Pancreatic Cancer and the Microbiome — In the Clinic
In the future, targets of drug development may be within the microbiome.
The human microbiome encompasses the viruses, bacteria, and fungi living in the human body.1,2 Changes in the composition of the microbiome can lead to dysbiosis, which affects the interactions with the normal host cells — in particular, the innate immune system.3 This imbalance is linked to multiple disease states within neurology, cardiology, pulmonology, gastroenterology, and oncology.
Although dysbiosis is not yet fully understood, it is thought to be driven by the “common ground” hypothesis, which posits that multiple exogenous and endogenous factors promote inflammation within the lining of the intestinal tract, leading to increased permeability.3 This facilitates the spread of pathogenic bacteria, viruses, and fungi to multiple organ systems.
One possible endogenous factor is a genetic predisposition in some people to dysbiosis throughout their lifetime, in which particular pathologic species within the microbiome are favored over “normal” flora. According to this hypothesis, once dysbiosis creates the type of environment that leads to disease, the resulting disease may be transmissible.
One key area where research into the microbiome is advancing is pancreatic cancer. While the development of pancreatic cancer is known to be multifaceted, evidence continues to support the role of the microbiome in its pathogenesis.
Bacteria such as Helicobacter pylori (HP) have been implicated in this process by causing a pro-inflammatory environment via ammonia and lipopolysaccharides (LPS).4 HP has also been shown to promote KRAS mutations, which are seen in over 90% of patients with pancreatic adenocarcinoma.4
Pseudomonas aeruginosa and Fusobacterium are also found in disproportionate amounts in patients with pancreatic cancer.4 Both of these bacteria interact with the immune system through complex signaling pathways including taste receptor 2 member 38 (T2R38), multi-drug resistance protein 1 (ABCB1), NF-KB, MAPK, and pattern recognition receptors (PRRs).
A recent study conducted by Pushalkar et al evaluated the interaction between the microbiome and pancreatic cancer cells.5 The authors showed that particular bacteria could migrate from the gut lumen into the pancreas. The most common bacteria found in patients with pancreatic ductal adenocarcinoma (PDA) included Proteobacteria, Bacteroidetes, and Firmicutes. Within actual PDA tissue, Proteobacteria (Pseudomonas and Elizabethkingia) were the dominant genera, indicating selective increases in translocation of these bacteria from the gut lumen into the pancreas. In contrast, Bacteroides and Prevotella were the most abundant genera within the gut lumen in patients with PDA.