## 4 Pancreatic Cancer
### Microbiota in Pancreatitis  
Pancreatic adenocarcinoma has been described as an inflammation-driven cancer and clinical evidence suggests that bacteria are likely to influence the progression of pancreatitis by activating immune receptors and perpetuating cancer-associated inflammation [62]. Environmental stress factors can lead to the overgrowth of Gram-negative bacteria in the intestine. Altered gut microflora increases intestinal permeability, thus allowing pathogenic (Gram negative) bacteria to gain access to the bloodstream and reach distant organs such as the pancreas. Elevated systemic levels of LPS can also lead to chronic pancreatitis [62]. [PERSON] et al. reported a significant decrease in _Faecalibacterium prausnitzii_ and _Ruminococcus bromii_ in the gut microbiota of patients suffering from chronic pancreatitis. Both bacteria are important butyrate-producing commensals, while _Faecalibacterium prausnitzii_ exhibits a wide range of beneficial effects on the host such as stimulation of the anti-inflammatory response, mucin synthesis, and tight-junction proteins in the gut, which improves gut barrier function [70]. Similarly, the gut microbiota of patients suffering from acute pancreatitis displayed higher levels of pathogenic _Enterococcus_ bacteria with a significant decrease in the numbers of _Bifidobacterium_ and Clostridium cluster XI, which are equally important butyrate producers [71].  
The role of _Enterococcus faecalis_ in cancer development remains unclear. It has been mostly reported as a gut commensal; however, owing to its wide range of virulence factors, especially its metalloproteinase production and ability to generate ROS (reactive oxygen species) and extracellular superoxide, it has drawn attention as a carcinogenic [72]. ROS and extracellular superoxide lead to DNA damage, which might result in carcinogenic mutations. In addition, metalloproteinase influences the gut epithelium, enhancing gut permeability and inducing inflammation [73]. The study of [PERSON] et al. suggested that _E. faecalis_ might enhance cell proliferation through hydrogen peroxide-mediated epidermal growth factor receptor activation (EGFR). THE EGFR signalling pathway plays a crucial role in the regulation of cell proliferation in many cell types [72]. In contrast, [PERSON] et al. have reported that oral administration of _Bifidobacterium_ to mice significantly increased anti-tumor immunity and improved tumor control on a comparable level to treatment with programmed cell death protein 1 ligand 1-specific antibodies [74].  
Statistically, most often, pancreatitis development is driven by excessive alcohol consumption and the presence of gallstones. The third largest group includes pancreatitis of an unknown base. Both alcohol overuse and the presence of billiard stones influence host microbiota. Excessive alcohol consumption impairs intestinal wall integrity and was correlated with overgrowth of Gram-negative bacteria in the intestine. An increased amount of LPS with dysfunction of intestinal barrier can lead to systemic inflammation and, in a further perspective, influence pancreatitis development [62]. [PERSON] et al. reported that intestinal microbiota of patients with alcoholic chronic pancreatitis (ACP) was enriched in pathogenic taxa such as _Klebsiella_, _Enterococcus_, and _Pseudomonas_, with a significant decrease in beneficial bacteria such as _Faecalibacterium prausnitzii_ and _Ruminococcus bromii_ from _Firmicutes phylum_. A study also reported that, overall, intestinal microbiota diversity in ACP patients was lower compared with healthy subjects [63]. Not much data are available, however, on microbiota changes in gallstone pancreatitis.