Background
Pancreatic cancer is very deadly, with low survival rates, largely attributed to the fact that it does not present clearly with symptoms until it has reached a more serious stage (Kamisawa et al., 2016). In fact, out of the top 10 cancer-related deaths, pancreatic cancer is ranked number 7 (Khalaf et al., 2021). The pancreas is located near the liver, spleen, and gallbladder; within the abdomen (Fig. 1 Cleveland clinic diagram). It aids in digestion as well as the release of certain hormones. Pancreatic tumors can grow and obstruct the path of bile through the common duct, resulting in jaundice (Puckett, 2024), therefore not only interfering with the aforementioned pancreatic functions, but those of the organs around it. According to the Mayo Clinic, some common symptoms of pancreatic cancer include weight loss, jaundice, back pain, and blood clots.
The human gut microbiome refers to the microbial environment within us that is made up of large numbers of bacteria, as well as archaea and viruses. Imbalances in the populations of gut microbes have been linked to various diseases and conditions such as irritable bowel syndrome, obesity, diabetes, cancer, and autism (DeGruttola et al., 2016). As research into this subject has pushed forward; we are finding more evidence that the microbes in our guts influence the maintenance of good health, and the development of disease. By looking inward at our microbiota and their influence, we could open new doors to the possibilities of early detection, treatment, or maybe even prevention of various diseases. Some recent studies have been looking at the relationship between our gut microbes and pancreatic cancer. If there was a way to detect a deadly disease such as pancreatic cancer in an earlier stage, despite clear symptoms not appearing at first; the survival rate could greatly rise.
Figure 1: this diagram of the pancreas and surrounding organs illustrates the location and orientation of the pancreas, from Cleveland Clinic.
Central Question
Considering the link between gut microbes and conditions such as pancreatic cancer, what is the difference in the microbiomes between patients with and without pancreatic cancer?
Evidence
In a recent study from Sono et. al. 2024; researchers found differences in gut bacteria between healthy and cancer-diagnosed people, and were able to examine the physical whereabouts of some bacteria as well, in some subjects, there were gut microbes inside the cancer tissue of the pancreas itself.
The researchers took samples from people at a hospital in Kyoto. Once they had samples from the patients they could then go about analyzing the DNA of the bacteria within the samples; identifying which types of bacteria were present.
By performing statistical analysis to observe the different proportions of microbes present in the samples of either of the cancer, or non-cancer groups, the researchers found that the number of individual bacteria was similar between the two groups (healthy vs. cancer) but it was the types of bacteria that were different (alpha-diversity, reflected by relative abundance), differing on the genus level. In healthy people, there are more butyrate-producing bacteria. Butyrate is a chemical produced by microbes that is used in the maintenance of gut health, and decreasing inflammation (Hodgkinson et al. 2023). People with cancer had less butyrate-producing bacteria, such as Holdemanella biformis, and significantly more bacteria from the genus Streptococcus (more specifically Streptococcus mitis) as seen in Figure 2.
Figure 2: gut-microbiome relative abundance at the genus level, comparing results from both healthy controls as well as those with pancreatic cancer, from Fig. 1B Sono et al. 2024
Streptococci are bacteria commonly found in humans that are part of our normal microbial communities, however, they can infect humans causing a variety of diseases. As the name would imply, strep throat (pharyngitis) is caused by Streptococci, other diseases can include even more serious cases such as necrotizing fasciitis.
While the researchers admit that further studies must happen to confirm this; It has been observed that bacteria within Streptococcus have been linked to chronic pancreatitis (Nagata et al. 2022), and because of this the researchers suspected that Streptococcus was promoting the growth of tumors.
To discover the presence of bacteria in the actual cancerous tissue itself, the researchers used an analysis method called FISH which stands for fluorescent in situ hybridization. As the name suggests, this process involves using fluorescence to detect the presence of specific bacteria. The researchers surgically removed sections of the cancerous pancreatic tissue, and using FISH found that there were two types of bacteria within the tissue, and one of them is the aforementioned Streptococcus mitis, the other being Holdemanella biformis, as seen in Figure 3.
Figure 3: Fluorescent in situ hybridization of A) Holdemanella biformis and B) Streptococcus mitis; within cancerous pancreatic tissue, from Fig. 5 Sono et al. 2024.
As you can imagine this result peaks interest because it directly points to the findings provided by the conclusions of the DNA analysis, with changes in S. mitis and H. biformis, both showing significant relative abundance differences while being observed comparing healthy controls and cancer patients. Furthermore, these results also coincided with the predictions of the researchers, again it is suspected that S. mitis acts as a tumor-promoter.
Conclusion
This study contains information regarding the observed changes and whereabouts of bacteria in cases of pancreatic cancer, however it does not explicitly show evidence of bacteria causing the cancer or vice versa. This study presents us with new questions about if the microbiome changing causes cancer or if it changes as a result of cancer. Future studies could look at this using animal models and observing change over time as cancer develops. Something of interest to note comes from another area of research in biology pertaining to the development of cancer. Chronic inflammation is a contributing factor to the development of cancer (Okada et al. 2014) and can be observed contributing to the development of cancer through other forms of inflammation, such as exposure to air pollution (Sathitsamitphong et al. 2024).
Now that the differences in composition between healthy and pancreatic cancer gut microbiomes have been observed, a good next step would be to look at the downstream consequences these different compositions have within the body. Further research could explore the potential role of Streptococci promoting the growth of tumors. The presence of H. biformis could be examined as well; H. biformis is a butyrate-producing bacteria, it could be tested to see if the presence of H. biformis in cancerous tissue is for anti-inflammatory/cancer-suppressive purposes, as butyrate is a chemical known to aid in the lessening of inflammation within the gut, as well as having other health benefits (Liu et al 2018).
For further reading:
Linked below is another article discussing the overarching implications of research between the microbiome and pancreatic cancer (pancreatic ductal adenocarcinoma) and what it means for early detection and treatment:
The Role of the Microbiome in Pancreatic Cancer
The following article follows a similar study design, using DNA analysis to help identify differences between healthy control and pancreatic cancer patient groups; however this article uses cohorts from the USA:
Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes
For more information on how unbalanced microbiomes can affect other diseases besides pancreatic cancer, look at this article about Inflammatory Bowel Disease:
Current understanding of dysbiosis in disease in human and animal models
This article discussed the impact of butyrate producing bacteria, this link provides more information about the chemical butyrate itself and its role in our gut:
Potential beneficial effects of butyrate in intestinal and extraintestinal diseases
References:
Sono, M., Iimori, K., Nagao, M., Ogawa, S., Maruno, T., Nakanishi, Y., Anazawa, T., Nagai, K., Masui, T., Mori, H., Hosomi, K., Kunisawa, J., Yokota, H., Tanaka, Y., Ohno, H., Hatano, E., Fukuda, A., & Seno, H. (2024). Reduction of butyrate-producing bacteria in the gut microbiome of Japanese patients with pancreatic cancer. Pancreatology, 24(7), 1031–1039. https://doi.org/10.1016/j.pan.2024.09.002
DeGruttola, A. K., Low, D., Mizoguchi, A., & Mizoguchi, E. (2016). Current Understanding of Dysbiosis in Disease in Human and Animal Models. Inflammatory bowel diseases, 22(5), 1137–1150. https://doi.org/10.1097/MIB.0000000000000750
Kamisawa, Dr. T., Wood, L. D., Itoi, T., & Takaori, K. (2016, January 29). Pancreatic cancer – the lancet. The Lancet. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00141-0/fulltext
professional, C. C. medical. (2024, June 27). Pancreas: What it is, how it works & living without one. Cleveland Clinic. https://my.clevelandclinic.org/health/body/21743-pancreas
Khalaf, N., El-Serag, H. B., Abrams, H. R., & Thrift, A. P. (2021). Burden of pancreatic cancer: From epidemiology to practice. Clinical Gastroenterology and Hepatology, 19(5), 876–884. https://doi.org/10.1016/j.cgh.2020.02.054
Mayo Foundation for Medical Education and Research. (2024, May 4). Pancreatic cancer. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/pancreatic-cancer/symptoms-causes/syc-20355421
Liu, H., Wang, J., He, T., Becker, S., Zhang, G., Li, D., & Ma, X. (2018). Butyrate: A double-edged sword for health? Advances in Nutrition, 9(1), 21–29. https://doi.org/10.1093/advances/nmx009
Puckett, Y. (2024, September 10). Pancreatic cancer. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK518996/
Hodgkinson, K., El Abbar, F., Dobranowski, P., Manoogian, J., Butcher, J., Figeys, D., Mack, D., & Stintzi, A. (2023). Butyrate’s role in human health and the current progress towards its clinical application to treat gastrointestinal disease. Clinical Nutrition, 42(2), 61–75. https://doi.org/10.1016/j.clnu.2022.10.024
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