Interacciones de las bacterias de la flora con el sistema inmune intestinal

La hipótesis de los estudios que constituyen esta tesis es que las bacterias no patógenas interactúan de manera cepa-específica con la mucosa intestinal humana induciendo un cambio o modulación en el patrón de secreción de citoquinas tanto en tejido normal como inflamado y que en el tejido intestinal inflamado, determinadas bacterias ejercen un efecto antiinflamatorio. Para ello se han realizado dos estudios que han sido publicados en revistas del área de gastroenterología. Estudio 1: «Effects of nonpathogenic bacteria on cytokine secretion by human intestinal mucosa.» N.Borruel, F.Casellas, M.Antolín, M.Llopis, M.Carol, E.Espín, J.Naval, F.Guarner, J.R.Malagelada. American Journal of Gastroenterology 2003;98:865-870. El objetivo de este estudio fue estudiar el efecto «ex vivo» de diferentes bacterias no patógenas sobre la secreción de citoquinas pro y anti-inflamatorias en la mucosa colónica normal. Estudio 2: «Increased mucosal tumor necrosis factor ? production in Crohn's disease can be downregulated ex-vivo by probiotic bacteria.» N.Borruel, M.Carol, F.Casellas, M.Antolín, F.De Lara, E.Espín, J.Naval, F.Guarner, J.R.Malagelada. Gut 2002;51:659-664. El objetivo del segundo estudio fue estudiar el efecto antiinflamatorio de diferentes bacterias no patógenas en la mucosa intestinal de pacientes con enfermedad de Crohn. Las conclusiones de los estudios son las siguientes: -Las bacterias no patógenas interactúan con la mucosa colónica normal e inducen cambios en la secreción de citoquinas que son cepa-específicos. Así: Lactobacillus casei DN 114 001 induce una disminución de la liberación de TNF? e IL-8; Lactobacillus casei DN 114 056 induce una disminución de la liberación de TNF?, ningún cambio en la liberación de IL-8 y una estimulación TNF?-independiente de la IL-10;Lactobacillus casei ATCC 334 induce una disminución de la liberación de TNF? sin cambios en el resto de citoquinas; Lactobacillus bulgaricus LB10 no induce cambios en la liberación de citoquinas y Escherichia coli ECOR-26 induce un incremento en la liberación de TNF? y un estímulo de la liberación de IL-10 TNF?-independiente. -La mucosa ileal inflamada de pacientes con enfermedad de Crohn presenta una producción aumentada de TNF? cuando se compara con ileon normal o no inflamado. Lactobacillus casei DN 114 001 y Lactobacillus bulgaricus LB10 inducen un potente efecto antiinflamatorio en la mucosa ileal inflamada mediante la inhibición de la liberación de TNF?. La incubación de la mucosa ileal inflamada con L.casei DN114 001 y L. bulgaricus LB10 induce además una disminución del número de linfocitos intraepiteliales y de la proporción de linfocitos activados tanto en el compartimiento intraepitelial como en la lámina propia.The hypothesis of the studies that constitute this thesis is that nonpathogenic bacteria interact in a strain-specific manner with human intestinal mucosa inducing a change or modulation in the cytokine secretion profile both in normal and inflamed tissue and that in inflamed intestinal tissue, certain bacteria exert an anti-inflammatory effect. To this purpose, it has been performed two studies published in gastroenteroloy area journals. Study 1: «Effects of nonpathogenic bacteria on cytokine secretion by human intestinal mucosa.» N.Borruel, F.Casellas, M.Antolín, M.Llopis, M.Carol, E.Espín, J.Naval, F.Guarner, J.R.Malagelada. American Journal of Gastroenterology 2003;98:865-870. The aim of this study was to investigate the effect «ex vivo» of different nonpathogenic bacteria on pro and antiinflammatory cytokine secretion by normal colonic mucosa. Study 2: «Increased mucosal tumor necrosis factor ? production in Crohn's disease can be downregulated ex-vivo by probiotic bacteria.» N.Borruel, M.Carol, F.Casellas, M.Antolín, F.De Lara, E.Espín, J.Naval, F.Guarner, J.R.Malagelada. Gut 2002;51:659-664. The aim of the second study was to investigate the anti-inflammatory effect of different nonpathogenic bacteria on the intestinal mucosa from patients with Crohn's disease. The conclusions of both studies were: -Nonpathogenic bacteria interact with normal colonic mucosa and induce changes on cytokine secretion that are strain-specific: Lactobacillus casei DN 114 001 induces an inhibition on TNF? and IL-8 release; Lactobacillus casei DN 114 056 induces an inhibition of TNF? release, no changes on IL-8 release and a TNF?-independient stimulation of IL-10 release; Lactobacillus casei ATCC 334 induces an inhibition of TNF? release without changes in other cytokines; Lactobacillus bulgaricus LB10 does not induce any changes on cytokine release and Escherichia coli ECOR-26 induces a stimulation on TNF? release and a TNF?-independent increase on IL-10 release. -Inflamed ileal mucosa from patients with Crohn's disease has an increased production of TNF? as compared with normal ileal mucosa or non-inflammed mucosa. Lactobacillus casei DN 114 001 and Lactobacillus bulgaricus LB10 induce a potent anti-inflammatory effect on inflamed ileal mucosa by the inhibition of TNF? release. Incubation of ileal inflamed mucosa with L.casei DN114 001 and L. bulgaricus LB10 induces a decrease in the number of intraepithelial lymphocytes and in the rate of activated lymphocytes both in the epithelium and in the lamina propria

Co Treatment With Biologic Agents and Immunotherapy in the Setting of irAEs of Difficult Management

Adverse drugs reaction; Immune check-point inhibitors therapy; Immunosuppression therapyReacción adversa a medicamentos; Terapia con inhibidores del punto de control inmunitario; Terapia inmunosupresoraReaccions adverses als fàrmacs; Teràpia amb inhibidors del punt de control immune; Teràpia d'immunosupressióIn recent years, immunotherapy has become an important pillar of cancer treatment, with high response rates regardless of tumor histology or baseline mutations, sometime in patients without any alternative of treatment. Moreover, these treatments are moving from later line therapies to front-line therapies in the metastasic setting. However, immune activation associated with immune check-point inhibitors (ICI) is not selective and a large variety of immune-related adverse events, with an increasing frequency, have been associated with anti-PD1, anti-PD-1/L-1 and anti-CTLA-4 agents. In clinical trials, and sometimes also in real life practice, patients who develop severe toxicities on ICI-based therapies are usually not allowed to resume ICI once their disease progresses, because of the chance of developing severe irAEs on rechallenge with immunotherapies. Moreover, patients with irAEs suffer important side effects due to the high dose corticosteroids that are used to treat them. Therapy with ICI is sometimes the only alternative for certain patients, and for this reason co treatment with classic (DMARDS) or biologic immunosuppression therapy and ICI must be considered. Co-treatment with this type of immunosuppressant drugs, apart from allowing the maintenance of ICI therapy, drive to a lesser use of corticosteroids, with an improvement of the safety and quality of life of the patients. Such a tailored scheme of treatment is mostly an expert opinion based on recommendation and currently there is scarce evidence supporting it. Herein we present comprehensive, current recommendations and real-world data on the use of co-treatment with ICI and DMARDS and biologic immunosuppression

Intercontinental Gut Microbiome Variances in IBD

The development of biomarkers for inflammatory bowel disease (IBD) diagnosis would be relevant in a generalized context. However, intercontinental investigation on these microbial biomarkers remains scarce. We examined taxonomic microbiome variations in IBD using published DNA shotgun metagenomic data. For this purpose, we used sequenced data from our previous Spanish Crohn's disease (CD) and ulcerative colitis (UC) cohort, downloaded sequence data from a Chinese CD cohort, and downloaded taxonomic and functional profiling tables from a USA CD and UC cohort. At the global level, geographical location and disease phenotype were the main explanatory covariates of microbiome variations. In healthy controls (HC) and UC, geography turned out to be the most important factor, while disease intestinal location was the most important one in CD. Disease severity correlated with lower alpha-diversity in UC but not in CD. Across geography, alpha-diversity was significantly different independently of health status, except for CD. Despite recruitment from different countries and with different disease severity scores, CD patients may harbor a very similar microbial taxonomic profile. Our study pointed out that geographic location, disease activity status, and other environmental factors are important contributing factors in microbiota changes in IBD. We therefore strongly recommend taking these factors into consideration for future IBD studies to obtain globally valid and reproducible biomarker

Influencia de los factores bióticos y abióticos sobre la estructura de las cuiseras de Microcavia australis.

Las cuiseras proveen de un microclima estable y dan protección a pequeños mamíferos de temperaturas extremas del ambiente y de depredadores. El objetivo fue determinar la influencia de los factores bióticos y abióticos sobre la estructura de las cuiseras utilizadas por Microcavia australis. El estudio se realizó en dos sitios con diferentes condiciones climáticas, riesgo de depredación y tamaño de parches de vegetación. Se caracterizaron un total de 18 cuiseras principales y 13 cuiseras satélites en Ñacuñán, y 12 cuiseras principales y 3 cuiseras satélites en El Leoncito. El mayor número de entradas y el gran desarrollo de cuiseras principales y satélites en Ñacuñán estarían relacionados con un mayor riesgo de depredación por rapaces. En ambos sitios, las cuiseras podrían tener la función como refugio ante temperaturas extremas externas debido a que la temperatura en los túneles es menor a la temperatura del suelo en el período del día más cálido. Además, en promedio las entradas activas están orientadas al Este en Ñacuñán, evitando los vientos predominantes del SE y S, y hacia el Noroeste en El Leoncito, recibiendo los vientos cálidos y secos del Noroeste. Debido a la inclinación de los túneles el sol ingresa en ellos con mayor profundidad en la estación fría (invierno) que en la estación cálida (verano). Entonces las cuiseras serían para los cuises un refugio ante depredadores y otorgarían un microclima estable.Burrows provide a stable microclimate and give small mammals protection from extreme temperatures and from predators on the ground surface. The objective was to determine the influence of biotic and abiotic factors on the structure of burrows used by the cavy Microcavia australis. The study was conducted on two sites with different climate conditions, predation risk and size of plant patches. A total of 18 main burrows and 13 satellite burrows were characterized at Ñacuñán, and 12 main and 3 satellite burrows at El Leoncito. The larger number of holes and higher development of main and satellite burrows at Ñacuñán is likely related to higher risk of raptor predation. At both sites burrows would function as shelter from the environment since temperature in the galleries is lower than soil temperature at the hottest time of the day. Moreover, active holes are eastoriented at Ñacuñán, avoiding SE and S winds, and northwest-oriented at El Leoncito, receiving the warm dry wind from the NW. Also due to gallery inclination the sun goes deeper into the tunnels in the coldest season (winter) than in the warmest one (summer). Burrows would afford cavies a refuge from predators and a stable microclimate.Fil: Taraborelli, Paula Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Provincia de Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Universidad Nacional de Cuyo. Instituto Argentino de Investigaciones de las Zonas Áridas; ArgentinaFil: Borruel Diaz, Natalia Gladys. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Provincia de Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Universidad Nacional de Cuyo. Instituto Argentino de Investigaciones de las Zonas Áridas; ArgentinaFil: Sandobal, Ana J.. Parque El Leoncito; ArgentinaFil: Giannoni, Stella Maris. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales; Argentin

JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases

JAK inhibitors; Oral therapies; Small moleculesInhibidors de JAK; Teràpies orals; Molècules petitesInhibidores de JAK; Terapias orales; Moléculas pequeñasInflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract that requires chronic treatment and strict surveillance. Development of new monoclonal antibodies targeting one or a few single cytokines, including anti-tumor necrosis factor agents, anti-IL 12/23 inhibitors, and anti-α4β7 integrin inhibitors, have dominated the pharmacological armamentarium in IBD in the last 20 years. Still, many patients experience incomplete or loss of response or develop serious adverse events and drug discontinuation. Janus kinase (JAK) is key to modulating the signal transduction pathway of several proinflammatory cytokines directly involved in gastrointestinal inflammation and, thus, probably IBD pathogenesis. Targeting the JAK-STAT pathway offers excellent potential for the treatment of IBD. The European Medical Agency has approved three JAK inhibitors for treating adults with moderate to severe Ulcerative Colitis when other treatments, including biological agents, have failed or no longer work or if the patient cannot take them. Although there are currently no approved JAK inhibitors for Crohn’s disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Other JAK inhibitors, including gut-selective molecules, are currently being studied IBD. This review will discuss the JAK-STAT pathway, its implication in the pathogenesis of IBD, and the most recent evidence from clinical trials regarding the use of JAK inhibitors and their safety in IBD patients

A Core Outcome Set for Inflammatory Bowel Diseases: Development and Recommendations for Implementation in Clinical Practice Through an International Multi-stakeholder Consensus Process

Quality of life; Socioeconomical and psychological end pointsQualitat de vida; Aspectes socioeconòmics i psicològicsCalidad de vida; Aspectos socioeconómicos y psicológicosBackground and Aims Standardising health outcome measurements supports delivery of care and enables data-driven learning systems and secondary data use for research. As part of the Health Outcomes Observatory [H2O] initiative, and building on existing knowledge, a core outcome set [COS] for inflammatory bowel diseases [IBD] was defined through an international modified Delphi method. Methods Stakeholders rated 90 variables on a 9-point importance scale twice, allowing score modification based on feedback displayed per stakeholder group. Two consecutive consensus meetings were held to discuss results and formulate recommendations for measurement in clinical practice. Variables scoring 7 or higher by ≥80% of the participants, or based on consensus meeting agreement, were included in the final set. Results In total, 136 stakeholders (45 IBD patients [advocates], 74 health care professionals/researchers, 13 industry representatives, and four regulators) from 20 different countries participated. The final set includes 18 case-mix variables, three biomarkers [haemoglobin to detect anaemia, C-reactive protein and faecal calprotectin to detect inflammation] for completeness, and 28 outcomes (including 16 patient-reported outcomes [PROs] and one patient-reported experience). The PRO-2 and IBD-Control questionnaires were recommended to collect disease-specific PROs at every contact with an IBD practitioner, and the Subjective Health Experience model questionnaire, PROMIS Global Health and Self-Efficacy short form, to collect generic PROs annually. Conclusions A COS for IBD, including a recommendation for use in clinical practice, was defined. Implementation of this set will start in Vienna, Berlin, Barcelona, Leuven, and Rotterdam, empowering patients to better manage their care. Additional centres will follow worldwide.This work was supported by the Innovative Medicines Initiative [IMI] 2 Joint Undertaking [945345-2]. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations [EFPIA], Trial Nation and the Juvenile Diabetes Research Foundation [JDRF]. The public grant funding is matched with in-kind contributions of EFPIA partners. About IMI: the Innovative Medicines Initiative is a partnership between the European Union and the European pharmaceutical industry, represented by EFPIA. It is working to improve health by speeding up the next generation of medicines, particularly in areas with unmet medical or social needs. It works by facilitating collaboration between the key players involved in health research, including universities, research centres, pharmaceutical and other industries, small and medium-sized enterprises [SMEs], patient organisations, and medicines regulators. IMI is the world’s most extensive public-private partnership [PPP] in the life sciences. This manuscript reflects only the authors’ views. The European Union and IMI are not responsible for any use that may be made of the information it contains

Perioperative management and early complications after intestinal resection with ileocolonic anastomosis in Crohn’s disease: analysis from the PRACTICROHN study

This study is aimed at describing the prevalence of and risk factors associated with early post-operative complications after Crohn’s disease-related intestinal resection. Methods: This was a retrospective analysis of data from the PRACTICROHN cohort. Adult Crohn’s disease patients who underwent ileocolonic resection with ileocolonic anastomosis between January 2007 and December 2010 were included. The complications evaluated included death, ileus, anastomotic leak, abscess, wound infection, catheter-related infection, digestive bleeding and other extra-abdominal infections that occurred in the 30 days after surgery.Results: A total of 364 patients (median age at surgery 38 years and 50% men) were included. Indication for surgery was: stricturing disease (46.4%), penetrating disease (31.3%), penetrating and stricturing disease (14.0%) or resistance to medical treatment (5.8%). Early complications were recorded in 100 (27.5%) patients, with wound infection, intra-abdominal abscess and anastomotic leakage being the most frequent complications. Median hospitalization duration was 16 days for patients with complications vs. 9 days without complications (P<0.001). Complications were more common among patients with penetrating disease (36/114, 31.6%) and those refractory to treatment (9/21, 42.9%) compared with stricturing disease (45/169, 26.6%) or stricturingþpenetrating disease (6/51, 11.8%) (P¼0.040). The rate of complications was higher among patients with diagnosis made at the time of surgery (15/31, 48.4%) compared with the rest (85/331, 25.7%) (P¼0.013). Medication received at the time of surgery did not affect the rate of complications. Conclusions: Almost a quarter of patients developed early complications after intestinal resection. Penetrating disease and urgent surgery were associated with an increased risk of complicationsThis study was supported by Merck Sharp and Dohme, Spai

Dysbiosis and relapse-related microbiome in inflammatory bowel disease: A shotgun metagenomic approach

© 2021 The Author(s).Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), affect several million people worldwide. CD and UC are characterized by periods of clinical remission and relapse. Although IBD patients present chronic alterations of the gut microbiome, called dysbiosis, little attention has been devoted to the relapse-related microbiome. To address this gap, we generated shotgun metagenomic data from the stools of two European cohorts—134 Spanish (followed up for one year) and 49 Belgian (followed up for 6 months) subjects—to characterize the microbial taxonomic and metabolic profiles present. To assess the predictive value of microbiome data, we added the taxonomic profiles generated from a previous study of 130 Americans. Our results revealed that CD was more dysbiotic than UC compared to healthy controls (HC) and that strategies for energy extraction and propionate production were different in CD compared to UC and HC. Remarkably, CD and UC relapses were not associated with alpha- or beta-diversity, or with a dysbiotic score. However, CD relapse was linked to alterations at the species and metabolic pathway levels, including those involved in propionate production. The random forest method using taxonomic profiles allowed the prediction of CD vs. non-CD with an AUC = 0.938, UC vs. HC with an AUC = 0.646, and CD relapse vs. remission with an AUC = 0.769. Our study validates previous taxonomic findings, points to different relapse-related growth and defence mechanisms in CD compared to UC and HC and provides biomarkers to discriminate IBD subtypes and predict disease activity.This study was supported by the Instituto de Salud Carlos III /FEDER, a government agency (grant numbers: PI17/00614; PI20/00130), and by the Crohn’s & Colitis Foundation of America (Award ID: 514634)

Multidisciplinary, evidence-based consensus guidelines for human papillomavirus (HPV) vaccination in high-risk populations, Spain, 2016

High-risk populations; Human papillomavirus infection; VaccinesPoblacions d'alt risc; Virus del papil·loma humà; VacunesPoblaciones de alto riesgo; Virus del papiloma humano; VacunasINTRODUCTION: Although human papillomavirus (HPV) routine vaccination programmes have been implemented around the world and recommendations have been expanded to include other high-risk individuals, current recommendations often differ between countries in Europe, as well as worldwide. AIM: To find and summarise the best available evidence of HPV vaccination in high-risk patients aiding clinicians and public health workers in the day-to-day vaccine decisions relating to HPV in Spain. METHODS: We conducted a systematic review of the immunogenicity, safety and efficacy/effectiveness of HPV vaccination in high-risk populations between January 2006 and June 2016. HPV vaccination recommendations were established with levels of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: A strong recommendation about HPV vaccination was made in the following groups: HIV infected patients aged 9-26 years; men who have sex with men aged 9-26 years; women with precancerous cervical lesions; patients with congenital bone marrow failure syndrome; women who have received a solid organ transplant or hematopoietic stem cell transplantation aged 9-26 years; and patients diagnosed with recurrent respiratory papillomatosis. CONCLUSIONS: Data concerning non-routine HPV vaccination in populations with a high risk of HPV infection and associated lesions were scarce. We have developed a document to evaluate and establish evidence-based guidelines on HPV vaccination in high-risk populations in Spain, based on best available scientific evidence

Leishmania infantum asymptomatic infection in inflammatory bowel disease patients under anti-TNF therapy

Background: In recent years anti-TNF therapy has been associated with leishmaniasis in immunocompromised patients from endemic areas. Nevertheless, data on asymptomatic Leishmania infection in such patients is scarce. The aim of this study was to determine the prevalence of asymptomatic infection in inflammatory bowel disease (IBD) patients treated with TNF inhibitors living in an endemic area (Catalonia) and to follow up them to study how the infection evolved. Methods: 192 IBD patients (143 Crohn's disease; 49 ulcerative colitis) from Catalonia (Spain), an area endemic for L. infantum, were recruited. Peripheral blood samples were collected and tested for anti-Leishmania antibodies by Western blotting (WB). Leishmania kinetoplast DNA was detected in peripheral blood mononuclear cells (PBMC) by a quantitative PCR. Results: Serology was positive in 3.1% and Leishmania DNA was found in 8.8%, with a low parasitic load and humoral response. The prevalence was 10.9%, patients being considered infected if they tested positive by at least one of the techniques. Eight out of the 21 patients with asymptomatic leishmaniasis were monitored for 3-8 months after the first test. None of them showed an increased parasitemia or humoral response, or developed leishmaniasis during the follow-up period. Conclusion: The prevalence of Leishmania asymptomatic infection detected in our IBD cohort is similar to that found in healthy population in close endemic areas. Due to the short monitoring period, it is not possible to reach a conclusion about the risk of Leishmania reactivation from this study