In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils-elusive granulocytes that are implicated in a plethora of human pathologies1-5-are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4+ T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.
- MeSH
- analýza genové exprese jednotlivých buněk MeSH
- antigeny CD80 metabolismus MeSH
- eozinofily * klasifikace cytologie imunologie metabolismus MeSH
- idiopatické střevní záněty imunologie MeSH
- imunita * MeSH
- interferon gama MeSH
- interleukin 33 MeSH
- kolitida * imunologie patologie MeSH
- lidé MeSH
- myši MeSH
- proteom MeSH
- střeva * imunologie patologie MeSH
- T-lymfocyty MeSH
- transkriptom MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Zánětlivá onemocnění tlustého střeva patří mezi častou problematiku v rutinní bioptické praxi. Jejich interpretace může být náročná s ohledem na omezené a značně překryvné spektrum morfologických změn, kterými se mohou jednotlivá onemocnění manifestovat. Adekvátně posouzená biopsie střevní sliznice však stále představuje důležitý článek multidisciplinárního diagnostického řetězu a rozpoznání základních morfologických vzorců nenádorových střevních onemocnění by tak mělo patřit do výbavy každého patologa. Tento doškolovací text si klade za cíl přiblížit systematický přístup k histopatologickému hodnocení kolitid a zaměřuje se zejména na onemocnění jiná než nespecifické střevní záněty (IBD).
Non-neoplastic inflammatory conditions of a large bowel mucosa are commonly encountered in bioptic practice. Their interpretation yields many challenges especially due to their limited and often non-specific and overlapping morphological spectrum. However, an accurate assessment of colonic biopsy still represents an important part of multidisciplinary diagnostic process and identification and subsequent interpretation of proper morphological pattern should be in a competence of any routine pathologist. This article provides systematic approach to histopathological assessment of inflammatory diseases of colonic mucosa, focusing mainly on diagnoses other than inflammatory bowel disease (IBD).
- MeSH
- biopsie MeSH
- diferenciální diagnóza MeSH
- histologické techniky * MeSH
- kolitida * diagnóza klasifikace patologie MeSH
- lidé MeSH
- tlusté střevo anatomie a histologie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Ulcerative colitis is caused by various external factors and is an inflammatory disease that causes decreased intestinal function. Tenebrio molitor larvae contain more than 30 % fat, and the fat component consists of 45 % oleic acid, 20 % linoleic acid and 20 % polyunsaturated fatty acids. In this study, after administering Tenebrio molitor larva oil (TMLO) in a dextran sodium sulphate (DSS)-induced ulcerative colitis mouse model, the pathological findings and inflammatory markers of colitis were analysed to assess whether a colitis mitigation effect was achieved. In the TMLO-administered group, the colon length increased, the spleen weight decreased, and the body weight increased compared with that in the DSS group. In addition, the disease activity index level decreased, the mRNA expression level of inflammatory cytokines in the colon decreased, and the myeloperoxidase activity level significantly decreased. Also, the activity of the NF-κB pathway involved in the regulation of the inflammatory response was lower in the TMLO group than in the DSS group. Taken together, these results suggest that TMLO suppresses occurrence of acute ulcerative colitis in the DSS mouse model. Therefore, TMLO has the potential to be developed as a health food for the prevention and treatment of ulcerative colitis.
- MeSH
- antiflogistika farmakologie terapeutické užití MeSH
- kolitida * chemicky indukované farmakoterapie patologie MeSH
- larva MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- síran dextranu toxicita MeSH
- Tenebrio * MeSH
- ulcerózní kolitida * chemicky indukované farmakoterapie patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
LST1 is a small adaptor protein expressed in leukocytes of myeloid lineage. Due to the binding to protein tyrosine phosphatases SHP1 and SHP2 it was thought to have negative regulatory function in leukocyte signaling. It was also shown to be involved in cytoskeleton regulation and generation of tunneling nanotubes. LST1 gene is located in MHCIII locus close to many immunologically relevant genes. In addition, its expression increases under inflammatory conditions such as viral infection, rheumatoid arthritis and inflammatory bowel disease and its deficiency was shown to result in slightly increased sensitivity to influenza infection in mice. However, little else is known about its role in the immune system homeostasis and immune response. Here we show that similar to humans, LST1 is expressed in mice in the cells of the myeloid lineage. In vivo, its deficiency results in alterations in multiple leukocyte subset abundance in steady state and under inflammatory conditions. Moreover, LST1-deficient mice show significant level of resistance to dextran sodium sulphate (DSS) induced acute colitis, a model of inflammatory bowel disease. These data demonstrate that LST1 regulates leukocyte abundance in lymphoid organs and inflammatory response in the gut.
- MeSH
- biologické markery MeSH
- dendritické buňky imunologie metabolismus MeSH
- fosforylace MeSH
- genotyp MeSH
- intracelulární signální peptidy a proteiny genetika metabolismus MeSH
- kolitida etiologie metabolismus patologie MeSH
- leukocyty imunologie metabolismus MeSH
- lidé MeSH
- lipopolysacharidy imunologie MeSH
- makrofágy imunologie metabolismus MeSH
- membránové proteiny genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši knockoutované MeSH
- myši MeSH
- náchylnost k nemoci MeSH
- regulace genové exprese * MeSH
- signální transdukce * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Eozinofilní záněty zažívacího traktu (eosinophilic gastrointestinal disorders, EGID) jsou onemocnění charakterizovaná patologickou eozinofilní infiltrací postihující jícen, žaludek, tenké střevo nebo tračník a způsobující poruchu funkce těchto orgánů a tím i odpovídající klinické příznaky. V závislosti na postiženém úseku hovoříme o eozinofilní ezofagitidě, gastritidě, enteritidě a kolitidě, v případě postižení více etáží označujeme nemoc jako eozinofilní gastroenteritidu. Krom toho, že eozinofilní zánět může postihnout různé úrovně gastrointestinálního traktu, může také infiltrovat různé vrstvy stěny od mukózy přes svalovinu až po serózu a tím přispívat k rozmanitosti symptomů. První část přehledového článku pojednává o eozinofilních zánětech trávicího traktu obecně, druhá část bude věnována nejčastější a nejlépe prozkoumané podjednotce – eozinofilní ezofagitidě.
Eosinophilic gastrointestinal disorders (EGID) are a group of disorders characterized by predominantly eosinophilic infiltration of the esophagus, stomach, small intestine, or colon leading to organ dysfunction and clinical symptoms. Depending on the affected location we encounter eosinophilic esophagitis, gastritis, enteritis, or colitis. If multiple segments are involved, we label the illness as eosinophilic gastroenteritis. Apart from being able to affect different organs in the gastrointestinal tract, eosinophilic infiltration can also involve multiple layers of the gastrointestinal wall, including mucosal, muscular or the subserosal layer, thus adding to variability of symptoms. First part of the review discusses eosinophilic gastrointestinal disorders in general, the second part will be focussed on eosinophilic esophagitis as the most common and well recognized disorder.
Circulating extracellular DNA (ecDNA) is known to worsen the outcome of many diseases. ecDNA released from neutrophils during infection or inflammation is present in the form of neutrophil extracellular traps (NETs). It has been shown that higher ecDNA concentration occurs in a number of inflammatory diseases including inflammatory bowel disease (IBD). Enzymes such as peptidyl arginine deiminases (PADs) are crucial for NET formation. We sought to describe the dynamics of ecDNA concentrations and fragmentation, along with NETosis during a mouse model of chemically induced colitis. Plasma ecDNA concentration was highest on day seven of dextran sulfate sodium (DSS) intake and the increase was time-dependent. This increase correlated with the percentage of cells undergoing NETosis and other markers of disease activity. Relative proportion of nuclear ecDNA increased towards more severe colitis; however, absolute amount decreased. In colon explant medium, the highest concentration of ecDNA was on day three of DSS consumption. Early administration of PAD4 inhibitors did not alleviate disease activity, but lowered the ecDNA concentration. These results uncover the biological characteristics of ecDNA in IBD and support the role of ecDNA in intestinal inflammation. The therapeutic intervention aimed at NETs and/or nuclear ecDNA has yet to be fully investigated.
- MeSH
- biologické markery metabolismus MeSH
- deoxyribonukleasy metabolismus MeSH
- DNA krev metabolismus MeSH
- endoskopie MeSH
- extracelulární pasti účinky léků metabolismus MeSH
- extracelulární prostor metabolismus MeSH
- kolitida krev chemicky indukované patologie MeSH
- mitochondriální DNA krev MeSH
- myši inbrední C57BL MeSH
- ornithin analogy a deriváty farmakologie MeSH
- peptidylarginindeiminasa typu 4 metabolismus MeSH
- síran dextranu MeSH
- streptonigrin farmakologie MeSH
- střeva účinky léků patologie MeSH
- střevní sliznice účinky léků patologie MeSH
- stupeň závažnosti nemoci MeSH
- zánět krev patologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diet is a strong modifier of microbiome and mucosal microenvironment in the gut. Recently, components of western-type diets have been associated with metabolic and immune diseases. Here, we studied how high-sugar diet (HSD) consumption influences gut mucosal barrier and immune response under steady state conditions and in a mouse model of acute colitis. We found that HSD significantly increased gut permeability, spleen weight, and neutrophil levels in spleens of healthy mice. Subsequent dextran sodium sulfate administration led to severe colitis. In colon, HSD significantly promoted neutrophil infiltration and increased the levels of IL-6, IL-1β, and TNF-α. Moreover, HSD-fed mice had significantly higher abundance of pathobionts, such as Escherichia coli and Candida, in fecal samples. Although germ-free mice colonized with microbiota of conventionally reared mice that consumed different diets had equally severe colitis, mice colonized with HSD microbiota showed markedly increased infiltration of neutrophils to the gut. The induction of colitis in Toll-like receptor 4 (TLR4)-deficient HSD-fed mice led to significantly milder colitis than in wild-type mice. In conclusion, our results suggested a significant role of HSD in disruption of barrier integrity and balanced mucosal and systemic immune response. In addition, these processes seemed to be highly influenced by resident potentially pathogenic microbiota or metabolites via the TLR4 signaling pathway.
- MeSH
- chronická nemoc MeSH
- dieta * MeSH
- DNA vazebné proteiny nedostatek metabolismus MeSH
- feces MeSH
- kolitida genetika imunologie patologie MeSH
- monosacharidy škodlivé účinky MeSH
- myši inbrední BALB C MeSH
- permeabilita MeSH
- regulace genové exprese MeSH
- signální transdukce * MeSH
- síran dextranu MeSH
- slizniční imunita MeSH
- střeva patologie MeSH
- střevní mikroflóra * MeSH
- stupeň závažnosti nemoci MeSH
- T-lymfocyty imunologie MeSH
- toll-like receptor 4 metabolismus MeSH
- zánět mikrobiologie patologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Crohn's disease is linked to a decreased diversity in gut microbiota composition as a potential consequence of an impaired anti-microbial response and an altered polarization of T helper cells. Here, we evaluated the immunomodulatory properties of two potential probiotic strains, namely a Bifidobacterium animalis spp. lactis Bl 5764 and a Lactobacillus reuteri Lr 5454 strains. Both strains improved colitis triggered by either 2,4,6-trinitrobenzenesulfonic acid (TNBS) or Citrobacter rodentium infection in mice. Training of dendritic cells (DC) with Lr 5454 efficiently triggered IL-22 secretion and regulatory T cells induction in vitro, while IL-17A production by CD4+ T lymphocytes was stronger when cultured with DCs that were primed with Bl 5764. This strain was sufficient for significantly inducing expression of antimicrobial peptides in vivo through the Crohn's disease predisposing gene encoding for the nucleotide-binding oligomerization domain, containing protein 2 (NOD2). In contrast, NOD2 was dispensable for the impact on antimicrobial peptide expression in mice that were monocolonized with Lr 5454. In conclusion, our work highlights a differential mode of action of two potential probiotic strains that protect mice against colitis, providing the rational for a personalized supportive preventive therapy by probiotics for individuals that are genetically predisposed to Crohn's disease.
- MeSH
- antiflogistika nesteroidní farmakologie MeSH
- Bifidobacterium animalis * MeSH
- Citrobacter rodentium patogenita MeSH
- dendritické buňky fyziologie MeSH
- enterobakteriální infekce mikrobiologie MeSH
- gnotobiologické modely MeSH
- kolitida chemicky indukované mikrobiologie patologie terapie MeSH
- kyselina trinitrobenzensulfonová toxicita MeSH
- Limosilactobacillus reuteri * MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- probiotika farmakologie MeSH
- proteiny asociované s pankreatitidou genetika MeSH
- regulační T-lymfocyty fyziologie MeSH
- střevní mikroflóra MeSH
- T-lymfocyty pomocné-indukující fyziologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- diferenciální diagnóza MeSH
- divertikl chirurgie diagnóza komplikace MeSH
- dolní gastrointestinální trakt krevní zásobení patologie MeSH
- gastrointestinální endoskopie metody MeSH
- gastrointestinální krvácení * diagnóza etiologie terapie MeSH
- kolitida patologie MeSH
- lidé MeSH
- střevní nádory komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND AND AIMS: Patient-reported outcome measures [PROMs] assessing inflammatory bowel disease [IBD] activity are of interest for monitoring in clinical practice, telemedicine systems, or trials. Different PROMs for follow-up of disease activity are available; however, none was developed with endoscopy as gold standard. The objective of this study was to develop and validate a PROM to predict endoscopic disease activity, following the recommendations of the Food and Drug Administration. METHODS: During development, 178 IBD patients undergoing a colonoscopy were asked to fill out 13 clinical questions derived from the literature. During endoscopy, inflammation was assessed with the simplified endoscopic score for Crohn's disease [CD] and the Mayo endoscopic subscore for ulcerative colitis [UC]. Based on correlation with endoscopic inflammation, questions were reduced to a total of six for CD and five for UC. The newly developed Monitor IBD At Home questionnaire [MIAH] was validated in an independent cohort of 135 CD and 131 UC patients. Additionally, diagnostic accuracy of the MIAH combined with a calprotectin home test [CHT] was assessed. RESULTS: The MIAH-CD includes questions on rectal bleeding, mucus, stool frequency, urgency, fatigue, and patient-reported disease activity. The MIAH-UC contains items on rectal bleeding, stool frequency, urgency, abdominal pain, and patient-reported disease activity. Both questionnaires showed to be valid, reliable, and responsive to changes. The MIAH and CHT combined had a sensitivity, specificity, negative predictive value [NPV], and positive predicitive value [PPV] of 96.7%, 66.7%, 94.7%, and 76.3% for CD and of 88.2%, 81.4%, 95.6%, and 60.0% for UC, respectively, compared with endoscopy. CONCLUSIONS: The MIAH is the first PROM developed to predict endoscopic inflammation in IBD patients. A combination of this questionnaire and a CHT shows excellent diagnostic accuracy to screen for patients who need further assessment of disease activity, and can be used in daily practice, telemedicine systems, and trials.
- MeSH
- Crohnova nemoc diagnóza patologie MeSH
- dospělí MeSH
- feces chemie MeSH
- hodnocení výsledků péče pacientem * MeSH
- idiopatické střevní záněty diagnóza patologie MeSH
- kolitida patologie MeSH
- kolonoskopie MeSH
- leukocytární L1-antigenní komplex analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- prospektivní studie MeSH
- průzkumy a dotazníky MeSH
- reprodukovatelnost výsledků MeSH
- střevní sliznice patologie MeSH
- ulcerózní kolitida diagnóza patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
