The Role of the Human Gut Microbiome in Pancreatic Cancer 

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Aishat Motolani

The incidence of pancreatic cancer is almost commensurate with its media mentions. As a fan of the wizarding world of the Harry Potter series and the quiz game show Jeopardy, the demise of Professor Snape and Alek Trebek came as a shock. “Neither a magic wand nor an encyclopedia could prevent this occurrence,” I pondered. But it is known that the villain who shook these two seemingly different worlds is none other than pancreatic cancer.

Currently, pancreatic cancer is the sixth leading cause of cancer deaths worldwide. Its incidence is projected to rise to the second position by 2030. For a disease that presents little to no symptoms at its early stage of development, such a projection is concerning. Researchers are constantly looking for new methods to diagnose and treat pancreatic cancer in its earlier stages. This endeavor entails peeking into one of the hidden parts of human anatomy: the gut.

The human gut houses more than a hundred trillion microorganisms, known as the gut microbiome. The gut microbiome has a significant effect on human health. They play a role in regulating human metabolism, digestion, and immune response. Hence, there is a high appeal of probiotic products commercially. While the gut microbiome can benefit human health, its imbalance has been associated with several gastrointestinal diseases. This phenomenon is called microbial dysbiosis. 

Although the pancreas does not have its own microbiome, the gut microbiota can migrate to the pancreas and change its normal function. Of notable mention in this category is Helicobacter pylori, a well-studied bacterium in association with pancreatic cancer. Currently, the literature is divided on the correlation of H. pylori with pancreatic cancer risk. 

The discordance is due to the genetic and environmental variations in the cases observed by different studies. However, the majority of the evidence points towards H. pylori association with a moderately increased risk for pancreatic cancer development. One plausible reason is that H. pylori produce inflammatory factors that cause DNA damage and result in the sprawling cell growth of the pancreas.

Scientists have discovered that pancreatic cancer patients primarily possess a group of bacteria that belongs to the class of Gammaproteobacteria within their pancreatic tumors. A 2017 study reported that these Gammaproteobacteria, taken from pancreatic tumors, can render gemcitabine treatment unsuccessful. Currently, gemcitabine is one of the standard treatments given to pancreatic cancer patients. Proteobacteria break down gemcitabine before it is able to bind to its target and prevent tumor growth. Thus, this study shows the ability of the gut microbiome to promote resistance to chemotherapy treatment in pancreatic cancer. 

In addition to promoting resistance to treatment, the gut microbiome also modulates the response of the immune cells to tumor growth. Cancer lethality is partly rooted in its ability to evade the body’s defense system. Cancer cells escape immune surveillance either by manipulating the body’s immune cells to produce tumor survival factors or by reducing the ability of the killer immune cells to eliminate tumors. In pancreatic cancer, the gut microbiome has been shown to promote the latter. Researchers from New York University showed that antimicrobial treatment led to increased immunoprotective cells and decreased immunosuppressive cells in pancreatic cancer mice models. Also, the extract of the gut microbiome, derived from the pancreatic cancer mice model, stimulated receptors that accelerate tumor growth. These receptors activate inflammatory pathways that drive pancreatic cancer progression.

The gut microbiota also increases pancreatic cancer risk factors (obesity, diabetes, smoking, etc) and vice versa, thus perpetuating the loop of cancer progression (table 1). For example, mice colonized with the gut microbiome of an obese twin developed increased body mass compared to the lean twin counterpart, leading to changes in metabolism. Also, smoking and heavy alcohol intake are associated with increased types of bacteria called Proteobacteria and Clostridium. In fecal samples of type 2 diabetes patients, there are variations in the abundance of bacteria species such as Lactobacillus and Roseburia intestinalis. Both of these species play essential roles in human metabolism and the resulting changes in metabolites serve as fuel for pancreatic cancer progression.

In summary, the human microbiome may hold the key to overcoming some of the challenges in pancreatic cancer treatment. Given that there are limited biomarkers for pancreatic cancer early diagnosis, researchers have touted the use of the gut microbial composition as a diagnostic/prognostic tool. This argument is partly motivated by a study that discovered that pancreatic cancer patients who had long-term survival also had higher gut microbial diversity with a distinct signature. Multiple factors such as diet, genes, and environment can influence the human microbiome. To account for the role of these factors in microbiome-mediated cancer, more large-scale studies are currently underway. Ultimately, these studies will further unravel the role of the gut microbiome in pancreatic cancer and better inform us of its translational potential.  

Edited by Sohini Basu Roy

Works Discussed

• Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D., … Straussman, R. (2017). Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science, 357(6356), 1156–1160.
• Paternoster, S., & Falasca, M. (2020). The intricate relationship between diabetes, obesity, and pancreatic cancer. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1873(1), 188326.
• Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A., … & Miller, G. (2018). The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discovery, 8(4), 403-416.
• Archibugi, Livia MD; Signoretti, Marianna MD; Capurso, Gabriele MD, Ph.D., The Microbiome and Pancreatic Cancer, Journal of Clinical Gastroenterology: November/December 2018 – Volume 52 – Issue – p S82-S85 DOI: 10.1097/MCG.0000000000001092.
• Rabelo-Gonçalves, E. M., Roesler, B. M., & Zeitune, J. M. (2015). Extragastric manifestations of Helicobacter pylori infection: Possible role of bacterium in liver and pancreas diseases. World journal of hepatology, 7(30), 2968–2979. https://doi.org/10.4254/wjh.v7.i30.2968
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