiara Figueiredo
- Departamento de Tecnologia e Inspeção de Produtos de Origem Animal, Escola de Veterinária, Brazil
| | - Sílvia Pedroso
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Felipe Sant'Anna
- Departamento de Tecnologia e Inspeção de Produtos de Origem Animal, Escola de Veterinária, Brazil
| | - Leonardo Acurcio
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Mário Abatemarco Junior
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Patrícia Barros
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Fabrício Oliveira
- Departamento de Patologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Valbert Cardoso
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Simone Generoso
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Marcelo Caliari
- Departamento de Patologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Jacques Nicoli
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Elisabeth Neumann
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Campus Pampulha, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - Álvaro Nunes
- Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Brazil
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Khafipour A, Eissa N, Munyaka PM, Rabbi MF, Kapoor K, Kermarrec L, Khafipour E, Bernstein CN, Ghia JE. Denosumab Regulates Gut Microbiota Composition and Cytokines in Dinitrobenzene Sulfonic Acid (DNBS)-Experimental Colitis. Front Microbiol 2020; 11:1405. [PMID: 32670246 PMCID: PMC7331113 DOI: 10.3389/fmicb.2020.01405] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022] Open
Abstract
The pro-inflammatory mediator receptor activator of nuclear factor-kappa B ligand (RANKL) plays a significant role in the development of rheumatoid arthritis; however, its role in inflammatory bowel disease is unknown. Genome-wide association meta-analysis for Crohn's disease (CD) identified a variant near the TNFSF11 gene that encodes RANKL and CD risk allele increased expression of RANKL in specific cell lines. This study aims to elucidate if the RANKL inhibitor denosumab can reduce the severity of experimental colitis and modify the gut microbiota composition using murine dinitrobenzenesulfonic acid (DNBS)-experimental model of colitis mimicking CD. In colitic conditions, denosumab treatment significantly decreased the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α within the colonic mucosa. Moreover, colitis was accompanied by disruption of gut microbiota, and preventative treatment with denosumab modulated this disruption. Denosumab treatment also modified the alpha- and beta diversity of colonic mucosa and fecal microbiota. These results provide a rationale for considering denosumab as a future potential therapy in CD; however, more detailed experimental and clinical studies are warranted.
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Affiliation(s)
- Azin Khafipour
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
| | - Nour Eissa
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.,Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada.,Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Peris M Munyaka
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.,Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada
| | - Mohammad F Rabbi
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.,Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada.,Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Kunal Kapoor
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.,Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Laetitia Kermarrec
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.,Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Ehsan Khafipour
- Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada
| | - Charles N Bernstein
- Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Jean-Eric Ghia
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.,Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada.,Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
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Collins SM. Interrogating the Gut-Brain Axis in the Context of Inflammatory Bowel Disease: A Translational Approach. Inflamm Bowel Dis 2020; 26:493-501. [PMID: 31970390 PMCID: PMC7054772 DOI: 10.1093/ibd/izaa004] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Indexed: 12/14/2022]
Abstract
This review examines preclinical and clinical studies relevant to our understanding of how the bidirectional gut-brain axis influences the natural history of inflammatory bowel disease. Preclinical studies provide proof of concept that preexisting behavioral illness, such as depression, results in increased susceptibility to inflammatory stimuli and that commonly used classes of antidepressants protect against this vulnerability. However, clinical studies suggesting behavioral illness as a risk factor for IBD and a protective role for antidepressants have relied primarily on symptom-reporting rather than objective measurements of inflammation. In terms of gut-to-brain signaling, there is emerging evidence from preclinical and clinical observation that intestinal inflammation alters brain functions, including the induction of mood disorders, alteration of circadian rhythm both centrally and peripherally, and changes in appetitive behaviors. Furthermore, preclinical studies suggest that effective treatment of intestinal inflammation improves associated behavioral impairment. Taken together, the findings of this review encourage a holistic approach to the management of patients with IBD, accommodating lifestyle issues that include the avoidance of sleep deprivation, optimized nutrition, and the monitoring and appropriate management of behavioral disorders. The review also acknowledges the need for better-designed clinical studies evaluating the impact of behavioral disorders and their treatments on the natural history of IBD, utilizing hard end points to assess changes in the inflammatory process as opposed to reliance on symptom-based assessments. The findings of the review also encourage a better understanding of changes in brain function and circadian rhythm induced by intestinal inflammation.
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Affiliation(s)
- Stephen M Collins
- Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada,Address correspondence to: Stephen M. Collins, MBBS, FRCPC, FRSC, Farncombe Family Digestive Health Research Institute, Faculty of Health Sciences, Room 3N8B, McMaster University Medical Centre, Hamilton, Ontario, CANADA L8N 3Z5. E-mail:
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49
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Sinagra E, Utzeri E, Morreale GC, Fabbri C, Pace F, Anderloni A. Microbiota-gut-brain axis and its affect inflammatory bowel disease: Pathophysiological concepts and insights for clinicians. World J Clin Cases 2020; 8:1013-1025. [PMID: 32258072 PMCID: PMC7103973 DOI: 10.12998/wjcc.v8.i6.1013] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/14/2020] [Accepted: 03/05/2020] [Indexed: 02/05/2023] Open
Abstract
Despite the bi-directional interaction between gut microbiota and the brain not being fully understood, there is increasing evidence arising from animal and human studies that show how this intricate relationship may facilitate inflammatory bowel disease (IBD) pathogenesis, with consequent important implications on the possibility to improve the clinical outcomes of the diseases themselves, by acting on the different components of this system, mainly by modifying the microbiota. With the emergence of precision medicine, strategies in which patients with IBD might be categorized other than for standard gut symptom complexes could offer the opportunity to tailor therapies to individual patients. The aim of this narrative review is to elaborate on the concept of the gut-brain-microbiota axis and its clinical significance regarding IBD on the basis of recent scientific literature, and finally to focus on pharmacological therapies that could allow us to favorably modify the function of this complex system.
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Affiliation(s)
- Emanuele Sinagra
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, Cefalù 90015, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo 90100, Italy
| | - Erika Utzeri
- Nuova Casa di Cura di Decimomannu, Cagliari 09100, Italy
| | | | - Carlo Fabbri
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena, Azienda USL Romagna, Forlì 47121, Italy
| | - Fabio Pace
- Unit of Gastroenterology, Bolognini Hospital, Bergamo 24100, Italy
| | - Andrea Anderloni
- Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Research Hospital, Rozzano 20089, Italy
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Abstract
OBJECTIVE Few studies report the impact of depression on inflammatory bowel disease (IBD)-related hospitalizations. We evaluated the association between depression and pediatric IBD-related hospitalizations. Our primary aim was to test the hypothesis that depression is associated with hospital length of stay (LOS); our secondary goal was to evaluate if patients with depression are at higher risk for undergoing additional imaging and procedures. METHODS Data were extracted from the 2012 Kids Inpatient Database (KID), the largest nationally representative publicly available all-payer pediatric inpatient cross-sectional database in the United States. Hospitalizations for patients less than 21 years with a primary diagnosis Crohn disease (CD) or ulcerative colitis (UC) by ICD-9 code were included. Multivariable logistic regression was used to predict long LOS controlling for patient- and hospital-level variables and for potential disease confounders. RESULTS For primary IBD-related hospitalizations (N = 8222), depression was associated with prolonged LOS (odds ratio [OR] 1.50; 95% confidence interval [CI] 1.19-1.90) and total parenteral nutrition use (OR 1.54; 95% CI 1.04-2.27). Depression was not associated with increased likelihood of surgery (OR 0.97; 95% CI 0.72-1.30), endoscopy (OR 0.91; 95% CI 0.74-1.14), blood transfusion (OR 0.85; 95% CI 0.58-1.23), or abdominal imaging (OR 1.15; 95% CI 0.53-2.53). CONCLUSIONS Depression is associated with prolonged LOS in pediatric patients with IBD, even when controlling for gastrointestinal disease severity. Future research evaluating the efficacy of standardized depression screening and early intervention may be beneficial to improving inpatient outcomes in this population.
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