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Papareddy P, Herwald H. From immune activation to disease progression: Unraveling the complex role of Serum Amyloid A proteins. Cytokine Growth Factor Rev 2025; 83:77-84. [PMID: 40240198 DOI: 10.1016/j.cytogfr.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/19/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025]
Abstract
Serum Amyloid A (SAA) proteins are critical mediators of immune activation and metabolic regulation, bridging the acute-phase response with long-term disease dynamics. Once considered mere biomarkers of inflammation, emerging research has revealed their central role in orchestrating immune responses, lipid metabolism, and tissue remodeling. SAA proteins display context-dependent functions: they promote immune defense and tissue regeneration in some conditions, while exacerbating chronic inflammation and disease progression in others. Recent studies highlight the intricate interplay between SAA isoforms, pattern recognition receptors, and metabolic pathways, with implications for autoimmune diseases, metabolic disorders, and inflammatory pathologies. Despite their well-documented role in acute inflammation, the therapeutic potential of SAA proteins remains underexplored. Ongoing research aims to dissect their multifaceted functions and isoform-specific effects, paving the way for novel diagnostic and therapeutic strategies in immune-mediated diseases.
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Affiliation(s)
- Praveen Papareddy
- Department of Laboratory Medicine Biomedical Center (BMC) Lund University, BMC, Floor C14, Lund 22184, Sweden.
| | - Heiko Herwald
- Department of Laboratory Medicine Biomedical Center (BMC) Lund University, BMC, Floor C14, Lund 22184, Sweden.
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Yao X, Qiao B, Shan F, Zhang Q, Song Y, Song J, Wang Y. Elevated Serum Amyloid A2 and A4 in Patients With Guillain-Barré Syndrome. J Clin Neurol 2025; 21:213-219. [PMID: 40308016 PMCID: PMC12056137 DOI: 10.3988/jcn.2024.0469] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/13/2025] [Accepted: 02/05/2025] [Indexed: 05/02/2025] Open
Abstract
BACKGROUND AND PURPOSE Guillain-Barré syndrome (GBS) is an autoimmune-mediated disorder characterized by demyelinating or axonal injury of the peripheral nerve. Our aim is to determine whether serum amyloid A (SAA) is a biomarker of demyelinating injury and disease severity in patients with GBS. METHODS This study retrospectively enrolled 40 patients with either the demyelinating or axonal GBS and sex- and age-matched controls with other neurological diseases as well as healthy subjects. The demographic and clinical features at entry were collected. The serum levels of the SAA isoforms SAA1, SAA2, and SAA4 were determined in the patients with GBS and the controls using the enzyme-linked immunosorbent assay and analyzed for the associations between levels of different SAA isoforms and the clinical features of the patients. RESULTS The levels of SAA2 and SAA4 were significantly higher in patients with GBS than in both the other neurological disease controls and the healthy subjects (p<0.05 for all). The level of SAA1 did not differ between patients with GBS and the controls. The level of SAA2 was considerably higher in GBS patients with antecedent infection than in those without infection (p=0.020). The levels of different SAA isoforms were not associated with the disease severity or other clinical features of patients with GBS (p>0.05 for all). CONCLUSIONS Increased levels of SAA2 and SAA4 may only represent the acute inflammatory status and so cannot be utilized as biomarkers of the disease severity or demyelinating injury in patients with GBS.
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Affiliation(s)
- Xiaoying Yao
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Baojun Qiao
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Fangzhen Shan
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Qingqing Zhang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Yan Song
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Jin Song
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
| | - Yuzhong Wang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China.
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Lisai-Goldstein Y, Focht G, Orlanski-Meyer E, Yogev D, Lev-Tzion R, Ledder O, Assa A, Navas-López VM, Baldassano RN, Otley A, Shouval DS, Griffiths AM, Turner D, Atia O. Serological Markers as Predictors of Anti-TNF Response in Children with Crohn's Disease. Dig Dis Sci 2025; 70:333-339. [PMID: 39604667 DOI: 10.1007/s10620-024-08732-y] [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: 09/30/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND To advance personalized medicine in pediatric Crohn's disease (CD), we aimed to explore the utility of serological biomarkers in predicting response to anti-tumor necrosis factor (TNF). METHODS Children with CD were enrolled at initiation of anti-TNF and followed prospectively at 4 and 12 months thereafter, as well as at last follow-up. At baseline, 10 serological markers of the "PROMETHEUS® IBD sgi Diagnostic test" were measured, including pANCA, ASCA IgG and IgA, anti-CBir1, anti-OmpC, anti-A4-Fla2, anti-Fla-X, SAA, ICAM-1 and VCAM-1. The primary outcome was sustained steroid-free remission (SSFR, i.e. clinical remission without steroids at both 4 and 12 months) and the secondary outcome was primary non-response (PNR). RESULTS Of the 72 included children (mean age, 12.8 ± 3.1 years; median disease duration, 6.4 months [IQR 2.5-17.3]), 42 (58%) were treated with adalimumab and 30 (42%) with infliximab. PNR was noted in 20 (28%) children and failure to achieve SSFR in 36 (50%). The most common positive serological markers were SAA (86%) and ICAM-1 (82%). In univariate analyses, none of the serological markers achieved statistical significance in association with SSFR or with PNR. In multivariable analysis, positivity of ASCA IgG (OR 3.3 [95%CI 0.8-14.4]) and pANCA (OR 5.3 [95%CI 0.9-48]) were the closest to achieving significance in predicting SSFR, with fair predictive performance for the model (AUC 0.67 [95%CI 0.55-0.80]). CONCLUSION The serological markers tested here have limited utility in predicting response to anti-TNF treatment. Further studies with larger sample sizes are needed to confirm the utility of ASCA IgG and pANCA.
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Affiliation(s)
- Yaara Lisai-Goldstein
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Gili Focht
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Esther Orlanski-Meyer
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Dotan Yogev
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Raffi Lev-Tzion
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Oren Ledder
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Amit Assa
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Victor Manuel Navas-López
- Pediatric Gastroenterology and Nutrition Unit, Regional University Hospital of Málaga, Málaga, Spain
| | - Robert N Baldassano
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Anthony Otley
- Department of Pediatrics, IWK Health, Dalhousie University, Halifax, NS, Canada
| | - Dror S Shouval
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikvah, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Ohad Atia
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel.
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Hamamoto Y, Kido K, Kawamura M, Sekido Y, Ogino T, Yasuoka H, Iijima H, Mizushima T. Subclinical amyloid deposition in inflammatory bowel diseases: A two hospital study. Pathol Res Pract 2024; 264:155682. [PMID: 39488117 DOI: 10.1016/j.prp.2024.155682] [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: 07/09/2024] [Accepted: 10/25/2024] [Indexed: 11/04/2024]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), predominantly affects young patients and leads to intestinal complications. Amyloidosis, which involves abnormal protein deposition, is a serious complication of IBD, with a low incidence. Early detection of subclinical amyloid deposits is crucial for preventing fatal outcomes; however, routine investigations are lacking. We aimed to retrospectively examine subclinical amyloid deposition in adult patients with IBD. Surgical specimens from 249 patients with IBD were collected from the databases of two hospitals. The specimens were subjected to staining and immunohistochemistry, and clinical information was collected simultaneously. The amyloid positivity rate was 0.8 % in CD (1/131) and 0 % in UC (0/118) based on Congo red staining. The patient with amyloid deposits was a female in her 80 s who lacked a family history of amyloidosis. The subtype was amyloid A. Clinical history revealed intestinal resection in her 30 s and subsequent abdominal symptoms. To the best of our knowledge, this is the first study to collect >100 surgically examined specimens from adults with CD or UC. In older patients with a long and complex clinical course, aggressive analysis of amyloids would be better.
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Affiliation(s)
- Yuichiro Hamamoto
- Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Diagnostic Pathology, Daini Osaka Keisatsu Hospital, Osaka, Osaka, Japan.
| | - Kansuke Kido
- Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Michihiro Kawamura
- Department of Clinical Laboratory, Kinki Central Hospital, Itami, Hyogo, Japan
| | - Yuki Sekido
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Takayuki Ogino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hironao Yasuoka
- Department of Diagnostic Pathology, Osaka Rosai Hospital, Sakai, Osaka, Japan
| | - Hideki Iijima
- Department of Internal Medicine, Osaka Keisatsu Hospital, Osaka, Osaka, Japan
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Chen Q, Zhang X, Tie Y, Zhang J, Huang P, Xie Y, Zhang L, Tang X, Zeng Z, Li L, Chen M, Chen R, Zhang S. Serum amyloid A for predicting prognosis in patients with newly diagnosed Crohn's disease. BMJ Open Gastroenterol 2024; 11:e001497. [PMID: 39266020 PMCID: PMC11404264 DOI: 10.1136/bmjgast-2024-001497] [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: 06/17/2024] [Accepted: 08/28/2024] [Indexed: 09/14/2024] Open
Abstract
OBJECTIVE Serum amyloid A (SAA) was found to be positively correlated with the activity of Crohn's disease (CD); however, its prognostic value remains uncertain. Here, we examined its predictive ability in newly diagnosed CD and explored genetic association. METHODS This retrospective cohort study included patients newly diagnosed as CD at the First Affiliated Hospital of Sun Yat-sen University between June 2010 and March 2022. We employed receiver operating characteristic curve, Cox proportional hazard regression models and restricted cubic splines to investigate the prognostic performance of SAA for surgery and disease progression. To assess possible causality, a two-sample Mendelian randomisation (MR) of published genome-wide association study data was conducted. RESULTS During 2187.6 person-years (median age, 28 years, 72.4% male), 87 surgery and 153 disease progression events were documented. A 100-unit increment in SAA level generated 14% higher risk for surgery (adjusted HR (95% CI): 1.14 (1.05-1.23), p=0.001) and 12% for disease progression (1.12 (1.05-1.19), p<0.001). Baseline SAA level ≥89.2 mg/L led to significantly elevated risks for surgery (2.08 (1.31-3.28), p=0.002) and disease progression (1.72 (1.22-2.41), p=0.002). Such associations were assessed as linear. Adding SAA into a scheduled model significantly improved its predictive performances for surgery and disease progression (p for net reclassification indexes and integrated discrimination indexes <0.001). Unfortunately, no genetic causality between SAA and CD was observed in MR analysis. Sensitivity analyses showed robust results. CONCLUSION Although causality was not found, baseline SAA level was an independent predictor of surgery and disease progression in newly diagnosed CD, and had additive benefit to existing prediction models.
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Affiliation(s)
- Qia Chen
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Xi Zhang
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yizhe Tie
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianwu Zhang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Pinwei Huang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yuxuan Xie
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Liqian Zhang
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xueer Tang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zhirong Zeng
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Li Li
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Minhu Chen
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rirong Chen
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shenghong Zhang
- Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, People's Republic of China
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Bahaa A, Elbaz T, Elmakhzangy H, Shehata M, Abd El-Kareem D, Gaber A, Hashem MB, El Raziky M. Assessment of IBD disease activity by Interleukin-6 and serum amyloid A in relation with fecal calprotectin and endoscopic indices. Arab J Gastroenterol 2024; 25:299-305. [PMID: 39039004 DOI: 10.1016/j.ajg.2024.07.003] [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: 03/14/2024] [Accepted: 07/05/2024] [Indexed: 07/24/2024]
Abstract
BACKGROUND AND STUDY AIMS Close monitoring of disease activity in IBD patients is essential to avoid long term complications. Although endoscopic assessment is the ideal monitoring tool, the usage of noninvasive biomarkers is more practical and patient friendly. We aimed to study the performance of Interleukin-6(IL-6) and Serum Amyloid A(SAA) as serum biomarkers in assessment of the disease activity of IBD patients in correlation to C-reactive protein (CRP), Fecal Calprotectin (FC) and endoscopic indices. METHODS 83 IBD (26 CD and 57 UC) patients on stable treatment regimen were recruited. Serum markers included CRP, CBC, IL-6, SAA were analyzed, together with FC. These markers were compared with the endoscopic and clinical disease parameters. Harvey-Bradshaw Index (HBI) and the Simple Clinical Colitis Activity Index (SCCAI) were used to assess clinical activity in CD and UC patients, respectively. Endoscopic activity was recorded using the Simple Endoscopic Score (SES) for Crohn's disease or the Mayo Endoscopic Score (MES) for ulcerative colitis. RESULTS In prediction of disease activity, IL-6, SAA and CRP demonstrated good area under receiver operating characteristics (AUC) (>0.7), with FC being the best (0.94) for endoscopically active disease (P < 0.01). Combining FC and IL-6 or SAA improved its discriminative accuracy with an AUC (∼0.96). CONCLUSIONS FC most accurately predicts endoscopic disease activity in IBD patients, in comparison to other studied serological biomarkers. The serum IL-6 and SAA are potential predictors of endoscopic disease activity, and they might be valuable for assessment of disease activity. Finally, a composite score of FC and SAA or IL-6 can increased its diagnostic accuracy.
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Affiliation(s)
- Ahmed Bahaa
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt; Integrated Clinical and Research Centre for Intestinal Disorders (ICRID), Faculty of Medicine, Cairo University, Egypt
| | - Tamer Elbaz
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt; Integrated Clinical and Research Centre for Intestinal Disorders (ICRID), Faculty of Medicine, Cairo University, Egypt
| | - Hesham Elmakhzangy
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt
| | - Mohammed Shehata
- Chemical Pathology Department, Faculty of Medicine, Cairo University, Egypt
| | | | - AbdelAziz Gaber
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt; Integrated Clinical and Research Centre for Intestinal Disorders (ICRID), Faculty of Medicine, Cairo University, Egypt
| | - Mohamed B Hashem
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt; Integrated Clinical and Research Centre for Intestinal Disorders (ICRID), Faculty of Medicine, Cairo University, Egypt
| | - Maissa El Raziky
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt
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Mestrovic A, Perkovic N, Bozic D, Kumric M, Vilovic M, Bozic J. Precision Medicine in Inflammatory Bowel Disease: A Spotlight on Emerging Molecular Biomarkers. Biomedicines 2024; 12:1520. [PMID: 39062093 PMCID: PMC11274502 DOI: 10.3390/biomedicines12071520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/30/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024] Open
Abstract
Inflammatory bowel diseases (IBD) remain challenging in terms of understanding their causes and in terms of diagnosing, treating, and monitoring patients. Modern diagnosis combines biomarkers, imaging, and endoscopic methods. Common biomarkers like CRP and fecal calprotectin, while invaluable tools, have limitations and are not entirely specific to IBD. The limitations of existing markers and the invasiveness of endoscopic procedures highlight the need to discover and implement new markers. With an ideal biomarker, we could predict the risk of disease development, as well as the possibility of response to a particular therapy, which would be significant in elucidating the pathogenesis of the disease. Recent research in the fields of machine learning, proteomics, epigenetics, and gut microbiota provides further insight into the pathogenesis of the disease and is also revealing new biomarkers. New markers, such as BAFF, PGE-MUM, oncostatin M, microRNA panels, αvβ6 antibody, and S100A12 from stool, are increasingly being identified, with αvβ6 antibody and oncostatin M being potentially close to being presented into clinical practice. However, the specificity of certain markers still remains problematic. Furthermore, the use of expensive and less accessible technology for detecting new markers, such as microRNAs, represents a limitation for widespread use in clinical practice. Nevertheless, the need for non-invasive, comprehensive markers is becoming increasingly important regarding the complexity of treatment and overall management of IBD.
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Affiliation(s)
- Antonio Mestrovic
- Department of Gastroenterology, University Hospital of Split, Spinciceva 2, 21000 Split, Croatia; (A.M.); (N.P.); (D.B.)
| | - Nikola Perkovic
- Department of Gastroenterology, University Hospital of Split, Spinciceva 2, 21000 Split, Croatia; (A.M.); (N.P.); (D.B.)
| | - Dorotea Bozic
- Department of Gastroenterology, University Hospital of Split, Spinciceva 2, 21000 Split, Croatia; (A.M.); (N.P.); (D.B.)
| | - Marko Kumric
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia;
- Laboratory for Cardiometabolic Research, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia
| | - Marino Vilovic
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia;
- Laboratory for Cardiometabolic Research, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia;
- Laboratory for Cardiometabolic Research, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia
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Sarb OF, Sarb AD, Iacobescu M, Vlad IM, Milaciu MV, Ciurmarnean L, Vacaras V, Tantau AI. From Gut to Brain: Uncovering Potential Serum Biomarkers Connecting Inflammatory Bowel Diseases to Neurodegenerative Diseases. Int J Mol Sci 2024; 25:5676. [PMID: 38891863 PMCID: PMC11171869 DOI: 10.3390/ijms25115676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/12/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
Inflammatory bowel diseases (IBDs) are characterized by chronic gastrointestinal inflammation due to abnormal immune responses to gut microflora. The gut-brain axis is disrupted in IBDs, leading to neurobiological imbalances and affective symptoms. Systemic inflammation in IBDs affects the brain's inflammatory response system, hormonal axis, and blood-brain barrier integrity, influencing the gut microbiota. This review aims to explore the association between dysregulations in the gut-brain axis, serum biomarkers, and the development of cognitive disorders. Studies suggest a potential association between IBDs and the development of neurodegeneration. The mechanisms include systemic inflammation, nutritional deficiency, GBA dysfunction, and the effect of genetics and comorbidities. The objective is to identify potential correlations and propose future research directions to understand the impact of altered microbiomes and intestinal barrier functions on neurodegeneration. Serum levels of vitamins, inflammatory and neuronal damage biomarkers, and neuronal growth factors have been investigated for their potential to predict the development of neurodegenerative diseases, but current results are inconclusive and require more studies.
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Affiliation(s)
- Oliviu-Florentiu Sarb
- Department of Neuroscience, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.-F.S.); (I.-M.V.)
- Department of Internal Medicine, 4th Medical Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (M.-V.M.); (L.C.); (A.-I.T.)
| | - Adriana-Daniela Sarb
- Department of Internal Medicine, Heart Institute, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Maria Iacobescu
- Department of Proteomics and Metabolomics, MEDFUTURE Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Irina-Maria Vlad
- Department of Neuroscience, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.-F.S.); (I.-M.V.)
| | - Mircea-Vasile Milaciu
- Department of Internal Medicine, 4th Medical Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (M.-V.M.); (L.C.); (A.-I.T.)
| | - Lorena Ciurmarnean
- Department of Internal Medicine, 4th Medical Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (M.-V.M.); (L.C.); (A.-I.T.)
| | - Vitalie Vacaras
- Department of Neuroscience, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.-F.S.); (I.-M.V.)
| | - Alina-Ioana Tantau
- Department of Internal Medicine, 4th Medical Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (M.-V.M.); (L.C.); (A.-I.T.)
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Campbell E, Hesser LA, Berni Canani R, Carucci L, Paparo L, Patry RT, Nagler CR. A Lipopolysaccharide-Enriched Cow's Milk Allergy Microbiome Promotes a TLR4-Dependent Proinflammatory Intestinal Immune Response. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:702-714. [PMID: 38169331 PMCID: PMC10872367 DOI: 10.4049/jimmunol.2300518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 12/12/2023] [Indexed: 01/05/2024]
Abstract
We have previously reported that the gut microbiota of healthy infants harbors allergy-protective bacteria taxa that are depleted in infants with cow's milk allergy (CMA). Few reports have investigated the role of the gut microbiota in promoting allergic responses. In this study we selected a CMA-associated microbiota with increased abundance of Gram-negative bacteria for analysis of its proinflammatory potential. LPS is the major component of the outer membrane of Gram-negative bacteria. Colonization of mice with a global or conditional mutation of the LPS receptor TLR4 with this CMA microbiota induced expression of serum amyloid A1 (Saa1) and other Th17-, B cell-, and Th2-associated genes in the ileal epithelium in a TLR4-dependent manner. In agreement with the gene expression data, mice colonized with the CMA microbiota have expanded populations of Th17 and regulatory T cells and elevated concentrations of fecal IgA. Importantly, we used both antibiotic-treated specific pathogen-free and germ-free rederived mice with a conditional mutation of TLR4 in the CD11c+ compartment to demonstrate that the induction of proinflammatory genes, fecal IgA, and Th17 cells is dependent on TLR4 signaling. Furthermore, metagenomic sequencing revealed that the CMA microbiota has an increased abundance of LPS biosynthesis genes. Taken together, our results show that a microbiota displaying a higher abundance of LPS genes is associated with TLR4-dependent proinflammatory gene expression and a mixed type 2/type 3 response in mice, which may be characteristic of a subset of infants with CMA.
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Affiliation(s)
- Evelyn Campbell
- Committee on Microbiology, The University of Chicago, Chicago, IL. U.S.A
| | - Lauren A. Hesser
- Department of Pathology, The University of Chicago, Chicago, IL. U.S.A
- Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL. U.S.A
| | - Roberto Berni Canani
- Department of Translational Medical Science and ImmunoNutrition Lab at CEINGE Advanced Biotechnologies Research Center and Task Force for Microbiome Studies, Section of Pediatrics, University of Naples Federico II, Naples, Italy
| | - Laura Carucci
- Department of Translational Medical Science and ImmunoNutrition Lab at CEINGE Advanced Biotechnologies Research Center and Task Force for Microbiome Studies, Section of Pediatrics, University of Naples Federico II, Naples, Italy
| | - Lorella Paparo
- Department of Translational Medical Science and ImmunoNutrition Lab at CEINGE Advanced Biotechnologies Research Center and Task Force for Microbiome Studies, Section of Pediatrics, University of Naples Federico II, Naples, Italy
| | - Robert T. Patry
- Department of Pathology, The University of Chicago, Chicago, IL. U.S.A
| | - Cathryn R. Nagler
- Department of Pathology, The University of Chicago, Chicago, IL. U.S.A
- Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL. U.S.A
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10
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Stute M, Kreysing M, Zorn M, Michl P, Gauss A. Serum Amyloid A as a Potential Biomarker in Inflammatory Bowel Diseases, Especially in Patients with Low C-Reactive Protein. Int J Mol Sci 2024; 25:1177. [PMID: 38256249 PMCID: PMC10816523 DOI: 10.3390/ijms25021177] [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: 01/24/2024] Open
Abstract
The acute phase protein Serum Amyloid A (SAA) is synthesised by the liver in response to inflammatory stimuli. Previous studies have revealed that SAA may be a better biomarker of disease activity in inflammatory bowel disease (IBD) compared to C-reactive protein (CRP). This retrospective monocentric study evaluated whether SAA correlates with biomarkers like faecal calprotectin (FC), CRP, the Neutrophil to Lymphocyte ratio (NLR), the platelet count and clinical disease activity of IBD patients. Serum samples from the IBD outpatient clinic of the University Hospital Heidelberg were analysed for SAA concentrations if an FC concentration measurement was available from ±14 days to collection of the serum sample. Three hundred and six serum samples from 265 patients (166 with Crohn's disease, 91 with ulcerative colitis and 8 with IBD unclassified) met the inclusion criteria. There was a significant positive correlation between SAA and FC, CRP, NLR, platelet count and the Simple Clinical Colitis Activity Index (SCCAI). The cut-off for SAA serum concentration at 4.55 mg/L achieved a sensitivity of 57.5% and a specificity of 69.7% for the detection of active inflammation in IBD. SAA may be used as an additional biomarker in the disease monitoring strategy of IBD patients, especially in patients with low CRP concentrations.
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Affiliation(s)
- Marie Stute
- Department of Gastroenterology and Hepatology, Heidelberg University, University Hospital, INF 410, 69120 Heidelberg, Germany; (M.S.); (M.K.); (P.M.)
| | - Martin Kreysing
- Department of Gastroenterology and Hepatology, Heidelberg University, University Hospital, INF 410, 69120 Heidelberg, Germany; (M.S.); (M.K.); (P.M.)
| | - Markus Zorn
- Central Laboratory of University Hospital Heidelberg, Department of Endocrinology and Metabolism, University Hospital Heidelberg, INF 671, 69120 Heidelberg, Germany;
| | - Patrick Michl
- Department of Gastroenterology and Hepatology, Heidelberg University, University Hospital, INF 410, 69120 Heidelberg, Germany; (M.S.); (M.K.); (P.M.)
| | - Annika Gauss
- Department of Gastroenterology and Hepatology, Heidelberg University, University Hospital, INF 410, 69120 Heidelberg, Germany; (M.S.); (M.K.); (P.M.)
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Hu X, Li J, Sun Y, Wu D, Zhao T, Ma M, Chen J, Wang M, Hou S. Combined use of CDAI and blood indices for assessing endoscopic activity in ileocolic Crohn's disease. BMC Gastroenterol 2023; 23:337. [PMID: 37770845 PMCID: PMC10540500 DOI: 10.1186/s12876-023-02968-0] [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: 03/29/2023] [Accepted: 09/21/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND Mucosal healing has become the primary treatment target for patients with Crohn's disease (CD). We aimed to develop a noninvasive and convenient tool to evaluate the endoscopic activity in patients with ileocolic CD. METHODS A retrospective multicenter study including 300 CD patients (training, 210 patients; test, 90 patients) was conducted at two tertiary referral centers. Independent risk factors associated with endoscopic activity were explored, which were then combined into a comprehensive index. The predictive performance was evaluated with the area under receiver operating characteristic curve (ROC). Cohen's Kappa was adopted to examine the consistency between each indicator and endoscopic activity. RESULTS A total of 210 CD patients were recruited in the training cohort. We found that Crohn's Disease Activity Index (CDAI), C-reactive protein (CRP) and platelet-to-lymphocyte percentage ratio (PLpR) were independently associated with endoscopic activity. Additionally, the comprehensive index generated from the above three indices achieved good discrimination and performed better than CDAI in AUC (0.849 vs. 0.769, P < 0.05). This was further well demonstrated by the external test cohort, which showed good discrimination (AUC: 0.84, 95% CI: 0.744-0.936). Intra-individual comparison revealed the comprehensive index to be superior in the prediction of endoscopic activity. In the subgroup analysis, the AUC of comprehensive index was significantly higher than CDAI especially in inflammatory phenotype (0.824 vs. 0.751, P < 0.05). CONCLUSION Combining CDAI, CRP and PLpR significantly improved the accuracy for predicting endoscopic activity in ileocolic CD, which can help better monitor an endoscopic flare.
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Affiliation(s)
- Xiaolin Hu
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu, China
- Medical College of Yangzhou University, Jiangsu, China
| | - Jiajia Li
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Yunyun Sun
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Dacheng Wu
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Tiantian Zhao
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu, China
- Medical College of Yangzhou University, Jiangsu, China
| | - Maofeng Ma
- Medical College of Yangzhou University, Jiangsu, China
| | - Jie Chen
- Department of Gastroenterology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225009, Jiangsu, China.
| | - Mei Wang
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu, China.
| | - Sicong Hou
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, Jiangsu, China.
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Van den Berghe N, Alsoud D, Verstockt B, Vermeire S, Declerck P, Thomas D. Evaluation of serum cytokines and acute phase proteins as possible pharmacodynamic biomarkers to monitor endoscopic remission during ustekinumab therapy in patients with Crohn's disease. Therap Adv Gastroenterol 2023; 16:17562848231189110. [PMID: 37655059 PMCID: PMC10467236 DOI: 10.1177/17562848231189110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 07/04/2023] [Indexed: 09/02/2023] Open
Abstract
Background Since not all Crohn's disease (CD) patients respond adequately to ustekinumab therapy, biomarkers could aid to monitor treatment response and optimize therapeutic outcomes. Objectives To explore the dynamics of serum biomarker concentrations to monitor the response to ustekinumab treatment in CD patients. Design Retrospective, exploratory study to evaluate concentrations of serum cytokines and acute phase proteins and their relation to endoscopic remission in CD patients during ustekinumab treatment. Methods Serum concentrations of 16 proteins including cytokines and acute phase proteins were measured using the Mesoscale Discovery Platform in serum of healthy controls (n = 13), and CD patients (n = 61) at baseline (week 0), week 8 and week 24 during ustekinumab treatment. Endoscopic remission was defined as simple endoscopic score for CD (SES-CD) <3 after 6 months of therapy. Results Absolute concentrations of serum amyloid A protein (SAA; week 8), IL-6 (week 24), AGP (weeks 8 and 24), interferon (IFN)-γ (weeks 8 and 24), lipopolysaccharide binding protein (LBP; weeks 8 and 24) and IL-22 (weeks 8 and 24) were significantly lower in endoscopic remitters compared to non-responders (p-values ranging between <0.001 and <0.05). SAA (week 8) and AGP (week 24) were the biomarkers with the highest area under the ROC curve (AUROC; 0.761 and 0.760, respectively) for identifying patients in endoscopic remission, though their performance was not superior to C-reactive protein (CRP) or faecal calprotectin. AUROCs of the predictive probability of biomarker combinations showed superiority in discriminating endoscopic remitters from non-responders in comparison to single biomarker measurements, but not as compared to faecal calprotectin. Conclusion Although not superior to faecal calprotectin, measurement of AGP, SAA, LBF, IFN-γ, IL-6 and IL-22 concentrations, and combinations thereof with or without CRP and faecal calprotectin, during ustekinumab therapy might contribute to adequate monitoring of treatment response in CD patients.
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Affiliation(s)
- Nathalie Van den Berghe
- Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Dahham Alsoud
- Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Bram Verstockt
- Tranational Research in Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium – Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium – Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Paul Declerck
- Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Debby Thomas
- Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Campus Gasthuisberg O&N2, PB 820, Herestraat 49, Leuven, B-3000, Belgium
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den Hartigh LJ, May KS, Zhang XS, Chait A, Blaser MJ. Serum amyloid A and metabolic disease: evidence for a critical role in chronic inflammatory conditions. Front Cardiovasc Med 2023; 10:1197432. [PMID: 37396595 PMCID: PMC10311072 DOI: 10.3389/fcvm.2023.1197432] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 05/15/2023] [Indexed: 07/04/2023] Open
Abstract
Serum amyloid A (SAA) subtypes 1-3 are well-described acute phase reactants that are elevated in acute inflammatory conditions such as infection, tissue injury, and trauma, while SAA4 is constitutively expressed. SAA subtypes also have been implicated as playing roles in chronic metabolic diseases including obesity, diabetes, and cardiovascular disease, and possibly in autoimmune diseases such as systemic lupus erythematosis, rheumatoid arthritis, and inflammatory bowel disease. Distinctions between the expression kinetics of SAA in acute inflammatory responses and chronic disease states suggest the potential for differentiating SAA functions. Although circulating SAA levels can rise up to 1,000-fold during an acute inflammatory event, elevations are more modest (∼5-fold) in chronic metabolic conditions. The majority of acute-phase SAA derives from the liver, while in chronic inflammatory conditions SAA also derives from adipose tissue, the intestine, and elsewhere. In this review, roles for SAA subtypes in chronic metabolic disease states are contrasted to current knowledge about acute phase SAA. Investigations show distinct differences between SAA expression and function in human and animal models of metabolic disease, as well as sexual dimorphism of SAA subtype responses.
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Affiliation(s)
- Laura J. den Hartigh
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, United States
- Diabetes Institute, University of Washington, Seattle, WA, United States
| | - Karolline S. May
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, United States
- Diabetes Institute, University of Washington, Seattle, WA, United States
| | - Xue-Song Zhang
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, United States
| | - Alan Chait
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, United States
- Diabetes Institute, University of Washington, Seattle, WA, United States
| | - Martin J. Blaser
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, United States
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Perez-Diaz-del-Campo N, Castelnuovo G, Ribaldone DG, Caviglia GP. Fecal and Circulating Biomarkers for the Non-Invasive Assessment of Intestinal Permeability. Diagnostics (Basel) 2023; 13:1976. [PMID: 37296827 PMCID: PMC10253128 DOI: 10.3390/diagnostics13111976] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/01/2023] [Accepted: 06/03/2023] [Indexed: 06/12/2023] Open
Abstract
The study of intestinal permeability is gaining growing interest due to its relevance in the onset and progression of several gastrointestinal and non-gastrointestinal diseases. Though the involvement of impaired intestinal permeability in the pathophysiology of such diseases is recognized, there is currently a need to identify non-invasive biomarkers or tools that are able to accurately detect alterations in intestinal barrier integrity. On the one hand, promising results have been reported for novel in vivo methods based on paracellular probes, i.e., methods that can directly assess paracellular permeability and, on the other hand, on fecal and circulating biomarkers able to indirectly assess epithelial barrier integrity and functionality. In this review, we aimed to summarize the current knowledge on the intestinal barrier and epithelial transport pathways and to provide an overview of the methods already available or currently under investigation for the measurement of intestinal permeability.
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Affiliation(s)
| | | | | | - Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (N.P.-D.-d.-C.); (G.C.); (D.G.R.)
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15
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Chen R, Chen Q, Zheng J, Zeng Z, Chen M, Li L, Zhang S. Serum amyloid protein A in inflammatory bowel disease: from bench to bedside. Cell Death Discov 2023; 9:154. [PMID: 37164984 PMCID: PMC10172326 DOI: 10.1038/s41420-023-01455-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 05/12/2023] Open
Abstract
Inflammatory bowel diseases (IBD) is featured by gastrointestinal inflammation and a disease course with alternating recurrence and remission. The global burden caused by IBD has significantly boosted in recent years, necessitating treatment optimization. Serum amyloid A (SAA) is a class of 104 amino acid conservative acute-phase proteins, which is essential in immune-mediated inflammatory processes, like IBD. The SAA monomeric structure is composed of four α-helical regions and a C-terminal amorphous tail. Its disordered structure enables multiple bindings to different ligands and permits multiple functions. It has been proven that SAA has dual roles in the inflammatory process. SAA stimulates the pro-inflammatory cytokine expression and promotes the pathogenic differentiation of TH17 cells. In addition, SAA can remove toxic lipids produced during inflammatory responses and membrane debris from dead cells, redirect HDL, and recycle cholesterol for tissue repair. In IBD, SAA acts on gut epithelium barriers, induces T-cell differentiation, and promotes phagocytosis of Gram-negative bacteria. Owing to the tight connection between SAA and IBD, several clinical studies have taken SAA for a biomarker for diagnosis, assessing disease activity, and predicting prognosis in IBD. Furthermore, 5-MER peptide, a drug specifically targeting SAA, has shown anti-inflammatory effects in some SAA-dependent animal models, providing novel insights into the therapeutic targets of IBD.
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Affiliation(s)
- Rirong Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qia Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jieqi Zheng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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16
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Yang LL, Stiernborg M, Skott E, Xu J, Wu Y, Landberg R, Arefin S, Kublickiene K, Millischer V, Nilsson IAK, Schalling M, Giacobini M, Lavebratt C. Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD-A Randomized Controlled Trial. Nutrients 2023; 15:1293. [PMID: 36904292 PMCID: PMC10004766 DOI: 10.3390/nu15051293] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/23/2023] [Accepted: 02/27/2023] [Indexed: 03/08/2023] Open
Abstract
Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota-gut-brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1β-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels.
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Affiliation(s)
- Liu L. Yang
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Miranda Stiernborg
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
| | - Elin Skott
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
- PRIMA Child and Adult Psychiatry Stockholm AB, 163 74 Rinkeby, Sweden
| | - Jingjing Xu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
| | - Yujiao Wu
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Rikard Landberg
- Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden
| | - Samsul Arefin
- Division of Renal Medicine, Department of Clinical Science, Intervention & Technology, Karolinska Institutet, 141 52 Huddinge, Sweden
| | - Karolina Kublickiene
- Division of Renal Medicine, Department of Clinical Science, Intervention & Technology, Karolinska Institutet, 141 52 Huddinge, Sweden
| | - Vincent Millischer
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Ida A. K. Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
| | - Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
| | - MaiBritt Giacobini
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
- PRIMA Child and Adult Psychiatry Stockholm AB, 163 74 Rinkeby, Sweden
| | - Catharina Lavebratt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
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Roblin X, Serone A, Yoon OK, Zhuo, L, Grant E, Woo J, Liu J, Galien R, D’Haens G. Effects of JAK1-Preferential Inhibitor Filgotinib on Circulating Biomarkers and Whole Blood Genes/Pathways of Patients With Moderately to Severely Active Crohn's Disease. Inflamm Bowel Dis 2022; 28:1207-1218. [PMID: 34741617 PMCID: PMC9340524 DOI: 10.1093/ibd/izab253] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Pro-inflammatory cytokines are dysregulated in Crohn's disease (CD) and could serve as surrogate markers to improve diagnostic and therapeutic approaches, potentially addressing an unmet need. We profiled circulating biomarkers and whole blood transcriptional pathway activity to identify those associated with CD using data from the phase 2 FITZROY study with filgotinib, an oral preferential janus kinase-1 inhibitor. METHODS Patients with serum and whole blood samples taken from the induction period were included. Serum cytokines were measured (ELISA), whole blood RNA sequenced, and stool samples taken to measure fecal calprotectin (FC). Spearman's Rank correlations were assessed between biomarkers and baseline disease activity; post-treatment endoscopic improvement was measured by the Simplified Endoscopy Score for CD (SES-CD), FC and the Crohn's Disease Activity Index. Effect of filgotinib on circulating biomarkers was also evaluated. RESULTS Serum biomarkers (n = 168) and whole blood RNA sequencing (n = 104) were assessed. Moderate correlation between serum analytes with SES-CD and FC was noted; most highly correlated were acute phase proteins CRP (rho = 0.35 [SES-CD] and 0.47 [FC]), serum amyloid A (rho = 0.40 and 0.39, respectively) and pro-inflammatory cytokines interleukin (IL)-6 (rho = 0.31 and 0.30, respectively), IL-22 (rho = 0.36 and 0.35, respectively), and oncostatin M (rho = 0.35 and 0.33, respectively). Filgotinib treatment was associated with reduction of many candidate biomarkers, particularly in patients with treatment response. Early changes in IL-6 and IL-10 may be prognostic for endoscopic response. CONCLUSIONS Several circulating factors with potential as CD activity biomarkers were identified. Larger studies are necessary to investigate the best utility of these markers for CD.
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Affiliation(s)
- Xavier Roblin
- Gastroenterology Unit, University Hospital of Saint Etienne, Saint-Priest-en-Jarez, France
| | | | | | | | | | - Jacky Woo
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | | | - Geert D’Haens
- Inflammatory Bowel Disease Centre, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands
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Comparison of Inflammatory Cytokine Levels between Single-Port and Three-Port Thoracoscopic Lobectomy in the Treatment of Non-Small-Cell Lung Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3240252. [PMID: 36033577 PMCID: PMC9402300 DOI: 10.1155/2022/3240252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/02/2022] [Accepted: 07/09/2022] [Indexed: 12/24/2022]
Abstract
Introduction Thoracoscopic minimally invasive surgery is the main method for the treatment of lung cancer. The reduction of surgical trauma can effectively reduce the intraoperative and postoperative inflammatory reaction. The aim of the study is to compare the intraoperative and postoperative inflammatory reactions in patients with non-small-cell lung cancer (NSCLC) treated by single-port thoracoscopic surgery and three-port thoracoscopic surgery. Methods A total of 68 NSCLC patients (stages I and II) of thoracoscopic surgery were selected and randomly divided into two groups where they received either single-port thoracoscopic surgery or three-port thoracoscopic surgery. Intraoperative and postoperative serum inflammatory markers (C-reactive protein, CRP; serum amyloid A protein, SAA; and interleukin 6, IL-6) were detected using the enzyme-linked immunosorbent assay. Results The CRP level of the single-port group was significantly lower than that of the three-port group during surgery, the first day after surgery, and third day after surgery (P < 0.05). The level of IL-6 in the single-port group was significantly lower than that in the three-port group during surgery on the first and third days after surgery (P < 0.05). The level of SAA in the single-port group was also significantly lower than that in the three-port group on the first and third days after surgery (P < 0.05). Conclusion Compared with three-port thoracoscopic surgery, single-port thoracoscopic surgery could reduce the inflammatory response and improve the recovery of NSCLC patients. Single-port thoracoscopic surgery is worthy of further promotion in the current treatment field of NSCLC in terms of reducing intraoperative and postoperative inflammatory reactions.
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The Proteomic Signature of Intestinal Acute Rejection in the Mouse. Metabolites 2021; 12:metabo12010023. [PMID: 35050145 PMCID: PMC8780989 DOI: 10.3390/metabo12010023] [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: 10/30/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 12/04/2022] Open
Abstract
Intestinal acute rejection (AR) lacks a reliable non-invasive biomarker and AR surveillance is conducted through frequent endoscopic biopsies. Although citrulline and calprotectin have been suggested as AR biomarkers, these have limited clinical value. Using a mouse model of intestinal transplantation (ITx), we performed a proteome-wide analysis and investigated rejection-related proteome changes that may eventually be used as biomarkers. ITx was performed in allogenic (Balb/C to C57Bl) and syngeneic (C57Bl) combinations. Graft samples were obtained three and six days after transplantation (n = 4/time point) and quantitative proteomic analysis with iTRAQ-labeling and mass spectrometry of whole tissue homogenates was performed. Histology showed moderate AR in all allografts post-transplantation at day six. Nine hundred and thirty-eight proteins with at least three unique peptides were identified in the intestinal grafts. Eighty-six proteins varying by >20% between time points and/or groups had an alteration pattern unique to the rejecting allografts: thirty-seven proteins and enzymes (including S100-A8 and IDO-1) were significantly upregulated whereas forty-nine (among other chromogranin, ornithine aminotransferase, and arginase) were downregulated. Numerous proteins showed altered expression during intestinal AR, several of which were previously identified to be involved in acute rejection, although our results also identified previously unreported proteome changes. The metabolites and downstream metabolic pathways of some of these proteins and enzymes may become potential biomarkers for intestinal AR.
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Mitselos IV, Fousekis FS, Lamouri C, Katsanos KH, Christodoulou DK. Current noninvasive modalities in Crohn's disease monitoring. Ann Gastroenterol 2021; 34:770-780. [PMID: 34815642 PMCID: PMC8596218 DOI: 10.20524/aog.2021.0648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/16/2021] [Indexed: 12/01/2022] Open
Abstract
Crohn’s disease (CD) is characterized by a remitting and relapsing course. Longstanding active CD may result in accumulating intestinal damage and disease-related complications. In contrast, mucosal healing is associated with significant improvement in the health-related quality of life, longer periods of disease remission and lower risk of disease progression, complications, hospitalizations, intestinal surgeries, as well as a lower risk of developing colorectal cancer. Mucosal healing, the new treatment endpoint in CD, made necessary the development of noninvasive, accurate, objective and reliable tools for the evaluation of CD activity. Ileocolonoscopy with biopsies remains the reference standard method for the evaluation of the colonic and terminal ileal mucosa. However, it is an invasive procedure with a low risk of complications, allowing the investigation of only a small part of the small bowel mucosa without being able to assess transmural inflammation. These disadvantages limit its role in the frequent follow up of CD patients. In this review, we present the currently available biomarkers and imaging modalities for the noninvasive assessment of CD activity.
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Affiliation(s)
- Ioannis V Mitselos
- Department of Gastroenterology, General Hospital of Ioannina (Ioannis V. Mitselos)
| | - Fotios S Fousekis
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina (Fotios S. Fousekis, Charikleia Lamouri, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece
| | - Charikleia Lamouri
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina (Fotios S. Fousekis, Charikleia Lamouri, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece
| | - Konstantinos H Katsanos
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina (Fotios S. Fousekis, Charikleia Lamouri, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece
| | - Dimitrios K Christodoulou
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina (Fotios S. Fousekis, Charikleia Lamouri, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece
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21
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Tang Y, Ling N, Li S, Huang J, Zhang W, Zhang A, Ren H, Yang Y, Hu H, Wang X. A panel of urine-derived biomarkers to identify sepsis and distinguish it from systemic inflammatory response syndrome. Sci Rep 2021; 11:20794. [PMID: 34675320 PMCID: PMC8531286 DOI: 10.1038/s41598-021-99595-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 09/15/2021] [Indexed: 11/10/2022] Open
Abstract
Sepsis is a potentially fatal condition caused by infection. It is frequently difficult to distinguish sepsis from systemic inflammatory response syndrome (SIRS), often resulting in poor prognoses and the misuse of antibiotics. Hence, highly sensitive and specific biomarkers are needed to differentiate sepsis from SIRS. Urine samples were collected and segregated by group (a sepsis group, a SIRS group, and a healthy control group). iTRAQ was used to identify the differentially expressed proteins among the three groups. The identified proteins were measured by ELISA in urine samples. Finally, all the acquired data were analyzed in SPSS. C-reactive protein, leucine-rich alpha glycoprotein-1 and serum amyloid A (SAA) protein were differentially expressed among the three groups. The adjusted median concentrations of urinary C-reactive protein were 1337.6, 358.7, and 2.4 in the sepsis, SIRS, and healthy control groups, respectively. The urinary leucine-rich alpha glycoprotein-1 levels in these three groups were 1614.4, 644.5, and 13.6, respectively, and the levels of SAA were 6.3, 2.9, and 0.07, respectively. For all three of these measures, the sepsis group had higher levels than the SIRS group (P < 0.001), and the SIRS group had higher levels than the healthy control group. When combined, the three biomarkers had a sensitivity of 0.906 and a specificity of 0.896 in distinguishing sepsis from SIRS. Urinary C-reactive protein, urinary leucine-rich alpha glycoprotein-1 and urinary SAA have diagnostic value in cases of sepsis. This initial study suggests the possibility of improved differential diagnosis between sepsis and systemic inflammatory response syndrome; additional confirmation is necessary to corroborate the findings.
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Affiliation(s)
- Yao Tang
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shiying Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Juan Huang
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wenyue Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - An Zhang
- Intensive Care Unit, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yixuan Yang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Huaidong Hu
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiaohao Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
- Department of Clinical Nutrition, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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22
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Davis TA, Conradie D, Shridas P, de Beer FC, Engelbrecht AM, de Villiers WJS. Serum Amyloid A Promotes Inflammation-Associated Damage and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer. Cell Mol Gastroenterol Hepatol 2021; 12:1329-1341. [PMID: 34217896 PMCID: PMC8463861 DOI: 10.1016/j.jcmgh.2021.06.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Identifying new approaches to lessen inflammation, as well as the associated malignant consequences, remains crucial to improving the lives and prognosis of patients diagnosed with inflammatory bowel diseases. Although it previously has been suggested as a suitable biomarker for monitoring disease activity in patients diagnosed with Crohn's disease, the role of the acute-phase protein serum amyloid A (SAA) in inflammatory bowel disease remains unclear. In this study, we aimed to assess the role of SAA in colitis-associated cancer. METHODS We established a model of colitis-associated cancer in wild-type and SAA double-knockout (Saa1/2-/-) mice by following the azoxymethane/dextran sulfate sodium protocol. Disease activity was monitored throughout the study while colon and tumor tissues were harvested for subsequent use in cytokine analyses, Western blot, and immunohistochemistry +experiments. RESULTS We observed attenuated disease activity in mice deficient for Saa1/2 as evidenced by decreased weight loss, increased stool consistency, decreased rectal bleeding, and decreased colitis-associated tissue damage. Macrophage infiltration, including CD206+ M2-like macrophages, also was attenuated in SAA knockout mice, while levels of interleukin 4, interleukin 10, and tumor necrosis factor-ɑ were decreased in the distal colon. Mice deficient for SAA also showed a decreased tumor burden, and tumors were found to have increased apoptotic activity coupled with decreased expression for markers of proliferation. CONCLUSION Based on these findings, we conclude that SAA has an active role in inflammatory bowel disease and that it could serve as a therapeutic target aimed at decreasing chronic inflammation and the associated risk of developing colitis-associated cancer.
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Affiliation(s)
| | | | - Preetha Shridas
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky
| | - Frederick C de Beer
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences; African Cancer Institute, Department of Global Health
| | - Willem J S de Villiers
- African Cancer Institute, Department of Global Health; Department of Internal Medicine, Stellenbosch University, Stellenbosch, South Africa.
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Shi L, Lu BL, Qiu Y, Huang L, Huang SY, Mao R, Lin JJ, Du JF, Feng ST, Li ZP, Sun CH, Li XH. Hepatic mosaic enhancement pattern correlates with increased inflammatory activity and adverse therapeutic outcomes in patients with Crohn's disease. Abdom Radiol (NY) 2021; 46:3149-3158. [PMID: 33646351 DOI: 10.1007/s00261-021-02979-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/25/2021] [Accepted: 02/09/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE This study aimed to evaluate the role of hepatic mosaic enhancement pattern (HMEP) on computed tomography images in the disease activity and therapeutic outcome of Crohn's Disease (CD). METHODS Twenty-five CD patients with HMEP comprised the HMEP group, and 25 CD patients without HMEP, who had a similar onset age, sex, and disease course with those in the HMEP group, comprised the non-HMEP group. No underlying liver/biliary disease was observed in any of the patients. Clinical characteristics, laboratory test results, Lémann index, and CD endoscopic index of severity (CDEIS) were compared between the groups using the Student t-, Mann-Whitney U, Chi square, or Fisher's exact tests. Patients received top-down, step-up, or traditional treatment during the follow-up period. After the 1-year follow-up, therapeutic outcomes (active inflammation [CDEIS > 3.5 if the endoscopic data were available, or C-reactive protein level > 5 mg/L if the endoscopic data were unavailable] or remission) were evaluated. RESULTS The occurrence rate of fistulas/abscesses was higher in the HMEP group (84%, 21/25) than in the non-HMEP group (48%, 12/25) with no statistical significance (P = 0.056). The HMEP group showed a higher C-reactive protein level (P = 0.001), erythrocyte sedimentation rate (P = 0.013), and blood platelet count (P = 0.005). There was no significant difference in therapeutic strategies between the groups (P = 0.509). The HMEP group showed a significantly lower remission ratio after anti-inflammatory treatment than the non-HMEP group (P = 0.045). CONCLUSIONS HMEP was correlated with increased inflammatory activity and adverse therapeutic outcomes in CD. This finding provided insights regarding novel markers of CD diagnosis and treatment.
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Affiliation(s)
- Li Shi
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
- Department of Radiology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150, People's Republic of China
| | - Bao-Lan Lu
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Li Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Si-Yun Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Jin-Jiang Lin
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Jin-Fang Du
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Zi-Ping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Can-Hui Sun
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.
| | - Xue-Hua Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.
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24
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Fritsch J, Garces L, Quintero MA, Pignac-Kobinger J, Santander AM, Fernández I, Ban YJ, Kwon D, Phillips MC, Knight K, Mao Q, Santaolalla R, Chen XS, Maruthamuthu M, Solis N, Damas OM, Kerman DH, Deshpande AR, Lewis JE, Chen C, Abreu MT. Low-Fat, High-Fiber Diet Reduces Markers of Inflammation and Dysbiosis and Improves Quality of Life in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol 2021; 19:1189-1199.e30. [PMID: 32445952 DOI: 10.1016/j.cgh.2020.05.026] [Citation(s) in RCA: 191] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/12/2020] [Accepted: 05/14/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS A high-fat diet has been associated with an increased risk of ulcerative colitis (UC). We studied the effects of a low-fat, high-fiber diet (LFD) vs an improved standard American diet (iSAD, included higher quantities of fruits, vegetables, and fiber than a typical SAD). We collected data on quality of life, markers of inflammation, and fecal markers of intestinal dysbiosis in patients with UC. METHODS We analyzed data from a parallel-group, cross-over study of 17 patients with UC in remission or with mild disease (with a flare within the past 18 mo), from February 25, 2015, through September 11, 2018. Participants were assigned randomly to 2 groups and received a LFD (10% of calories from fat) or an iSAD (35%-40% of calories from fat) for the first 4-week period, followed by a 2-week washout period, and then switched to the other diet for 4 weeks. All diets were catered and delivered to patients' homes, and each participant served as her or his own control. Serum and stool samples were collected at baseline and week 4 of each diet and analyzed for markers of inflammation. We performed 16s ribosomal RNA sequencing and untargeted and targeted metabolomic analyses on stool samples. The primary outcome was quality of life, which was measured by the short inflammatory bowel disease (IBD) questionnaire at baseline and week 4 of the diets. Secondary outcomes included changes in the Short-Form 36 health survey, partial Mayo score, markers of inflammation, microbiome and metabolome analysis, and adherence to the diet. RESULTS Participants' baseline diets were unhealthier than either study diet. All patients remained in remission throughout the study period. Compared with baseline, the iSAD and LFD each increased quality of life, based on the short IBD questionnaire and Short-Form 36 health survey scores (baseline short IBD questionnaire score, 4.98; iSAD, 5.55; LFD, 5.77; baseline vs iSAD, P = .02; baseline vs LFD, P = .001). Serum amyloid A decreased significantly from 7.99 mg/L at baseline to 4.50 mg/L after LFD (P = .02), but did not decrease significantly compared with iSAD (7.20 mg/L; iSAD vs LFD, P = .07). The serum level of C-reactive protein decreased numerically from 3.23 mg/L at baseline to 2.51 mg/L after LFD (P = .07). The relative abundance of Actinobacteria in fecal samples decreased from 13.69% at baseline to 7.82% after LFD (P = .017), whereas the relative abundance of Bacteroidetes increased from 14.6% at baseline to 24.02% on LFD (P = .015). The relative abundance of Faecalibacterium prausnitzii was higher after 4 weeks on the LFD (7.20%) compared with iSAD (5.37%; P = .04). Fecal levels of acetate (an anti-inflammatory metabolite) increased from a relative abundance of 40.37 at baseline to 42.52 on the iSAD and 53.98 on the LFD (baseline vs LFD, P = .05; iSAD vs LFD, P = .09). The fecal level of tryptophan decreased from a relative abundance of 1.33 at baseline to 1.08 on the iSAD (P = .43), but increased to a relative abundance of 2.27 on the LFD (baseline vs LFD, P = .04; iSAD vs LFD, P = .08); fecal levels of lauric acid decreased after LFD (baseline, 203.4; iSAD, 381.4; LFD, 29.91; baseline vs LFD, P = .04; iSAD vs LFD, P = .02). CONCLUSIONS In a cross-over study of patients with UC in remission, we found that a catered LFD or iSAD were each well tolerated and increased quality of life. However, the LFD decreased markers of inflammation and reduced intestinal dysbiosis in fecal samples. Dietary interventions therefore might benefit patients with UC in remission. ClinicalTrials.gov no: NCT04147598.
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Affiliation(s)
- Julia Fritsch
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Luis Garces
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Maria A Quintero
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Judith Pignac-Kobinger
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Ana M Santander
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Irina Fernández
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Yuguang J Ban
- Sylvester Comprehensive Cancer Center, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Deukwoo Kwon
- Sylvester Comprehensive Cancer Center, University of Miami-Leonard Miller School of Medicine, Miami, Florida; Division of Biostatistics, Department of Public Health Sciences, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Matthew C Phillips
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Karina Knight
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Qingqing Mao
- Department of Food Science and Nutrition, University of Minnesota, St Paul, Minnesota
| | - Rebeca Santaolalla
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Xi S Chen
- Sylvester Comprehensive Cancer Center, University of Miami-Leonard Miller School of Medicine, Miami, Florida; Division of Biostatistics, Department of Public Health Sciences, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Mukil Maruthamuthu
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Norma Solis
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Oriana M Damas
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - David H Kerman
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Amar R Deshpande
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - John E Lewis
- Department of Psychiatry and Behavioral Sciences, University of Miami-Leonard Miller School of Medicine, Miami, Florida
| | - Chi Chen
- Department of Food Science and Nutrition, University of Minnesota, St Paul, Minnesota
| | - Maria T Abreu
- Division of Gastroenterology, Department of Medicine, University of Miami-Leonard Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami-Leonard Miller School of Medicine, Miami, Florida.
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Postoperative Ratio of C-Reactive Protein to Albumin as a Predictive Marker in Patients with Crohn's Disease Undergoing Bowel Resection. Gastroenterol Res Pract 2021; 2021:6629608. [PMID: 33727917 PMCID: PMC7936899 DOI: 10.1155/2021/6629608] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/08/2021] [Accepted: 02/14/2021] [Indexed: 01/08/2023] Open
Abstract
Background The ratio of C-reactive protein (CRP) to albumin (CAR) has a significant correlation with postoperative complications and acts as a predictor in patients with pancreatic cancer and colorectal cancer. However, whether the CAR can be used to predict complications in Crohn's disease (CD) patients after surgery has not yet been reported. Methods A total of 534 CD patients undergoing surgery between 2016 and 2020 were enrolled. The risk factors of postoperative complications were assessed by univariate and multivariate analyses. The cutoff values and the accuracy of diagnosis for the CAR and postoperative CRP levels were examined with receiver operating characteristic (ROC) curves. Results The rate of postoperative complications was 32.2%. The postoperative CAR (OR 13.200; 95% CI 6.501-26.803; P < 0.001) was a significant independent risk factor for complications. Compared with the CRP level on postoperative day 3, the CAR more accurately indicated postoperative complications in CD patients (AUC: 0.699 vs. 0.771; Youden index: 0.361 vs. 0.599). ROC curves showed that the cutoff value for the CAR was 3.25. Patients with a CAR ≥ 3.25 had more complications (P < 0.001), a longer postoperative stay (15.5 ± 0.6 d vs. 9.0 ± 0.2 d, P < 0.001), and more surgical site infections (48.2% vs. 5.7%, P < 0.001) than those with a CAR < 3.25. Conclusions Compared to the CRP level, the CAR can more accurately predict postoperative complications and can act as a predictive marker in CD patients after surgery.
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Yang LL, Stiernborg M, Skott E, Söderström Å, Giacobini M, Lavebratt C. Proinflammatory mediators and their associations with medication and comorbid traits in children and adults with ADHD. Eur Neuropsychopharmacol 2020; 41:118-131. [PMID: 33160793 DOI: 10.1016/j.euroneuro.2020.10.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/24/2020] [Accepted: 10/16/2020] [Indexed: 12/25/2022]
Abstract
Peripheral immune activation can influence neurodevelopment and is increased in autism, but is less explored in attention deficit hyperactivity disorder (ADHD). Patients with ADHD often display comorbid autism traits and gastrointestinal (GI) symptoms. Plasma protein levels of two acute phase reactants, C-reactive protein (CRP) and serum amyloid A (SAA), and two endothelial adhesion molecules, soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1), which share important roles in inflammation, were analyzed in 154 patients with ADHD and 61 healthy controls. Their associations with ADHD diagnosis, severity, medication and comorbid autistic symptoms, emotion dysregulation and GI symptoms were explored. The ADHD patients had increased levels of sICAM-1 and sVCAM-1 compared to healthy controls (p = 8.6e-05, p = 6.9e-07, respectively). In children with ADHD, the sICAM-1 and sVCAM-1 levels were higher among those with ADHD medication than among children (p = 0.0037, p = 0.0053, respectively) and adults (p = 3.5e-09, p = 1.9e-09, respectively) without ADHD medication. Among the adult ADHD patients, higher sICAM-1 levels were associated with increased comorbid autistic symptoms in the domains attention to detail and imagination (p = 0.0081, p = 0.00028, respectively), and higher CRP levels were associated with more GI symptoms (p = 0.014). sICAM-1 and sVCAM-1 levels were highly correlated with each other, and so were CRP and SAA levels. To conclude, vascular inflammatory activity may be overrepresented in ADHD, with elevated sICAM-1 and sVCAM-1 levels and this may in children be a consequence of current ADHD medication, and in adults relate to increased comorbid autistic symptoms. Replication is warranted.
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Affiliation(s)
- Liu L Yang
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Miranda Stiernborg
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Elin Skott
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; PRIMA Child and Adult Psychiatry, Stockholm, Sweden
| | | | - MaiBritt Giacobini
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; PRIMA Child and Adult Psychiatry, Stockholm, Sweden
| | - Catharina Lavebratt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.
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Dragoni G, Innocenti T, Galli A. Biomarkers of Inflammation in Inflammatory Bowel Disease: How Long before Abandoning Single-Marker Approaches? Dig Dis 2020; 39:190-203. [PMID: 32942275 DOI: 10.1159/000511641] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 09/16/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronically relapsing disease with a continuous need for proactive monitoring to decide appropriate treatments and follow-up strategies. To date, gastrointestinal endoscopy with histologic examination of biopsies and contrast-enhanced imaging are mandatory techniques for the diagnosis and the activity assessment of IBD. SUMMARY In recent decades, many research efforts in the IBD field have been placed on finding non-invasive and reliable biomarkers of disease burden that can be easily tested in body fluids without impacting the quality of life of patients. Unfortunately, the ideal biomarker is yet to be discovered and recent studies have investigated the possibility to increase the accuracy of such measurements by combining different markers. In this review, we provide an update about the current knowledge on biomarkers of intestinal inflammation in IBD, focussing on disease diagnosis, correlation with endoscopic findings, and prediction of relapse. We also summarize composite scores of clinical and laboratory markers that have been recently proposed in various scenarios of disease activity. Key Messages: To date, only C-reactive protein and faecal calprotectin can be considered reliable markers of disease activity with demonstrated utility in IBD management. The combination of different parameters has recently shown higher accuracy and might substitute single-marker approaches in the future of research and clinical practice.
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Affiliation(s)
- Gabriele Dragoni
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy, .,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy, .,Department of Medical Biotechnologies, University of Siena, Siena, Italy,
| | - Tommaso Innocenti
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy.,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
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Vidal-Lletjós S, Khodorova NV, Piscuc M, Gaudichon C, Blachier F, Lan A. Tissue-specific effect of colitis on protein synthesis in mice: impact of the dietary protein content. Eur J Nutr 2020; 60:1669-1677. [PMID: 32808061 DOI: 10.1007/s00394-020-02365-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 08/10/2020] [Indexed: 01/17/2023]
Abstract
PURPOSE Inflammatory bowel diseases are associated with an increase in the whole-body protein turnover, thus possibly requiring an additional supply of dietary proteins. Our aim was to evaluate whether increasing dietary protein content could alleviate protein metabolism alterations in the injured splanchnic and peripheral tissues during colitis and spontaneous mucosal healing. METHODS Mice with acute chemically induced colitis received either a normal protein (P14, 14% as energy), a moderately (P30, 30%) and a very high-protein (P53, 55%) diets. At different times after the challenge, protein synthesis rate was determined in tissues using a flooding dose of 13C valine. RESULTS Colon, liver and spleen protein synthesis rates were significantly increased after colitis induction, while being decreased in the caecum, kidneys and muscle. Contrastingly to the two other diets, P30 diet consumption allowed faster recovery of the animals, and this coincided with a rapid resaturation of the initial protein synthesis in the colon. In the other tissues studied, the high-protein diets show different effects depending on the dietary protein content consumed and on the examined tissues, with a general trend of P53 in lowering anabolism rates. CONCLUSION This study highlights the severe impact of acute colonic inflammation on protein metabolism in different organs. In addition, dietary protein content modulated the recovery of the initial protein synthesis rate in the various tissues following colitis induction. P30 diet consumption notably showed a better ability to alleviate protein metabolism perturbations induced by colitis, that may explain its documented beneficial effect on colon mucosal healing.
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Affiliation(s)
- Sandra Vidal-Lletjós
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Equipe Apports protéiques et Adaptations Intestinales, 16 rue Claude Bernard, 75005, Paris, France
| | - Nadezda V Khodorova
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Equipe Apports protéiques et Adaptations Intestinales, 16 rue Claude Bernard, 75005, Paris, France
| | - Maria Piscuc
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Equipe Apports protéiques et Adaptations Intestinales, 16 rue Claude Bernard, 75005, Paris, France
| | - Claire Gaudichon
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Equipe Apports protéiques et Adaptations Intestinales, 16 rue Claude Bernard, 75005, Paris, France
| | - François Blachier
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Equipe Apports protéiques et Adaptations Intestinales, 16 rue Claude Bernard, 75005, Paris, France
| | - Annaïg Lan
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, Equipe Apports protéiques et Adaptations Intestinales, 16 rue Claude Bernard, 75005, Paris, France.
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Schoultz I, Keita ÅV. The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability. Cells 2020; 9:1909. [PMID: 32824536 PMCID: PMC7463717 DOI: 10.3390/cells9081909] [Citation(s) in RCA: 285] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 02/08/2023] Open
Abstract
The intestinal barrier is essential in human health and constitutes the interface between the outside and the internal milieu of the body. A functional intestinal barrier allows absorption of nutrients and fluids but simultaneously prevents harmful substances like toxins and bacteria from crossing the intestinal epithelium and reaching the body. An altered intestinal permeability, a sign of a perturbed barrier function, has during the last decade been associated with several chronic conditions, including diseases originating in the gastrointestinal tract but also diseases such as Alzheimer and Parkinson disease. This has led to an intensified interest from researchers with diverse backgrounds to perform functional studies of the intestinal barrier in different conditions. Intestinal permeability is defined as the passage of a solute through a simple membrane and can be measured by recording the passage of permeability markers over the epithelium via the paracellular or the transcellular route. The methodological tools to investigate the gut barrier function are rapidly expanding and new methodological approaches are being developed. Here we outline and discuss, in vivo, in vitro and ex vivo techniques and how these methods can be utilized for thorough investigation of the intestinal barrier.
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Affiliation(s)
- Ida Schoultz
- Faculty of Medicine and Health, School of Medical Sciences, Örebro University, 703 62 Örebro, Sweden;
| | - Åsa V. Keita
- Department of Biomedical and Clinical Sciences, Linköping University, 581 85 Linköping, Sweden
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30
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Sato N, Yuzawa M, Aminul MI, Tomokiyo M, Albarracin L, Garcia-Castillo V, Ideka-Ohtsubo W, Iwabuchi N, Xiao JZ, Garcia-Cancino A, Villena J, Kitazawa H. Evaluation of Porcine Intestinal Epitheliocytes as an In vitro Immunoassay System for the Selection of Probiotic Bifidobacteria to Alleviate Inflammatory Bowel Disease. Probiotics Antimicrob Proteins 2020; 13:824-836. [PMID: 32779098 DOI: 10.1007/s12602-020-09694-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The use of in vitro systems that allow efficient selection of probiotic candidates with immunomodulatory properties could significantly minimize the use of experimental animals. In this work, we generated an in vitro immunoassay system based on porcine intestinal epithelial (PIE) cells and dextran sodium sulfate (DSS) administration that could be useful for the selection and characterization of potential probiotic strains to be used in inflammatory bowel disease (IBD) patients. Our strategy was based on two fundamental pillars: on the one hand, the capacity of PIE cells to create a monolayer by attaching to neighboring cells and efficiently mount inflammatory responses and, on the other hand, the use of two probiotic bifidobacteria strains that have been characterized in terms of their immunomodulatory capacities, particularly in mouse IBD models and patients. Our results demonstrated that DSS administration can alter the epithelial barrier created in vitro by PIE cells and induce a potent inflammatory response, characterized by increases in the expression levels of several inflammatory factors including TNF-α, IL-1α, CCL4, CCL8, CCL11, CXCL5, CXCL9, CXCL10, SELL, SELE, EPCAM, VCAM, NCF2, and SAA2. In addition, we demonstrated that Bifidobacterium breve M-16V and B. longum BB536 are able to regulate the C-jun N-terminal kinase (JNK) intracellular signalling pathway, reducing the DSS-induced alterations of the in vitro epithelial barrier and differentially regulating the inflammatory response in a strain-dependent fashion. The good correlation between our in vitro findings in PIE cells and previous studies in animal models and IBD patients shows the potential value of our system to select new probiotic candidates in an efficient way.
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Affiliation(s)
- Nana Sato
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Mao Yuzawa
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Md Islam Aminul
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Mikado Tomokiyo
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Leonardo Albarracin
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), San Miguel de Tucuman, Tucuman, Argentina.,Laboratory of Computing Science, Faculty of Exact Sciences and Technology, Tucuman University, San Miguel de Tucuman, Tucuman, Argentina
| | - Valeria Garcia-Castillo
- Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Wakako Ideka-Ohtsubo
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Noriyuki Iwabuchi
- Food Science and Technology Institute, Morinaga Milk Industry Co. Ltd, Zama, Kanagawa, Japan
| | - Jin-Zhong Xiao
- Food Science and Technology Institute, Morinaga Milk Industry Co. Ltd, Zama, Kanagawa, Japan
| | - Apolinaria Garcia-Cancino
- Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Julio Villena
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan. .,Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), San Miguel de Tucuman, Tucuman, Argentina.
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan. .,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
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31
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Brand EC, Elias SG, Minderhoud IM, van der Veen JJ, Baert FJ, Laharie D, Bossuyt P, Bouhnik Y, Buisson A, Lambrecht G, Louis E, Pariente B, Pierik MJ, van der Woude CJ, D'Haens GRAM, Vermeire S, Oldenburg B. Systematic Review and External Validation of Prediction Models Based on Symptoms and Biomarkers for Identifying Endoscopic Activity in Crohn's Disease. Clin Gastroenterol Hepatol 2020; 18:1704-1718. [PMID: 31881273 DOI: 10.1016/j.cgh.2019.12.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 12/02/2019] [Accepted: 12/13/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Endoscopic healing, an important target of treatment for Crohn's disease (CD), requires ileocolonoscopy, which is costly and burdensome. We investigated whether published noninvasive models (based on symptoms and biomarkers) to evaluate CD activity have sufficient accuracy to replace ileocolonoscopy. METHODS We performed a systematic review of published noninvasive diagnostic models to evaluate CD activity that used endoscopic features of activity (endoscopic activity) or healing as the reference standard. We externally validated these models for the outcome endoscopic activity (CD endoscopic index of severity scores, ≥3) using data from the a randomized controlled trial investigating tailored treatment with infliximab for active luminal Crohn's disease (TAILORIX) study (346 ileocolonoscopies in 155 patients) and the Utrecht Activity Index (UAI) study (93 ileocolonoscopies in 82 patients). We calculated the area under the receiver operating characteristic curves (AUROCs) for the models using data from these studies, and compared the performance of these models against measurements of fecal calprotectin (FC) and C-reactive protein (CRP). RESULTS We screened 5303 articles and identified 27 models (from 21 studies) for our analysis. Seven models could be validated externally; in the TAILORIX data set, these models identified patients with endoscopic activity with AUROC values ranging from 0.61 (95% CI, 0.51-0.70) to 0.81 (95% CI, 0.76-0.86). In this data set, the AUROC value for FC concentration was 0.79 (95% CI, 0.74-0.85) and the AUROC value for CRP level was 0.72 (95% CI, 0.66-0.77). The AUROC values for the validation in the UAI data set were similar. In the TAILORIX and/or UAI data set, 4 of the 7 models, as well as the FC and CRP assays, were able to identify patients with endoscopic activity with positive predictive values of 90% or more. Two of the 7 models (but not the FC or CRP values) identified patients without endoscopic activity with a negative predictive value (NPV) of 90% or more, leading to correct prediction of endoscopic healing in 3.2% to 11.3% of all patients. For example, applying the Herranz-Bachiller model (1 of 7 models) at a NPV of 92.1% and a positive predictive value of 91.9% correctly identified 35.7% of all patients in whom ileocolonoscopy could be avoided for expected endoscopic activity or healing but incorrectly identified 3.2% of all patients. Most ileocolonoscopies (66.5% in TAILORIX and 72.6% in the UAI of all ileocolonoscopies) could be avoided correctly based on concentrations of FC of 100 μg/g or less and 250 μg/g or higher. However, using this range of FC concentrations to identify patients who do not require ileocolonoscopy caused 18.7% of all patients in the TAILORIX cohort and 19.8% of all patients in the UAI cohort to be predicted incorrectly to have endoscopic activity or healing. CONCLUSIONS In a systematic review and external validation of noninvasive models to identify patients with endoscopic activity of CD, we found only 2 of 7 models evaluated to have NPVs of 90% or more, however, leading to correctly predicted EH in only a small proportion of patients. Ileocolonoscopy therefore remains the mainstay to evaluate CD mucosal disease activity and healing.
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Affiliation(s)
- Eelco C Brand
- Department of Gastroenterology and Hepatology, Utrecht, The Netherlands; Center for Translational Immunology, Utrecht, The Netherlands
| | - Sjoerd G Elias
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Itta M Minderhoud
- Department of Gastroenterology and Hepatology, Tergooi Hospitals, Blaricum/Hilversum, The Netherland
| | | | - Filip J Baert
- Department of Gastroenterology, AZ Delta, Roeselare, Belgium
| | - David Laharie
- Service d'Hépato-gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, Bordeaux, France
| | - Peter Bossuyt
- Inflammatory Bowel Disease Clinic, Imelda General Hospital, Bonheiden, Belgium
| | - Yoram Bouhnik
- Department of Gastroenterology, Beaujon Hospital, Assistance publique - Hôpitaux de Paris (APHP), Paris Diderot University, Clichy, France
| | - Anthony Buisson
- Department of Gastroenterology, Estaing University Hospital, Clermont-Ferrand, France
| | - Guy Lambrecht
- Department of Gastroenterology, Algemeen Ziekenhuis (AZ), Damiaan, Oostende, Belgium
| | - Edouard Louis
- Department of Gastroenterology, Liège University Hospital Centre Hospitalier Universitaire (CHU), Liège, Belgium
| | - Benjamin Pariente
- Department of Gastroenterology, Huriez Hospital, Lille 2 University, Lille, France
| | - Marieke J Pierik
- Department of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Geert R A M D'Haens
- Department of Gastroenterology, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Bas Oldenburg
- Department of Gastroenterology and Hepatology, Utrecht, The Netherlands.
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Krzystek-Korpacka M, Kempiński R, Bromke M, Neubauer K. Biochemical Biomarkers of Mucosal Healing for Inflammatory Bowel Disease in Adults. Diagnostics (Basel) 2020; 10:E367. [PMID: 32498475 PMCID: PMC7344443 DOI: 10.3390/diagnostics10060367] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/29/2020] [Accepted: 05/30/2020] [Indexed: 02/06/2023] Open
Abstract
Mucosal healing (MH) is the key therapeutic target of inflammatory bowel disease (IBD). The evaluation of MH remains challenging, with endoscopy being the golden standard. We performed a comprehensive overview of the performance of fecal-, serum-, and urine-based biochemical markers in colonic IBD to find out whether we are ready to replace endoscopy with a non-invasive but equally accurate instrument. A Pubmed, Web of Knowledge, and Scopus search of original articles as potential MH markers in adults, published between January 2009 and March 2020, was conducted. Finally, 84 eligible studies were identified. The most frequently studied fecal marker was calprotectin (44 studies), with areas under the curves (AUCs) ranging from 0.70 to 0.99 in ulcerative colitis (UC) and from 0.70 to 0.94 in Crohn`s disease (CD), followed by lactoferrin (4 studies), matrix metalloproteinase-9 (3 studies), and lipocalin-2 (3 studies). The most frequently studied serum marker was C-reactive protein (30 studies), with AUCs ranging from 0.60 to 0.96 in UC and from 0.64 to 0.93 in CD. Fecal calprotectin is an accurate MH marker in IBD in adults; however, it cannot replace endoscopy and the application of calprotectin is hampered by the lack of standardization concerning the cut-off value. Other markers are either not sufficiently accurate or have not been studied extensively enough.
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Affiliation(s)
| | - Radosław Kempiński
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Mariusz Bromke
- Department of Medical Biochemistry, Wroclaw Medical University, Chalubinskiego 10, 50-368 Wroclaw, Poland;
| | - Katarzyna Neubauer
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
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Association of serum interleukin-6 and soluble interleukin-2-receptor levels with disease activity status in patients with inflammatory bowel disease: A prospective observational study. PLoS One 2020; 15:e0233811. [PMID: 32470973 PMCID: PMC7259981 DOI: 10.1371/journal.pone.0233811] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/12/2020] [Indexed: 12/17/2022] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by overexpression of proinflammatory cytokines. We determined the association of serum levels of interleukin (IL)-6, soluble-IL-2-receptor (sIL-2R) and CRP as well as of faecal calprotectin (FC) values with disease activity in CD and UC patients. This prospective study included 145 CD and 84 UC patients. Serum proinflammatory biomarkers and FC levels were measured and demographic, clinical and endoscopic characteristics were collected. Uni- and multivariate statistical analyses were performed. Serum IL-6 and CRP levels as well as FC values of CD patients were associated with clinical and endoscopic remission. In multivariate analysis serum IL-6 levels remained significantly associated with clinical and endoscopic remission. FC levels were also associated with endoscopic remission in CD patients. CD patients under the threshold levels of 8.5 pg/mL and 5.5 pg/mL for serum IL-6 were in 70% and 66% in clinical and endoscopic remission, respectively. Serum sIL-2R, CRP levels and FC values of UC patients were associated in univariate analysis with clinical and endoscopic remission. In multivariate analysis CRP and FC values were associated with clinical remission and serum sIL-2R as well as FC levels with endoscopic remission. UC patients under the threshold levels of 759 IU/mL and 646 IU/mL for serum sIL-2R were in 76% and 76% in clinical and endoscopic remission, respectively. Beside CRP and FC, serum IL-6 levels in CD patients and sIL-2R levels in UC patients can be a further useful non-invasive biomarker to identify the disease activity status.
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Gobbetti T, Berger SB, Fountain K, Slocombe T, Rowles A, Pearse G, Harada I, Bertin J, Haynes AC, Beal AM. Receptor-interacting protein 1 kinase inhibition therapeutically ameliorates experimental T cell-dependent colitis in mice. Cell Death Dis 2020; 11:220. [PMID: 32249785 PMCID: PMC7136199 DOI: 10.1038/s41419-020-2423-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 01/07/2023]
Affiliation(s)
- Thomas Gobbetti
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
| | - Scott B Berger
- Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA, USA
| | - Kathryn Fountain
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, Hertfordshire, UK
| | - Tom Slocombe
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, Hertfordshire, UK
| | - Alison Rowles
- Department of Pathology, GlaxoSmithKline, Ware, Hertfordshire, UK
| | - Gail Pearse
- Department of Pathology, GlaxoSmithKline, Ware, Hertfordshire, UK
| | | | - John Bertin
- Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA, USA
| | - Andrea C Haynes
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, Hertfordshire, UK
| | - Allison M Beal
- Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA, USA
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Vietri L, Bargagli E, Bennett D, Fossi A, Cameli P, Bergantini L, d'Alessandro M, Paladini P, Luzzi L, Gentili F, Mazzei MA, Spina D, Sestini P, Rottoli P. Serum Amyloid A in lung transplantation. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2020; 37:2-7. [PMID: 33093763 PMCID: PMC7569538 DOI: 10.36141/svdld.v37i1.8775] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 12/10/2019] [Indexed: 12/01/2022]
Abstract
Background: Serum Amyloid A (SAA) is an acute phase protein and we analyzed its concentrations in lung transplantated patients (LTX). Methods: 26 LTX patients (58.6 ± 11 years) and 11 healthy controls (55 ± 11.3 years). Three groups of LTX patients: acute rejection (AR, 7) bronchiolitis obliterans syndrome (BOS, 3), acute infection (INF, 9) and stable patients (NEG, 7). Results: In LTX patients SAA concentrations were significantly increased, particularly in AR and INF. In LTX-AR patients were observed a correlation between SAA levels and peripheral CD4+ lymphocyte percentage (r=0.9, p<0.01) and a reverse correlation with FVC percentages (r -0.94, p=0.01). Conclusions: SAA may represent a potential biomarker of LTX acute complications, with a prognostic value in AR. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 2-7)
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Affiliation(s)
- Lucia Vietri
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
| | - Elena Bargagli
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
| | - David Bennett
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
| | - Antonella Fossi
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
| | - Paolo Cameli
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
| | - Laura Bergantini
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
| | - Miriana d'Alessandro
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
| | - Piero Paladini
- Thoracic Surgery Unit, Department of Medicine, Surgery and Neuroscences, Siena University Hospital Siena, Italy
| | - Luca Luzzi
- Thoracic Surgery Unit, Department of Medicine, Surgery and Neuroscences, Siena University Hospital Siena, Italy
| | - Francesco Gentili
- Department of Medical, Surgical and Neuro Sciences, Diagnostic Imaging, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Maria Antonietta Mazzei
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy.,Thoracic Surgery Unit, Department of Medicine, Surgery and Neuroscences, Siena University Hospital Siena, Italy.,Department of Medical, Surgical and Neuro Sciences, Diagnostic Imaging, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.,Pathology Unit, Siena University Hospital Siena, Italy
| | | | - Piersante Sestini
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
| | - Paola Rottoli
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, AOUS, Siena, Italy
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D'Haens G, Kelly O, Battat R, Silverberg MS, Laharie D, Louis E, Savarino E, Bodini G, Yarur A, Boland BS, Afif W, Li XJ, Hale M, Ho J, Kondragunta V, Huang B, Kuy C, Okada L, Hester KD, Bray KR, Mimms L, Jain A, Singh S, Collins A, Valasek MA, Sandborn WJ, Vermeire S, Dulai PS. Development and Validation of a Test to Monitor Endoscopic Activity in Patients With Crohn's Disease Based on Serum Levels of Proteins. Gastroenterology 2020; 158:515-526.e10. [PMID: 31711925 DOI: 10.1053/j.gastro.2019.10.034] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/21/2019] [Accepted: 10/26/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Noninvasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI], using samples from 278 patients with CD from a multinational training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naive patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤2 and ≤1 in each segment, or a total CD endoscopic index of severity score <3) was assessed by using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum C-reactive protein (CRP) and fecal calprotectin. RESULTS The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% confidence interval, 0.942-0.982) and an AUROC of 0.693 in validation cohort 2 (95% confidence interval, 0.619-0.767), regardless of CD location or phenotype. A cutoff value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cutoff value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P < .001 in validation cohort 1 and 0.624, P = .109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC; P = .147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC; P = .298 in validation cohort 2). CONCLUSIONS We developed an index called the EHI to identify patients with CD in endoscopic remission based on blood levels of 13 proteins. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice to assess endoscopic activity in patients with CD.
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Affiliation(s)
- Geert D'Haens
- Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands.
| | | | - Robert Battat
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | | | | | - Edouard Louis
- University Hospital Centre Hospitalier Universitaire (CHU) Liege, Liege, Belgium
| | | | | | - Andres Yarur
- Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Brigid S Boland
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | | | - Xiao-Jun Li
- Prometheus Laboratories Inc, San Diego, California
| | - Michael Hale
- Prometheus Laboratories Inc, San Diego, California
| | - Jessica Ho
- Prometheus Laboratories Inc, San Diego, California
| | | | | | - Crystal Kuy
- Prometheus Laboratories Inc, San Diego, California
| | - Lauren Okada
- Prometheus Laboratories Inc, San Diego, California
| | | | | | - Larry Mimms
- Prometheus Laboratories Inc, San Diego, California
| | - Anjali Jain
- Prometheus Laboratories Inc, San Diego, California
| | - Siddharth Singh
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Angelina Collins
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Mark A Valasek
- Department of Pathology, University of California San Diego, La Jolla, California
| | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | | | - Parambir S Dulai
- Division of Gastroenterology, University of California San Diego, La Jolla, California
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Lee JY, Hall JA, Kroehling L, Wu L, Najar T, Nguyen HH, Lin WY, Yeung ST, Silva HM, Li D, Hine A, Loke P, Hudesman D, Martin JC, Kenigsberg E, Merad M, Khanna KM, Littman DR. Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease. Cell 2019; 180:79-91.e16. [PMID: 31866067 DOI: 10.1016/j.cell.2019.11.026] [Citation(s) in RCA: 273] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 09/27/2019] [Accepted: 11/15/2019] [Indexed: 12/20/2022]
Abstract
Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.
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Affiliation(s)
- June-Yong Lee
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Jason A Hall
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Lina Kroehling
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Lin Wu
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Tariq Najar
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Henry H Nguyen
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Woan-Yu Lin
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Stephen T Yeung
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - Hernandez Moura Silva
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Dayi Li
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Ashley Hine
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; Inflammatory Bowel Disease Center, Division of Gastroenterology, New York University School of Medicine, New York, NY 10016, USA
| | - P'ng Loke
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - David Hudesman
- Inflammatory Bowel Disease Center, Division of Gastroenterology, New York University School of Medicine, New York, NY 10016, USA; Department of Medicine, Division of Gastroenterology, New York University School of Medicine, New York, NY 10016, USA
| | - Jerome C Martin
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ephraim Kenigsberg
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Miriam Merad
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kamal M Khanna
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA
| | - Dan R Littman
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York, NY 10016, USA.
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He Y, Ma C, Xing J, Wang S, Ji C, Han Y, Zhang J. Serum amyloid a protein as a potential biomarker in predicting acute onset and association with in-hospital death in acute aortic dissection. BMC Cardiovasc Disord 2019; 19:282. [PMID: 31810459 PMCID: PMC6898938 DOI: 10.1186/s12872-019-1267-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 11/18/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Acute aortic dissection (AAD) is a life-threatening disorder in vascular surgery with a high early mortality. Serum amyloid A (SAA) is a kind of acute-phase protein with a rapid diagnostic value in other diseases. However, the researches on the performance of SAA for the diagnosis of AAD is still lacking. This retrospective study aimed to evaluate the SAA levels and further explore its potential diagnostic role in AAD patients. METHODS SAA levels were measured by enzyme-linked immunosorbent assay (ELISA) in 63 controls and 87 AAD patients. Laboratory examinations were also performed. And relative clinical information was collected from participants included in this study. RESULTS SAA levels were significantly higher in AAD patients than those in healthy controls. SAA levels were independently associated with the risk of AAD. There was a positive significant correlation between SAA and C reactive protein (R = 0.442, and P = 0.001). Based on receiver-operating characteristic (ROC) analysis, the area under the curve (AUC) of SAA for the diagnosis of AAD were 0.942 with optimal cut-off points of 0.427 mg/L. For in-hospital mortality, the AUC of SAA were 0.732 with optimal cut-off points of 0.500 mg/L. According to logistic regression analysis, higher SAA levels represent a higher risk of in-hospital mortality (OR = 1.25; 95%CI: 1.07-1.47; P = 0.005). CONCLUSION Our findings demonstrated that SAA levels were significantly enhanced in AAD. SAA was closely correlated with inflammatory parameters and coagulation-related parameters in AAD. Furthermore, SAA could be a potential bio-marker for identifying AAD in the early diagnosis. Finally, SAA > 5.0 mg/L are independently related to AAD in-hospital mortality.
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Affiliation(s)
- Yuchen He
- Department of Vascular Surgery, the First Hospital of China Medical University, and Key Laboratory of pathogenesis, prevention and therapeutics of aortic aneurysm Liaoning Province, No. 155 Nanjing Bei Street, Shenyang, 110001, China
| | - Changcheng Ma
- Department of Clinical Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jia Xing
- Department of Histology and Embryology, China Medical University, Shenyang, China
| | - Shiyue Wang
- Department of Vascular Surgery, the First Hospital of China Medical University, and Key Laboratory of pathogenesis, prevention and therapeutics of aortic aneurysm Liaoning Province, No. 155 Nanjing Bei Street, Shenyang, 110001, China
| | - Chao Ji
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yanshuo Han
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China. .,School of Life Science and Medicine, Dalian University of Technology, No. 2 Dagong Road, Liaodongwan New District, Liaoning, 124221, China.
| | - Jian Zhang
- Department of Vascular Surgery, the First Hospital of China Medical University, and Key Laboratory of pathogenesis, prevention and therapeutics of aortic aneurysm Liaoning Province, No. 155 Nanjing Bei Street, Shenyang, 110001, China.
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Yuan ZY, Zhang XX, Wu YJ, Zeng ZP, She WM, Chen SY, Zhang YQ, Guo JS. Serum amyloid A levels in patients with liver diseases. World J Gastroenterol 2019; 25:6440-6450. [PMID: 31798280 PMCID: PMC6881510 DOI: 10.3748/wjg.v25.i43.6440] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 09/23/2019] [Accepted: 11/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Serum amyloid A (SAA) is an acute phase protein mainly synthesized by the liver. SAA induces inflammatory phenotype and promotes cell proliferation in activated hepatic stellate cells, the major scar forming cells in the liver. However, few studies have reported on the serum levels of SAA in human liver disease and its clinical significance in various liver diseases.
AIM To investigate the serum levels of SAA in patients with different liver diseases and analyze the factors associated with the alteration of SAA levels in chronic hepatitis B (CHB) patients.
METHODS Two hundred and seventy-eight patients with different liver diseases and 117 healthy controls were included in this study. The patients included 205 with CHB, 22 with active autoimmune liver disease (AILD), 21 with nonalcoholic steatohepatitis (NASH), 14 with drug-induced liver injury (DILI), and 16 with pyogenic liver abscess. Serum levels of SAA and other clinical parameters were collected for the analysis of the factors associated with SAA level. Mann-Whitney U test was used to compare the serum SAA levels of patients with various liver diseases with those of healthy controls. Bonferroni test was applied for post hoc comparisons to control the probability of type 1 error (alpha = 0.05/6 = 0.008). For statistical tests of other variables, P < 0.05 was considered statistically significant. Statistically significant factors determined by single factor analysis were further analyzed by binary multivariate logistic regression analysis.
RESULTS All patients with active liver diseases had higher serum SAA levels than healthy controls and the inactive CHB patients, with the highest SAA level found in patients with pyogenic liver abscess (398.4 ± 246.8 mg/L). Patients with active AILD (19.73 ± 24.81 mg/L) or DILI (8.036 ± 5.685 mg/L) showed higher SAA levels than those with active CHB (6.621 ± 6.776 mg/L) and NASH (6.624 ± 4.891 mg/L). Single (P < 0.001) and multivariate logistic regression analyses (P = 0.039) for the CHB patients suggested that patients with active CHB were associated with an SAA serum level higher than 6.4 mg/L. Serum levels of SAA and CRP (C-reactive protein) were positively correlated in patients with CHB (P < 0.001), pyogenic liver abscess (P = 0.045), and active AILD (P = 0.02). Serum levels of SAA (0.80-871.0 mg/L) had a broader fluctuation range than CRP (0.30-271.3 mg/L).
CONCLUSION Serum level of SAA is a sensitive biomarker for inflammatory activity of pyogenic liver abscess. It may also be a weak marker reflecting milder inflammatory status in the liver of patients with CHB and other active liver diseases.
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Affiliation(s)
- Zi-Ying Yuan
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
- Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China
| | - Xing-Xin Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Yu-Jing Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Zhi-Ping Zeng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Wei-Min She
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Shi-Yao Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Yuan-Qing Zhang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Jin-Sheng Guo
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
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Abouelasrar Salama S, Lavie M, De Buck M, Van Damme J, Struyf S. Cytokines and serum amyloid A in the pathogenesis of hepatitis C virus infection. Cytokine Growth Factor Rev 2019; 50:29-42. [PMID: 31718982 DOI: 10.1016/j.cytogfr.2019.10.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/17/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Expression of the acute phase protein serum amyloid A (SAA) is dependent on the release of the pro-inflammatory cytokines IL-1, IL-6 and TNF-α during infection and inflammation. Hepatitis C virus (HCV) upregulates SAA-inducing cytokines. In line with this, a segment of chronically infected individuals display increased circulating levels of SAA. SAA has even been proposed to be a potential biomarker to evaluate treatment efficiency and the course of disease. SAA possesses antiviral activity against HCV via direct interaction with the viral particle, but might also divert infectivity through its function as an apolipoprotein. On the other hand, SAA shares inflammatory and angiogenic activity with chemotactic cytokines by activating the G protein-coupled receptor, formyl peptide receptor 2. These latter properties might promote chronic inflammation and hepatic injury. Indeed, up to 80 % of infected individuals develop chronic disease because they cannot completely clear the infection, due to diversion of the immune response. In this review, we summarize the interconnection between SAA and cytokines in the context of HCV infection and highlight the dual role SAA could play in this disease. Nevertheless, more research is needed to establish whether the balance between those opposing activities can be tilted in favor of the host defense.
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Affiliation(s)
- Sara Abouelasrar Salama
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Muriel Lavie
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
| | - Mieke De Buck
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium.
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Vietri L, Bennett D, Cameli P, Bergantini L, Cillis G, Sestini P, Bargagli E, Rottoli P. Serum amyloid A in patients with idiopathic pulmonary fibrosis. Respir Investig 2019; 57:430-434. [PMID: 31031123 DOI: 10.1016/j.resinv.2019.03.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/20/2019] [Accepted: 03/28/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND Serum amyloid A (SAA) is an apo-lipoprotein (12-14 kDa) produced by the liver in response to proinflammatory cytokines from activated monocytes. The precursor of SAA is an acute-phase protein involved in the pathogenesis of sarcoidosis and has been found to be increased during exacerbation of chronic obstructive pulmonary disease and lung cancer. However, no data are available on SAA levels in patients with idiopathic pulmonary fibrosis (IPF), the most common and severe idiopathic form of interstitial pneumonitis associated with a usual interstitial histological and radiological pattern. The aim of this preliminary study was to evaluate SAA concentration in patients with IPF and to explore its potential use as a clinical biomarker. METHODS SAA levels were determined by enzyme-linked immunosorbent assay in a population of 21 patients with IPF (14 male, aged 64.8 ± 8.1 years) and compared with those in 11 healthy controls (3 male, aged 55 ± 11.3 years). Clinical, functional, and immunological data were collected in a database. RESULTS SAA levels were significantly higher in patients with IPF than in controls (p = 0.03). In patients with IPF, statistically significant correlations were found between SAA and HDL cholesterol levels (r = -0.62, p = 0.05) and FVC % predicted value (r = -0.52, p = 0.01). CONCLUSIONS SAA is a promising marker of disease severity in patients with IPF. Our preliminary data suggest a potential pathogenetic role of alteration in lipid metabolism in this rare disease.
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Affiliation(s)
- Lucia Vietri
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, Viale Bracci, 53100 Siena, Italy.
| | - David Bennett
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, Viale Bracci, 53100 Siena, Italy.
| | - Paolo Cameli
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, Viale Bracci, 53100 Siena, Italy.
| | - Laura Bergantini
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, Viale Bracci, 53100 Siena, Italy.
| | - Giuseppe Cillis
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, Viale Bracci, 53100 Siena, Italy.
| | - Piersante Sestini
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, Viale Bracci, 53100 Siena, Italy.
| | - Elena Bargagli
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, Viale Bracci, 53100 Siena, Italy.
| | - Paola Rottoli
- Department of Medical and Surgical Sciences and Neurosciences, Respiratory Disease and Lung Transplant Unit, University of Siena, Viale Bracci, 53100 Siena, Italy.
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Burgueño JF, Lang JK, Santander AM, Fernández I, Fernández E, Zaias J, Abreu MT. Fluid supplementation accelerates epithelial repair during chemical colitis. PLoS One 2019; 14:e0215387. [PMID: 31002683 PMCID: PMC6474653 DOI: 10.1371/journal.pone.0215387] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 04/01/2019] [Indexed: 12/28/2022] Open
Abstract
The dextran sulfate sodium (DSS) model of colitis is a common animal model of inflammatory bowel disease that causes pain and distress. In this study, we aimed to determine whether fluid supplementation can be used as a welfare-based intervention to minimize animal suffering. C57Bl/6 females undergoing acute colitis by administration of 3% DSS in drinking water were supplemented with 1 mL intraperitoneal injections of NaCl and compared to non-supplemented control mice. Mouse behavior and locomotive activity were assessed on days 5–6 after DSS initiation by means of tail suspension, novel object recognition and open field activity tests. Mice were euthanized after either the acute (day 7) or the recovery phase (day 12) of colitis and inflammation, epithelial proliferation, and differentiation were assessed by means of histology, immunohistochemistry, quantitative PCR, and western blot. We found that fluid-supplemented mice had reduced signs of colitis with no alterations in behavior or locomotive activity. Furthermore, we observed an accelerated epithelial repair response after fluid hydration during the acute phase of colitis, characterized by increased crypt proliferation, activation of ERK1/2, and modulation of TGF-β1 expression. Consistent with these findings, fluid-supplemented mice had increased numbers of goblet cells, upregulated expression of differentiation markers for absorptive enterocytes, and reduced inflammation during the recovery phase. Our results show that fluid hydration does not reduce stress in DSS-treated mice but alters colitis evolution by reducing clinical signs and accelerating epithelial repair. These results argue against the routine use of fluid supplementation in DSS-treated mice.
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Affiliation(s)
- Juan F. Burgueño
- Division of Gastroenterology, Department of Medicine, University of Miami–Leonard Miller School of Medicine, Miami, FL, United States of America
- * E-mail:
| | - Jessica K. Lang
- Division of Gastroenterology, Department of Medicine, University of Miami–Leonard Miller School of Medicine, Miami, FL, United States of America
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, United States of America
| | - Ana M. Santander
- Division of Gastroenterology, Department of Medicine, University of Miami–Leonard Miller School of Medicine, Miami, FL, United States of America
| | - Irina Fernández
- Division of Gastroenterology, Department of Medicine, University of Miami–Leonard Miller School of Medicine, Miami, FL, United States of America
| | - Ester Fernández
- Animal Physiology Unit, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| | - Julia Zaias
- Division of Veterinary Resources, University of Miami Miller School of Medicine, Miami, FL, United States of America
- Department of Pathology and Laboratory Medicine, University of Miami–Leonard Miller School of Medicine, Miami, FL, United States of America
| | - Maria T. Abreu
- Division of Gastroenterology, Department of Medicine, University of Miami–Leonard Miller School of Medicine, Miami, FL, United States of America
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Zhang Y, Zhang J, Sheng H, Li H, Wang R. Acute phase reactant serum amyloid A in inflammation and other diseases. Adv Clin Chem 2019; 90:25-80. [PMID: 31122611 DOI: 10.1016/bs.acc.2019.01.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Acute-phase reactant serum amyloid A (A-SAA) plays an important role in acute and chronic inflammation and is used in clinical laboratories as an indicator of inflammation. Although both A-SAA and C-reactive protein (CRP) are acute-phase proteins, the detection of A-SAA is more conclusive than the detection of CRP in patients with viral infections, severe acute pancreatitis, and rejection reactions to kidney transplants. A-SAA has greater clinical diagnostic value in patients who are immunosuppressed, patients with cystic fibrosis who are treated with corticoids, and preterm infants with late-onset sepsis. Nevertheless, for the assessment of the inflammation status and identification of viral infection in other pathologies, such as bacterial infections, the combinatorial use of A-SAA and other acute-phase proteins (APPs), such as CRP and procalcitonin (PCT), can provide more information and sensitivity than the use of any of these proteins alone, and the information generated is important in guiding antibiotic therapy. In addition, A-SAA-associated diseases and the diagnostic value of A-SAA are discussed. However, the relationship between different A-SAA isotypes and their human diseases are mostly derived from research laboratories with limited clinical samples. Thus, further clinical evaluations are necessary to confirm the clinical significance of each A-SAA isotype. Furthermore, the currently available A-SAA assays are based on polyclonal antibodies, which lack isotype specificity and are associated with many inflammatory diseases. Therefore, these assays are usually used in combination with other biomarkers in the clinic.
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Affiliation(s)
- Yan Zhang
- Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, China
| | - Jie Zhang
- Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, China
| | - Huiming Sheng
- Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haichuan Li
- C.N. Maternity & Infant Health Hospital, Shanghai, China
| | - Rongfang Wang
- Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, China.
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Drobin K, Assadi G, Hong MG, Andersson E, Fredolini C, Forsström B, Reznichenko A, Akhter T, Ek WE, Bonfiglio F, Hansen MB, Sandberg K, Greco D, Repsilber D, Schwenk JM, D’Amato M, Halfvarson J. Targeted Analysis of Serum Proteins Encoded at Known Inflammatory Bowel Disease Risk Loci. Inflamm Bowel Dis 2019; 25:306-316. [PMID: 30358838 PMCID: PMC6327232 DOI: 10.1093/ibd/izy326] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Few studies have investigated the blood proteome of inflammatory bowel disease (IBD). We characterized the serum abundance of proteins encoded at 163 known IBD risk loci and tested these proteins for their biomarker discovery potential. METHODS Based on the Human Protein Atlas (HPA) antibody availability, 218 proteins from genes mapping at 163 IBD risk loci were selected. Targeted serum protein profiles from 49 Crohn's disease (CD) patients, 51 ulcerative colitis (UC) patients, and 50 sex- and age-matched healthy individuals were obtained using multiplexed antibody suspension bead array assays. Differences in relative serum abundance levels between disease groups and controls were examined. Replication was attempted for CD-UC comparisons (including disease subtypes) by including 64 additional patients (33 CD and 31 UC). Antibodies targeting a potentially novel risk protein were validated by paired antibodies, Western blot, immuno-capture mass spectrometry, and epitope mapping. RESULTS By univariate analysis, 13 proteins mostly related to neutrophil, T-cell, and B-cell activation and function were differentially expressed in IBD patients vs healthy controls, 3 in CD patients vs healthy controls and 2 in UC patients vs healthy controls (q < 0.01). Multivariate analyses further differentiated disease groups from healthy controls and CD subtypes from UC (P < 0.05). Extended characterization of an antibody targeting a novel, discriminative serum marker, the laccase (multicopper oxidoreductase) domain containing 1 (LACC1) protein, provided evidence for antibody on-target specificity. CONCLUSIONS Using affinity proteomics, we identified a set of IBD-associated serum proteins encoded at IBD risk loci. These candidate proteins hold the potential to be exploited as diagnostic biomarkers of IBD.
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Affiliation(s)
- Kimi Drobin
- Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden
| | - Ghazaleh Assadi
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Mun-Gwan Hong
- Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden
| | - Eni Andersson
- Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden
| | - Claudia Fredolini
- Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden
| | - Björn Forsström
- Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden
| | - Anna Reznichenko
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Tahmina Akhter
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Weronica E Ek
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Ferdinando Bonfiglio
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain
| | - Mark Berner Hansen
- AstraZeneca R&D Mölndal, Innovative and Global Medicines, Mölndal, Sweden
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Kristian Sandberg
- Science for Life Laboratory, Drug Discovery & Development Platform & Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Dario Greco
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Dirk Repsilber
- School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Jochen M Schwenk
- Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden
| | - Mauro D’Amato
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- BioDonostia Health Research Institute, San Sebastian and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Address correspondence to: Jonas Halfvarson, PhD, Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 70182, Örebro, Sweden ()
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Battat R, Dulai PS, Vande Casteele N, Evans E, Hester KD, Webster E, Jain A, Proudfoot JA, Mairalles A, Neill J, Singh S, Chang JT, Rivera-Nieves J, Sandborn WJ, Boland BS. Biomarkers Are Associated With Clinical and Endoscopic Outcomes With Vedolizumab Treatment in Ulcerative Colitis. Inflamm Bowel Dis 2019; 25:410-420. [PMID: 30295781 PMCID: PMC6327228 DOI: 10.1093/ibd/izy307] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Indexed: 02/07/2023]
Abstract
Background Vedolizumab inhibits α4β7-mediated lymphocyte trafficking and is effective in ulcerative colitis (UC). This study evaluated drug and biomarker concentrations and patient outcomes during vedolizumab treatment in UC. Methods Prospectively scored maintenance clinical (26.5 weeks; interquartile range [IQR], 16.3-37.0 weeks) and endoscopic (23.5 weeks; IQR, 16.8-35.6 weeks) outcomes were compared with serum vedolizumab concentrations, antivedolizumab antibodies, and serum biomarkers at baseline and weeks 2, 6, 14, and 26. A linear mixed-effects model compared biomarker trajectories over time between clinical and endoscopic remitters and nonremitters. Results Thirty-two patients were included. Soluble (s)-tumor necrosis factor (TNF)-α, s-α4β7, s-mucosal addressin cell adhesion molecule (s-MAdCAM-1), and s-amyloid A (s-AA) significantly changed with treatment. A linear mixed-effects model demonstrated that s-α4β7 (P = 0.044) increased and s-MAdCAM-1 (P = 0.006) and s-vascular cell adhesion molecule-1 (s-VCAM-1, P = 0.001) decreased more rapidly in patients achieving clinical remission in maintenance. S-MAdCAM-1 (P = 0.005), s-intracellular adhesion molecule-1 (ICAM-1; P = 0.014), s-VCAM-1 (P < 0.001), and s-TNF (P = 0.052) decreased more rapidly in endoscopic remitters. In clinical remitters, higher week 14 (20.3 ng/mL vs 6.0 ng/mL; P = 0.013) and week 26 (14.1 ng/mL vs 8.6 ng/mL; P = 0.05) s-α4β7 were observed. In endoscopic remitters, week 2 (6.7 pg/mL vs 17.8 pg/mL; P = 0.038) and week 6 (3.9 pg/mL vs 15.6 pg/mL; P = 0.005) s-TNF and week 14 s-VCAM (589.1 ng/mL vs 746.0 ng/mL; P = 0.05) were lower. Conclusion Serum biomarkers were associated with outcomes in vedolizumab-treated UC patients. s-α4β7 increased, whereas s-MAdCAM-1, s-VCAM-1, s-ICAM-1, and s-TNF decreased more rapidly in remitters. At individual time points, induction s-TNF and maintenance s-VCAM-1 concentrations were lower, whereas maintenance s-α4β7 concentrations were higher in remitters.
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Affiliation(s)
- Robert Battat
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Parambir S Dulai
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Niels Vande Casteele
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Elisabeth Evans
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | | | | | - Anjali Jain
- Prometheus Laboratories Inc., San Diego, California
| | - James A Proudfoot
- Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California
| | - Ara Mairalles
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Jennifer Neill
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Siddharth Singh
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - John T Chang
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Jesus Rivera-Nieves
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - William J Sandborn
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Brigid S Boland
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
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