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SUMMARYThe human intestinal tract harbors a profound variety of microorganisms that live in symbiosis with the host and each other. It is a complex and highly dynamic environment whose homeostasis directly relates to human health. Dysbiosis of the gut microbiota and polymicrobial biofilms have been associated with gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel diseases, and colorectal cancers. This review covers the molecular composition and organization of intestinal biofilms, mechanistic aspects of biofilm signaling networks for bacterial communication and behavior, and synergistic effects in polymicrobial biofilms. It further describes the clinical relevance and diseases associated with gut biofilms, the role of biofilms in antimicrobial resistance, and the intestinal host defense system and therapeutic strategies counteracting biofilms. Taken together, this review summarizes the latest knowledge and research on intestinal biofilms and their role in gut disorders and provides directions toward the development of biofilm-specific treatments.
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Gastrointestinal biofilms are highly heterogenic and spatially organized polymicrobial communities that can expand and cover large areas in the gastrointestinal tract. Gut microbiota dysbiosis, mucus disruption, and epithelial invasion are associated with pathogenic biofilms that have been linked to gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel diseases, gastric cancer, and colon cancer. Intestinal biofilms are highly prevalent in ulcerative colitis and irritable bowel syndrome patients, and most endoscopists will have observed such biofilms during colonoscopy, maybe without appreciating their biological and clinical importance. Gut biofilms have a protective extracellular matrix that renders them challenging to treat, and effective therapies are yet to be developed. This review covers gastrointestinal biofilm formation, growth, appearance and detection, biofilm architecture and signalling, human host defence mechanisms, disease and clinical relevance of biofilms, therapeutic approaches, and future perspectives. Critical knowledge gaps and open research questions regarding the biofilm's exact pathophysiological relevance and key hurdles in translating therapeutic advances into the clinic are discussed. Taken together, this review summarizes the status quo in gut biofilm research and provides perspectives and guidance for future research and therapeutic strategies.
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BACKGROUND & AIMS: Irritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS, diagnosis and treatment options are limited, but evidence for involvement of the gut microbiome in disease pathophysiology is emerging. Here we analyzed the prevalence of endoscopically visible mucosal biofilms in gastrointestinal disease and associated changes in microbiome composition and metabolism. METHODS: The presence of mucosal biofilms was assessed in 1426 patients at 2 European university-based endoscopy centers. One-hundred and seventeen patients were selected for in-depth molecular and microscopic analysis using 16S ribosomal RNA gene amplicon-sequencing of colonic biopsies and fecal samples, confocal microscopy with deep learning-based image analysis, scanning electron microscopy, metabolomics, and in vitro biofilm formation assays. RESULTS: Biofilms were present in 57% of patients with IBS and 34% of patients with ulcerative colitis compared with 6% of controls (P < .001). These yellow-green adherent layers of the ileum and right-sided colon were microscopically confirmed to be dense bacterial biofilms. 16S-sequencing links the presence of biofilms to a dysbiotic gut microbiome, including overgrowth of Escherichia coli and Ruminococcus gnavus. R. gnavus isolates cultivated from patient biofilms also formed biofilms in vitro. Metabolomic analysis found an accumulation of bile acids within biofilms that correlated with fecal bile acid excretion, linking this phenotype with a mechanism of diarrhea. CONCLUSIONS: The presence of mucosal biofilms is an endoscopic feature in a subgroup of IBS and ulcerative colitis with disrupted bile acid metabolism and bacterial dysbiosis. They provide novel insight into the pathophysiology of IBS and ulcerative colitis, illustrating that biofilm can be seen as a tipping point in the development of dysbiosis and disease.
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Bacterias/crecimiento & desarrollo , Biopelículas/crecimiento & desarrollo , Colitis Ulcerosa/microbiología , Colon/microbiología , Colonoscopía , Microbioma Gastrointestinal , Mucosa Intestinal/microbiología , Síndrome del Colon Irritable/microbiología , Austria , Bacterias/metabolismo , Bacterias/ultraestructura , Estudios de Casos y Controles , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Colon/metabolismo , Colon/patología , Aprendizaje Profundo , Alemania , Humanos , Interpretación de Imagen Asistida por Computador , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Síndrome del Colon Irritable/metabolismo , Síndrome del Colon Irritable/patología , Metabolómica , Microscopía Confocal , Microscopía Electrónica de Rastreo , Valor Predictivo de las Pruebas , RibotipificaciónRESUMEN
Iron deficiency (ID) is globally prevalent, and apart from anemia is associated with thrombocytosis. While considered benign, studies linking thrombotic events with prior ID anemia suggest otherwise. Herein we used animal models to assess the influence of ID on thrombotic tendency. Sprague-Dawley rats were fed control or iron deficient diets and ferric carboxymaltose was used to reverse ID. Thrombosis was induced via stenosis of the inferior vena cava or damage to the right carotid artery using ferric chloride. Thrombi were evaluated histologically and via high frequency ultrasound in the venous model. ID consistently induced thrombocytosis alongside anemia. Venous thrombus growth and final dimensions in both arterial and venous thrombi were largest in ID. In both models, platelet numbers correlated with the final thrombus size, with ID thrombi having the largest platelet areas. Platelet function was also evaluated in surgically naive rats. Coagulability on thromboelastography and hemostasis on tail transection were augmented in ID. Platelet and plasma P-selectin expression were both higher in ID. Platelet adhesion and aggregation in ID was impaired under shear flow but was intact on static assays. Iron replacement therapy reversed all ID-related changes in hematological parameters, thrombus dimensions, and platelet assays. In summary, ID alone increases thrombotic tendency. Iron replacement therapy reverses these changes, making it a viable strategy for prevention of ID-related thrombotic disease. This may be of importance in patients with chronic illnesses which may already be at increased risk for thrombosis such as inflammatory bowel disease, chronic kidney disease, or cancer.
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Anemia Ferropénica , Trombocitosis , Trombosis , Anemia Ferropénica/etiología , Animales , Plaquetas , Humanos , Ratas , Ratas Sprague-Dawley , Trombocitosis/etiología , Trombosis/etiologíaRESUMEN
Colorectal cancer is a multifactorial disease involving inherited DNA mutations, environmental factors, gut inflammation and intestinal microbiota. Certain germline mutations within the DNA mismatch repair system are associated with Lynch syndrome tumors including right-sided colorectal cancer with mucinous phenotype and presence of an inflammatory infiltrate. Such tumors are more often associated with bacterial biofilms, which may contribute to disease onset and progression. Inflammatory bowel diseases are also associated with colorectal cancer and intestinal dysbiosis. Herein we addressed the question, whether inflammation can aggravate colorectal cancer development under mismatch repair deficiency. MSH2loxP/loxP Vill-cre mice were crossed into the IL-10-/- background to study the importance of inflammation and mucosal bacteria as a driver of tumorigenesis in a Lynch syndrome mouse model. An increase in large bowel tumorigenesis was found in double knockout mice both under conventional housing and under specific pathogen-free conditions. This increase was mostly due to the development of proximal tumors, a hotspot for tumorigenesis in Lynch syndrome, and was associated with a higher degree of inflammation. Additionally, bacterial invasion into the mucus of tumor crypts was observed in the proximal tumors. Inflammation shifted fecal and mucosal microbiota composition and was associated with enrichment in Escherichia-Shigella as well as Akkermansia, Bacteroides and Parabacteroides genera in fecal samples. Tumor-bearing double knockout mice showed a similar enrichment for Escherichia-Shigella and Parabacteroides. Lactobacilli, Lachnospiraceae and Muribaculaceae family members were depleted upon inflammation. In summary, chronic inflammation aggravates colonic tumorigenesis under mismatch repair deficiency and is associated with a shift in microbiota composition.
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Carcinogénesis/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/microbiología , Neoplasias Colorrectales Hereditarias sin Poliposis/parasitología , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/patología , Animales , Bacterias/patogenicidad , Biopelículas/crecimiento & desarrollo , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Modelos Animales de Enfermedad , Disbiosis/genética , Disbiosis/microbiología , Disbiosis/patología , Microbioma Gastrointestinal/genética , Mutación de Línea Germinal/genética , Inflamación/genética , Inflamación/microbiología , Inflamación/patología , Interleucina-10/genética , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Recent evidence points to a plausible role of diet and the microbiome in the pathogenesis of both Crohn's disease (CD) and Ulcerative Colitis (UC). Dietary therapies based on exclusion of table foods and replacement with nutritional formulas and/or a combination of nutritional formulas and specific table foods may induce remission in CD. In UC, specific dietary components have also been associated with flare of disease. While evidence of varying quality has identified potential harmful or beneficial dietary components, physicians and patients at the present time do not have guidance as to which foods are safe, may be protective or deleterious for these diseases. The current document has been compiled by the nutrition cluster of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) based on the best current evidence to provide expert opinion regarding specific dietary components, food groups and food additives that may be prudent to increase or decrease in the diet of patients with inflammatory bowel diseases to control and prevent relapse of inflammatory bowel diseases.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Microbiota , Dieta , HumanosRESUMEN
BACKGROUND: Iron deficiency and anemia are common findings in IBD. Treatment of anemia improves quality of life. Neurological symptoms like depression or anxiety are also common in IBD; however, their relationship with ID has not been studied in detail. METHODS: Prospective, single center, non-interventional trial in an IBD cohort (nâ=â98), which is generally at risk for ID. Quality of sleep (using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Insomnia Severity Index) and the presence of fatigue (Piper fatigue scale), depression (Self-rating Depression Scale [SDS]) or anxiety (Self-rating Anxiety Scale [SAS]) were related to ID (ferritin, transferrin saturation), anemia (hemoglobin), and inflammatory disease activity (CRP). RESULTS: ID was present in 35â%, anemia in 16â%, and inflammation in 30â%. The overall quality of sleep in this cohort was similar to that reported for the general population. ID, anemia, or inflammation had no influence on the PSQI (median 4.0 [CI 3.0-5.0]), the ESS 5.5 (5.0-7.0), and the ISI 4.00 (2.5-5.5). Fatigue (PFS; present in 30â%), anxiety (SAS; present in 24â%), and depression (SDS; present in 33â%) were more common than in the general population. Iron deficient and anemic patients were more likely to be depressed (pâ=â0.02 and pâ<â0.01) and showed a trend towards presence of fatigue (pâ=â0.06 and 0.07). Systemic inflammation as measured by CRP had no effect on any of these conditions. CONCLUSION: In this IBD cohort, ID and anemia affect depression and possibly fatigue independent of the presence of inflammation.
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Anemia Ferropénica/etiología , Depresión/etiología , Fatiga/etiología , Enfermedades Inflamatorias del Intestino/complicaciones , Calidad de Vida , Anemia Ferropénica/epidemiología , Anemia Ferropénica/psicología , Depresión/epidemiología , Depresión/psicología , Fatiga/epidemiología , Fatiga/psicología , Humanos , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/psicología , Estudios ProspectivosRESUMEN
Inflammatory bowel disease (IBD) is a group of chronic relapsing inflammatory disorders affecting the large and small intestine, with a rising worldwide incidence and prevalence. Anaemia is the most common extraintestinal manifestation of IBD, correlating with disease activity, and tending to relapse even after successful therapy. Iron deficiency is the most common cause; however, it often manifests in combination with anaemia of inflammation. As such, multiple parameters are used for the diagnosis of iron deficiency anaemia in IBD. Timely recognition and selection of appropriate therapy leads to an improvement in the quality of life and prevention of potential sequelae. Oral iron can be effective under specific circumstances; however, as luminal iron changes microbiota and bacterial metabolism, oral administration should be avoided. Intravenous iron is preferred as it bypasses the sites of inflammation. Nevertheless, the optimization of IBD treatment should occur simultaneously, as this improves both patient condition and response to iron therapy. Herein, we discuss the screening, diagnosis, selection of therapy, and follow-up for iron deficiency anaemia in IBD.
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Anemia Ferropénica/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/patología , Hierro/administración & dosificación , Anemia Ferropénica/complicaciones , Anemia Ferropénica/patología , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Linfocitos/citología , Linfocitos/metabolismo , Calidad de Vida , Índice de Severidad de la Enfermedad , Trombocitosis/complicaciones , Trombocitosis/patologíaRESUMEN
BACKGROUND AND AIM: Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC. METHODS: Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute. RESULTS: For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities. CONCLUSIONS: Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.
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Colitis Ulcerosa/complicaciones , Enfermedad de Crohn/complicaciones , Fístula Intestinal/etiología , Mucosa Intestinal/patología , Índice de Severidad de la Enfermedad , Absceso Abdominal/etiología , Actividades Cotidianas , Adulto , Anciano , Productos Biológicos/uso terapéutico , Proteína C-Reactiva/metabolismo , Colitis Ulcerosa/sangre , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Enfermedad de Crohn/patología , Enfermedad de Crohn/cirugía , Técnica Delphi , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de SíntomasRESUMEN
Microsatellite instability (MSI) is present in ulcerative colitis (UC) and colitis-associated colorectal cancers (CAC). Certain factors released by polymorphonuclear cells (PMNs) may drive mucosal frameshift mutations resulting in MSI and cancer. Here, we applied a co-culture system with PMNs and colon epithelial cells to identify such culprit factors. Subjecting HCT116 + chr3 and human colonic epithelial cells (HCEC)-1CT MSI-reporter cell lines harboring mono-, di- or tetranucleotide DNA repeats linked to enhanced green fluorescent protein (EGFP) to activated PMNs induced frameshift mutations within all repeats, as quantified by flow cytometry. Activated PMNs released superoxide and hydrogen peroxide (H2O2), as measured by lucigenin-amplified chemiluminescence and fluorometry, respectively. Catalase, which scavenges H2O2, reduced such PMN-induced MSI. The NADPH-oxidase inhibitor apocynin, which blocks the oxidative burst in PMNs, similarly inhibited PMN-induced MSI. A bead-based multiplex assay revealed that PMNs release a wide range of cytokines such as interleukin (IL)-8, IL-6 and tumor necrosis factor-α (TNF-α). In vitro, these cytokines increased MSI in colon epithelial cells, and the Janus kinase (JAK) inhibitor tofacitinib abolished IL-6-induced or PMN-induced MSI. Intracellular reactive oxygen species (ROS) formation, as measured by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, was induced upon cytokine treatment. DNA oxidation upon IL-6 was present, as detected by formamidopyrimidine glycosylase (FPG)-modified comet assay. In conclusion, activated PMNs induce frameshift mutations in colon epithelial cells resulting in MSI. Both oxidative burst with release of ROS and PMN-secreted cytokines, such as IL-8, IL-6 or TNF-α, contribute to MSI. ROS scavengers and/or specific inhibitors of cytokine signaling may delay or prevent cancer development in the setting of colitis.
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Colitis/complicaciones , Neoplasias Colorrectales/etiología , Inestabilidad de Microsatélites , Mutagénesis/fisiología , Neutrófilos/metabolismo , Línea Celular Tumoral , Técnicas de Cocultivo , Colitis/metabolismo , Citocinas/metabolismo , Mutación del Sistema de Lectura , Humanos , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/efectos adversos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVE: miR-21 was found to be overexpressed in the colon tissues and serum of patients with UC and colorectal cancer (CRC); however, the exact roles of miR-21 in colitis-associated CRC remain unclear. The aim of our study was to investigate the biological mechanisms of miR-21 in colitis-associated colon cancer (CAC). DESIGN: miR-21 expression was examined in the tumours of 62 patients with CRC from China and 37 colitis-associated neoplastic tissues from Japan and Austria. The biological functions of miR-21 were studied using a series of in vitro, in vivo and clinical approaches. RESULTS: miR-21 levels were markedly upregulated in the tumours of 62 patients with CRC, 22 patients with CAC, and in a mouse model of CAC. Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group. The absence of miR-21 resulted in the reduced expression of Ki67 and the attenuated proliferation of tumour cells with a simultaneous increase in E-cadherin and decrease in ß-catenin and SOX9 in the tumours of CAC mice. Furthermore, the absence of miR-21 increased the expression of its target gene PDCD4 and subsequently modulated nuclear factor (NF)-κB activation. Meanwhile, miR-21 loss reduced STAT3 and Bcl-2 activation, causing an increase in the apoptosis of tumour cells in CAC mice. CONCLUSIONS: These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.
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Carcinogénesis , Colitis/genética , Colon/patología , Neoplasias del Colon/genética , MicroARNs/genética , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Cadherinas/metabolismo , Carcinogénesis/genética , Carcinogénesis/patología , Proliferación Celular/genética , Colitis/patología , Colitis/fisiopatología , Neoplasias del Colon/patología , Neoplasias del Colon/fisiopatología , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción SOX9/metabolismo , beta Catenina/metabolismoRESUMEN
P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling and its role in colitis-driven carcinogenesis. PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry, immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single intraperitoneal TNFα injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFα. NF-κB and PPARγ were analyzed upon PAK1 overexpression and silencing for transcriptional/translational regulation. PAK1 expression and activation was increased on the luminal intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer. PAK1 was phosphorylated upon treatment with IFNγ, IL-1ß, and TNFα. In vivo, mice administered with TNFα showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-κB activation. p65 nuclear translocation downstream of TNFα was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1-p65 interaction as visualized by co-immunoprecipitation, nuclear translocation, and increased NF-κB transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPARγ and mesalamine recovered PPARγ through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-κB, which was recovered using BADGE, a PPARγ antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-κB activity via suppression of PPARγ in intestinal epithelial cells.
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Colitis/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/metabolismo , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Transducción de Señal , Quinasas p21 Activadas/metabolismo , Animales , Línea Celular , Colitis/genética , Colitis/patología , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/patología , Neoplasias Intestinales/genética , Neoplasias Intestinales/metabolismo , Neoplasias Intestinales/patología , Intestinos/patología , Ratones , Ratones Noqueados , FN-kappa B/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , PPAR gamma/genética , Quinasas p21 Activadas/genéticaRESUMEN
OBJECTIVE: Lynch syndrome is caused by germline mutations in DNA mismatch repair genes leading to microsatellite instability (MSI) and colorectal cancer. Mesalazine, commonly used for the treatment of UC, reduces MSI in vitro. Here, we tested natural compounds for such activity and applied mesalazine and thymoquinone in a Msh2(loxP/loxP) Villin-Cre mouse model for Lynch syndrome. DESIGN: Flow cytometry was used for quantitation of mutation rates at a CA13 microsatellite in human colon cancer (HCT116) cells that had been stably transfected with pIREShyg2-enhanced green fluorescent protein/CA13, a reporter for frameshift mutations. Mice were treated for 43â weeks with mesalazine, thymoquinone or control chow. Intestines were analysed for tumour incidence, tumour multiplicity and size. MSI testing was performed from microdissected normal intestinal or tumour tissue, compared with mouse tails and quantified by the number of mutations per marker (NMPM). RESULTS: Besides mesalazine, thymoquinone significantly improved replication fidelity at 1.25 and 2.5â µM in HCT116 cells. In Msh2(loxP/loxP) Villin-Cre mice, tumour incidence was reduced by mesalazine from 94% to 69% (p=0.04) and to 56% (p=0.003) by thymoquinone. The mean number of tumours was reduced from 3.1 to 1.4 by mesalazine (p=0.004) and to 1.1 by thymoquinone (p<0.001). Interestingly, MSI was reduced in normal intestinal tissue from 1.5 to 1.2 NMPM (p=0.006) and to 1.1 NMPM (p=0.01) by mesalazine and thymoquinone, respectively. Thymoquinone, but not mesalazine, reduced MSI in tumours. CONCLUSIONS: Mesalazine and thymoquinone reduce tumour incidence and multiplicity in Msh2(loxP/loxP) Villin-Cre mice by reduction of MSI independent of a functional mismatch repair system. Both substances are candidate compounds for chemoprevention in Lynch syndrome mutation carriers.
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Antiinflamatorios no Esteroideos/uso terapéutico , Benzoquinonas/uso terapéutico , Neoplasias Colorrectales Hereditarias sin Poliposis/prevención & control , Mesalamina/uso terapéutico , Proteína 2 Homóloga a MutS/genética , Animales , Antiinflamatorios no Esteroideos/farmacología , Benzoquinonas/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Modelos Animales de Enfermedad , Femenino , Mutación del Sistema de Lectura , Células HCT116 , Humanos , Mucosa Intestinal/metabolismo , Masculino , Mesalamina/farmacología , Ratones , Inestabilidad de Microsatélites/efectos de los fármacos , Proteína 2 Homóloga a MutS/metabolismo , Tasa de Mutación , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Diverticular disease is increasingly prevalent in Western societies and is associated with significant morbidity. OBJECTIVE: Two-stage endoscopic device development for inversion and secured ligation of colonic diverticula; first, human cadaver studies were performed to measure forces required for diverticular inversion; second, a novel set of devices (elastic spiked O-ring with delivery system) was tested in animals. DESIGN: Prospective, observational study of human cadavers and prospective, interventional study of a porcine model. SETTING: University hospital pathology laboratory and animal facility. INTERVENTION: Full-thickness inversion of the colonic wall with a pipelike delivery instrument to produce an inverted pseudodiverticulum that was secured with a spiked O-ring. MAIN OUTCOME MEASUREMENTS: The forces required for diverticular inversion, the secured closure of inverted pseudodiverticula, and the time until necrotic tissue falls off. RESULTS: A total of 248 of 248 of cadaveric sigmoid diverticula could be inverted by means of vacuum or forceps. The forces required for inversion ranged from 0.28 to 0.47 N (median, 0.37 N). Twenty-four spiked O-rings were delivered in 6 living pigs to produce 24 inverted pseudodiverticula. One animal died the day after the procedure of a pulmonary thromboembolism. In the remaining 5 pigs, all delivered spiked O-rings remained in place for 7 to 22 days. At necropsy, none of the inverted sites showed signs of perforation but rather full-thickness reparative scarring with ingrowth of connective tissue. LIMITATIONS: Animal model, stiff pipelike delivery instrument, variations in diverticular location, diameter, and size. CONCLUSIONS: Endoluminal inversion and securing of colonic diverticula induces tissue necrosis, diverticular sloughing, and full-thickness scarring.
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Divertículo del Colon/cirugía , Laparoscopía/métodos , Animales , Femenino , Humanos , Laparoscopía/instrumentación , Estudios Prospectivos , Porcinos , VacioRESUMEN
Colorectal cancer has become one of the most prevalent malignant diseases for both men and women. Patients with inflammatory bowel diseases or certain inherited cancer syndromes are at high risk of developing colorectal cancer and have naturally the highest need for cancer prevention. In familial adenomatous polyposis (FAP) and Lynch syndrome, most of the underlying germline mutations can be detected by DNA sequencing, and medical counselling of affected individuals involves both surveillance tests and chemopreventive measures. However, as the mechanisms leading to colorectal cancer differ in these high-risk groups, the molecular action of chemopreventive drugs needs to be adjusted to the certain pathway of carcinogenesis. In the last decades, a number of drugs have been tested, including sulindac, aspirin, celecoxib, and mesalazine, but some of them are still controversially discussed. This review summarizes the advances and current standards of colorectal cancer prevention in patients with inflammatory bowel disease, FAP and Lynch syndrome.
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Quimioprevención , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/prevención & control , Antiinflamatorios/uso terapéutico , Suplementos Dietéticos , Quimioterapia Combinada , Humanos , Fitoquímicos/uso terapéuticoRESUMEN
BACKGROUND: Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD). In clinical practice, many patients receive initial treatment with iron tablets although intravenous (i.v.) iron supplementation is often preferable. AIM: This study investigated whether systemic inflammation at initiation of treatment (assessed by C-reactive protein [CRP] and interleukin-6 [IL-6] measurements) predicts response to iron therapy. METHODS: Data from a previously published phase III trial were retrospectively analyzed after stratification of patients according to baseline CRP (> 4 vs. ≤ 4 mg/L) and IL-6 (> 6 vs. ≤ 6 pg/mL) levels. The study population consisted of patients with Crohn's disease or ulcerative colitis and IDA (Hb ≤ 110 g/L and TSAT < 20 % or serum ferritin < 100 ng/mL), randomized to either oral (ferrous sulfate) or i.v. iron (ferric carboxymaltose). RESULTS: A total of 196 patients were evaluated (oral iron: n = 60; i.v. iron: n = 136). Baseline CRP and IL-6 levels were independent of patients' initial Hb levels and iron status (serum ferritin and TSAT; all p > 0.05). Among iron tablet-treated patients, Hb increase was significantly smaller in the high- versus low-CRP subgroup (1.1 vs. 2.0, 2.3 vs. 3.1, and 3.0 vs. 4.0 g/dL at weeks 2, 4, and 8, respectively; all p < 0.05). Differences were less pronounced with stratification according to baseline IL-6. Response to i.v. iron was mainly independent of inflammation. CONCLUSIONS: Patients with high baseline CRP achieved a lower Hb response with oral iron therapy. Our results suggest that CRP may be useful to identify IBD patients who can benefit from first-line treatment with i.v. iron to improve their IDA.
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Anemia Ferropénica/tratamiento farmacológico , Proteína C-Reactiva/análisis , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Compuestos Férricos/administración & dosificación , Compuestos Ferrosos/administración & dosificación , Hematínicos/administración & dosificación , Mediadores de Inflamación/sangre , Maltosa/análogos & derivados , Administración Intravenosa , Administración Oral , Anemia Ferropénica/sangre , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/inmunología , Biomarcadores/sangre , Ensayos Clínicos Fase III como Asunto , Colitis Ulcerosa/sangre , Colitis Ulcerosa/diagnóstico , Enfermedad de Crohn/sangre , Enfermedad de Crohn/diagnóstico , Hemoglobinas/metabolismo , Humanos , Interleucina-6/sangre , Maltosa/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
P-21 activated kinases (PAKs) are effectors of Rac1/Cdc42 which coordinate signals from the cell membrane to the nucleus. Activation of PAKs drive important signalling pathways including mitogen activated protein kinase, phospoinositide 3-kinase (PI3K/AKT), NF-κB and Wnt/ß-catenin. Intestinal PAK1 expression increases with inflammation and malignant transformation, although the biological relevance of PAKs in the development and progression of GI disease is only incompletely understood. This review highlights the importance of altered PAK activation within GI inflammation, emphasises its effect on oncogenic signalling and discusses PAKs as therapeutic targets of chemoprevention.
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Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica , Neoplasias Gastrointestinales/enzimología , Inflamación/enzimología , Quinasas p21 Activadas/metabolismo , Progresión de la Enfermedad , Neoplasias Gastrointestinales/patología , Humanos , Inflamación/patología , Transducción de SeñalRESUMEN
BACKGROUND: Chronic appendicitis may be detected in as many as 10% of patients with right lower quadrant pain. Although the appendiceal orifice is easily identified during colonoscopy, its lumen has not been investigated so far. OBJECTIVES: To determine the feasibility of endoscopic appendix imaging to identify features of chronic appendicitis in patients with recurrent right lower quadrant pain. DESIGN: Prospective, proof-of-concept study. SETTING: University-based tertiary referral hospital. PATIENTS: Colonoscopy scheduled because of right lower quadrant pain. INTERVENTIONS: First, the appendix orifice was cannulated with a guidewire and a Jagtome. Next fluoroscopic imaging was performed by injection of contrast agent into the appendix orifice, and then a SpyGlass endoscope was inserted for imaging of the appendiceal mucosa and for biopsy. Patients were monitored 3 hours after investigation, with follow-up at 4 weeks. MAIN OUTCOME MEASUREMENTS: Cannulation rate. RESULTS: Thirteen patients were included. Endoscopic imaging of the appendix was successful in 9 of 13 patients (69%). In 10 patients, a guidewire was placed; in 7 patients, biopsy specimens were taken, revealing histological signs of inflammation in 5. In 4 patients, visible fecoliths were removed by flushing. All patients were discharged on the same day. No adverse events occurred. Three patients reported resolution of pain at follow-up. One patient with strictures at appendicoscopy underwent surgical appendectomy. Histology confirmed the findings of chronic appendicitis with fibrosis. LIMITATIONS: Patient number limits power for analysis. CONCLUSION: Endoscopic imaging of the appendix is feasible, safe, and clinically useful in patients with suspected chronic appendicitis.
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Apendicitis/patología , Apéndice/patología , Colonoscopía/métodos , Dolor Abdominal/etiología , Adulto , Apendicitis/complicaciones , Biopsia , Cateterismo , Enfermedad Crónica , Colonoscopía/efectos adversos , Colonoscopía/instrumentación , Estudios de Factibilidad , Femenino , Fluoroscopía , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Imagen Óptica , Estudios Prospectivos , Adulto JovenRESUMEN
Iron deficiency is a common cause of reactive thrombocytosis, however, the exact pathways have not been revealed. Here we aimed to study the mechanisms behind iron deficiency-induced thrombocytosis. Within few weeks, iron-depleted diet caused iron deficiency in young Sprague-Dawley rats, as reflected by a drop in hemoglobin, mean corpuscular volume, hepatic iron content and hepcidin mRNA in the liver. Thrombocytosis established in parallel. Moreover, platelets produced in iron deficient animals displayed a higher mean platelet volume and increased aggregation. Bone marrow studies revealed subtle alterations that are suggestive of expansion of megakaryocyte progenitors, an increase in megakaryocyte ploidy and accelerated megakaryocyte differentiation. Iron deficiency did not alter the production of hematopoietic growth factors such as thrombopoietin, interleukin 6 or interleukin 11. Megakaryocytic cell lines grown in iron-depleted conditions exhibited reduced proliferation but increased ploidy and cell size. Our data suggest that iron deficiency increases megakaryopoietic differentiation and alters platelet phenotype without changes in megakaryocyte growth factors, specifically TPO. Iron deficiency-induced thrombocytosis may have evolved to maintain or increase the coagulation capacity in conditions with chronic bleeding.