Particular genomic and virulence traits associated with preterm infant-derived toxigenic Clostridium perfringens strains.

Clostridium perfringens is an anaerobic toxin-producing bacterium associated with intestinal diseases, particularly in neonatal humans and animals. Infant gut microbiome studies have recently indicated a link between C. perfringens and the preterm infant disease necrotizing enterocolitis (NEC), with specific NEC cases associated with overabundant C. perfringens termed C. perfringens-associated NEC (CPA-NEC). In the present study, we carried out whole-genome sequencing of 272 C. perfringens isolates from 70 infants across 5 hospitals in the United Kingdom. In this retrospective analysis, we performed in-depth genomic analyses (virulence profiling, strain tracking and plasmid analysis) and experimentally characterized pathogenic traits of 31 strains, including 4 from CPA-NEC patients. We found that the gene encoding toxin perfringolysin O, pfoA, was largely deficient in a human-derived hypovirulent lineage, as well as certain colonization factors, in contrast to typical pfoA-encoding virulent lineages. We determined that infant-associated pfoA+ strains caused significantly more cellular damage than pfoA- strains in vitro, and further confirmed this virulence trait in vivo using an oral-challenge C57BL/6 murine model. These findings suggest both the importance of pfoA+ C. perfringens as a gut pathogen in preterm infants and areas for further investigation, including potential intervention and therapeutic strategies.

Reciprocal Interactions Between the Gut Microbiome and Mammary Tissue Mast Cells Promote Metastatic Dissemination of HR+ Breast Tumors.

Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, before breast tumor initiation, enhances early dissemination of hormone receptor-positive (HR+) mammary tumor cells. Here, we sought to determine whether cellular changes occurring in normal mammary tissues, before tumor initiation and in response to dysbiosis, enhanced dissemination of HR+ tumors. Commensal dysbiosis increased both the frequency and profibrogenicity of mast cells in normal, non-tumor-bearing mammary tissues, a phenotypic change that persisted after tumor implantation. Pharmacological and adoptive transfer approaches demonstrated that profibrogenic mammary tissue mast cells from dysbiotic animals were sufficient to enhance dissemination of HR+ tumor cells. Using archival HR+ patient samples, we determined that enhanced collagen levels in tumor-adjacent mammary tissue positively correlated with mast cell abundance and HR+ breast cancer recurrence. Together, these data demonstrate that mast cells programmed by commensal dysbiosis activate mammary tissue fibroblasts and orchestrate early dissemination of HR+ breast tumors.

Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumor growth.

The gut microbiota's function in regulating health has seen it linked to disease progression in several cancers. However, there is limited research detailing its influence in breast cancer (BrCa). This study found that antibiotic-induced perturbation of the gut microbiota significantly increases tumor progression in multiple BrCa mouse models. Metagenomics highlights the common loss of several bacterial species following antibiotic administration. One such bacteria, Faecalibaculum rodentium, rescued this increased tumor growth. Single-cell transcriptomics identified an increased number of cells with a stromal signature in tumors, and subsequent histology revealed an increased abundance of mast cells in the tumor stromal regions. We show that administration of a mast cell stabilizer, cromolyn, rescues increased tumor growth in antibiotic treated animals but has no influence on tumors from control cohorts. These findings highlight that BrCa-microbiota interactions are different from other cancers studied to date and suggest new research avenues for therapy development.

The ß3-integrin endothelial adhesome regulates microtubule-dependent cell migration.

Integrin ß3 is seen as a key anti-angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro- or anti-angiogenic depends on the context in which it is expressed. To understand precisely ß3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the ß3-dependent adhesome. We show that depletion of ß3-integrin in this cell type leads to changes in microtubule behaviour that control cell migration. ß3-integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2-driven control of active Rac1 localisation. Our findings reveal that angiogenic processes, both in vitro and in vivo, are more sensitive to microtubule targeting agents when ß3-integrin levels are reduced.