Approximately 60% of patients with ulcerative colitis (UC) exhibit steroid resistance or dependence, highlighting the need for reliable biomarkers to predict therapeutic response1. This study employed a systems biology and machine learning approach to integrate microRNA (miR) and mRNA expression data from both rectal biopsies and plasma samples from UC patients undergoing corticosteroid therapy, aiming to uncover the molecular mechanisms underlying steroid refractoriness. Whole-transcriptome and miR profiling were performed at baseline and after three days of corticosteroid therapy. Corticosteroid-treated UC patients were classified as responders (R) or non-responders (NR) after seven days of treatment. Mathematical modelling and protein-miR interaction mapping were used to identify mechanistically relevant biomarker candidates. Selected findings were validated in a TNBS-induced colitis mouse model. Key transcriptional co-regulators such as NCOA3, CBP, NCOR1, and NRIP1 were differentially expressed between R and NR, influencing glucocorticoid receptor (GCR) signalling. Multiple miRNAs, including miR-145-5p, miR-10b-5p, and miR-16-5p, were identified as potential biomarkers and regulators of inflammatory and GCR-related pathways. The cross-correlation between plasma and tissue miRs revealed consistent molecular patterns, some of which were also conserved in the murine model, supporting the existence of cross-species steroid response mechanisms. This integrative multi-omic approach provides new insights into molecular steroid-refractoriness in UC and offers a promising framework for developing predictive tools and advancing personalised therapeutic strategies in inflammatory bowel disease. Reference: 1. Llaó J et al. J Crohns Colitis. 2014;8(11). Conflict of interest: Dr. Ginés Mir, Iris: No conflict of interest Suau, Roger: No conflict of interest Naves, Juan E.: No conflict of interest Bernal, Carla: No conflicts Clua, Laura: No conflict of interest Monfort-Ferré, Diandra: No conflict of interest Pluvinet, Raquel: No conflict of interest Sánchez Herrero, José Francisco: No conflict of interest Segú, Cristina: No conflict of interest Aransay, Ana Maria: No conflict of interest Mañosa Ciria, Miriam: No conflict of interest Sumoy, Lauro: No conflict of interest Serena, Carolina: No conflict of interest Domènech Moral, Eugeni: No conflict of interest Manyé Almero, Josep: No conflict of interest
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated disorders characterized by heterogeneous clinical courses and unpredictable therapeutic responses. Despite the availability of biologics and small molecules, treatment selection remains empirical, delaying remission, increasing exposure to ineffective drugs, and highlighting urgent need for biomarker-driven, precision-guided strategies. A multi-omics analysis was performed, integrating transcriptomics, proteomics, metabolomics, and metagenomic across intestinal tissue, serum, urine, serum-derived extracellular vesicles (EVs), and stool from 130 IBD patients treated with anti-TNFα, ustekinumab, vedolizumab, or tofacitinib (Figure 1). Clinical and demographic characteristics are summarised in Table 1. Analyses revealed distinct, therapy-specific molecular signatures capable of discriminating responders from non-responders, with all markers achieving a predictive performance of area under the curve > 0.9. In CD, PDIA1 and IGHV4-28 in serum EVs and intestinal tissue predicted anti-TNFα response, while LINC02802 and MIR567 distinguished ustekinumab responders. In UC, vedolizumab response was associated with SCIMP and CYP39A1 in intestinal tissue, and tofacitinib response with CAVN2 in serum EVs. Metabolomic profiling highlighted coordinated serum and urinary alterations in amino acids, organic acids, and lipid metabolism linked to therapeutic efficacy. Metagenomic analysis identified genera associated with response, including Prevotella and Anaerotruncus for anti-TNFα, Faecalibacterium for ustekinumab, Catenibacterium for vedolizumab, and Phascolarctobacterium for tofacitinib. Integration of multi-omics layers provided complementary insights, emphasizing the central role of the intestinal microenvironment and host-microbiota interactions in mediating treatment outcomes. These findings establish a comprehensive framework for precision therapy in IBD, identifying predictive biomarkers with translational potential to optimize personalized therapy, minimize ineffective treatment, and reduce disease burden. Conflict of interest: Baldan-Martin, Montserrat: No conflict of interest Azkargorta, Mikel: No conflict of interest Aransay, Ana M.: No conflict of interest Gil-Redondo, Rubén: No conflict of interest Moreno-Indias, Isabel: No conflict of interest Iloro, Ibon: No conflict of interest Martínez González, Paula Julia: No conflict of interest Soleto, Irene: No conflict of interest Suarez-Trujillo, Fabio: No conflict of interest Ramírez, Cristina: No conflict of interest Lucendo, Alfredo: No conflict of interest Rodríguez Gutiérrez, Cristina: No conflict of interest Gutiérrez Casbas, Ana: No conflict of interest Martin Arranz, Eduardo: Personal Fees: Olympus and Janssen Non-financial Support: Support for conference attendance, education or research from Abbvie, Pfizer, Janssen Bujanda, Luis: Not Rodríguez-Lago, Iago: No conflict of interest De Francisco Garcia, Ruth Maria: No conflict of interest Iglesias Flores, Eva: No conflict of interest Bermejo San Jose, Fernando: No conflict of interest Van Domselaar, Manuel: No conflict of interest García, María José: Other: MJ García has received financial support for travelling and educational activities from Janssen, Pfizer, Abbvie, Takeda and Ferring. Fernandez, José Luis: No conflict of interest Garcia Alonso, Francisco Javier: I have acted as a speaker for Abbvie, Lilly and Johnson and Johnson Calvet Calvo, Xavier: Xavier Calvet has received grants for research from AbbVie Janssen, Kern and Vifor, and fees for advisory board services form Abbvie, MSD, Takeda and Vifor. He has also given lectures for Abbvie, Janssen and Takeda. Torrealba Medina, Leyanira: No conflict of interest Bastón Rey, Iria: Personal Fees: Iria Bastón Rey has received financial support for travelling and educational activities from or has served as an advisory board member for Abbvie, Johnson & Johnson, Takeda, Pfizer, Alfasigma, Ferring, Faes Farma and Otsuka Pharmaceutical and Adacyte. Pallarés-Manrique, Héctor: No conflict of interest Ber, Yolanda: Non Leo Carnerero, Eduardo: I have received grants or fees for scientific activities or as a scientific advisor for MSD, Pfizer, Abbvie, Takeda, Janssen, Tillotts Pharma, Shire Pharmaceuticals, Ferring, Dr. Falk Pharma, Lilly, Adacyte and Otsuka Pharmaceutical. Casanova, María José: María José Casanova, has received education funding from Pfizer, Takeda, Janssen, MSD, Dr. Falk, Shire, Ferring, Galápagos and Abbvie, and research funding from Lilly. Millet, Oscar: No conflict of interest Elortza, Félix: No conflict of interest Mato, José M: No conflict of interest Tinahones, Francisco J.: No conflict of interest Chaparro, María: Grants: Pfizer, Janssen, Biogen, Abbvie, Lilly Personal Fees: Pfizer, Faes, Lilly, Abbvie, Janssen Gisbert, Javier: Grant: MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos/Alfasigma, Lilly, Sanofi, STADA, Teva, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine, Italfarmaco, and Vifor Pharma. Personal Fees: MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos/Alfasigma, Lilly, Sanofi, STADA, Teva, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine, Italfarmaco, and Vifor Pharma. Other: MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos/Alfasigma, Lilly, Sanofi, STADA, Teva, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine, Italfarmaco, and Vifor Pharma.
Female breast development occurs at puberty and undergoes many cyclic changes under normal physiological conditions, like pregnancy, lactation and involution. The breast epithelium is surrounded by a heterogenous stroma that encompasses various cell types, including fibroblasts, immune cells, adipocytes, endothelial cells and an extracellular matrix (ECM). The ECM is a complex molecular meshwork composed of a variety of matricellular proteins and ECM remodelling enzymes, including proteases. Dynamic remodelling of the ECM is fundamental to the organisation and function of the mammary gland and is associated with stemness. It is often aberrantly regulated in breast cancer, which still has the highest incidence and mortality rates in women worldwide. Improved models could contribute to a better understanding of cell-matrix interactions, including in the stem cell niche, and ECM remodelling in health and tumorigenesis. This could lay the groundwork for therapeutic strategies that also target the breast cancer ECM for improved precision medicine tools.
