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Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 31485

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Dr. Gian Paolo Caviglia

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Department of Medical Sciences, University of Turin, 10126 Turin, Italy
Interests: biomarkers; cirrhosis; hepatitis B virus; hepatocellular carcinoma; hepatitis D virus; inflammatory bowel disease; liver fibrosis; non-alcoholic fatty liver disease
Special Issues, Collections and Topics in MDPI journals

Dr. Davide Giuseppe Ribaldone

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Department of Medical Sciences, University of Turin, 10124 Turin, Italy
Interests: inflammatory bowel diseases; Crohn’s disease; ulcerative colitis; celiac disease; microbiota; eosinophilic esophagitis; irritable bowel syndrome; biologics; diverticular disease; Helicobacter pylori
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis, both of which are characterized by chronic and uncontrolled inflammation of the intestinal tract. Despite the fact that pathogenesis remains poorly understood, IBD is known to result from the interaction between genetic and environmental factors which influence immune responses to components of the intestinal microbiome. From an epidemiological point of view, the global burden of IBD continues to increase worldwide. Considering the strongly debilitating clinical course of the disease that causes serious implications for the patients, IBD has recently become a serious challenge in medical science.

New biologics (anti-integrin, anti-IL12-23) and small molecules (anti-Janus kinase) are increasingly entering in the market, but it is not clear if these drugs are able to reduce the number of surgical resections and to change the natural history of the disease. In particular, since the therapeutic choices are always wider, the main focus of the research will be to find predictors of the therapeutic response (pattern of interleukins, markers of bowel permeability) to help clinicians to choose between drugs with different mechanisms of action and to determine when surgery should be used instead of drugs.

This Special Issue aims to present and discuss novel immunological concepts applied in the treatment and management of patients with IBD.

Dr. Gian Paolo Caviglia
Dr. Davide Giuseppe Ribaldone
Guest Editors

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Keywords

inflammatory bowel disease
biological therapy
non-invasive biomarkers
Crohn’s disease
ulcerative colitis
intestinal permeability
inflammation

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Published Papers (8 papers)

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Research

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9 pages, 1055 KiB

Open AccessArticle

The Usefulness of Microencapsulated Sodium Butyrate Add-On Therapy in Maintaining Remission in Patients with Ulcerative Colitis: A Prospective Observational Study

by Marta Vernero, Federico De Blasio, Davide Giuseppe Ribaldone, Elisabetta Bugianesi, Rinaldo Pellicano, Giorgio Maria Saracco, Marco Astegiano and Gian Paolo Caviglia

J. Clin. Med. 2020, 9(12), 3941; https://doi.org/10.3390/jcm9123941 - 4 Dec 2020

Cited by 39 | Viewed by 3781

Abstract

Butyrate is a short-chain fatty acid that plays a key role in maintaining gut homeostasis as well as the integrity of the intestinal barrier. In the present study, we investigated the effect of oral microencapsulated sodium butyrate (BLM) administration in maintaining remission and improving residual symptoms and inflammatory markers in a population of patients with ulcerative colitis (UC). Forty-two patients with UC in clinical remission were enrolled in the study. Three patients were lost to follow up; 39 patients (18 treated with BLM add-on therapy and 21 with standard mesalamine only) that reached 12 months of follow up were included in the final analysis. Therapeutic success (defined as Mayo partial score ≤ 2 and faecal calprotectin (FC) < 250 µg/g at 12 months of follow up) was achieved in 25 patients (64.1%); 15/18 (83.3%) in BLM group and 10/21 (47.6%) in control group (p = 0.022). Consistently, 13/18 patients (72.2%) receiving BLM improved residual symptoms compared to 5/21 patients (23.8%) in control group (p = 0.003). FC values significantly diminished from the baseline to the end of follow up in patients that received BLM, while FC values remained almost stable in the control group. In conclusion, oral BLM supplementation appears to be a valid add-on therapy in order to maintain remission in patients with UC. Further randomized, placebo-controlled, double-blind clinical trials are needed to validate our results on a larger population or cohort of patients. Full article

(This article belongs to the Special Issue Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease)

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15 pages, 4308 KiB

Open AccessArticle

Inflammation-Induced Mucosal KYNU Expression Identifies Human Ileal Crohn’s Disease

by Meik Huhn, Martina Herrero San Juan, Balint Melcher, Caroline Dreis, Katrin G. Schmidt, Anja Schwiebs, Janet Collins, Josef M. Pfeilschifter, Michael Vieth, Jürgen Stein and Heinfried H. Radeke

J. Clin. Med. 2020, 9(5), 1360; https://doi.org/10.3390/jcm9051360 - 6 May 2020

Cited by 16 | Viewed by 4062

Abstract

The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise questions regarding the unclarified heterogeneity of pathological mechanisms promoting disease progression. While biomarkers for the differentiation of Crohn’s disease (CD) versus ulcerative colitis (UC) have been suggested, specific markers for a CD subclassification in ileal CD versus colonic CD are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterize potential biomarkers by focusing on the downstream enzymes and metabolites of kynurenine metabolism. Using immunohistochemical stainings, we analyzed and compared the mucosal tryptophan immune metabolism in bioptic samples from patients with active inflammation due to UC or CD versus healthy controls. Localization-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. We found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T cell and neutrophil granulocyte infiltration in the ileum compared with the colon. Furthermore, we observed decreased kynurenine levels as well as strong kynureninase (KYNU) expression specifically in patients with ileal CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in the ileal CD samples. Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD. Full article

(This article belongs to the Special Issue Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease)

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13 pages, 838 KiB

Open AccessArticle

Serum Interleukin-6 and -8 as Predictors of Response to Vedolizumab in Inflammatory Bowel Diseases

by Lorenzo Bertani, Gian Paolo Caviglia, Luca Antonioli, Rinaldo Pellicano, Sharmila Fagoonee, Marco Astegiano, Giorgio Maria Saracco, Elisabetta Bugianesi, Corrado Blandizzi, Francesco Costa and Davide Giuseppe Ribaldone

J. Clin. Med. 2020, 9(5), 1323; https://doi.org/10.3390/jcm9051323 - 2 May 2020

Cited by 24 | Viewed by 3415

Abstract

Vedolizumab, a monoclonal antibody directed against integrin α4β7, is an effective treatment for inflammatory bowel diseases. However, a significant number of patients do not achieve steroid-free clinical remission in the first year of treatment. An early identification of these patients is one of the most important challenges for clinicians and offers the possibility of therapeutic optimization in order to personalize biological therapy. The aim of our study was to test the prediction ability of interleukin (IL)-6 and -8 of clinical response after 12 months of therapy with vedolizumab (T2). We performed a prospective, multicentre study in patients affected by inflammatory bowel disease by analysing cytokines level before starting vedolizumab (T0) and after 10 weeks of therapy (T1). In the overall cohort (n = 54), IL-8 decrease > 2.6 pg/mL in the first 10 weeks of therapy was able to predict clinical response (area under the curve (AUC) = 0.70, sensitivity = 66%, specificity = 75%, p = 0.010), negative C-reactive protein (CRP) (AUC = 0.71, sensitivity = 64%, specificity = 80%, p = 0.009) and calprotectin < 250 mg/kg (AUC = 0.69, sensitivity = 64%, specificity = 78%, p = 0.030) after 44 weeks of therapy. In patients with ulcerative colitis (n = 40), baseline IL-8 values > 8.6 pg/mL and a decrease of IL-6 values > 0.4 pg/mL from T0 to T1 were significant and independent predictors of clinical response after 12 months of vedolizumab therapy (odds ratio (OR) = 6.96, 95% CI 1.27–38.22, p = 0.026 and OR = 7.29, 95% CI 1.42–37.50, p = 0.017, respectively). In patients with Crohn’s disease (n = 14), baseline IL-8 values > 8.6 pg/mL and baseline IL-6 values > 1.6 pg/mL allowed the identification of patients achieving negative CRP at T2 (AUC = 0.75, sensitivity = 74%, specificity = 76%, p < 0.001) and patients with faecal calprotectin values < 250 mg/kg at T2 (AUC = 0.71, sensitivity = 78%, specificity = 63%, p = 0.004). In conclusion, our study highlights a potential clinical role of serum cytokine levels for the prediction of clinical and biochemical steroid-free response in patients treated with vedolizumab. Full article

(This article belongs to the Special Issue Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease)

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16 pages, 2534 KiB

Open AccessArticle

Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn’s Disease Patients

by Andrew Y.F. Li Yim, Nicolette W. Duijvis, Mohammed Ghiboub, Catriona Sharp, Enrico Ferrero, Marcel M.A.M. Mannens, Geert R. D’Haens, Wouter J. de Jonge, Anje A. te Velde and Peter Henneman

J. Clin. Med. 2020, 9(4), 1055; https://doi.org/10.3390/jcm9041055 - 8 Apr 2020

Cited by 15 | Viewed by 3730

Abstract

Crohn’s disease (CD) is a multifactorial incurable chronic disorder. Current medical treatment seeks to induce and maintain a state of remission. During episodes of inflammation, monocytes infiltrate the inflamed mucosa whereupon they differentiate into macrophages with a pro-inflammatory phenotype. Here, we sought to characterize the circulating monocytes by profiling their DNA methylome and relate it to the level of CD activity. We gathered an all-female age-matched cohort of 16 CD patients and 7 non-CD volunteers. CD patients were further subdivided into 8 CD patients with active disease (CD-active) and 8 CD patients in remission (CD-remissive) as determined by the physician global assessment. We identified 15 and 12 differentially methylated genes (DMGs) when comparing CD with non-CD and CD-active with CD-remissive, respectively. Differential methylation was predominantly found in the promoter regions of inflammatory genes. Comparing our observations with gene expression data on classical (CD14⁺⁺CD16^-), non-classical (CD14⁺CD16⁺⁺) and intermediate (CD14⁺⁺CD16⁺) monocytes indicated that while 7 DMGs were differentially expressed across the 3 subsets, the remaining DMGs could not immediately be associated with differences in known populations. We conclude that CD activity is associated with differences in DNA methylation at the promoter region of inflammation-associated genes. Full article

(This article belongs to the Special Issue Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease)

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12 pages, 2104 KiB

Open AccessArticle

On-Treatment Decrease of Serum Interleukin-6 as a Predictor of Clinical Response to Biologic Therapy in Patients with Inflammatory Bowel Diseases

by Gian Paolo Caviglia, Chiara Rosso, Francesco Stalla, Martina Rizzo, Alessandro Massano, Maria Lorena Abate, Antonella Olivero, Angelo Armandi, Ester Vanni, Ramy Younes, Sharmila Fagoonee, Rinaldo Pellicano, Marco Astegiano, Giorgio Maria Saracco, Elisabetta Bugianesi and Davide Giuseppe Ribaldone

J. Clin. Med. 2020, 9(3), 800; https://doi.org/10.3390/jcm9030800 - 15 Mar 2020

Cited by 33 | Viewed by 4927

Abstract

In patients with inflammatory bowel diseases (IBD) undergoing biologic therapy, biomarkers of treatment response are still scarce. This study aimed to evaluate whether serum zonulin, a biomarker of intestinal permeability; soluble CD163 (sCD163), a macrophage activation marker; and a panel of serum cytokines could predict the response to biologic treatment in patients with IBD. For this purpose, we prospectively enrolled 101 patients with IBD and 19 patients with irritable bowel syndrome (IBS) as a control group; 60 out of 101 patients underwent treatment with biologics. Zonulin, sCD163, and cytokines were measured at the baseline in all patients and after 10 weeks of treatment in the 60 patients who underwent biologic therapy. We observed that zonulin levels were higher in IBD patients with active disease compared to those in remission (p = 0.035), and that sCD163 values were higher in patients with IBD compared to those with IBS (p = 0.042), but no association with therapy response was observed for either biomarker. Conversely, interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha showed a significant reduction from baseline to week 10 of treatment, particularly in responder patients. By multivariate logistic regression analysis corrected for disease (Crohn’s disease or ulcerative colitis), type of biologic drug (Infliximab, Adalimumab, Vedolizumab, or Ustekinumab) and disease activity, the reduction in IL-6 values was associated with a clinical response at 12 months of biological therapy (odds ratio (OR) = 4.75, 95% confidence interval (CI) 1.25–18.02, p = 0.022). In conclusion, the measurement of serum IL-6 in biologics-treated IBD patients may allow for the prediction of response to treatment at 12 months of therapy and thus may help with tailoring personalized treatment strategies. Full article

(This article belongs to the Special Issue Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease)

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16 pages, 318 KiB

Open AccessArticle

Serum Catestatin Levels and Arterial Stiffness Parameters Are Increased in Patients with Inflammatory Bowel Disease

by Piero Marin Zivkovic, Andrija Matetic, Ivana Tadin Hadjina, Doris Rusic, Marino Vilovic, Daniela Supe-Domic, Josip Andelo Borovac, Ivana Mudnic, Ante Tonkic and Josko Bozic

J. Clin. Med. 2020, 9(3), 628; https://doi.org/10.3390/jcm9030628 - 26 Feb 2020

Cited by 25 | Viewed by 3089

Abstract

Catestatin (CST) is an important peptide in the pathophysiology of chronic inflammatory disorders. However, clinical studies on inflammatory bowel disease (IBD) patients are lacking. Our goal was to investigate CST concentrations in IBD patients compared to healthy subjects. Additionally, we aimed to determine arterial stiffness parameters in relation to CST. This cross-sectional study compared 80 IBD patients (45 Crohn’s disease (CD) and 35 ulcerative colitis (UC) patients) with 75 control subjects. Serum CST levels were significantly higher in the IBD group compared to control subjects (11.29 ± 9.14 vs. 7.13 ± 6.08 ng/mL, p = 0.001) and in the UC group compared to CD patients (13.50 ± 9.58 vs. 9.03 ± 6.92 ng/mL, p = 0.021), irrespective of age and BMI. IBD patients exhibited significantly higher values of heart rate adjusted central augmentation index (cAIx-75) (14.88 ± 10.59 vs. 6.87 ± 9.50 %, p < 0.001) and pulse wave velocity (PWV) (8.06 ± 3.23 vs. 6.42 ± 1.47 m/s, p < 0.001) compared to control group. Furthermore, PWV was the only significant independent correlate of CST (B = 1.20, t = 4.15, p < 0.001), while CST, PWV, cAIx-75, high-sensitivity C-reactive protein and BMI were significant predictors of positive IBD status (1.089 (1.022–1.161), 1.515 (1.166–1.968), 1.060 (1.024–1.097), 1.458 (1.116–1.906), 0.793 (0.683–0.920), respectively). Serum CST levels were significantly higher in IBD patients compared to controls and an independent positive correlation of CST with PWV existed. Therefore, it is possible that CST could have a role in the complex pathophysiology of IBD and its cardiovascular complications. Full article

(This article belongs to the Special Issue Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease)

12 pages, 565 KiB

Open AccessArticle

Measuring Vitamin D Status in Chronic Inflammatory Disorders: How does Chronic Inflammation Affect the Reliability of Vitamin D Metabolites in Patients with IBD?

by Aysegül Aksan, Dilem Tugal, Nathalena Hein, Katharina Boettger, Yurani Caicedo-Zea, Ina Diehl, Claudia Schumann, Franz-Paul Armbruster and Jürgen Stein

J. Clin. Med. 2020, 9(2), 547; https://doi.org/10.3390/jcm9020547 - 17 Feb 2020

Cited by 12 | Viewed by 3347

Abstract

Evidence gained from recent studies has generated increasing interest in the role of vitamin D in extraskeletal functions such as inflammation and immunoregulation. Although vitamin D deficiency has been implicated in the pathophysiology of inflammatory diseases including inflammatory bowel disease (IBD), evidence as to whether vitamin D supplementation may cure or prevent chronic disease is inconsistent. Since 25OH-vitamin D (25OHD) has been suggested to be an acute-phase protein, its utility as a vitamin D status marker is therefore questionable. In this study, possible interactions of vitamin D and inflammation were studied in 188 patients with IBD, with high-sensitivity C-reactive protein (hsCRP) levels ≥ 5 mg/dL and/or fecal calprotectin ≥ 250 µg/g defined as biochemical evidence of inflammatory activity. Levels of 25OHD and vitamin D-binding protein (VDBP) were determined by ELISA, and 1,25-dihydroxyvitamin D (1,25OHD) and dihydroxycholecalciferol (24,25OHD) by LC-MS/MS. Free and bioavailable vitamin D levels were calculated with the validated formula of Bikle. Serum 1,25OH2D and vitamin D binding protein (VDBP) levels were shown to differ between the inflammatory and noninflammatory groups: patients with inflammatory disease activity had significantly higher serum concentrations of 1,25OH2D (35.0 (16.4–67.3) vs. 18.5 (1.2–51.0) pg/mL, p < 0.001) and VDBP (351.2 (252.2–530.6) vs. 330.8 (183.5–560.3) mg/dL, p < 0.05) than patients without active inflammation. Serum 24,25OH2D levels were negatively correlated with erythrocyte sedimentation rate (ESR) (−0.155, p = 0.049) while concentrations of serum 1,25OH2D correlated positively with hsCRP (0.157, p = 0.036). Correlations with serum VDBP levels were found for ESR (0.150, p = 0.049), transferrin (0.160, p = 0.037) and hsCRP (0.261, p < 0.001). Levels of serum free and bioavailable 25OHD showed a negative correlation with ESR (−0.165, p = 0.031, −0.205, p < 0.001, respectively) and hsCRP (−0.164, p = 0.032, −0.208, p < 0.001 respectively), and a moderate negative correlation with fecal calprotectin (−0.377, p = 0.028, −0.409, p < 0.016, respectively). Serum total 25OHD concentration was the only vitamin D parameter found to have no specific correlation with any of the inflammatory markers. According to these results, the traditional parameter, total 25OHD, still appears to be the best marker of vitamin D status in patients with inflammatory bowel disease regardless of the presence of inflammation. Full article

(This article belongs to the Special Issue Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease)

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Review

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25 pages, 412 KiB

Open AccessReview

Metabolomics as a Promising Resource Identifying Potential Biomarkers for Inflammatory Bowel Disease

by Cristina Bauset, Laura Gisbert-Ferrándiz and Jesús Cosín-Roger

J. Clin. Med. 2021, 10(4), 622; https://doi.org/10.3390/jcm10040622 - 6 Feb 2021

Cited by 26 | Viewed by 4118

Abstract

Inflammatory bowel disease (IBD) is a relapsing chronic disorder of the gastrointestinal tract characterized by disruption of epithelial barrier function and excessive immune response to gut microbiota. The lack of biomarkers providing early diagnosis or defining the status of the pathology difficulties an accurate assessment of the disease. Given the different metabolomic profiles observed in IBD patients, metabolomics may reveal prime candidates to be studied, which may help in understanding the pathology and identifying novel therapeutic targets. In this review, we summarize the most current advances describing the promising metabolites such as lipids or amino acids found through untargeted metabolomics from serum, faecal, urine and biopsy samples. Full article

(This article belongs to the Special Issue Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease)

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