Connections in the Microbiome.

Author: Calvin Inners

This figure is taken from the Castaño-Rodríguez et al. paper. In part C, it shows the connection between different bacteria present in the stomach. Boxes that are dark purple are bacteria that heavily present in gastric cancer patients with as many variables controlled for as possible. Pink boxes are bacteria that are heavily present in gastric cancer patients that have varying different variables. Yellow boxes are the bacteria that are connected in healthy patients. Lastly, blue boxes were bacteria that were not found in large amounts in gastric cancer patients.

 

Hundreds of thousands of people suffer from cancer every year. Of these hundreds of thousands of people, it is estimated that 26,000 people will develop cancer in their stomach every year in the United states. Additionally, there are about 11,000 people who die of stomach cancer every year. This is a much higher rate than some other common cancers1. Since this disease is impacting many people each year, it is important to understand the etiology of this disease. One idea that became popular in the 2000’s was that the biome that live in one’s stomach may be responsible for the diseases such as cancer.

In the early 2000’s the microbiome was starting to be explored by a few laboratories around the world. Editors at the journal Science, published an brief article predicting that the study of the microbiome will become a hot topic through the decade2. This popularity started to take hold when the National Institute of Health funded a huge study named The Human Microbiome Project. This study was as major breakthrough for the understanding of the microbiome of people3. Work on this topic brought this new field to a stage where we are starting to identify the bacteria, their needs , and what happens when these needs are not met.

Recently in class, we talked about a paper by Sonnenburg et al. discussing what occurs when these microbiomes are not fed with the proper nutrients. Simply put, the genetic diversity of the microbiome suffers4. This damaged diversity resulted in the incorrect metabolism of many nutrients.

While Sonnenburn and their lab is investigating how the diversity is depleted, other groups are investigating what are the effects of this lack of diversity. Castaño-Rodríguez et al. recently published an article suggesting that when the diversity of the microbiome is negatively impacted, carcinogenesis in the stomach can occur5. Castaño-Rodríguez’s lab looks at the diversity of the microbiome in gastric cancer patients and noticed numerous differences when compared to people without the cancer. They noticed that the Heliobacter pylori ( a common bacterium that is linked to gastric cancer) bacteria has a role in the diversity and amount or richness of bacteria in the microbiome6. Also, they noticed that there were numerous bacterial interactions that lead to the gastric carcinogenesis. Lastly, the authors suggested a mechanism on how these interactions lead to gastric carcinogenesis.

Castaño-Rodríguez et al. found that patients who had gastric cancer had an increased population of bacteria in their stomach with a greater diversity of bacteria. When these patients were tested, there was an increased level of H. pylori bacteria. It was known that the presence of H. pylori  was responsible for the carcinogenesis of gastric cancers but a mechanism for the phenomenon was not known6. When statistics were used to study the levels of H. pylori in the patients, Castaño-Rodríguez et al. found that there was not an increase in diversity and richness of bacteria due to H. pylori – eliminating the possibility that H. pylori was responsible for the increase in bacteria that was eventually to lead to gastric cancer.

To better understand the role of H. pylori Castaño-Rodríguez et al, looked at the levels of other bacteria present in the microbiome and found that patients who had cancer and high levels of H. pylori had 38 different types of bacteria with 23 of them being in large amounts. This increase in diversity coincides with the increased amount of H. pylori.

Castaño-Rodríguez et al. continued to examine the connection between this increase in diversity and the gastric cancers. This group was the first reported group to look at the rRNA transcripts of the microbiome to see what pathways were being followed. After collecting data from these transcripts, the group was able to see that there was a lot of rRNA responsible for over 20 different metabolic pathways. For example, pathways for carbohydrate metabolism and absorption resulting in metabolic molecules like short chain fatty acids were enriched.

Once the bacteria species responsible for promoting these pathways were identified, Castaño-Rodríguez et al. used software to map the relations they had to each other. Through the figures created from this technique, the authors were able to find the bacteria in the cancer patients had many more interactions than the bacteria in the healthy people. They hypothesize this is because H. pylori is no longer the dominate species in the gastric cancer patients.

Castaño-Rodríguez et al. work through a series of experiments to elucidate the role H. pylori has on patients with gastric cancer. It is originally thought that H. pylori is responsible for giving cancer to patients, but Castaño-Rodríguez et al. prove this is not the case. First, they show H. pylori is linked to having higher levels of diversity and higher richness of bacteria in a patient’s stomach. After proving that, they see what is happening at a molecular level and see that the microbiome is encouraging pathways involved in metabolism. Lastly, the group creates a map and shows that the patients with cancer have microbiomes that are working together to encourage these pathways. This is dangerous since lactic acid can by the cancer cells as fuel.

Building on the studies conducted, the group hypothesized that one of the issues present in the gastric cancer patients is that there is the wrong combination of microbes in the microbiome. This wrong combination can have errors in metabolism like previous said or be linked to other conditions like inflammation and other types of cancer. This group clearly elucidates the importance of having the right bacteria in one’s microbiome. Additionally, the group does a great job at demonstrating the subtle nuances in the richness of bacteria present. For example, prior to this study, it was thought that H. pylori was responsible for gastric cancer, but it is simply another marker for it. I foresee studies like the one conducted by Castaño-Rodríguez et al. be used to examine the ‘right’ combination and richness of bacteria. Further studies will be able to further pin down the mechanism at which the wrong combination of microbes lead to various disease.

 

Link to the paper: http://rdcu.be/Hpoj or https://www.nature.com/articles/s41598-017-16289-2

References

(1)          Siegel, R. L.; Miller, K. D.; Jemal, A. Cancer Statistics, 2016. CA. Cancer J. Clin. 2016, 66 (1), 7–30.

(2)          Lederberg, J. Infectious History. Science 2000, 288 (5464), 287–293.

(3)          Turnbaugh, P. J.; Ley, R. E.; Hamady, M.; Fraser-Liggett, C. M.; Knight, R.; Gordon, J. I. The Human Microbiome Project https://www.nature.com/articles/nature06244 (accessed Feb 20, 2018).

(4)          Sonnenburg, E. D.; Smits, S. A.; Tikhonov, M.; Higginbottom, S. K.; Wingreen, N. S.; Sonnenburg, J. L. Diet-Induced Extinctions in the Gut Microbiota Compound over Generations. Nature 2016, 529 (7585), 212–215.

(5)          Castaño-Rodríguez, N.; Goh, K.-L.; Fock, K. M.; Mitchell, H. M.; Kaakoush, N. O. Dysbiosis of the Microbiome in Gastric Carcinogenesis. Sci. Rep. 2017, 7 (1), 15957.

(6)          Wroblewski, L. E.; Peek, R. M.; Wilson, K. T. Helicobacter Pylori and Gastric Cancer: Factors That Modulate Disease Risk. Clin. Microbiol. Rev. 2010, 23 (4), 713–739.

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