Table 1.
Preclinical evidence supporting a role of microbial pathogens in pancreatic carcinogenesis
| Model | Microbe / Microbial component investigated | Mediator(s) / Mechanism(s) | Findings | Refs |
|---|---|---|---|---|
| Caerulein-induced pancreatitis | LPS | - | • LPS synergizes with caerulein to induce severe acute pancreatitis. | 52 |
| Caerulein-induced pancreatitis; L-arginine-induced pancreatitis | LPS; cultivable bacteria* | TLR4 CD14 |
•Genetic ablation of TLR4 or CD14 protects mitigates acute pancreatitis •Inoculation of blood agar plates with blood and pancreas samples from mice undergoing pancreatitis did not result in bacterial growth * •No LPS was detected in any tissue sample higher than 1 unit of LPS per ml (using the chromogenic Limulus amebocyte lysate assay) |
36 |
| Caerulein-induced pancreatitis | - | TLR9 NLRP3 inflammasome |
•TLR9 blockade mitigates pancreatitis •Genetic ablation of TLR9, or the inflammasome components ASC, NLRP3, and Caspase 1 decreased the severity of pancreatitis |
55 |
| Caerulein-induced pancreatitis | intestinal microbiota; ampicillin- and kanamycin-resistant E. coli | TLR4 NOD1 |
•TLR4−/− and NOD1−/− mice but not TLR2−/− or TLR9−/− are protected from acute pancreatitis •Bowel sterilization with broad-spectrum antibiotics protected from acute pancreatitis •Repeated administration of antibiotic-resistant E. coli to antibiotic-pretreated mice exacerbated acute pancreatitis |
56 |
| Combination of caerulein and glycodeoxycholic acid-induced pancreatitis; concurrent terminal loop ileostomy | Small bowel -vs- colon microbiota | Small bowel–mesenteric lymph nodes–pancreas as source of superinfection during pancreatitis | •Selective decontamination of the small bowel reduced bacterial overgrowth in the small bowel, bacterial translocation to mesenteric lymph nodes, and subsequent superinfection of pancreatic necrosis •Selective decontamination of the colon did not have significant effects |
59 |
| Human PDAC cell lines | H. pylori | NF-κB, AP-1, CagA | •Human PDAC cell lines exposed to H. pylori increased the activities of proliferation factors NF-kB, AP-1, and SRE, and secreted higher levels of IL-8 and VEGF •H. pylori secreted CagA into pancreatic cancer cells |
60 |
| p48+/Cre;LsL-KrasG12D/+ | LPS | TLR4 | •LPS accelerates pancreatic carcinogenesis •TLR4 and TRIF blockade attenuate carcinogenesis •MyD88 blockade exacerbates carcinogenesis through DC-mediated skewing of CD4+ T cells towards TH2 phenotype |
51 |
| Ela-CreERT;LsL-KrasG12D/+ | LPS | NF-κB | • LPS synergizes with Kras mutation in acinar cells to induce pancreatitis and accelerate pancreatic carcinogenesis | 18 |
| p48+/Cre;LsL-KrasG12D/+ | ssRNA | TLR7 | •ssRNA accelerates pancreatic carcinogenesis •Ablation of TLR7 in immune cells attenuate carcinogenesis |
50 |
AP-1, activator protein 1; CagA, cytotoxin-associated gene-A; DC, dendritic cell; E. coli, Escherichia coli; H. pylori, Helicobacter pylori; IL-8, interleukin-8; LPS, lipopolysaccharide; MyD88, myeloid differentiation primary response gene (88); NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-like receptor family, pyrin domain containing 3; NOD1, nucleotide-binding oligomerization domain-containing protein 1; PDAC, pancreatic ductal adenocarcinoma; SRE, serum response elements; ssRNA, single-stranded RNA; TRIF, TIR-domain-containing adapter-inducing interferon-β; TLR, toll-like receptor; VEGF, vascular endothelial growth factor.
We question the reliability of these results due to significant limitations of the techniques employed37.