Esophageal microbiome in active eosinophilic esophagitis and changes induced by different therapies.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory esophageal disease triggered by food antigens. Cumulative evidence supports the implication of microbiota and the innate immune system in the pathogenesis of EoE. Changes in the esophageal microbiome were investigated by applying 16S rRNA gene sequencing on esophageal biopsies of adult patients with active EoE at baseline (n = 30), and after achieving remission with either proton pump inhibitors (PPI, n = 10), swallowed topical corticosteroids (STC, n = 10) or food-elimination diets (FED, n = 10). Ten non-EoE biopsies were also characterized as controls. Compared to controls, no differences in alpha (intra-sample) diversity were found in EoE microbiota overall. However, it decreased significantly among patients who underwent FED. As for beta (inter-sample) diversity, non-EoE controls separated from EoE baseline samples. Post-treatment samples from patients treated with PPI and FED had a more similar microbiota composition, while those receiving STC were closer to controls. Differential testing of microbial relative abundance displayed significant changes for Filifactor, Parvimonas and Porphyromonas genera. Analysis of predicted functions indicated alterations in metabolic pathways and abundance of sulphur-cytochrome oxidoreductases. Our findings demonstrate changes in microbiota associated with EoE, as well as a treatment effect on the microbiome.

Systematic review: health-related quality of life in children and adults with eosinophilic oesophagitis-instruments for measurement and determinant factors.

BACKGROUND: Several measures have been used to assess the health-related quality of life (HRQoL) of patients with eosinophilic oesophagitis (EoE). AIMS: To systematically review these HRQoL measures, to appraise measurement properties of specific instruments and to evaluate determinant factors influencing HRQoL in paediatric and adult EoE patients. METHODS: We searched the PubMed, Embase, Scopus, Web of Science (WOS) and PsycINFO databases for documents providing original information on the development of measurement tools and/or evaluation of HRQoL outcomes in EoE patients of all ages. RESULTS: Of the 596 references identified, data was collected from 34 studies (with only 16 of them being published as full papers) including a total of 1,689 individual patients. Three disease-specific HRQoL measures in EoE covering different aspects of patients' lives and developed in English, were scored positive regarding measurement properties. The PedsQL inventory (including parent and child report forms) and the Peds-QoL EoE module were the generic and specific instruments respectively used in children, while the SF-36 and EoE-QoL-A were the most used questionnaires in adults. Patients with EoE show an impaired HRQoL compared to controls, which greatly depends on symptom severity and disease duration. Severity of endoscopic features and female gender may also determine an impaired HRQoL. The effect of treatments on HRQoL requires further assessment. CONCLUSIONS: HRQoL is a relevant outcome that should be considered in clinical practice and research of EoE. Further validation studies in several languages and populations are required to support the use of disease-specific HRQoL measures.

P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance.

5-Fluorouracil (5-FU), together with other drugs such as oxaliplatin, is one of the most important pharmacological agents in the treatment of colorectal cancer. Although mitogen-activated protein kinases (MAPKs) have been extensively connected with resistance to platinum compounds, no role has been established in 5-FU resistance. Here we demonstrate that p38MAPK activation is a key determinant in the cellular response to 5-FU. Thus, inhibition of p38MAPKα by SB203580 compound or by short-hairpin RNA interference-specific knockdown correlates with a decrease in the 5-FU-associated apoptosis and chemical resistance in both HaCaT and HCT116 cells. Activation of p38MAPK by 5-FU was dependent on canonical MAP2K, MAPK kinase (MKK)-3 and MKK6. In addition, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) showed a redundancy of function for the final activation of p38MAPK. Resistance associated with p38MAPK inhibition correlates with an autophagic response that was mediated by a decrease in p53-driven apoptosis, without effect onto p53-dependent autophagy. Moreover, the results with colorectal cancer-derived cell lines with different p53 status and patterns of resistance to 5-FU suggest that de novo and acquired resistance was controlled by similar mechanisms. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the cellular response to 5-FU by controlling the balance between apoptosis and autophagy.