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Bacteria and Colon Cancer

Let’s catch on some non-coronavirus research today with an interesting approach against a very bad disease, metastatic colon cancer. This new paper (from groups at Virginia Tech and Wake Forest) adds to our understanding of something that’s been noticed for some time: colon cancer tissue is often infected with Fusobacterium nucleatum. This bacterium (an anaerobic Gram-negative beast) especially seems to be associated with accelerating or metastatic disease, but it’s been unclear what the relationship is. Is this an accident, or is there a causal effect – and if so, what causes what? F. nucleatum, I should note, is already known as a problem: it’s normally considered one of the major players in peridontal disease and (weirdly) may also have an as-yet-unexplained relationship with preterm births and other complications of pregnancy.

Using the well-known HCT116 colon-cancer cell line, this paper shows that the bacteria bind to the cell membrane and actually force their way into the cells themselves. There’s a good amount of work in the paper going into just what surface proteins are involved in this process and what the entry mechanism might be, but I’m going to skip ahead to what happens after the infection: the cells start to secrete significant quantities of the cytokines IL-8 and CXCL1, as measured floating around in the culture medium. And that’s not good news, because both of those have already been shown to be associated with colon cancer progression and invasiveness.

That’s just what this group saw in their cell culture: as the amounts of these cytokines increased, the cells became more mobile and less attached to their original positions. And the mobile ones weren’t just the cells that had the bacteria inside their cytoplasm: the cytokine secretion meant that cells that weren’t infected at all felt the effects and became more mobile themselves. The entry into the cells is a key part of the process, though – the paper shows that when key surface proteins were knocked out (blocking the whole entry process) that the cytokines don’t get secreted like this.

So it appears that the relationship is indeed causal, and it’s the bacterial infection that makes colon cancer worse. That immediately suggests some therapeutic options, of course. The paper shows that administering antisera (a mixture of antibodies) to F. nucleatum in the cell assay decreased this whole process, but did not eliminate it entirely. But what if you were to take it out of commission before it even got to the colon? The belief, in both colon cancer and pregnancy complications, is that the bacterium migrates from the mouth into the bloodstream (bleeding gums) and from there into other organs. A vaccine against it could potentially clear it from the blood before it has a chance to cause trouble later on. Given this species’ association with human disease, this sounds like it could be a good idea, and I hope that it’s taken up. More immediately, this bacterium seems to respond to a number of well-known antibiotics, and you have to wonder if treatment with those might improve outcomes in early-stage colon cancer. The problem there is, of course, that you don’t often even catch it early enough, but in patients who are diagnosed with non-metastatic disease it might be worth a look.

As a side note – gotta work in some coronavirus-related content somehow – it has been reported that our old friend chloroquine might inhibit colon cancer cell mobility in vitro. This paper found, though, that it doesn’t appear to do this through effects on this F. nucleatum-driven pathway – treatment with chloroquine didn’t make secretion of the two cytokines go down at all. So there’s another mechanism at work here. . .

48 comments on “Bacteria and Colon Cancer”

  1. Silverlake Bodhisattva says:

    Sounds like still another reason to brush and floss!

    1. Anon says:

      I wonder if there’s a study on people diagnosed whether they have good/bad dental hygiene.

      1. John Wayne says:

        There are huge correlations between dental hygiene and health outcomes. It is hard to draw hard conclusions because good dental habits also correlate with socioeconomic status, food choice, and other important lifestyle risks.

        On the negative side, piercings in your mouth are usually bad for you. The metal in there often reduces the pH of your saliva leading to poor dental outcomes. If you want to pierce something, go elsewhere.

        On the positive side, going to the dentist twice a year is probably one of the best health decisions a person can make.

        1. Harvey 6'3.5" says:

          On piercings, does it matter if the insert is gold, silver, or copper? Given the anti-bacterial effects of silver and copper, they might seem like better choices.

          1. John Wayne says:

            The explanation I have heard is that the poor dental outcomes related to mouth piercings is related at least in part to the average pH of your mouth. Having metal in there is the same as eating lots of sugary foods (which definitely cause pH drops as the bacteria feed.) I’m not sure how strong the data is behind the pH/metal assertion, but if it is true then a material that doesn’t cause a pH drop would be superior.

            There are other issues with piercings in the mouth: infection, tooth chipping, reduced ability to brush, etc. Again, I’m not an expert. One of my relatives is a dental hygienist and her view of it isn’t positive.

          2. Rich says:

            Titanium is a common piercing material, for the same reasons as it’s used in surgical implants.

        2. Nick K says:

          Why would anyone WANT a facial piercing in the first place?

          1. Barry says:

            well facial piercings go back at least as far as Genesis 24:30

      2. eyesoars says:

        It’s well-known that there is an association between poor gum health and heart disease and stroke.

  2. NMH says:

    May not even be relevant:

    https://elifesciences.org/articles/25801

    “Editors’ Summary: This Replication Study did not reproduce those experiments in the original paper that it attempted to reproduce.”

  3. Giannis says:

    Another type of bacteria that cause gum disease is implicated in Alzheimer’s disease. What both P. gingivalis and F. nucleatus is that they can enter mammalian cells and our immune system has a very hard time controlling them.

    http://sitn.hms.harvard.edu/flash/2019/oral-bacteria-may-responsible-alzheimers-disease/

    1. mp says:

      Could science develop a way to target these individual bacteria species?

      1. Barry says:

        Vaccines are exquisitely specific to pathogen species (the trick is that even small mutations may escape the protection they offer) when they work. Antibiotics by contrast are much blunter tools.

  4. Len says:

    Has this methodology been applied to study if H. pylori infection, a major risk factor for the development of duodenal and gastric cancer, to determine if it can function similarly to F. nucleatus? I feel that this is worth pursuing.

  5. Old Country Doctor says:

    ” This paper found, though, that it doesn’t appear to do this through effects on this F. nucleatus-driven pathway – treatment with chloroquine didn’t make secretion of the two cytokines go down at all.”

    It needs zinc. Duh.

  6. David E. Young, MD says:

    Back in 1986, when I was in oncology fellowship, my mentor was studying fecapentanes, and the idea that fiber absorbs bile acids and prevents the bacterial formation of the carcinogens known as fecapentanes. I don’t hear much of that any more, so maybe the theory has fallen out of favor.

    Now, we hear much about colonic microbiota and how it can cause cancer (if disturbed) or prevent cancer (if it is young and pristine) and the idea that our health might be improved if we get fecal implants from 20-year-olds. All interesting stuff.

  7. In Vivo Veritas says:

    Derek, you point at bleeding gums as the entry point. Any evidence that a leaky gut might play a role as well? More and more diseases are becoming associated with barrier permeability….. Of course this would require that F. nucleatus is able to survive the stomach. But gut permeability…. I used to be a skeptic, but I’m starting to think that there might be a target in there…..

    1. Wallace Grommet says:

      Leaky gut is a false diagnosis and an overwhelmingly fictitious disease. https://sciencebasedmedicine.org/leaky-brain-leaky-gut-are-they-real/

      1. In Vivo Veritas says:

        And yet, the same article says intestinal permeability is real, and I have generated clinical and preclinical data showing that to be true. The article you post is really more about the colloquial “leaky gut” experienced by our friends with “gluten insensitivity” and other self-imagined disorders.

  8. Barry says:

    Curiously, there has been a drop in premature births around the world corresponding to the Covid19 pandemic. Many reasons are possible, but it’s consistent with an infectious agent that has been curtailed incidentally by public health measures instituted for the novel coronavirus.

    1. Martin (still no Shkreli) says:

      You know, this is really interesting.
      I wonder what we’ll learn, in a few years, when looking at the prevalence of various diseases: if the number went down with the Corona crisis, maybe infectious causes should be considered. And maybe we’ll discover new, as-yet-undiscovered, ties between infectious diseases and others…

    2. Irene says:

      Birth rates in general are way down due to economic uncertainty (and I’m fairly sure a lot of people feel, as I do, that this would be a terrible time to take any unnecessary risk to one’s health — not that I am having any more babies anyway). I suppose that’s factored in to the drop in prematurity? i.e., percentage is down, not just raw numbers?

      1. Barry says:

        births drop nine months after conceptions. Barring abortions, we should not yet have seen the first impact of the pandemic in births.

  9. Len says:

    One issue I had was how an anaerobe survives in circulating blood in & be able of infect other parts of the body. While searching for this I found an interesting but scary article: Viable Bacteria Associated with Red Blood Cells and Plasma in Freshly Drawn Blood Donations by Christian Damgaard, et al. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120826
    Now I am concerned should I ever require a blood transfusion because
    anaerobes can accomplish this feat.

    1. Kaleberg says:

      Deliberate misreading: I will make sure not to accept any blood donated by Christian Damgaard.

      1. Len says:

        What follows are the last 2 paragraphs of the Christian Damgaard, et al. study that cannot be blown off as having been misread.

        At least three factors may contribute to the high frequency of contaminated blood products found in this study: Unlike most other studies, we only included donors of 50 years of age, or older. This inclusion criterion increases the risk of unreported infections such as periodontitis, which might explain the high prevalence of bacterial growth detected. Secondly, the majority of bacteria identified in the present study were either facultative anaerobic (59.5%) or anaerobic (27.8%) species, which are not likely to be detected using current screening procedures. Thirdly, the RBC fraction is not routinely tested for contamination.
        Obviously, larger studies are required to confirm our findings, and since symptomatic TTIs [transfusion-transmitted infections] are rare, screening of RBC preparations and cultivation under anaerobic conditions are probably not recommendable in general. Such procedures may be applied to blood products intended for immunocompromised individuals, e.g. patients undergoing chemotherapy. Moreover, surveillance for staphylococci and propionibacteria in patients with post-transfusion infections may be considered. Finally, it should be tested specifically whether periodontal disease may enhance the frequency of donor blood contamination.

  10. DTX says:

    The link between periodontal disease and atherosclerotic vascular disease is well-known. However, as John Wayne noted, it’s just an association. Many things are “associated.” The key is: are they causally associated?

    In the most in-depth analysis of this I’ve seen (done for the American Heart Assoc), Lockhart et al., (2012) concluded “Observational studies to date support an association between PD and ASVD independent of known confounders. They do not, however, support a causative relationship.” https://pubmed.ncbi.nlm.nih.gov/22514251/

  11. Marko says:

    I’d think that what’s needed is an effective sterilizing antibiotic treatment regimen rather than a vaccine. It sounds like the bug happily resides in much of the population under a condition of immune tolerance. For the unexposed population , a vaccine might make sense if you can overcome that tendency towards tolerance.

    Disease-causing bugs that take up residence in the body but are lie dormant or are very slow-growing are challenging both for the immune system and for therapeutic interventions. Sometimes a chronic low-level immune response and the associated inflammation is more damaging than if a more complete level of tolerance is achieved.

    Some are even proposing various methods to induce tolerance to COV-2 in those patients that appear to be on a fast-track to a cytokine storm. Effectively , that appears to be what dex and other steroids are doing.

    1. Barry says:

      Vaccines are far cheaper than antibiotics when they work. But but yes, a pathogen that is often tolerated for years or decades is a lousy candidate for a vaccine.

    2. James Cross says:

      You want to nuke the gut to save it?

      Might make more sense to change the ecology of the gut with better bacteria.

  12. ScientistSailor says:

    A vaccine for a Gram(-)?

    1. Barry says:

      is there not an effective vaccine against (Gram negative) Meningococcus?

      1. Vaudaux says:

        There are also vaccines for several other Gram-negative infections, including pertussis (whooping cough), cholera, typhoid, and Haemophilus influenzae type b (Hib).

        H influenzae type b is one of the bugs Marko describes as “happily resid[ing] in much of the population”. It is usually benign but occasionally causing moderate mucosal infections like otitis media and more rarely causing extremely serious infections like meningitis. The vaccine was designed to prevent the life-threatening infections, but surprisingly also turned out to reduce the level of pharyngeal colonization.

        You would not want to use a sterilizing antibiotic treatment for either Fusobacterium nucleatum or H influenzae, unless you have a very specific drug that does not kill the “good” bacteria in those niches (mouth and throat, respectively).

        1. ScientistSailor says:

          Isn’t the pertussis vaccine against the toxin, not the organism?

          1. aairfccha says:

            As far as I know both.

    2. A Nonny Mouse says:

      We were developing a vaccine for caries back in the 1980s. It had to be abandoned due to cardiovascular problems.

      1. metaphysician says:

        Any more information? That sounds like a very weird and interesting side effect, especially given reported connections between dental health and heart disease.

        1. Marko says:

          The reported connection between dental health and heart disease is , on the one hand , a good reason to seek out a vaccine to vanquish the possible culprit and , on the other , a good reason to be on the lookout for CV side effects of that vaccine.

          If caries bacteria and/or their antigens infiltrate the heart and blood vessels and result in chronic inflammation there that leads to CV disease , you’d have to be wary that a vaccine directed against the same might cause a rapid and catastrophic inflammatory response in those tissues.

          1. Barry says:

            So there’s the prospect that such a vaccine might work best on a naive population or might work only on a naive population? Surely that’s not an unusual scenario?

          2. Mark Updike says:

            Yes , you’d think a naive population wouldn’t experience the CV problems , so it makes me curious why the vaccine was abandoned.

            It could be that the vaccine-targeted bug is just so common in the population that there aren’t many “naives” around. A naive-only vaccine would also require some sort of pre-screen , which could get pricey depending on what sort of test(s) was required.

          3. Barry says:

            Or there may be ethical (consent) barriers to doing Phase I in pediatrics if they’re the only naives?

      2. Barry says:

        Fascinating. Did you think you were wiping out a beneficial commensal?

  13. En Passant says:

    My comment here is entirely off-topic. My lame excuse: I don’t know any other other way to note for Pipeline readers our gracious and modest host’s national television appearance.

    Derek was interviewed briefly today on the nationally broadcast PBS News Hour, on the subject of COVID19 vaccines.

    The PBS News Hour for today 7/22/2020, can be viewed at:

    https://www.youtube.com/watch?v=W5czBH9pU2A

    The “Vaccine Hunt” segment begins about 28 minutes 44 seconds in.

    Derek appears at about 34 minutes 14 seconds in.

    Congratulations, Derek!

    I will now duck and run.

    1. Tourettes of Chemistry says:

      Thanks for the pointer to this larger audience event.

      With that communication platform in play, the opportunity to highlight the purest medchem post of all time would have been a superlative sidebar.

      A throwback needing more air time. The limits of natural and legacy fragments are keys to small molecule drug discoveries.

      https://blogs.sciencemag.org/pipeline/archives/2007/03/29/i_want_a_new_nitro

      Not as widely engaging as TIWWW yet the news that needs more visibility towards interventions that are safe and authetically innovative.

      Ducking and Running as Well…

  14. AnonPD says:

    It was always a stereotype of MDs back in grad school that they knew the books and knew the stats, but they didn’t know the nuts and bolts. There are very few strait Phds on the coronavirus task force, and so we are seeing the downside from that now. Stats tests stats tests stats…..money flowing as always….no solutions. Compare that to the Manhattan project or biden’s moonshot project.

  15. Orange says:

    Did they dose the cells with the cytokines in absemce of bacteria? Would be interesting if that causes the mobility or some other factor.

  16. Steven Linder says:

    Chocolate Pecan Pie is the ultimate antidote to anorexia, at least.

  17. The Fusibacterium connection has been floated for a while (there’s also an apparent association with CRC stage, with Fusibacterium, along with Solbacterium are more abundant in late stage disease, with other bugs being more abundant in early stage). As with all things microbiome related I suspect the cause-effect relationship to have many strands and that practical exploitation is a long way off and that modulating any single species or genera could potential lead to unwelcome changes in the microbiome.

    Certain bacterial taxa are more frequently observed or depleted in faecal samples from CRC patients: Bacteroidetes is enriched, whereas Firmicutesis is depleted, and carriage of genera Fusobacterium, Atopobium and Porphyromonas is increased.

    Excellent overview by Wong & Yu: Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Rev Gastroenterol Hepatol. 2019 Nov;16(11):690-704. doi: 10.1038/s41575-019-0209-8. Epub 2019 Sep 25.

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