Intratumor Microbiome Analysis Identifies Positive Association Between Megasphaera and Survival of Chinese Patients With Pancreatic Ductal Adenocarcinomas.

Human tumors harbor a plethora of microbiota. It has been shown that the composition and diversity of intratumor microbiome are significantly associated with the survival of patients with pancreatic ductal adenocarcinoma (PDAC). However, the association in Chinese patients as well as the effect of different microorganisms on inhibiting tumor growth are unclear. In this study, we collected tumor samples resected from long-term and short-term PDAC survivors and performed 16S rRNA amplicon sequencing. We found that the microbiome in samples with different survival time were significantly different, and the differential bacterial composition was associated with the metabolic pathways in the tumor microenvironment. Furthermore, administration of Megasphaera, one of the differential bacteria, induced a better tumor growth inhibition effect when combined with the immune checkpoint inhibitor anti-programmed cell death-1 (anti-PD-1) treatment in mice bearing 4T1 tumor. These results indicate that specific intratumor microbiome can enhance the anti-tumor effect in the host, laying a foundation for further clarifying the underlying detailed mechanism.

Huang Y ，Zhu N ，Zheng X ，Liu Y ，Lu H ，Yin X ，Hao H ，Tan Y ，Wang D ，Hu H ，Liang Y ，Li X ，Hu Z ，Yin Y ... -  《Frontiers in Immunology》

Alterations of the bile microbiome is associated with progression-free survival in pancreatic ductal adenocarcinoma patients.

Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals. However, knowledge regarding the bile microbiome and its potential impact on progression-free survival in PDACs remains limited. Patients with PDAC (n = 45), including 20 matched pairs before and after surgery, and benign controls (n = 16) were included prospectively. The characteristics of the microbiomes of the total 81 bile were revealed by 16  S-rRNA gene sequencing. PDAC patients were divided into distinct groups based on tumor marker levels, disease staging, before and after surgery, as well as progression free survival (PFS) for further analysis. Disease diagnostic model was formulated utilizing the random forest algorithm. PDAC patients harbor a unique and diverse bile microbiome (PCoA, weighted Unifrac, p = 0.038), and the increasing microbial diversity is correlated with dysbiosis according to key microbes and microbial functions. Aliihoeflea emerged as the genus displaying the most significant alteration among two groups (p < 0.01). Significant differences were found in beta diversity of the bile microbiome between long-term PFS and short-term PFS groups (PCoA, weighted Unifrac, p = 0.005). Bacillota and Actinomycetota were identified as altered phylum between two groups associated with progression-free survival in all PDAC patients. Additionally, we identified three biomarkers as the most suitable set for the random forest model, which indicated a significantly elevated likelihood of disease occurrence in the PDAC group (p < 0.0001). The area under the receiver operating characteristic (ROC) curve reached 80.8% with a 95% confidence interval ranging from 55.0 to 100%. Due to the scarcity of bile samples, we were unable to conduct further external verification. PDAC is characterized by an altered microbiome of bile ducts. Biliary dysbiosis is linked with progression-free survival in all PDACs. This study revealed the alteration of the bile microbiome in PDACs and successfully developed a diagnostic model for PDAC.

Jiang H ，Tian Y ，Xu L ，Chen X ，Huang Y ，Wu J ，Wang T ，Liu T ，Wu X ，Ye C ，Wu H ，Ye W ，Fang L ，Zhang Y ... -  《BMC MICROBIOLOGY》

Microbiome and pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) incidence and related-deaths are increasing worldwide. PDAC is characterized by poor prognosis due to late diagnosis, high metastatic capacity and resistance to therapy. This is partially due to its specific microenvironment, where the stroma is prominent over tumor cells. Besides the oral and gut microbiota, the intratumor microbiome, i.e. the bacterial and fungal microorganisms present within the tumor, was recently introduced as a new partner of the tumor microenvironment of PDAC modulating pancreatic carcinogenesis, intratumor immune infiltrates, and response to chemotherapy. In this review, we propose an overview of current knowledge about the roles of bacteria and fungi in PDAC development and biology, and discuss potential therapeutic implications.

Tijeras-Raballand A ，Hilmi M ，Astorgues-Xerri L ，Nicolle R ，Bièche I ，Neuzillet C ... -  《-》

Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes.

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.

Riquelme E ，Zhang Y ，Zhang L ，Montiel M ，Zoltan M ，Dong W ，Quesada P ，Sahin I ，Chandra V ，San Lucas A ，Scheet P ，Xu H ，Hanash SM ，Feng L ，Burks JK ，Do KA ，Peterson CB ，Nejman D ，Tzeng CD ，Kim MP ，Sears CL ，Ajami N ，Petrosino J ，Wood LD ，Maitra A ，Straussman R ，Katz M ，White JR ，Jenq R ，Wargo J ，McAllister F ... -  《-》

Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States yet data are scant regarding host factors influencing pancreatic carcinogenesis. Increasing evidence support the role of the host microbiota in carcinogenesis but its role in PDAC is not well established. Herein, we report that antibiotic-mediated microbial depletion of KrasG12D/PTENlox/+ mice showed a decreased proportion of poorly differentiated tumors compared to microbiota-intact KrasG12D/PTENlox/+ mice. Subsequent 16S rRNA PCR showed that ~50% of KrasG12D/PTENlox/+ mice with PDAC harbored intrapancreatic bacteria. To determine if a similar observation in humans correlates with presence of PDAC, benign and malignant human pancreatic surgical specimens demonstrated a microbiota by 16S bacterial sequencing and culture confirmation. However, the microbial composition did not differentiate PDAC from non-PDAC tissue. Furthermore, murine pancreas did not naturally acquire a pancreatic microbiota, as germ-free mice transferred to specific pathogen-free housing failed to acquire intrapancreatic bacteria over time, which was not augmented by a murine model of colitis. Finally, antibiotic-mediated microbial depletion of Nod-SCID mice, compared to microbiota-intact, showed increased time to PDAC xenograft formation, smaller tumors, and attenuated growth. Interestingly, both xenograft cohorts were devoid of intratumoral bacteria by 16S rRNA PCR, suggesting that intrapancreatic/intratumoral microbiota is not the sole driver of PDAC acceleration. Xenografts from microbiota-intact mice demonstrated innate immune suppression by immunohistochemistry and differential regulation of oncogenic pathways as determined by RNA sequencing. Our work supports a long-distance role of the intestinal microbiota on PDAC progression and opens new research avenues regarding pancreatic carcinogenesis.

Thomas RM ，Gharaibeh RZ ，Gauthier J ，Beveridge M ，Pope JL ，Guijarro MV ，Yu Q ，He Z ，Ohland C ，Newsome R ，Trevino J ，Hughes SJ ，Reinhard M ，Winglee K ，Fodor AA ，Zajac-Kaye M ，Jobin C ... -  《-》