Connections in the Microbiome.

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.

19 Comments

  1. Hi Calvin,
    this seems like an extremely topical paper you have decided to report on. I was wondering what experiments, exactly, Castaño-Rodríguez et al. performed that allows you to summarize the conclusion that the cancer-affected microbiome has increased metabolism. You also reference the production of lactic acid but with no obvious connection to any specific results or data. Was this a reference to the Warburg effect, in which cancerous tissues promote anabolic pathways over the normally assumed catabolic ones? If so, does this mean the Warburg effect can translate into a cancerous microbiome system, from a tumorogenic system?
    Suzi

    1. Hey Suzi, thank you for your questions! If I understand your question correctly, there is no one experiment that drives home the point that the increased metabolism is responsible for causing cancer. With this being said, Castaño-Rodríguez et al used a series of references and observations to come to the conclusion that it must be the metabolism of the microbiome that is affecting the patient. One thing they noticed was there was a different group of bacteria present in GC patients that had an increased lactic acid production. What would have been really nice of Castaño-Rodríguez et al. to do was to measure the levels of lactic acid production or to mark it but unfortunately, they do not do this, so there is not specific data supporting that lactic acid produced from these specific bacteria are causing cancer, but it has been stated that excessive lactic acid production can cause angiogenesis of tumor cells in other pieces literature. They do not know definitely that GC patients are supplying tumors with ‘Warburg effect friendly’ materials but they are making this assumption based upon the GC patients having the bacteria that prefer lactic acid production, being positive for the cancer diagnosis, and having specific bacteria interactions. Lastly, I believe we could suggest that a cancerous promoting microbiome can cause tumorigenesis through effects such as the Warburg effect.

  2. Hi Calvin,
    Thanks for the interesting paper! The authors seemed to keep mentioning something called “Shannon’s diversity”. Did you investigate what this means? Also, I just need some clarification on a topic discussed. Does the disease cause the higher activity of metabolic pathways, does the presence of diversity in the microbiome, or does the mere presence of H. Pylori? The paper could be a bit clearer of this. I do see that the authors mention that they are unsure of what is a cause and what is a consequence of GC, so it seems a lot more investigation of this topic would need to be done before anything can translate into treatment or medicine.

    1. Hello Brittany, thanks for the questions. When I was looking at the Shannon Diversity it said it was a measure of diversity that took into account how many bacteria there were and how different they were. This is different from other diversity indexes since some other indexes only look at differences in one site or over any sites. In regard to the paper, Castaño-Rodríguez et al did not do the best job organizing the paper and making clear what was done in the past and what they are doing. Basically, how I understood it, the GC patients had abnormal bacteria (such as H. Pylori) in their gastric system that created and increased level of metabolites that could be used for angiogenesis for cancer cells. This is different from what was previously thought since it was thought that H. Pylori was solely responsible for causing cancer though an alternative way. Now, they see H. Pylori is only a symptom of having GC, not the etiological source. Since they are assuming that the angiogenesis is occurring through the metabolites produced without proving it, they recognize that a lot of research still needs to be done.

  3. Hey Calvin, great summary of a dense and complicated paper! I was wondering, why do higher levels of H. pylori correlate with higher diversity of species in the guy microbiome? I would assume that relatively larger populations of H. pylori would be able to out-compete other species. Is there something the literature is familiar with going on here?

    1. Hello, Andrew, this is a great question. I have not seen any literature explaining why the high levels of H. pylori were associated with higher diversity. I believe this paper is the first to suggest this and I have not see this paper be cited yet. With this being said, I think this question is vital to ask and is probably being investigated as we type. For you question regarding the H. pylori population, I did not see any literature explaining why it would not be able to out-compete other species. I would assume that there is not a strong evolutionary advantage this bacteria has over the other ones present therefore it did not eliminate their fellow bacteria even thought it is present in large amount. I would also hypothesize that there is a symbiotic relationship between the bacteria since there was some suggestions that there are interactions between different bacteria species.

  4. Hi Calvin,
    Nice job bringing out the relevant parts in this high impact paper. I’m just a little confused as to how the authors knew that it was the fact that the bacteria were working together more that led to the cancer? Also, you mention that the authors propose that this occurs because H. pylori is no longer the dominant species. How did they come to that hypothesis?

    1. Hey Lily! This is a great question. I don’t believe that the authors know that the cooperation of bacteria lead to cancer but they do know that there are more metabolites being made from this cooperation and that these metabolites can promote angiogenesis. There is subtle but very important distinction. Onto your next question, the authors summarized the levels of the different bacteria in Fig. 3. Here they show that GC patients have significantly lower levels of H. pylori. Experimentally, I believe they quantified the amount of H. pylori by using IgG antibodies.

  5. Hi Calvin! Thank you for reviewing a thought-provoking paper that helps to push microbiota research forward. Many implications of microbiota have yet to be understood, and I think you hit the nail on the head when you mentioned that the wrong combination of microbiota can lead to disease. The question is, however, what is the right combination of microbiota since everyone has a different combination of microbiota? The “wrong” combination can cause metabolic shifts that lead to increased lactic acid production and cancer pathology. What do you think the next step is in preventing the “wrong” combinations of microbiota from causing these harmful effects?

    1. Hey Brandon, that is a really great question! I think there needs to more exploration to see what bacteria create the metabolites that are ‘food’ for the tumor cells. Once this is figured out, the field needs to move to why it occurs and where the metabolites go. When I was answering Suzi’s question I was thinking about experiments that can be done to verify the results and I would really enjoy seeing a study use radioactive tagged carbohydrates for the bacteria to break down and see where these molecules go. If a lab did this and saw that the metabolites are concentrated into cancer cells I would feel much more confident to say that these microbiotas have a metabolism that leads to cancer. Also, I would like to see researchers understand why these microbiotas create the metabolites. It would be interesting to see an in-depth study comparing the mRNA’s about glycolysis across different types of cancers and different mixes of bacteria.

  6. Calvin,
    I was wondering if there was any literature cited by the authors that made mention of whether or not the different ratios of stomach microbiota had any impact on the type of gastric cancer that was developed, since it is very unlikely they are all the same. Otherwise, a very interesting read since for a long time I know I remember hearing that H. pylori was a “huge issue” but now it seems it was merely a contributing factor!

    1. Hello Brandon, thank you for your question. This is such an intricate question. The “type” of cancer can refer to the primary location of the tumor or it can be related to what Dr. Solit from LVHN talked about. From my knowledge, there is no information about the different genetic types of gastric cancer being favored. Additionally, when I was looking at the surrounding literature, I did not see any specific type of gastric caner being favored from the presence of H. pylori.

  7. Hi Calvin, this was an interesting read. The implications of the presence of H. pylori in carcinogenesis on the role of the microbiome in human health is interesting. Due to the correlation of high biodiversity with H. pylori, is this implicating a threshold to biodiversity and health? On the other hand, authors are showing an increase in biodiversity in cancer patients, but is it possible that this increase is due to improper diet or other factors that influence biodiversity?

    1. Hello Will, thank you for your questions. I would say that the authors are not quite suggesting a threshold but a change from ‘normal’. This of course is very tricky since ‘normal’ does not really exist since everyone’s microbiome is different. For your second question, I would say that diet, microbiome, carcinogenesis, and other factors are all related in some unknown fashion. As we have seen in other papers, as soon as we sort out one piece of the puzzle, many more pieces are revealed.

  8. Hi Calvin,

    Thank you for an excellent review! It seems to me that understanding the health implications of microbiota on human health continues to become more complex. From the paper we read in class, we reached the conclusion that less fiber intake leads to decreased bacterial diversity, which is linked to many diseases like IBD and colon cancer. From this paper, we get the impression that increased bacterial diversity can be just as bad with respect to individual health, and that increased interactions among these populations are not favorable. Therefore, do you envision a potential for being able to characterize abnormalities resulting from these biota and precisely identifying the correct composition that individuals “are supposed to have/maintain”? If so, would that only be controlled by the food we eat, or would there be other (environmental) factors to consider as well?

    1. Greetings John. Thank you for your question. I believe that the authors of the paper were on the right track by looking at the levels of mRNA to look at the population of bacteria. I believe that similar approaches will be needed to characterize the bacteria in the microbiome to determine what is toxic and what is not. In regards to determining what is the ‘correct’ combination of bacteria, I believe it will take a long time to determine this and by the time we do this, I can see that we will discover something more important. Lastly, I could see there being a host of different factors that play a role in microbiome health. Diet and heredity certainly play a role but one can easily see how environmental factors could impact the health of the microbiome.

  9. Calvin – the importance of a diverse microbiota is imperative for the proper function pathways of the human body, especially on its implications in metabolism and in cancer. How do you propose scientists can discover the “right” combination of bacteria? And do you think somehow these bacteria can be ingested to attempt to establish diversity?

    1. Hello Camille. Thank you for your question. I believe discovering the “right” combination of bacteria is going to be very complicated. I believe the authors are on track by looking at mRNA to determine what bacteria is there. What I could see happening is scientists discovering the mechanism of disease then deducing what the right balance is. For your last question, I do not see why one could not ingest bacteria to reestablish a “right” combination. To my knowledge, there has been some medical therapies being tested to determine the benefits of this type of therapy.

  10. Hi Calvin I found it very interesting that an increase in biodiversity can actually lead to cancer when many times i believed that an increase in gut bacteria was a good thing. The authors in this article mentioned that lactic acid producing bacteria (Lactococcus and Lactobacillus) were common in any GC patients; throughout your research have you found any reason as to why increased lactic acid levels in the gastrointestinal tract can lead to cancer? If so, how does it happen?

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