Integrative analysis of metabolome and gut microbiota in Patients with pancreatic ductal adenocarcinoma

Abstract

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.

Interaction between Acute Pancreatitis and Gastrointestinal Microbiome: A Bidirectional Two-sample Mendelian Randomization Study

“…Anaerotruncus correlated with cholesterol diet-induced nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC), and a study demonstrated a progressive increase in the abundance of Anaerotruncus during the NAFLD-HCC disease process [44]. The accumulation of Anaerotruncus in the intestine increased the risk of anal stula, and Anaerotruncus was increased in unresectable pancreatic ductal adenocarcinoma (PDAC) [45]. The overexpression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in hepatocellular carcinoma could reduce the abundance of Anaerotruncus in the intestine [46].…”

Role of microbiota and microbiota‐derived short‐chain fatty acids in PDAC

“…There was not any significant difference between the duodenal fluid microbiota profiles of patients with pancreatic cysts and healthy individuals. 35 Finally, more recently, Guo et al (2022) reported that microbiome variation is related to pancreatic cancer. 36…”

“…In 2019, Del Castillo et al reported that, the relative abundances of Fusobacterium, Porphyromonas, Capnocytophaga, idocharacter, Prevotella, Gemella and Selemonas was higher in pancreatic cancer patients when compared with healthy people 39 . The changes in microbiome in vivo are highly correlated with in cancer patients and cancer progression 36 . Future human studies are necessary to fully understand the effect of microbiome in different periods of pancreatic cancer.…”

“… 35 Finally, more recently, Guo et al (2022) reported that microbiome variation is related to pancreatic cancer. 36 …”

“… 39 The changes in microbiome in vivo are highly correlated with in cancer patients and cancer progression. 36 Future human studies are necessary to fully understand the effect of microbiome in different periods of pancreatic cancer.…”