Diverticular disease (DD) is one of the most prevalent diseases of the large bowel. Lately, imbalance of neuro-muscular transmission has been recognized as a major etiological factor for DD. Neuronal ...calcitonin gene-related peptide (CGRP) is a potent gastrointestinal smooth muscle relaxant shown to have a widespread effect within the alimentary tract. Nevertheless, CGRPergic innervation of the enteric ganglia has never been considered in the context of motility impairment observed in DD patients. Changes in CGRP and calcitonin receptor-like receptor (CRLR) abundance within enteric ganglia were investigated in sigmoid samples from symptomatic and asymptomatic DD patients using quantitative fluorescence microscopy. CGRP effect on gastrointestinal smooth muscle was investigated using organ bath technique. We found CGRP levels within the enteric ganglia to be declined by up to 52% in symptomatic DD patients. Conversely, CRLR within the enteric ganglia was upregulated by 41% in symptomatic DD. Longitudinal smooth muscle displayed an elevated (+10.5%) relaxant effect to the exogenous application of CGRP in colonic strips from symptomatic DD patients. Samples from asymptomatic DD patients consistently showed intermediate values across different experiments. In conclusion, the present study demonstrates that CGRPergic signaling is subject to alteration in DD. Our results suggest that a hypersensitization mechanism to gradually decreasing levels of CGRP-IR nerve fibers takes place during DD progression. Alterations to CGRPergic signaling in DD disease may have implications for physiological abnormalities associated with colonic DD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background : MiRNAs represent a class of small non-coding RNAs which are involved in regulation of protein-coding gene expression. Being implicated in various processes such as development and ...regu-latory circuits of cells, miRNAs also play an important role in the etiology of a variety of diseases. Imbalance of the regulatory pro-cesses within immune system development and response may lead to disturbed production of pro-inflammatory cytokines and over-reactivity of the immune cells, thus causing relapsing inflamma-tion, a characteristic feature of inflammatory bowel disease (IBD). Recent studies of colonic miRNAs employed NGS for the distinction between CD, UC and healthy controls, or among different CD sub-types. However, NGS-based profiles of blood-circulating miRNAs have thus far not been investigated in the context of IBD together with other immune-mediated diseases, including ankylosing spon-dylitis, psoriasis, systemic lupus erythematosus, rheumatoid arthritis and sarcoidosis, as well as non-immune hemolytic-uremic syndrome.
Methods : Study participants were recruited in Germany and Sweden, where peripheral blood samples (PAXgene) as well as phenotypical and clinical information (such as treatment status, dis-ease activity and location) was collected. Small RNA transcriptomes of 680 individuals (Figure 1) were sequenced using Illumina NGS platform. Small RNA-seq data preprocessing and quantification were performed using cutadapt and miraligner (ref. miRBase v22), respectively. Differential expression analysis (DESeq2) and correla-tion (Spearman) analysis have been performed to identify disease activity-, trait- and treatment-specific miRNA signatures. These sig-natures were then utilized in a machine-learning approach to build classification models for IBD diagnostics.
Results : The results of multiple pairwise differential expression anal-yses among different immune-mediated inflammatory conditions and healthy controls revealed inflammation-specific as well and dis-ease-specific deregulation of miRNAs. Correlation analysis identified miRNAs positively and negatively correlated with IBD activity. The preliminary results of machine learning classifiers based on miRNA profiles showed that median Matthews correlation coefficient for all model types showed remarkable predictive performance estimated as being 1.00 (median over main diagnoses), as well as ranging from 0.68 to 0.76 (median over CD location) and from 0.69 to 0.77 (median over UC extent).
Conclusions : Immune-mediated inflammatory diseases share com-mon and distinct differentially expressed miRNAs, which have a potential to be used in the diagnostics of IBD, including the evalua-tion of the disease activity.
Abstract
Background
Microscopic colitis (MC) is an autoimmune inflammatory condition that causes watery diarrhoea along with other symptoms like bowel incontinence, resulting in impaired quality of ...life and morbidity. MC is localized to the colon, although other autoimmune disorders are known to be more prevalent among MC patients.
Methods
A retrospective analysis of consecutive MC patients treated in Lithuanian University of Health Sciences Hospital Kauno Klinikos over the last 6 years was performed. Patient information was obtained from electronic records and reviewed for demographic characteristics and diagnosed conditions.
Results
94 MC patients were treated in our centre since 2017, 46 (49 %) with collagenous colitis (CC), 39 (41.5 %) with lymphocytic colitis (LC), 2 (2.1 %) with incomplete CC and 7 (7.4 %) with incomplete LC. 77 patients were female (82 %). Median age was 59 years 44.8-70.3. There was a tendency for men to be younger (median 42 37-68) than women (median 60 50-70.5) but not significantly (p>0.05).
31 MC patients (33 %) we diagnosed with concomitant autoimmune disorders. 20 patients (21.3 %) had autoimmune thyroiditis, 7 (7.4 %) had coeliac disease, 7 (7.4 %) had autoimmune skin conditions, 5 (5.3 %) had rheumatoid arthritis, 1 (1.1 %) had spondyloarthritis and 2 (2.1 %) had autoimmune hepatitis. 9 patients (9.6 %) had 2 autoimmune conditions in addition to MC and 1 patient (1.1 %) had 3.
16 (34.8 %) CC patients, 11 (28.2 %) LC patients and 4 (57 %) incomplete LC patients had autoimmune comorbidities. 3 (6.5 %) CC patients, 3 (7.7 %) LC patients and 1 (14.3) incomplete LC patient had coeliac disease. Autoimmune thyroiditis was observed in 11 (23.9 %) CC patients, 6 (15.4 %) LC patients and 3 (42.9 %) incomplete LC patients. 2 (4.3 %) CC patients and 3 (7.7 %) LC patients had rheumatoid arthritis. 5 (10.9 %) CC patients and 2 (5.1 %) LC patients has autoimmune skin disorders. The differences between CC and LC patients were not statistically significant. Both patients with autoimmune hepatitis had LC and the patient with spondyloarthritis had incomplete LC.
Conclusion
MC patients in our centre were frequently diagnosed with additional autoimmune disorders warranting vigilance in clinical practice. There was no difference between CC and LC patients. Incomplete LC patients had a higher proportion of autoimmune comorbidities and though the number of cases was low, this opens up prospects for future investigation.
Our aim was to prospectively assess the antibiotic resistance rates in
strains in Europe in 2018 and to study the link between antibiotic consumption in the community and
resistance levels in the ...different countries.
The proportion of primary antibiotic resistance cases of
and their corresponding risk factors were investigated in 24 centres from 18 European countries according to a standardised protocol. Data on antibiotic consumption in the community were collected for the period 2008-2017. The link between antibiotic consumption and resistance data was assessed using generalised linear mixed models. The model with the best fit was selected by means of the Akaike Information Criterion.
resistance rates for the 1211 adult patients included were 21.4% for clarithromycin, 15.8% for levofloxacin and 38.9% for metronidazole and were significantly higher in Central/Western and Southern than in the Northern European countries.The best model fit was obtained for the Poisson distribution using 2013 consumption data. A significant association was found between
clarithromycin resistance and consumption in the community of macrolides (p=0.0003) and intermediate-acting macrolides (p=0.005), and between levofloxacin resistance and consumption of quinolones (p=0.0002) and second-generation quinolones (p=0.0003).
This study confirms the positive correlation between macrolide and quinolone consumption in the community and corresponding
resistance in European countries. Hence,
treatment with clarithromycin and levofloxacin should not be started without susceptibility testing in most European countries.
Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We ...report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.
Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.
We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near
with a p value of 2.3×10
and 0.002 (OR
=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis,
(OR 1.32, 95% CI 1.12 to 1.56),
(OR 1.21, 95% CI 1.04 to 1.42),
(OR 1.17, 95% CI 1.03 to 1.33) and
(OR 1.17, 95% CI 1.03 to 1.33).
In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
Microbiota and cancer therapy J. Kupcinskas; G. Hold
Microbiota in health and disease,
01/2020, Volume:
2
Journal Article
Peer reviewed
Open access
The current article is a review of the most important, accessible, and relevant literature published between April 2018 and March 2019 on the gut microbiota and cancer therapy. The first part of the ...review focuses on literature describing changes in the gut microbiota in response to therapeutic interventions, including checkpoint inhibitors, radiotherapy, and microbial therapeutics whilst the subsequent section focuses on the mechanistic aspects of the process.
Abstract
Background
Ulcerative Colitis (UC) is a chronic, relapsing inflammatory disease of the lower gastrointestinal tract. The frequency of UC is increasing worldwide, however, existing methods ...for both diagnostics and treatment of this disease are not efficient enough. It is known that besides comprised immune response, environmental and genetic factors, gut microbiota play a major role in the onset and course of UC. Therefore, efforts are currently being made to find and develop new gut microbiome-based tools to improve the management of UC. The aim of this study was to identify changes in the gut microbiome during active and quiescent UC.
Methods
Study included 72 subjects, who were divided into three age- and sex-matched groups: control (n=25), active UC (n=27) and quiescent UC (n=20). Total DNA was extracted from faeces, which was further subjected to the next generation sequencing of 16S rRNA-coding gene V1-V2 hypervariable region on MiSeq (Illumina) platform. Further, bioinformatics and statistical analysis were performed.
Results
Bacterial α-diversity, as assessed by Richness, Shannon and Simpson diversity indexes, revealed that control patients had highest α-diversity compared to patients with active UC or quiescent UC (p<0.05), but there were no differences between UC disease states (p>0.05). Significant microbial community clusters (β-diversity), as assessed by the Bray-Curtis dissimilarity index, were identified between control subjects and patients with active or quiescent UC (p=0.02, p<0.01, respectively). However, no significant clusters were found between different disease states (p=0.22). In-between samples dissimilarity assessed by Bray-Curtis dissimilarity index showed that samples from control subjects had higher in-between sample similarity (mean 0.542 ± 0.117) than patients with active (mean 0.638 ± 0.161) and quiescent (0.6 ± 0.145) UC. In addition, 16, 13 and 27 core taxa were identified in active, quiescent UC and control group, respectively. Differential abundance of Cuneatibacter, Faecalibacterium and Prevotellamassilia genera was detected when comparing control vs UC (both active and quiescent), Paraprevotella and Cuneatibacter genera – control vs active UC, Faecalibacterium, Prevotellamassilia, Mediterraneibacter and Cuneatibacter genera – control vs quiescent UC.
Conclusion
In conclusion, this study revealed both qualitative and quantitative gut microbiota changes in active and quiescent UC.
Study was funded by the Research Council of Lithuania (Grant No. S-MIP-20-56).
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