Comprehensive Assessment of the Intrinsic Pancreatic Microbiome

Eckhoff, A. M.; Fletcher, A. A.; Kelly, M. S.; Dohlman, A.; McIntyre, C. A.; Shen, X.; Iyer, M. K.; Nussbaum, D. P.; Allen, P. J.

doi:10.1101/2023.08.12.553074

bioRxiv · 10.1101/2023.08.12.553074

Comprehensive Assessment of the Intrinsic Pancreatic Microbiome

Eckhoff, A. M.·Fletcher, A. A.·Kelly, M. S.·Dohlman, A.·McIntyre, C. A.·Shen, X.·Iyer, M. K.·Nussbaum, D. P.·Allen, P. J.

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Abstract

BackgroundSmall studies in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) have suggested that intra-pancreatic microbial dysbiosis may drive malignant transformation. We sought to comprehensively profile tissue and cyst fluid in patients with benign, precancerous, and cancerous conditions of the pancreas to characterize the intrinsic pancreatic microbiome. MethodsPancreatic samples were collected at the time of resection from 109 patients. Samples included tumor tissue (control, n=20; IPMN, n=20; PDAC, n=19) and pancreatic cyst fluid (IPMN, n=30; SCA, n=10; MCN, n=10). Assessment of bacterial DNA by quantitative PCR and 16S ribosomal RNA gene sequencing was performed. Downstream analyses determined the relative abundances of individual taxa between groups and compared intergroup diversity. Whole-genome sequencing data from 140 patients with PDAC in the National Cancer Institutes Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to validate findings. ResultsSequencing of pancreatic tissue yielded few microbial reads regardless of diagnosis, and analysis of pancreatic tissue showed no difference in the abundance and composition of bacterial taxa between normal pancreas, IPMN, or PDAC groups. Low-grade dysplasia (LGD) and high-grade dysplasia (HGD) IPMN were characterized by low bacterial abundances with no difference in tissue composition and a slight increase in Pseudomonas and Sediminibacterium in HGD cyst fluid. Decontamination analysis using the CPTAC database confirmed a low-biomass, low-diversity intrinsic pancreatic microbiome that did not differ by pathology. ConclusionsOur analysis of the pancreatic microbiome demonstrated very low intrinsic biomass that is relatively conserved across diverse neoplastic conditions and thus unlikely to drive malignant transformation. Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSO_LIMicrobial colonization, infection, and dysbiosis have been implicated in the oncogenesis of various gastrointestinal tumors (e.g.: Helicobacter pylori in gastric cancer, hepatitis B and C in hepatocellular carcinoma, colon dysbiosis in colon cancer progression). C_LIO_LIFew studies have analyzed the intrinsic pancreatic microbiome, and these have produced conflicting results regarding microbial presence and alterations associated with malignant disease. C_LIO_LIIPMN is a precursor lesion to pancreatic cancer that represents a whole gland defect without an established driver event, and microbiome changes have been implicated as a possible etiology of cyst formation and dysplastic progression. C_LI What are the new findings?O_LIA low-biomass, low-diversity intrinsic pancreatic microbiome is present in both pancreatic tissue and cyst fluid. C_LIO_LIThis intrinsic pancreatic microbiome does not differ in terms of abundance, composition, or diversity between patients with PDAC, IPMN, or other benign conditions of the pancreas. C_LI How might it impact clinical practice in the foreseeable future?O_LIMicrobiome dysbiosis does not appear to be a driver of malignant degeneration of IPMN, and further research is needed to identify drivers of oncogenesis in order for possible chemoprevention strategies to be developed. C_LI

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Eckhoff, A. M., Fletcher, A. A., Kelly, M. S., Dohlman, A., McIntyre, C. A., Shen, X., Iyer, M. K., Nussbaum, D. P., Allen, P. J.. 2023-08-12. Comprehensive Assessment of the Intrinsic Pancreatic Microbiome. https://doi.org/10.1101/2023.08.12.553074

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