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Abstract Background Mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC‐EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro‐regenerative, anti‐apoptotic, and antifibrotic properties. Consequently, MSC‐EVs represent a cell‐free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non‐immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage. Main Topics Covered This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC‐EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC‐EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC‐EV cargoes. We also discuss available preclinical studies demonstrating that MSC‐EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials. Conclusions Finally, we highlight the potential of MSC‐EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice. Highlights The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC‐derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose‐derived MSC‐EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD). MicroRNAs are consistently present in MSC‐EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR‐let‐7a is associated with inhibition of apoptosis, miR‐100 supports cell survival, miR‐125b helps suppress pro‐inflammatory cytokines and miR‐20 promotes anti‐inflammatory M2 macrophage polarisation. Preclinical studies in IBD models have shown that MSC‐EVs reduce intestinal inflammation by suppressing pro‐inflammatory mediators (e.g., TNF‐α, IL‐1β, IL‐6) and increasing anti‐inflammatory factors (e.g., IL‐4, IL‐10). They also promote mucosal healing and strengthen the integrity of the gut barrier, suggesting their potential to address IBD pathology.

Abstract Background Previous studies suggested that Interleukin‐10 (IL‐10) depletion in Crohn's disease (CD) could predict outcome. Aim: To determine IL‐10 in blood and at different intestinal locations in patients with active CD and to assess its potential prognostic capacity to identify aggressive CD. Methods Twenty‐three patients with CD were included. Ulcerative colitis (UC), infectious colitis and healthy individuals acted as controls. Serum and mucosal samples were taken at baseline and 1 month after steroid initiation in CD patients. Patients were classified according to steroid response. Control samples were obtained from different intestinal locations. IL‐10 expression was measured with real‐time polymerase chain reaction, immunofluorescence (intestine) and ELISA (serum, biopsy cultures' supernatants and tissue homogenates). Results CD and UC showed an increase in IL‐10 messenger RNA (mRNA) versus controls (p

BACKGROUND:The implementation of successful strategies to achieve an HIV cure has become a priority in HIV research. However, the current location and size of HIV reservoirs is still unknown since there are limited tools to evaluate HIV latency in viral sanctuaries such as gut-associated lymphoid tissue (GALT). As reported in the so called "Boston Patients", despite undetectable levels of proviral HIV-1 DNA in blood and GALT, viral rebound happens in just few months after ART interruption. This fact might imply that current methods are not sensitive enough to detect residual reservoirs. Showing that, it is imperative to improve the detection and quantification of HIV-1 reservoir in tissue samples. Herein, we propose a novel non-enzymatic protocol for purification of Lamina Propria Leukocytes (LPL) from gut biopsies combined to viral HIV DNA (vDNA) quantification by droplet digital PCR (ddPCR) to improve the sensitivity and accuracy of viral reservoir measurements (LPL-vDNA assay). METHODS:Endoscopic ileum biopsies were sampled from 12 HIV-1-infected cART-suppressed subjects. We performed a DTT/EDTA-based treatment for epithelial layer removal followed by non-enzymatic disruption of the tissue to obtain lamina propria cell suspension (LP). CD45+ cells were subsequently purified by flow sorting and vDNA was determined by ddPCR. RESULTS:vDNA quantification levels were significantly higher in purified LPLs (CD45+) than in bulk LPs (p

Glucocorticosteroids are the first line therapy for moderate-severe flare-ups of ulcerative colitis. Despite that, up to 60% of patients do not respond adequately to steroid treatment. Previously, we reported that low IL-10 mRNA levels in intestine are associated with a poor response to glucocorticoids in active Crohn's disease. Here, we test whether IL-10 can favour the response to glucocorticoids by improving the TNFα-induced intestinal barrier damage (assessed by transepithelial electrical resistance) in Caco-2 monolayers, and their possible implications on glucocorticoid responsiveness in active ulcerative colitis. We show that the association of IL-10 and glucocorticoids improves the integrity of TNFα-treated Caco-2 cells and that p38 MAPK plays a key role. In vitro, IL-10 facilitates the nuclear translocation of p38 MAPK-phosphorylated thereby modulating glucocorticoids-receptor-α, IL-10-receptor-α and desmoglein-2 expression. In glucocorticoids-refractory patients, p38 MAPK phosphorylation and membrane desmoglein-2 expression are reduced in colonic epithelial cells. These results suggest that p38 MAPK-mediated synergism between IL-10 and glucocorticoids improves desmosome straightness contributing to the recovery of intestinal epithelium and reducing luminal antigens contact with lamina propria in ulcerative colitis. This study highlights the link between the intestinal epithelium in glucocorticoids-response in ulcerative colitis.