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Cited by 227Pancreatic and Hepatic Oncology ResearchGut microbiota and healthOral microbiology and periodontitis research

The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.

Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer

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Gaiser, Rogier Aäron, Halimi, Asif, Alkharaan, Hassan, Lu, Liyan, Davanian, Haleh, Healy, Katie, Hugerth, Luisa W, Ateeb, Zeeshan, Valente, Roberto, Fernández Moro, Carlos, Del Chiaro, Marco, Sällberg Chen, Margaret·2019·Gut
DOI 10.1136/gutjnl-2018-317458PMC PMC6872446
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Abstract

Objectives: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can progress to invasive pancreatic cancer. Associations between oncogenesis and oral microbiome alterations have been reported. This study aims to investigate a potential intracystic pancreatic microbiome in a pancreatic cystic neoplasm (PCN) surgery patient cohort. Design: Paired cyst fluid and plasma were collected at pancreatic surgery from patients with suspected PCN (n=105). Quantitative and qualitative assessment of bacterial DNA by qPCR, PacBio sequencing (n=35), and interleukin (IL)-1β quantification was performed. The data were correlated to diagnosis, lesion severity and clinical and laboratory profile, including proton-pump inhibitor (PPI) usage and history of invasive endoscopy procedures. Results: Intracystic bacterial 16S DNA copy number and IL-1β protein quantity were significantly higher in IPMN with high-grade dysplasia and IPMN with cancer compared with non-IPMN PCNs. Despite high interpersonal variation of intracystic microbiota composition, bacterial network and linear discriminant analysis effect size analyses demonstrated co-occurrence and enrichment of oral bacterial taxa including Fusobacterium nucleatum and Granulicatella adiacens in cyst fluid from IPMN with high-grade dysplasia. The elevated intracystic bacterial DNA is associated with, but not limited to, prior exposure to invasive endoscopic procedures, and is independent from use of PPI and antibiotics. Conclusions: Collectively, these findings warrant further investigation into the role of oral bacteria in cystic precursors to pancreatic cancer and have added values on the aetiopathology as well as the management of pancreatic cysts.

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Figure 1 Intracystic quantities of (A) bacterial 16S DNA and (B) IL-1β in ’non-IPMN' (n=21), ’IPMN' (n=57), ’IPMN Cancer' (n=27) patients, and in paired plasma (D, E) of ’non-IPMN' (n=10), ’IPMN' (n=15), ’IPMN Cancer' (n=7) patients. Dotted line indicates assay cut-off value. Geometric mean for 16S DNA and mean for IL-1β are indicated per each group. Spearman’s correlation analysis on 16S DNA and IL-1β quantities in (C) cyst fluid and (F) plasma, displaying non-linear fit curve (solid line) and 95% CI (dashed line). Statistically significant differences were determined using Kruskal-Wallis test with Dunn’s multiple comparison test with *p<0.05, **p<0.01, ***p<0.001. IL, interleukin; IPMN, intraductal papillary mucinous neoplasm; LLD, lower limit of detection; n.d., not determined.
Figure 1 Intracystic quantities of (A) bacterial 16S DNA and (B) IL-1β in ’non-IPMN' (n=21), ’IPMN' (n=57), ’IPMN Cancer' (n=27) patients, and in paired plasma (D, E) of ’non-IPMN' (n=10), ’IPMN' (n=15), ’IPMN Cancer' (n=7) patients. Dotted line indicates assay cut-off value. Geometric mean for 16S DNA and mean for IL-1β are indicated per each group. Spearman’s correlation analysis on 16S DNA and IL-1β quantities in (C) cyst fluid and (F) plasma, displaying non-linear fit curve (solid line) and 95% CI (dashed line). Statistically significant differences were determined using Kruskal-Wallis test with Dunn’s multiple comparison test with *p<0.05, **p<0.01, ***p<0.001. IL, interleukin; IPMN, intraductal papillary mucinous neoplasm; LLD, lower limit of detection; n.d., not determined.CC BY-NC · PubMed Central
Figure 2 Violin plot showing the distribution with median of (A) total bacterial 16S DNA in ’IPMN LGD' (n=45) and ’IPMN HGD' (n=14) and (B) IL-1β in ’IPMN LGD' (n=35) and ’IPMN HGD' (n=10) cyst fluid samples, determined by TaqMan qPCR and ELISA, respectively. Statistical comparisons between groups were made using Mann-Whitney U test with *p<0.05 and **p<0.01. Dotted line indicates assay cut-off value. HGD, high-grade dysplasia; IL, interleukin; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; LLD, lower limit of detection.
Figure 2 Violin plot showing the distribution with median of (A) total bacterial 16S DNA in ’IPMN LGD' (n=45) and ’IPMN HGD' (n=14) and (B) IL-1β in ’IPMN LGD' (n=35) and ’IPMN HGD' (n=10) cyst fluid samples, determined by TaqMan qPCR and ELISA, respectively. Statistical comparisons between groups were made using Mann-Whitney U test with *p<0.05 and **p<0.01. Dotted line indicates assay cut-off value. HGD, high-grade dysplasia; IL, interleukin; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; LLD, lower limit of detection.CC BY-NC · PubMed Central
Figure 3 Box plot displaying (A) Chao1 richness (white), (B) Shannon entropy (light grey) and (C) inverted Simpson’s (dark grey) indices per diagnose group at operational taxonomic unit (OTU) level. Bar plots showing relative abundance of OTUs per sample at (D) phylum level and (E) genus level. HGD, high-grade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia.
Figure 3 Box plot displaying (A) Chao1 richness (white), (B) Shannon entropy (light grey) and (C) inverted Simpson’s (dark grey) indices per diagnose group at operational taxonomic unit (OTU) level. Bar plots showing relative abundance of OTUs per sample at (D) phylum level and (E) genus level. HGD, high-grade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia.CC BY-NC · PubMed Central
Figure 4 Beta diversity between samples visualised by (A) clustered heatmap showing Bray-Curtis dissimilarity at OTU level for each sample, characterised horizontally by diagnose group and vertically by previous endoscopic procedures, PPI use and antibiotic medication <1 month prior to surgery. (B) PCoA spider plots displaying dimensions 1 and 2 and (C) dimensions 3 and 4. Samples are coloured according to final diagnose (yellow=IPMN LGD, orange=IPMN HGD, red=IPMN Cancer). (D) Bacterial co-occurrence and antioccurrence visualised in a network, with nodes representing bacterial species (coloured according to phylum, size corresponds to mean relative abundance) and edges representing interactions (green=co-occurrence, red=mutual exclusion) supported by >3 methods at statistical significance of q<0.01. HGD, high-grade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; PPI, proton-pump inhibitor.
Figure 4 Beta diversity between samples visualised by (A) clustered heatmap showing Bray-Curtis dissimilarity at OTU level for each sample, characterised horizontally by diagnose group and vertically by previous endoscopic procedures, PPI use and antibiotic medication <1 month prior to surgery. (B) PCoA spider plots displaying dimensions 1 and 2 and (C) dimensions 3 and 4. Samples are coloured according to final diagnose (yellow=IPMN LGD, orange=IPMN HGD, red=IPMN Cancer). (D) Bacterial co-occurrence and antioccurrence visualised in a network, with nodes representing bacterial species (coloured according to phylum, size corresponds to mean relative abundance) and edges representing interactions (green=co-occurrence, red=mutual exclusion) supported by >3 methods at statistical significance of q<0.01. HGD, high-grade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; PPI, proton-pump inhibitor.CC BY-NC · PubMed Central
Figure 5 (A) Cladogram representing linear discriminant analysis effect size results which identified 15 features that are differentially abundant between the three diagnose classes (red=Cancer, orange=IPMN HGD, yellow=IPMN LGD). (B–G) Violin plot showing relative abundance distribution and median of selected differentially abundant bacterial genera per diagnose group. Validation of Fusobacterium nucleatum genome quantification by TaqMan qPCR in (H) cyst fluid and (I) DNA extracted from 25 formalin-fixed PCN tissue samples (non-IPMN n=9, IPMN LGD n=6, IPMN HGD n=4, Cancer n=6). Statistically significant differences were determined using Kruskal-Wallis test with Dunn’s multiple comparison test **p<0.01. HGD, high-grade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; PCN, pancreatic cystic neoplasm.
Figure 5 (A) Cladogram representing linear discriminant analysis effect size results which identified 15 features that are differentially abundant between the three diagnose classes (red=Cancer, orange=IPMN HGD, yellow=IPMN LGD). (B–G) Violin plot showing relative abundance distribution and median of selected differentially abundant bacterial genera per diagnose group. Validation of Fusobacterium nucleatum genome quantification by TaqMan qPCR in (H) cyst fluid and (I) DNA extracted from 25 formalin-fixed PCN tissue samples (non-IPMN n=9, IPMN LGD n=6, IPMN HGD n=4, Cancer n=6). Statistically significant differences were determined using Kruskal-Wallis test with Dunn’s multiple comparison test **p<0.01. HGD, high-grade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; PCN, pancreatic cystic neoplasm.CC BY-NC · PubMed Central
Figure 6 Patient stratification based on previous pancreatic invasive procedures (IEP), classified as ’no' (n=65) and ’yes' (n=40), comprising those with '1' IEP (n=26) and '≥2' (n=14), or use of proton-pump inhibitors (PPI), classified as ’no' (n=90) and ’yes' (n=15). Panels display intracystic (A) 16S DNA quantities, (B) interleukin (IL)-1β quantity and (C) Fusobacterium nucleatum genome copies, with the geometric mean value indicated per group stratified on IEP, and intracystic (D) 16S DNA quantities, (E) IL-1β quantity and (F) F. nucleatum genome copies, with the geometric mean value indicated per group stratified on PPI use. Statistically significant differences between ’no' and ’yes' groups, and '1' and '≥2' groups, respectively, were determined using Mann-Whitney U test, with **p<0.01. LLD, lower limit of detection; ns, not significant.
Figure 6 Patient stratification based on previous pancreatic invasive procedures (IEP), classified as ’no' (n=65) and ’yes' (n=40), comprising those with '1' IEP (n=26) and '≥2' (n=14), or use of proton-pump inhibitors (PPI), classified as ’no' (n=90) and ’yes' (n=15). Panels display intracystic (A) 16S DNA quantities, (B) interleukin (IL)-1β quantity and (C) Fusobacterium nucleatum genome copies, with the geometric mean value indicated per group stratified on IEP, and intracystic (D) 16S DNA quantities, (E) IL-1β quantity and (F) F. nucleatum genome copies, with the geometric mean value indicated per group stratified on PPI use. Statistically significant differences between ’no' and ’yes' groups, and '1' and '≥2' groups, respectively, were determined using Mann-Whitney U test, with **p<0.01. LLD, lower limit of detection; ns, not significant.CC BY-NC · PubMed Central

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Authors
Gaiser, R. A., Halimi, A., Alkharaan, H., Lu, L., Davanian, H., Healy, K., Hugerth, L. W., Ateeb, Z., Valente, R., Fernández Moro, C., Del Chiaro, M., & Sällberg Chen, M.
Affiliations
  • Karolinska Institutet (SE)
  • Karolinska University Hospital (SE)
  • Tongji University (CN)
  • Science for Life Laboratory (SE)
  • Division of Pathology, Department of Laboratory Medicine (LABMED), Karolinska Institutet, Huddinge, Sweden
  • Pancreatic Surgery Unit, Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Universitetsjukhuset i Huddinge, Huddinge, Sweden
  • Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
ORCID
Venue
Gut
Publisher
BMJ
Published
2019-03-14
Volume
68
Issue
12
Pages
2186-2194
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
DOI
10.1136/gutjnl-2018-317458
PMC
PMC6872446
OpenAlex
W2921125196
Cited by
227
References
48
Citations by year
2026: 15 · 2025: 31 · 2024: 29 · 2023: 28 · 2022: 42 · 2021: 47 · 2020: 28 · 2019: 6
FWCI
12.85
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Gut (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Ruth och Richard Julins funds
  • Karolinska Institutet funds
  • ALF
  • Cancerfonden
  • SOF Strategic Odontological Research
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
Keywords
intraductal papillary mucinous neoplasm, pancreatic cysts, oral microbiota, Fusobacterium nucleatum, Granulicatella adiacens, IL-1β, high-grade dysplasia, cyst fluid, bacterial DNA, endoscopy, proton pump inhibitors, pancreatic cancer precursors
MeSH terms
Adult, Aged, Aged, 80 and over, Biopsy, DNA, Bacterial, Female, Humans, Male, Middle Aged, Mouth, Neoplasm Invasiveness, Pancreatectomy, Pancreatic Ducts, Pancreatic Neoplasms, Retrospective Studies, Carcinoma, Pancreatic Ductal, Microbiota

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