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. 2024 Nov 7:15:1487242.
doi: 10.3389/fimmu.2024.1487242. eCollection 2024.

Succession of the multi-site microbiome along pancreatic ductal adenocarcinoma tumorigenesis

Yiqing Zhu #  1   2   3   4 , Xiao Liang #  1   2   3   4 , Mengfan Zhi #  5   6 , Lixiang Li  1   2   3   4 , Guoming Zhang  1   2   3   4 , Changxu Chen  1   2   3   4 , Limei Wang  1   2   3   4 , Peng Wang  1   2   3   4 , Ning Zhong  1   2   3   4 , Qiang Feng  5   6 , Zhen Li  1   2   3   4
Affiliations

Succession of the multi-site microbiome along pancreatic ductal adenocarcinoma tumorigenesis

Yiqing Zhu et al. Front Immunol. .

Abstract

Background: To investigate microbial characteristics across multibody sites from chronic pancreatitis (CP), through pancreatic benign tumors, to pancreatic ductal adenocarcinoma (PDAC) at different stages.

Methods: 16S ribosomal RNA (rRNA) amplicon sequencing was conducted on saliva, duodenal fluid, and pancreatic tissue obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of patients with CP, pancreatic benign tumors, PDAC in stage I/II, III, and IV. The neutral community model (NCM) assessed the microbial assembly contribution and MaAslin2 identified the differential microbes.

Results: From CP to stage IV PDAC patients, there was a marked surge in influence of salivary and duodenal microbiota on constitution of pancreatic microbial communities. Our observations revealed a successive alteration in microbial species across various bodily sites during PDAC tumorigenesis. Notably, Porphyromonas gingivalis, Treponema denticola, Peptoanaerobacter stomatis, Propionibacterium acidifaciens, Porphyromonas endodontalis, Filifactor alocis, etc., sequentially increased along PDAC progression in pancreatic tissue, whereas bacteria commonly used as probiotics Bifidobacterium breve, Lactiplantibacillus plantarum, etc., declined. Furthermore, the sequentially escalating trends of Peptoanaerobacter stomatis and Propionibacterium acidifaciens during PDAC tumorigenesis were mirrored in duodenal fluid and saliva. Porphyromonas gingivalis, Porphyromonas endodontalis, and Filifactor alocis, which intensified from CP to stage IV PDAC in pancreatic tissue, were also found to be enriched in saliva of patients with short-term survival (STS) compared with those with long-term survival (LTS).

Conclusions: Salivary and duodenal microorganisms were prominent factors in shaping pancreatic microbial landscape in PDAC context. Further exploration of these microbial entities is imperative to unravel their specific roles in PDAC pathogenesis, potentially yielding insights for future therapeutic strategies.

Keywords: endoscopic ultrasound-guided fine needle aspiration; microbiota; pancreatic neoplasms; pancreatitis; time series analysis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Microbial composition across CP, pancreatic benign tumors, PDAC in stage I/II, III, and IV groups in the multibody sites. (A–C) The principal co-ordinates analysis (PCoA) analysis was used to evaluate the microbial composition in pancreatic tissue (A), duodenal fluid (B), and saliva (C) across the five groups. (D, E) The microbial relative abundance across the five groups of the multibody sites at the phylum (D) and genus (E) levels.
Figure 2
Figure 2
Differential species across the five groups in pancreatic tissue (A), duodenal fluid (B), and saliva (C). The heatmap showed the average relative abundance of differential microbes across the groups, with the z-score representing the row-scaled average relative abundance. The small graphs on the right of each panel displayed the clustering results of the expression trends of the average relative abundance of differential microbes, representing the fitted trend from CP to stage IV PDAC patients for each cluster.
Figure 3
Figure 3
The relationships of differential species in the four clusters across the five groups in the multibody sites. (A–C) The interrelationships of differential species between the four clusters in pancreatic tissue (A), duodenal fluid (B), and saliva (C) across the five groups. The node sizes represent the mean relative abundance. Lines between nodes represent correlations between the nodes connected by the lines, with red representing positive correlation and green representing negative correlation.
Figure 4
Figure 4
Interactions of the microbes across the five groups in the multibody sites. (A–E) Neutral community model (NCM) of salivary microbes to the pancreatic microbial assembly in patients with CP (A), benign tumor (B), stage I/II PDAC (C), stage III PDAC (D), stage IV PDAC (E). The coefficient of determination (R2 ) was the goodness of fit of the neutral model. It ranged from ≤ 0 (no fit) to 1 (perfect fit). (F–J) NCM of salivary microbes to the duodenal microbial assembly in patients with CP (F), benign tumor (G), stage I/II PDAC (H), stage III PDAC (I), stage IV PDAC (J).
Figure 5
Figure 5
The microbial alpha-diversity and differential species between the groups with different chemotherapy responses in the multibody sites. (A, B) The Chao1 (A) and Shannon (B) indices of alpha-diversity between CR/PR group and SD/PD group in the multibody sites. (C–E) Differential species between CR/PR group and SD/PD group in pancreatic tissue (C), duodenal fluid (D), and saliva (E). CR/PR, complete response/partial response; SD/PD, stable disease/progressive disease.
Figure 6
Figure 6
Differential species between the groups with different survival in pancreatic tissue (A), duodenal fluid (B), and saliva (C). LTS, long-term survival; STS, short-term survival.
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