Gastroenterology最新文献

Background & aims: Faecalibacterium prausnitzii, a highly abundant gut bacterium, has been linked to overall health, and is decreased in several pathologic conditions, such as inflammatory bowel disease (IBD). F prausnitzii has shown anti-inflammatory properties in human and mouse models, notably through the induction of interleukin 10 (IL10) signaling. Here, we investigated which cell types from human blood and intestinal tissue are responsible for producing IL10 induced by F prausnitzii and provide the first mechanistic insights.

Methods: Immune cells isolated from human blood and intestinal lamina propria of IBD patients and noninflamed controls, were stimulated with F prausnitzii EXL01 strain, Coprococcus comes 27758 strain, and Escherichia coli MG1655 strain, with or without lipopolysaccharide (LPS), and analyzed by LEGENDplex, enzyme-linked immunosorbent assay, flow cytometry, RNA sequencing, and Seahorse technology.

Results: F prausnitzii induced a direct and dose-dependent production of IL10 in cluster of differentiation 14⁺ monocytes from the systemic circulation and intestinal tissue, without inducing a proinflammatory response compared with LPS stimulation. RNA sequencing and Seahorse analyses corroborated these results, revealing that F prausnitzii affects cellular energy metabolism in healthy and inflammatory conditions, in a different way from 2 other tested bacteria and LPS. The anti-inflammatory response induced by F prausnitzii in monocytes was dependent on mitochondrial respiration.

Conclusions: F prausnitzii induces an anti-inflammatory response and rewires energy metabolism in human monocytes in healthy and inflamed conditions, potentially explaining its beneficial impact on intestinal inflammation and human health in general. These results provide new insight into the mechanisms underlying the anti-inflammatory effects of F prausnitzii and are crucial for a better understanding of its potential use in IBD treatment.

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic disease that provokes dysregulation of the coagulation system. Patients exhibit significantly elevated circulating levels of blood clotting protein fibrin(ogen). Extravascular fibrin deposits contribute to the complex tumor microenvironment in PDAC.

Methods: We depleted fibrinogen in 3 PDAC patient-derived xenograft models using technology platforms that are currently being tested clinically (antisense oligonucleotide or lipid nanoparticles containing small interfering RNAs) and monitored tumor growth and metastasis. Proteomics and spatial transcriptomics were used to interrogate the mechanisms behind the in vivo work.

Results: The role of fibrin on tumor progression was evaluated in vitro and in vivo and reduction of fibrin led to decreased tumor cell proliferation in vitro and significantly suppressed primary orthotopic tumor growth. Fibrin depletion provoked a significant shift in extracellular matrix-associated proteins and serine protease inhibitors, suggesting a decrease in the activity of serine proteases known to be responsible for extracellular matrix remodeling and metastatic dissemination. Spatial transcriptomics revealed that tumors from fibrinogen-depleted mice exhibit significantly increased presence of stromal components, including tumor-restraining cancer-associated fibroblasts. Congruently, fibrinogen knockdown in a metastatic orthotopic model markedly impaired spontaneous metastasis to the liver. However, fibrinogen knockdown did not affect liver colonization in an intrasplenic injection model, which recapitulates the late stages of metastasis.

Conclusions: These data suggest that fibrin(ogen) reprograms the primary tumor microenvironment to support growth and promote early, but not late, metastatic steps. Our findings support prospective evaluation of a novel clinical approach involving the integration of fibrin(ogen)-targeting or depleting agents into chemotherapy regimens to control the spread of pancreatic cancer.