Butyrate enhances gut dysbiosis by activating the cAMP/PKA/CREB signaling pathway to inhibit the progression of endometrial carcinoma

Gut microbiota may contribute to the progression and prognosis of extra-intestinal tumors. The relationship and mechanism between endometrial carcinoma (EC), the gut microbiota, and short-chain fatty acids (SCFAs) remain ambiguous. This study aimed to ascertain whether alterations in gut microbiota and SCFAs are associated with EC. We assessed the gut microbiota composition and SCFAs concentrations in healthy volunteers and patients with EC using 16S ribosomal RNA and liquid chromatography–mass spectrometry, respectively. Subsequently, we investigated the impacts and associated mechanisms of the gut microbiota and SCFAs on cell phenotypes through cell experiments and comprehensive RNA sequencing. The gut microbiota of patients with EC exhibited significant variation compared to that of healthy volunteers. At the phylum level, the abundance of Proteobacteria elevated in patients with EC relative to healthy individuals, whereas the abundance of Firmicutes and Bacteroidetes were diminished. Furthermore, the concentrations of acetic acid and butyric acid in the feces of patients were remarkably lower than those in healthy individuals. The fecal supernatant of patients with EC promoted the proliferation, invasion, and migration of EC cells and inhibited cell apoptosis. However, these effects were reversed following the addition of sodium butyrate (NaB) and sodium acetate. On further investigating the mechanisms underlying SCFAs involvement in regulating EC, RNA-seq analysis revealed enrichment of the cAMP/PKA/CREB signaling pathway in the EC supernatant plus NaB compared with EC. The tumor growth rate was accelerated in mice treated with the feces of patients with EC compared to untreated mice. Nevertheless, these effects were reversed by NaB gavage. NaB supplementation to EC feces increased Occludin and Claudin 1 protein expression in the colon of mice with EC, reshaped the structure of the mouse colon, decreased the interleukin (IL)-1β and tumor necrosis factor(TNF)-α levels, increased the IL-10 level, and exerted a protective role in EC progression. Feces of patients with EC revealed gut dysbiosis. Furthermore, fecal microbiota transplantation could promote tumor growth and disrupt the normal structure of the mouse colon; however, these effects were alleviated by butyrate, highlighting it as a viable therapeutic option.