## 4 Pancreatic Cancer
### Microflora in Pancreatic Adenocarcinoma  
While most gastrointestinal cancers are influenced by local microbiota, PDAC has been linked to dysbiosis in gut and oral microflora. [PERSON] et al. reported that the cancerous pancreas harbors a significantly different and more abundant gut microbiota compared with that of the normal pancreas in both mice and humans. The PDAC-related gut microbiota was found to be significantly enriched in Gram-negative Proteobacteria, Fusobacteria, Gram positive Actinobacteria, and Verrucomicrobia compared with healthy subjects. Even though these phyla are also abundant in healthy gut microbiota, their presence is modest compared with Firmicutes and Bacteroidetes [75; 76]. Other studies reported that _Acinetobacter_, _Enterobacter_, _Pseudomonas_, _Delftia_, _Enterococcus_, _Streptococcus_, _Corynebacterium_, _Propioniibacterium_, _Klebsiella_, _Spingomonas_, and _Staphylococcus_ are thought to be thedominant bacterial genera in the gut microbiota of PDAC patients, with _Klebsiella_ being the most abundant [75; 76]. Increased _Klebsiella pneumoniae_ abundance and K. Pneumonia infection has been already reported in many cancers [77]. [PERSON] et al. demonstrated on a murine model that _Klebsiella oxytoca_ behaves as a gut pathobiont, that is, it increases gut permeability, and thus influences cancer progression [78]. [PERSON] et al. demonstrated a significant decrease in commensal _Bifidobacterium_ and butyrate-producing bacteria such as _Coprococcus_, _Clostridium_ IV, _Blautia_, _Flavourifactor_, and _Anaerosipes_ in PDAC patients [79]. These data suggest that enrichment in Gram-negative bacteria with a decrease in butyrate producers is positively correlated with pancreatic cancer development. Moreover, the study of [PERSON] et al. reported that sole presence of microbiota in the gut as well as in the pancreas might accelerate PDAC development. A study suggest that \(\text{Kras}^{\text{G12D}}/\text{PTEN}^{\text{lov}/+}\) 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. Interestingly, alterations in pancreatic and gut microbiota connected to PDAC in an animal model was found to result in both innate and adaptive immune suppression, which leads to faster cancer progression. It was suggested that translocation of Proteobacteria from gut to pancreas, which activates Toll-like receptors (TLRs) by bacterial lipopolysaccharidesaccharides and flagellins, can promote tolerogenic macrophage phenotype in the tumour microenvironment [75]. The same study found that, while Proteobacteria were the most abundant phyla in both the gut and pancreatic microbiotas. Proteobacteria genera, that is, _Pseudomonas_ and _Elizabethkingia_, were the most abundant in the pancreatic microbiota, and _Prevotella_ and _Bacteroides_ were more abundant in the gut [75]. PDAC development is also influenced by alterations in the oral microbiota. The human oral cavity harbors a complex microbial community known to contain over 700 species of bacteria, more than half of which have not been cultivated [80]. Even though oral microbiota can play a protective role against pancreatic cancer in a healthy, commensal state, it may also promote malignancy under pathologic conditions, especially while enriched in taxa related to periodontal disease [81; 82]. Dysbiosis of oral bacteria resulting from poor oral hygiene, as well as associated diseases such as periodontitis and tooth loss, may promote bacterial translocation and increase the risk of pancreatic cancer [82]. A positive association between periodontal disease and pancreatic cancer has been observed; men reporting a positive history of periodontal disease showed a 64% higher risk of pancreatic cancer compared with those reporting no periodontal disease [83].