Interleukin-24 regulates mucosal remodeling in inflammatory bowel diseases

Abstract Background Recently, increased interleukin (IL)-24 expression has been demonstrated in the colon biopsies of adult patients with inflammatory bowel disease (IBD). However, the role of IL-24 in the pathomechanism of IBD is still largely unknown. Methods Presence of IL-24 was determined in the samples of children with IBD and in the colon of dextran sodium sulfate (DSS) treated mice. Effect of inflammatory factors on IL24 expression was determined in peripheral blood (PBMCs) and lamina propria mononuclear cells (LPMCs). Also, the impact of IL-24 was investigated on HT-29 epithelial cells and CCD-18Co colon fibroblasts. Expression of tissue remodeling related genes was investigated in the colon of wild type (WT) mice locally treated with IL-24 and in the colon of DSS treated WT and Il20rb knock out (KO) mice. Results Increased amount of IL-24 was demonstrated in the serum and colon samples of children with IBD and DSS treated mice compared to that of controls. IL-1β, LPS or H2O2 treatment increased the expression of IL24 in PBMCs and LPMCs. IL-24 treatment resulted in increased amount of TGF-β and PDGF-B in HT-29 cells and enhanced the expression of extracellular matrix (ECM)-related genes and the motility of CCD-18Co cells. Similarly, local IL-24 treatment increased the colonic Tgfb1 and Pdgfb expression of WT mice. Moreover, expression of pro-fibrotic Tgfb1 and Pdgfb were lower in the colon of DSS treated Il20rb KO compared to that of WT mice. The disease activity index of colitis was less severe in DSS treated Il20rb KO compared to WT mice. Conclusion Our study suggest that IL-24 may play a significant role in the mucosal remodeling of patients with IBD by promoting pro-fibrotic processes.

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Serum Adalimumab Levels After Induction Are Associated With Long-Term Remission in Children With Inflammatory Bowel Disease

Frontiers in Pediatrics ◽

10.3389/fped.2021.646671 ◽

2021 ◽

Vol 9 ◽

Author(s):

Marianna Lucafò ◽

Debora Curci ◽

Matteo Bramuzzo ◽

Patrizia Alvisi ◽

Stefano Martelossi ◽

...

Keyword(s):

Disease Activity ◽

Activity Index ◽

Disease Activity Index ◽

Therapeutic Drug ◽

Serum Samples ◽

Level Measurement ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Term Response

Introduction: Adalimumab is effective in inducing and maintaining remission in children with inflammatory bowel diseases (IBD). Therapeutic drug monitoring is an important strategy to maximize the response rates, but data on the association of serum adalimumab levels are lacking. This study aimed to assess the association of adalimumab concentrations at the end of induction and early during maintenance for long-term response.Materials and Methods: Serum samples for adalimumab level measurement were collected during routine visits between adalimumab administrations and therefore not necessarily at trough, both during the induction (week 4 ± 4) and maintenance phases (week 22 ± 4, 52 ± 4, and 82 ± 4). Adalimumab and anti-adalimumab antibodies were measured retrospectively using enzyme-linked immunosorbent assays (ELISA). Disease activity was determined by Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index.Results: Thirty-two children (median age 14.9 years) were enrolled. Sixteen, 15, 14, and 12 patients were in remission at weeks 4, 22, 52, and 82, respectively. Median adalimumab concentration was higher at all time points in patients achieving sustained clinical remission. Adalimumab levels correlated with clinical and biochemical variables. Adalimumab concentration above 13.85 and 7.54 μg/ml at weeks 4 and 22 was associated with remission at weeks 52 and 82.Conclusions: Adalimumab non-trough levels are associated with long-term response in pediatric patients with IBD.

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Salvia miltiorrhiza Ameliorates Disease Progression in Dextran-Sodium-Sulfate Induced Colitis in Mice

10.21203/rs.3.rs-1006608/v1 ◽

2021 ◽

Author(s):

Juan Chen ◽

Danyu Chen ◽

Lu Cheng ◽

YongKang Yang ◽

Weidong Gu ◽

...

Keyword(s):

Sodium Sulfate ◽

Activity Index ◽

Salvia Miltiorrhiza ◽

Disease Activity Index ◽

Cerebrovascular Diseases ◽

Dextran Sodium Sulfate ◽

Inflammatory Factors ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

Inflammatory Effect

Abstract Salvia miltiorrhiza (SM, or Danshen) extract has been approved by China FDA for the treatment of cardiovascular and cerebrovascular diseases owing to its potent anti-inflammatory effects. Whether SM may be used to treat inflammatory bowel disease (IBD) remains elusive. In the current study, Dextran-Sodium-Sulfate (DSS) induced colitis in mice was used as a model of IBD, and SM was given orally for 7 days. SM administration has significantly reduced the disease activity index (DAI) score and weight lost and colon shortening in the DSS-induced colitis mice. The macrophage infiltration was significantly reduced in the SM treatment group. To explore the mechanisms, macrophage processor cell line Raw 264.7 was used to verify the anti-inflammatory effect of SM. SM treatment inhibited lipopolysaccharide (LPS)-induced macrophage activation in RAW264.7 cells and significantly reduced the production of pro-inflammatory factors. The current study provided evidence that oral administration of SM ameliorates pathological deterioration of IBD in mice, and warrants future clinical application of SM for the management of IBD.

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Vitamin D level in Hungarian patients with inflammatory bowel diseases

Orvosi Hetilap ◽

10.1556/oh.2013.29750 ◽

2013 ◽

Vol 154 (46) ◽

pp. 1821-1828 ◽

Cited By ~ 2

Author(s):

Katalin Lőrinczy ◽

Péter László Lakatos ◽

Miklós Tóth ◽

Ágnes Salamon ◽

Adrienn Nemes ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Vitamin D ◽

Vitamin D Deficiency ◽

Inflammatory Bowel Diseases ◽

Bowel Disease ◽

Activity Index ◽

Disease Activity Index ◽

Clinical Activity ◽

Bowel Diseases ◽

Inflammatory Bowel

Introduction: Vitamin D has an important role in the immune regulation. Vitamin D is essential for innate and adaptive immune systems and it plays a significant role in the formation of immune tolerance, as well. Aim: Vitamin D deficiency has been observed in patients with inflammatory bowel diseases in Western Europe, but there is no data available from Eastern Europe. Method: The study included 169 patients with inflammatory bowel disease. Results: The median vitamin D level was 22.7±10.6 ng/ml. Only 20% of the patients had adequate vitamin D level (>30 ng/ml), 52% had vitamin D insufficiency (15–30 ng/ml), and 28% of them had severe vitamin D deficiency (<15 ng/ml). Vitamin D concentration failed to correlate with clinical activity indexes (partial Mayo score: r = –0.143; Crohn’s disease activity index: r = –0.253) and with inflammatory parameters (C-reactive protein: r = 0.008; erythrocyte sedimentation rate: r = 0.012). Conclusions: Since vitamin D deficiency can be frequently observed in Hungarian patients with inflammatory bowel disease, its level should be tested in these patients. Orv. Hetil., 154(46), 1821–1828.

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Calprotectin Is a Useful Tool in Distinguishing Coexisting Irritable Bowel-Like Symptoms from That of Occult Inflammation among Inflammatory Bowel Disease Patients in Remission

Gastroenterology Research and Practice ◽

10.1155/2013/620707 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4 ◽

Cited By ~ 27

Author(s):

Lars-Petter Jelsness-Jørgensen ◽

Tomm Bernklev ◽

Bjørn Moum

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Disease Activity Index ◽

Fecal Calprotectin ◽

Elisa Test ◽

Rome Ii Criteria ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Irritable Bowel

Background and Aim. In the inflammatory bowel diseases (IBDs), many symptoms are similar to the functional disorder irritable bowel syndrome (IBS). A challenge is thus to distinguish symptoms of IBD from IBS. The aim of this study was to investigate the levels of calprotectin in IBS-positive IBD patients in remission.Methods. Remission was defined as a simple clinical colitis activity index (SCCAI) or simple crohn’s disease activity index (SCDAI) score of less than three and less than four, respectively. The Rome II criteria were used to identify cases, and the calprotectin ELISA test was used to quantify calprotectin in stools.Results. The Rome II criteria were fulfilled in 24.6% of ulcerative colitis (UC) patients, while the comparable number for Crohn's disease (CD) was 21.4%. There was a tendency for elevated fecal calprotectin levels in IBS-positive patients, regardless of diagnosis. However, these differences were only significant in CD.Conclusions. Calprotectin levels are elevated in subgroups of IBD patients that are in remission and have coexisting IBS-like symptoms. This study underscores the clinical usefulness of a noninvasive marker to distinguish patients in need of intensified followup from those that do not need further workup.

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Potential clinical treatment of colitis with cardiotrophin-1

Clinical Science ◽

10.1042/cs20171626 ◽

2018 ◽

Vol 132 (20) ◽

pp. 2169-2174 ◽

Cited By ~ 1

Author(s):

Xavier Escoté

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Activity Index ◽

Disease Activity Index ◽

Tnf Α ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Factor Α

In a recent issue of Clinical Science, Prieto-Vicente et al. [Clin. Sci. (2018) 132, 985–1001] have smartly demonstrated a potential new use of cardiotrophin-1 (CT-1) to treat and palliate an inflammatory bowel disease such as ulcerative colitis. In that work, authors report that in ulcerative colitic mice, administration of exogenous recombinant CT-1 (rCT-1) promotes lower colon damage and lower disease activity index, reducing systemic levels of tumor necrosis factor α (TNF-α) and also diminishing TNF-α expression in colon together with the reduction in other common inflammation markers. Besides, in vivo rCT-1 administration induces activation of several molecular pathways, including nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-3, and abolishes bacterial translocation from intestine to other organs, including mesenteric ganglia, lungs, and spleen. Additionally, these results were nicely corroborated in CT-1 depleted mice; in which colon damage and ulcerative colitis severity were greater compared with the wild-type counterparts. All together, these results suggested that CT-1 could be a promising new therapeutic approach for treating inflammatory bowel disease, particularly ulcerative colitis. However, further studies are required to determine its major mechanisms of action and the potential efficacy of CT-1 in human inflammatory bowel diseases.

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Gut microbiota changes in inflammatory bowel diseases and ankylosing spondilytis

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld-2823 ◽

2021 ◽

Author(s):

Anca Cardoneanu ◽

Catalina Mihai ◽

Elena Rezus ◽

Alexandra Burlui ◽

Iolanda Popa ◽

...

Keyword(s):

Intestinal Microbiota ◽

Crohn Disease ◽

Inflammatory Bowel Diseases ◽

Activity Index ◽

Disease Activity Index ◽

Control Group ◽

Bacterial Group ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Activity Index Score

Background and Aims: Both inflammatory bowel diseases (IBD) and ankylosing spondylitis (AS) can be considered chronic immune disorders sharing common etiopathogenetic mechanisms. Changes in the composition of the intestinal microbiota, which can lead to an abnormal mucosal response, could be the missing link between these two diseases. Our study evaluate the composition of intestinal microbiota and to characterize gut dysbiosis in patients with IBD and AS. Methods: We conducted a prospective case-control study that enrolled 124 patients [20 Crohn’s disease (CD), 27 ulcerative colitis (UC), 28 AS, 17 IBD + AS and 32 controls). Intestinal microbiota analysis was performed by real-time polymerase chain reaction in stool samples. Results: The total quantity of bacteria was decreased in all investigated groups compared to the control group. In studied groups, we noticed an increased percentage of Bacteroides and Escherichia coli (E.coli) and a decreased percentage of Clostridium coccoides, Clostridium leptum, and Faecalibacterium prausnitzii compared to the control group. The percentages of Bifidobacterium (p=0.010) as well as Lactobacillus group (p=0.023) were higher in the L3 form of CD patients. In the E2 form of UC, the quantity of Bacteroides was much higher compared to the E3 form (p=0.004). In AS patients, significant correlations were observed only for the Bifidobacterium species, significantly increased in the axial form compared to peripheral disease (p=0.035). Statistically significant correlations were demonstrated between the Crohn Disease Activity Index score and the total bacterial group (p=0.023, r=-0.507), respectively Bacteroides (p=0.021, r=-0.511) and between the Mayo score and Lactobacillus (p=0.001), respectively E. coli (p=0.001). In IBD + AS group, the Crohn Disease Activity Index score was inversely correlated with the total bacterial group (p=0.010) and directly correlated with Lactobacillus (p=0.047). Conclusions: Intestinal dysbiosis is associated with both IBD and AS. In the association of IBD with AS, dysbiosis is intermediate, but it is associated with the more severe articular disease. Bifidobacterium and Lactobacillus (commonly used as probiotics!) were found to be increased in the association between active IBD and active AS. Further studies are needed to understand how dysbiosis regulates the gut immune system and contributes to intestinal and articular inflammation.

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Outcomes of Passable and Non-passable Strictures in Clinical Trials of Crohn’s Disease: A Post-hoc Analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab045 ◽

2021 ◽

Author(s):

Neeraj Narula ◽

Emily C L Wong ◽

Parambir S Dulai ◽

John K Marshall ◽

Jean-Frederic Colombel ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Disease Activity Index ◽

Symptom Improvement ◽

Logistic Regression Models ◽

Post Hoc Analysis ◽

Endoscopic Remission ◽

Post Hoc ◽

The Impact

Abstract Background and Aims There is paucity of evidence on the reversibility of Crohn’s disease [CD]-related strictures treated with therapies. We aimed to describe the clinical and endoscopic outcomes of CD patients with non-passable strictures. Methods This was a post-hoc analysis of three large CD clinical trial programmes examining outcomes with infliximab, ustekinumab, and azathioprine, which included data on 576 patients including 105 with non-passable strictures and 45 with passable strictures, as measured using the Simple Endoscopic Score for Crohn’s Disease [SES-CD]. The impact of non-passable strictures on achieving clinical remission [CR] and endoscopic remission [ER] was assessed using multivariate logistic regression models. CR was defined as a Crohn’s Disease Activity Index [CDAI] <150, clinical response as a CDAI reduction of ≥100 points, and ER as SES-CD score <3. Results After 1 year of treatment, patients with non-passable strictures demonstrated the ability to achieve passable or no strictures in 62.5% of cases, with 52.4% and 37.5% attaining CR and ER, respectively. However, patients with non-passable strictures at baseline were less likely to demonstrate symptom improvement compared with those with passable or no strictures, with reduced odds of 1-year CR (adjusted odds ratio [aOR] 0.17, 95% CI 0.03–0.99, p = 0.048). No significant differences were observed between patients with non-passable strictures at baseline and those with passable or no strictures in rates of ER [aOR 0.82, 95% CI 0.23–2.85, p = 0.751] at 1 year. Conclusions Patients with non-passable strictures can achieve symptomatic and endoscopic remission when receiving therapies used to treat CD, although they are less likely to obtain CR compared with patients without non-passable strictures. These findings support the importance of balancing the presence of non-passable strictures in trial arms.

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Isolation and Characterization of Potentially Probiotic Bacterial Strains from Mice: Proof of Concept for Personalized Probiotics

Nutrients ◽

10.3390/nu10111684 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1684 ◽

Cited By ~ 2

Author(s):

Larissa Celiberto ◽

Roseli Pinto ◽

Elizeu Rossi ◽

Bruce Vallance ◽

Daniela Cavallini

Keyword(s):

Intestinal Inflammation ◽

Activity Index ◽

Disease Activity Index ◽

Bacterial Strains ◽

Dss Colitis ◽

Isolation And Characterization ◽

Inflammatory Bowel ◽

Commercial Probiotics ◽

Lower Disease Activity

Modulation of the gut microbiota through the use of probiotics has been widely used to treat or prevent several intestinal diseases. However, inconsistent results have compromised the efficacy of this approach, especially in severe conditions such as inflammatory bowel disease (IBD). The purpose of our study was to develop a personalized probiotic strategy and assess its efficacy in a murine model of intestinal inflammation. Commensal bacterial strains were isolated from the feces of healthy mice and then administered back to the host as a personalized treatment in dextran sodium sulfate (DSS)-induced colitis. Colonic tissues were collected for histological analysis and to investigate inflammatory markers such as Il-1β, Il-6, TGF-β, and Il-10, and the enzyme myeloperoxidase as a neutrophil marker. The group that received the personalized probiotic showed reduced susceptibility to DSS-colitis as compared to a commercial probiotic. This protection was characterized by a lower disease activity index and reduced histopathological damage in the colon. Moreover, the personalized probiotic was more effective in modulating the host immune response, leading to decreased Il-1β and Il-6 and increased TGF-β and Il-10 expression. In conclusion, our study suggests that personalized probiotics may possess an advantage over commercial probiotics in treating dysbiotic-related conditions, possibly because they are derived directly from the host’s own microbiota.

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Intestinal Taxa Abundance and Diversity in Inflammatory Bowel Disease Patients: An Analysis including Covariates and Confounders

Nutrients ◽

10.3390/nu14020260 ◽

2022 ◽

Vol 14 (2) ◽

pp. 260

Author(s):

Adelaide Teofani ◽

Irene Marafini ◽

Federica Laudisi ◽

Daniele Pietrucci ◽

Silvia Salvatori ◽

...

Keyword(s):

Dairy Products ◽

Dietary Habits ◽

Rrna Gene ◽

Disease Extent ◽

Intestinal Dysbiosis ◽

Gene Sequence Analysis ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Abundance And Diversity ◽

The Impact

Intestinal dysbiosis has been widely documented in inflammatory bowel diseases (IBDs) and is thought to influence the onset and perpetuation of gut inflammation. However, it remains unclear whether such bacterial changes rely in part on the modification of an IBD-associated lifestyle (e.g., smoking and physical activity) and diet (e.g., rich in dairy products, cereals, meat and vegetables). In this study, we investigated the impact of these habits, which we defined as confounders and covariates, on the modulation of intestinal taxa abundance and diversity in IBD patients. 16S rRNA gene sequence analysis was performed using genomic DNA extracted from the faecal samples of 52 patients with Crohn’s disease (CD) and 58 with ulcerative colitis (UC), which are the two main types of IBD, as well as 42 healthy controls (HC). A reduced microbial diversity was documented in the IBD patients compared with the HC. Moreover, we identified specific confounders and covariates that influenced the association between some bacterial taxa and disease extent (in UC patients) or behaviour (in CD patients) compared with the HC. In particular, a PERMANOVA stepwise regression identified the variables “age”, “eat yogurt at least four days per week” and “eat dairy products at least 4 days per week” as covariates when comparing the HC and patients affected by ulcerative proctitis (E1), left-sided UC (distal UC) (E2) and extensive UC (pancolitis) (E3). Instead, the variables “age”, “gender”, “eat meat at least four days per week” and “eat bread at least 4 days per week” were considered as covariates when comparing the HC with the CD patients affected by non-stricturing, non-penetrating (B1), stricturing (B2) and penetrating (B3) diseases. Considering such variables, our analysis indicated that the UC extent differentially modulated the abundance of the Bifidobacteriaceae, Rikenellaceae, Christensenellaceae, Marinifilaceae, Desulfovibrionaceae, Lactobacillaceae, Streptococcaceae and Peptostreptococcaceae families, while the CD behaviour influenced the abundance of Christensenellaceae, Marinifilaceae, Rikenellaceae, Ruminococcaceae, Barnesiellaceae and Coriobacteriaceae families. In conclusion, our study indicated that some covariates and confounders related to an IBD-associated lifestyle and dietary habits influenced the intestinal taxa diversity and relative abundance in the CD and UC patients compared with the HC. Indeed, such variables should be identified and excluded from the analysis to characterize the bacterial families whose abundance is directly modulated by IBD status, as well as disease extent or behaviour.

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Stiffness Regulates Intestinal Stem Cell Fate

10.1101/2021.03.15.435410 ◽

2021 ◽

Author(s):

Shijie He ◽

Peng Lei ◽

Wenying Kang ◽

Priscilla Cheung ◽

Tao Xu ◽

...

Keyword(s):

Cell Fate ◽

Nuclear Translocation ◽

Goblet Cells ◽

Metabolic Phenotype ◽

Hydrogel Matrix ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

The Impact

SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate of intestinal stem cells (ISCs)? To address this question we first developed a novel long-term culture of quasi-3D gut organoids plated on hydrogel matrix of varying stiffness. Stiffening from 0.6kPa to 9.6kPa significantly reduces Lgr5high ISCs and Ki67+ progenitor cells while promoting their differentiation towards goblet cells. These stiffness-driven events are attributable to YAP nuclear translocation. Matrix stiffening also extends the expression of the stemness marker Olfactomedin 4 (Olfm4) into villus-like regions, mediated by cytoplasmic YAP. We next used single-cell RNA sequencing to generate for the first time the stiffness-regulated transcriptional signatures of ISCs and their differentiated counterparts. These signatures confirm the impact of stiffening on ISC fate and additionally suggest a stiffening-induced switch in metabolic phenotype, from oxidative phosphorylation to glycolysis. Finally, we used colon samples from IBD patients as well as chronic colitis murine models to confirm the in vivo stiffening-induced epithelial deterioration similar to that observed in vitro. Together, these results demonstrate stiffness-dependent ISC reprograming wherein YAP nuclear translocation diminishes ISCs and Ki67+ progenitors and drives their differentiation towards goblet cells, suggesting stiffening as potential target to mitigate gut epithelial deterioration during IBD.

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