Emerging evidence suggests that gut microbiota is associated with functional gastrointestinal disorders (FGIDs). However, findings regarding microbial alterations in FGIDs have been inconsistent across observational studies, and the direction and causality of these associations remain unclear. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate potential causal associations between gut microbiota and two common FGIDs, irritable bowel syndrome (IBS) and functional dyspepsia (FD). Genome-wide association study (GWAS) summary statistics of gut microbiota, IBS, and FD were obtained from public databases and applied to our MR analysis. The inverse-variance-weighted method was used as the primary analysis, with weighted median and complementary sensitivity analyses used to assess the consistency and robustness of the findings. Higher genetically predicted abundances of
order Bifidobacteriales
(OR: 0.741, 95% CI: 0.570 to 0.963,
P
= 0.025) and
genus Eubacterium ventriosum group
(OR: 0.684, 95% CI: 0.524 to 0.893,
P
= 0.005) were associated with a lower risk of IBS.
Genus Lachnospiraceae NK4A136 group
(OR: 1.368, 95% CI: 1.086 to 1.722,
P
= 0.008) correlated to a high risk of FD while
family Desulfovibrionaceae
and
order Desulfovibrionales
(OR: 0.649, 95% CI: 0.471 to 0.893,
P
= 0.008) were protective for FD. In the reverse MR analysis, genetically predicted IBS risk was associated with lower abundances of
Turicibacter
and
Slackia
, whereas no robust reverse associations were observed for FD. These findings identify several microbial taxa as candidates for further mechanistic and clinical validation rather than established risk factors or therapeutic targets. Further experimental research to investigate the underlying mechanisms is warranted.
Yu-Tong Cheng, Qiu-Ai Shu, Zi-Wei Wang et al.· Experimental biology and med...· 0 citations
BACKGROUND
Hepatocellular carcinoma is an aggressive malignancy with poor outcomes. Emerging studies highlight the importance of the tumor microenvironment in HCC progression, where exosomes serve as critical messengers linking tumor cells with surrounding stromal components. Although circRNAs are abundantly present in tumor-derived exosomes, their precise roles and mechanisms in HCC remain poorly defined.
METHODS
Exosomes were characterized using transmission electron microscopy and flow cytometry. Differentially expressed circRNAs were identified by RNA sequencing. Macrophage polarization and metabolic reprogramming were evaluated by western blotting, immunofluorescence and metabolomics. The role of hsa_circ_0057320, miR-28-5p, and E2F6 in HCC progression was examined through transwell, tube formation, and spheroid-sprouting assays. Xenograft mouse models were constructed to verify the role of them in metastasis and angiogenesis, exosomes in progression of HCC. Interactions among hsa_circ_0057320, miR-28-5p, and E2F6 were explored using RIP and dual-luciferase reporter assays.
RESULTS
In this study, we found that exosomes derived from HOXD3-treated HCCs induced macrophage polarization toward the M2 phenotype via metabolic reprogramming. In addition, HOXD3-stimulated HCC cells secreted exosomes enriched in hsa_circ_0057320, which induce the alternatively activated (M2) macrophage phenotype and enhanced angiogenesis and metastatic capability in vivo and vitro. The role of hsa_circ_0057320 in the metastasis and invasion of HCC was reversed after the enhance of miR-28-5p. E2F6, a target of miR-28-5p, was markedly upregulated in HCC tissues and cells. Additionally, a positive relationship was established between hsa_circ_0057320 and E2F6, contrasting with a negative association with miR-28-5p.
CONCLUSIONS
Exosomes derived from HOXD3-induced HCC cells promotes M2 macrophage polarization via metabolic reprogramming. In addition, HOXD3-induced exosomal hsa_circ_0057320 promotes macrophage M2 polarization via the miR-28-5p/E2F6 axis, thereby accelerating HCC malignancy. These findings reveal the interactive communication mechanism between HCCs and TME, and highlight hsa_circ_0057320 as a potential exosomal indicator and therapeutic target for metastatic HCC.
Lumin Wang, Chenyang Qiao, Zhiqiang Wang et al.· Journal of Translational Med...· 0 citations
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