Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumour with a poor prognosis and a high mortality rate. It is of great significance to explore sensitive or specific biomarkers for early diagnosis and prognosis. We first examined the metabolome and gut microbiota of resectable and unresectable PDAC patients to comprehensively investigate the characteristics of PDAC at different stages of progression. At the genus level, we found that the relative abundances of Alistipes, Anaerostipes, Faecalibacterium and Parvimonas were reduced in unresectable PDAC patients, whereas Pseudonocardia, Cloacibacterium, Mucispirillum, and Anaerotruncus were increased. Metabolomics analysis showed that the main changed metabolites were amino acids, carnitine derivatives, lipids and fatty acids. ROC analysis showed that Oleic acid, Linoleic acid, Palmitic acid, Linoelaidyl carnitine, 2-Octenedioic acid, 3R, 7R-1,3,7-Octanetriol, LysoPE (P-16:0/0:0) and 3-Hydroxyanthranilic acid had high AUC values (>0.9). Function and network analyses showed that these altered metabolites correlated with NF-kappa B signalling, the FXR/RXR pathway, mitochondrial dysfunction, mTOR signalling and IL-6 signalling. In particular, the abundance of Palmitic acid, Oleic acid, Linoelaidyl carnitine and 2-Octenedioic acid positively correlated with g_Anaerostipes, g_Alistipes, s_indistinctus, s_catus and s_formicigenerans but negatively correlated with g_Cloacibacterium, s_reuteri and s_hathewayi. Meanwhile,We also found that s_catus, s_ formicigenerans, s_ hathewayi, g_ Alistipes, g_ Anaerostipes, PE (22:6 (4Z, 7z, 10z, 13z, 16Z, 19Z)/p-18:1 (11z)), (3R, 7R) - 1,3,7-octanetriol and linoelaidyl carnitine were positively correlated with the survival time of patients.These findings may be helpful for the differentiation of resectable and unresectable PDAC based on changes in intestinal flora and metabolites at different stages of PDAC. This study also provides a strategy for preventing the deterioration of PDAC by regulating the gut microbiota and metabolism.

Purpose In our previous study, we found that corylifol A (CYA), an active component derived from Psoralea corylifolia L, exhibited ameliorating effects on cancer cachexia. Anamorelin (AML), a ghrelin receptor agonist, is the only approved drug for the clinical treatment of cancer cachexia. Here, we checked the combination of CYA and AML on muscle atrophy and fat lipolysis in cancer cachexia mice to explore the possible clinic therapeutic potency of the combination on cancer cachexia. Methods C26 colon tumor-bearing mice, a well-established animal model of cancer cachexia, were used to evaluate the effects of combined therapy involving CYA and AML on cancer cachexia and compared with those of CYA or AML alone. Histological analysis was performed to assess the changes in gastrocnemius (GAS) muscle tissue and epididymal adipose tissue (eWAT) and the possible involved molecular pathways were explored using western blotting and ELISA. Results Treatments of CYA, AML, or CYA+AML all significantly ameliorated the body weight decrease, muscle atrophy as well as fat loss in the tumor-bearing mice. Notably, the ameliorating effects of CYA+AML on fat loss were more significant than CYA or AML alone. The eWAT weight of mice in healthy control, C26 model, C26 +CYA, C26 +AML or C26 +CYA +AML group was 0.48 ± 0.07, 0.21 ± 0.10, 0.26 ± 0.10, 0.37 ± 0.10 and 0.48 ± 0.18 g, respectively. CYA+AML could increase food intake, significantly decrease the serum levels of inflammatory cytokines (TNF-α and IL-6) and inhibit the activation (phosphorylation) of hormone-sensitive lipase (HSL) in the eWAT tissues of the C26 tumor-bearing mice. Treatment of CYA along could significantly decrease the serum TNF-α level of the C26 tumor-bearing mice. Treatment of AML alone could increase food intake but could not decrease the serum levels of inflammatory cytokines of the C26 tumor-bearing mice. Conclusion These results suggested that the effects of CYA+AML include both the appetite-stimulating effects of AML and the anti-inflammatory effects of CYA. CYA+AML was better than CYA or AML alone in ameliorating cancer cachexia, especially fat loss, of C26 tumor-bearing mice and might be a novel and beneficial therapeutic option for cancer cachexia.