Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models

Abstract

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.

The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View

“…However, microbes in unexpected tissues can impact on cancer progression and response to therapy. Pancreatic cancers can have bacteria accidentally introduced by medical intervention [26][27][28], and colorectal cancers can bring along gut bacteria when they metastasize to other tissues such as the liver [29]. Regardless of whether a tissue is already colonized, the direct interaction between microbes and cancer cells remains poorly understood.…”

Microbiota Alterations in Gastrointestinal Cancers

“…The human pancreas has been reported to harbor its own microflora; however, little data have been obtained on this subject. It has been found that Acinetobacter, Pseudomonas, and Propionibacterium predominate in the microbiota of the healthy human pancreas; nevertheless, these data need further investigation owing to the limited size of the cohort used in the study (n = 7) [69].…”

“…A study suggest that Kras G12D /PTEN lox/+ mice with intact microbiota developped PDAC faster than mice lacking microflora after antibiotic treatment. They also point to the role of microbiome in immune system stimulation [69]. However, the study lacks data about specific bacterial taxa that might accelerate PDAC development.…”

Fecal Microbial Transplantation for Diseases Beyond Recurrent Clostridium Difficile Infection

“…Researchers demonstrated a functional link between intestinal microbiota and the development of pancreatic cancer in mice. 73,74 One study showed that development of pancreatic ductal adenocarcinoma was prevented when Pdx1-Cre; LSL-Kras mice were bred under germ-free conditions. 74 Development of tumors in Ptf1aCre; LSL-KrasG12D (KC) mice increased upon fecal transfer of microbiota from KPC mice compared to WT biota.…”

“…74 A study of Kras G12D ; PTEN lox/þ mice showed that pancreatic ductal adenocarcinoma progression was attenuated when the intestinal bacterial community was depleted with antibiotics compared to microbiota-intact mice. 73 Changes in the intestinal microbiota have also been associated with liver cancer progression, affecting metabolism of bile acid from primary to secondary structures. Secondary bile acids inhibit recruitment of natural killer T cells, which have anti-tumor effects, to the liver.…”