Patients With Microscopic Colitis Have Altered Levels of Inhibitory and Stimulatory Biomarkers in Colon Biopsies and Sera Compared to Non-inflamed Controls

Introduction: Microscopic colitis (MC) is an inflammatory bowel condition with two subtypes, lymphocytic colitis (LC) and collagenous colitis (CC). Unlike patients with ulcerative colitis (UC) and non-inflamed individuals, MC patients have reduced risk of developing colorectal cancer, possibly due to increased immune surveillance in MC patients.Aim: To examine differences in levels of immunomodulatory molecules, including those involved in immune checkpoint mechanisms, in sera from patients with MC and in colonic biopsies from patients with MC and UC compared with controls.Methods: Using Luminex, 23 analytes (4-1BB, 4-1BBL, APRIL, BAFF, BTLA, CD27, CD28, CD80, CTLA-4, E-cadherin, Galectin-3, GITR, HVEM, IDO, IL-2Rα, LAG-3, MICA, MICB, PD-1, PD-L1, PD-L2, sCD40L and TIM-3) were studied in serum from patients with active MC (n = 35) and controls (n = 23), and in colonic biopsies from patients with active LC (n = 9), active CC (n = 16) and MC in histological remission (LC n = 6, CC n = 6), active UC (n = 15) and UC in remission (n = 12) and controls (n = 58).Results: In serum, IDO, PD-1, TIM-3, 4-1BB, CD27, and CD80 were decreased whereas 4-1BBL and IL-2Rα were increased in MC patients compared with controls. In contrast, in biopsies, levels of PD-L2 and 4-1BB were increased in MC and UC patients with active disease. Furthermore, in biopsies from CC and UC but not LC patients with active disease, CTLA-4, PD-1, APRIL, BAFF, and IL-2Rα were increased compared with controls. PD-L1 was increased in CC but not UC or LC patients. CD27 and TIM-3 were decreased in biopsies from MC patients in comparison to controls whereas levels of MICB were decreased in patients with active UC compared with controls.Conclusions: Compared with non-inflamed controls, levels of soluble and membrane-bound immunomodulatory molecules were systemically and locally altered in MC and UC patients, with most analytes being decreased in serum but enhanced in colonic biopsies. These findings contribute to knowledge about checkpoint molecules and their role as biomarkers in MC and may also contribute to knowledge about possible mechanisms behind the seemingly protective effects of MC against colorectal cancer.

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Enhanced Levels of Chemokines and Their Receptors in the Colon of Microscopic Colitis Patients Indicate Mixed Immune Cell Recruitment

Mediators of Inflammation ◽

10.1155/2015/132458 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 11

Author(s):

Sezin Günaltay ◽

Ashok Kumar Kumawat ◽

Nils Nyhlin ◽

Johan Bohr ◽

Curt Tysk ◽

...

Keyword(s):

Immune Cell ◽

Receptor Gene ◽

Collagenous Colitis ◽

Microscopic Colitis ◽

Cell Recruitment ◽

Protein Levels ◽

Protein Expressions ◽

Immune Cell Recruitment ◽

Active Disease ◽

Chemokine Receptor Gene

Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX3CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX3CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

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Gly972Arg Variant of Insulin Receptor Substrate 1 Gene and Colorectal Cancer Risk in Overweight/Obese Subjects

The International Journal of Biological Markers ◽

10.5301/jbm.5000159 ◽

2016 ◽

Vol 31 (1) ◽

pp. 68-72 ◽

Cited By ~ 3

Author(s):

Touraj Mahmoudi ◽

Keivan Majidzadeh-A ◽

Khatoon Karimi ◽

Hamid Farahani ◽

Reza Dabiri ◽

...

Keyword(s):

Colorectal Cancer ◽

Insulin Receptor ◽

Case Control Study ◽

Insulin Receptor Substrate ◽

Protective Effects ◽

Insulin Receptor Substrate 1 ◽

Pcr Rflp ◽

Obese Subjects ◽

Control Study

Background Given the major role of obesity and insulin resistance (IR) in colorectal cancer (CRC), we investigated whether genetic variants in ghrelin ( GHRL), resistin ( RETN) and insulin receptor substrate 1 ( IRS1) were associated with CRC risk. Methods This study was conducted as a case-control study, and 750 subjects, including 438 controls and 312 patients with CRC, were enrolled and genotyped using the PCR-RFLP method. Results No significant differences were observed for GHRL (rs696217), RETN (rs3745367) and IRS1 (rs1801278, Gly972Arg or G972R) gene variants between the cases and controls. However, the IRS1 G972R R allele compared with the G allele and the G972R RR+GR genotype compared with the GG genotype appeared to be markers of decreased CRC susceptibility in the overweight/obese subjects (p = 0.024; odds ratio [OR] = 0.42, 95% confidence interval [95% CI], 0.20-0.91; and p = 0.048; OR = 0.42, 95% CI, 0.17-0.99, respectively). Furthermore, the R allele and RR+GR genotype were also associated with decreased risks for obesity in the patients with CRC (p = 0.007; OR = 0.35, 95% CI, 0.15-0.77; and p = 0.015; OR = 0.35, 95% CI, 0.15-0.72, respectively). Conclusions In accordance with previous studies, our findings suggest that the IRS1 G972R R allele and RR+GR genotype have protective effects for CRC in overweight/obese patients and for obesity in patients with CRC. Nevertheless, further studies are required to confirm these findings.

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Flavonoid intake from vegetables and fruits is inversely associated with colorectal cancer risk: a case–control study in China

British Journal Of Nutrition ◽

10.1017/s0007114516003196 ◽

2016 ◽

Vol 116 (7) ◽

pp. 1275-1287 ◽

Cited By ~ 26

Author(s):

Ming Xu ◽

Yu-Ming Chen ◽

Jing Huang ◽

Yu-Jing Fang ◽

Wu-Qing Huang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Risk ◽

Regression Models ◽

Case Control Study ◽

Colorectal Cancer Risk ◽

Protective Effects ◽

Flavonoid Intake ◽

Vegetables And Fruits ◽

Dietary Flavonoids ◽

Control Study

AbstractFlavonoids may play an important role in the protective effects of vegetables, fruits and tea against colorectal cancer. However, associations between flavonoids and colorectal cancer risk are inconsistent, and a few studies have evaluated the effect of flavonoids from different dietary sources separately. This study aimed to evaluate associations of flavonoids intake from different dietary sources with colorectal cancer risk in a Chinese population. From July 2010 to December 2015, 1632 eligible colorectal cancer cases and 1632 frequency-matched controls (age and sex) completed in-person interviews. A validated FFQ was used to estimate dietary flavonoids intake. Multivariate logistical regression models were used to calculate the OR and 95 % CI of colorectal cancer risk after adjusting for various confounders. No significant association was found between total flavonoids and colorectal cancer risk, with an adjusted OR of 1·06 (95 % CI 0·85, 1·32) comparing the highest with the lowest quartile. Anthocyanidins, flavanones and flavones intakes from total diet were found to be inversely associated with colorectal cancer risk. Compared with the lowest quartile, the adjusted OR for the highest quartile were 0·80 (95 % CI 0·64, 1·00) for anthocyanidins, 0·28 (95 % CI 0·22, 0·36) for flavanones and 0·54 (95 % CI 0·43, 0·67) for flavones. All subclasses of flavonoids from vegetables and fruits were inversely associated with colorectal cancer. However, no significant association was found between tea flavonoids and colorectal cancer risk. These data indicate that specific flavonoids, specifically flavonoids from vegetables and fruits, may be linked with the reduced risk of colorectal cancer.

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Familial Microscopic Colitis

Canadian Journal of Gastroenterology ◽

10.1155/2001/920825 ◽

2001 ◽

Vol 15 (5) ◽

pp. 341-343 ◽

Cited By ~ 33

Author(s):

Ayman Assad Abdo ◽

Peter Jeffrey Zetler ◽

Lawrence S Halparin

Keyword(s):

Chronic Diarrhea ◽

Present Report ◽

Disease Process ◽

Collagenous Colitis ◽

Microscopic Colitis ◽

Familial Occurrence ◽

Lymphocytic Colitis ◽

The Third ◽

Inflammatory Conditions ◽

Colonic Biopsy

Collagenous and lymphocytic colitis are two inflammatory conditions of the colon that are often collectively referred to as microscopic colitis. The present report describes what is believed to be the third published case of familial microscopic colitis. A 55-year-old woman who suffered from chronic diarrhea was diagnosed with lymphocytic colitis on colonic biopsy. Subsequently, her 36-year-old daughter was diagnosed with collagenous colitis. The familial occurrence of these diseases may support an immunological hypothesis for their etiology. In addition, it supports the assumption that collagenous and lymphocytic colitis are two manifestations of the same disease process rather than two completely separate entities. The familial tendency of this disease may make a case for early colonoscopy and biopsy in relatives of patients diagnosed with microscopic colitis if they present with suggestive symptoms.

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Case Report: Ramipril and microscopic colitis; a necessary tool of cardiologists can rarely be devastating for patients

F1000Research ◽

10.12688/f1000research.25552.1 ◽

2020 ◽

Vol 9 ◽

pp. 1113

Author(s):

Saad Hasan ◽

Haseeb Ur Rahman ◽

Stephen Hutchison

Keyword(s):

Case Report ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Pancreatic Enzyme ◽

Collagenous Colitis ◽

Microscopic Colitis ◽

Chronic Diarrhoea ◽

Converting Enzyme Inhibitors ◽

Enzyme Replacement ◽

Pancreatic Enzyme Replacement Therapy

Angiotensin converting enzyme inhibitors could lead to severe diarrhoea related to microscopic colitis. Few of such cases have been reported before and this serious problem, from a widely used class of drugs in hypertension and heart failure, needs to be more recognised. We describe the case of collagenous colitis related to ramipril use in the following case report. A 74-year-old farmer who had a history of triple vessel coronary artery disease was admitted to district general hospital with non-ST elevation myocardial infarction. He had known alcohol-related chronic pancreatitis with chronic diarrhoea as a complication, which was managed with pancreatic enzyme replacement therapy. However, he developed severe worsening of diarrhoea causing bowel incontinence and nocturnal symptoms during his admission to hospital. The explosive and watery nature of diarrhoea with urgency was so troublesome that it delayed coronary revascularisation and lead him to have significant psychological distress and low mood while nocturnal bowel motions meant he was unable to sleep. He was compliant with his pancreatic enzyme replacement therapy during this period. Infective causes were ruled out by stool microbiology examination and coeliac disease by oesophagogastroscopy and biopsy. It was noticed that he was recently prescribed ramipril that was later stopped as a possible diarrhoea trigger. Diarrhoea started settling immediately and resolved to his baseline within a week. A colonoscopy was performed in the meantime and biopsies demonstrated microscopic colitis (MC). He did not tolerate budesonide well so was stopped. However, a follow-up colonoscopy with biopsy in two months showed resolution of MC.

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Protective effects of fullerenol against chronic doxorubicin-induced cardiotoxicity and hepatotoxicity in rats with colorectal cancer

Hemijska industrija ◽

10.2298/hemind0903259i ◽

2009 ◽

Vol 63 (3) ◽

pp. 259-268 ◽

Cited By ~ 1

Author(s):

Rade Injac ◽

Natasa Radic ◽

Biljana Govedarica ◽

Aleksandar Djordjevic ◽

Borut Strukelj

Keyword(s):

Colorectal Cancer ◽

Liver Tissue ◽

Time Span ◽

Free Radical Scavengers ◽

Male Rat ◽

Antioxidant Vitamin ◽

Protective Effects ◽

Radical Scavengers ◽

Derivatives Of

Since the introduction of Doxorubicin (Dox) for the treatment of cancer in 1969, this compound has demonstrated high antitumor efficacy. Dox's use in chemotherapy has been limited largely due to its diverse toxicities, including cardiac, liver, renal, pulmonary, hematological and testicular toxicity. Various attempts have been made to reduce Dox-induced toxicity. These include dosage optimization, synthesis and use of analogues. Moreover, a number of agents have been investigated as protective agents during Dox therapy. Polyhydroxilated derivatives of fullerene, named fullerenols C60(OH)n, are being extensively studied due to their great potential as antioxidants. It is proposed that they might act as free radical scavengers in biological systems, in xenobiotics-induced oxidative stress as well as against radioactive irradiation. We have investigated the effects of fullerenol C60(OH)24 (Frl) at doses of 25, 50 and 100 mg kg-1 week (for a time-span of three weeks) on heart and liver tissue after Doxorubicin (Dox)-induced toxicity in rats with colorectal cancer. In the present study, in vivo Wistar male rat model was used to explore whether Frl could protect against Dox-induced (1.5 mg/kg/week for three weeks) chronic cardio- and hepatotoxicity and compared the effect with a well-known antioxidant, vitamin C (100 mg/kg/week for three weeks). Commercially available methods were used for blood and pathohystological analysis and for the measurement of enzyme activity (SOD, MDA, GSH, GSSH, GPx, GR, CAT, CK, LDH, ?-HBDH, AST, ALT) in serum and homogenate samples of heart and liver tissues. According to macroscopic, microscopic, hematological, biochemical, physiological, pharmacological, and pharmacokinetic results, we confirmed that, at all examined doses, Frl exhibits a protective influence on the heart and liver tissue against chronic toxicity induced by Dox.

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Microscopic colitis: A literature review

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.62.09.895 ◽

2016 ◽

Vol 62 (9) ◽

pp. 895-900 ◽

Cited By ~ 1

Author(s):

ANA PAULA HAMER SOUSA CLARA ◽

FLÁVIA DRAGO MAGNAGO ◽

JULIANA NEVES FERREIRA ◽

THAIS GAGNO GRILLO

Keyword(s):

Scientific Evidence ◽

Collagenous Colitis ◽

Gastrointestinal Disorder ◽

Normal Mucosa ◽

Term Treatment ◽

Diagnostic Methods ◽

Microscopic Colitis ◽

Older Individuals ◽

Short Term Treatment ◽

Pubmed Database

SUMMARY Microscopic colitis (MC) refers to chronic inflammation of the colon which is characterized by histologic changes at the level of a radiologically and endoscopically normal mucosa. It is a common cause of chronic non-bloody diarrhea that occurs primarily in older individuals; however, there are few studies in the literature with strong scientific evidence compared to other inflammatory bowel diseases (IBD), which limits the knowledge of physicians and pathologists. This article aims to review the information on MC, describing diagnostic methods and drugs available for treatment. We conducted a search of the Pubmed database and CAPES Portal using the keywords “microscopic colitis”, “collagenous colitis”, “lymphocytic colitis”, and “review” for selection of articles published between 1996 and 2015 related to the topic. Based on the studies discussed in this review, we conclude that MC is a relatively new gastrointestinal disorder, most studies are incipient particularly with respect to pathophysiology and immunology, and budesonide is the best documented short-term treatment. However, further studies are needed to elucidate the best strategy for treatment in the long term.

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Microscopic Colitis (Lymphocytic or Collagenous Colitis)

Netter's Gastroenterology ◽

10.1016/b978-1-4377-0121-0.50161-6 ◽

2010 ◽

pp. 407-408

Author(s):

Martin H. Floch

Keyword(s):

Collagenous Colitis ◽

Microscopic Colitis

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Increased Mast Cell Counts and Degranulation in Microscopic Colitis

Gastroenterology Research and Practice ◽

10.1155/2020/9089027 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Zhikai Chi ◽

Jing Xu ◽

Romil Saxena

Keyword(s):

Mast Cell ◽

Cell Count ◽

Cell Activation ◽

Collagenous Colitis ◽

Microscopic Colitis ◽

Mast Cell Activation ◽

Mucosal Inflammation ◽

High Power Field ◽

Cell Counts ◽

Mast Cell Count

Objectives. Microscopic colitis (MC) is characterized by chronic diarrhea, normal colonoscopy findings, and mucosal inflammation in colonic biopsies and can be classified as collagenous colitis (CC) or lymphocytic colitis (LC). However, the pathogenesis of MC is largely unknown. In this study, we aimed to study mast cell counts and activation in MC. Methods. We investigated 64 biopsy samples from the surgical pathology database of Indiana University Health, which met the diagnostic criteria for CC or LC along with 20 control samples collected from 2014 to 2015. The specimens were used for the quantification of mast cells by examining the presence of intracellular and extracellular tryptase by immunohistochemistry. Results. In the lamina propria, the mast cell count was higher in both CC and LC groups than the control (mean highest count, 39/high-power field (HPF) vs. 30/HPF vs. 23/HPF; P<0.01). Extracellular tryptase was present in 10% of control subjects as compared to 41% of CC (P<0.05) and 60% of LC (P<0.001) patients. When LC patients were stratified into two groups with either <80% or >80% of fragments affected by inflammation, increased mast cell counts are only observed in the >80% involvement group compared with the control, but not the <80% involvement group. Conclusions. The increased mast cell count and degranulation are identified in MC, suggesting that mast cell activation might be involved in the pathogenesis of MC.

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