Gut bacteria amplifies immunotherapy: the power of Probiotics

Today, I came across this very interesting news, adding support to a fast growing amount of knowledge suggesting a strong connection between gut bacteria and the immune system:

Gut bacteria can dramatically amplify cancer immunotherapy “Introducing certain bacteria into the digestive tracts of mice with melanoma can help their immune systems attack tumor cells. The gains were comparable to treatment with anti-cancer drugs known as checkpoint inhibitors. The combination of bacteria and anti-PD-L1 nearly abolished tumor outgrowth, report scientists.”

Gut microbes give anticancer treatments a boost “Checkpoint inhibitors, which aim to unleash the power of the immune system on tumors, are some of the most impressive new cancer treatments. But most patients who receive them don€™t benefit. Two new studies of mice suggest a surprising reason why€”these people may not have the right mixture of bacteria in their guts. Both studies demonstrate that the composition of the gut microbiome€”the swarms of microorganisms naturally dwelling in the intestines€”determines how effective these cancer immunotherapies are.”

The articles above were written based on two recent publication in a well known journal, i.e. Science. Here are the journal articles:

  1. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota http://www.sciencemag.org/content/early/2015/11/04/science.aad1329  Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, or by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that anti€“CTLA-4 treatment of melanoma patients favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
  2. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy http://www.sciencemag.org/content/early/2015/11/04/science.aac4255 T cell infiltration of solid tumors is associated with favorable patient outcomes, yet the mechanisms underlying variable immune responses between individuals are not well understood. One possible modulator could be the intestinal microbiota. We compared melanoma growth in mice harboring distinct commensal microbiota and observed differences in spontaneous antitumor immunity, which were eliminated upon cohousing or following fecal transfer. 16S ribosomal RNA sequencing identified Bifidobacterium as associated with the antitumor effects. Oral administration of Bifidobacterium alone improved tumor control to the same degree as anti-PD-L1 therapy (checkpoint blockade), and combination treatment nearly abolished tumor outgrowth. Augmented dendritic cell function leading to enhanced CD8+ T cell priming and accumulation in the tumor microenvironment mediated the effect. Our data suggest that manipulating the microbiota may modulate cancer immunotherapy.
    Here is the article available to read via Research Gate.

In summary, with these studies it has been shown that:

  • Bacteroides thetaiotaomicron or Bacteroides fragilis were associated with the efficacy of CTLA-4 blockade
  • Bifidobacterium alone (combination of B. breveB. longum and B. adolescentis) improved tumor control to the same degree as anti€“PD-L1 therapy (checkpoint blockade), and combination treatment nearly abolished tumor outgrowth. (Note, that administration of Lactobacillus murinus had no effect on tumor growth while administration of commercially available probiotics containing B. breveB. longum did lead to anti-tumor effects.)

Therefore, when doing the CTLA-4, anti-PD1 or anti-PD-L1 therapy but even if not doing that, it makes sense to get the above bacteria as supplements if possible in order to enhance the immune system capabilities.

Good sources of probiotic bacteria: Sauerkraut, Milk Kefir, Probiotics, etc.
Bifido is even in Activia Yougurt 🙂
Here is a good list of probiotic http://www.thecandidadiet.com/list-of-probiotics/
This also seems to be an interesting probiotics source.
Diet and fiber content is essential for a balanced gut bacteria Ref
You can nourish healthful flora with prebiotics, which contain nondigestible carbohydrates – found e.g. in whole grains, onions, garlic, leeks, artichokes, asparagus, and chicory root. Here is a nice list on various probiotic foods to add to the diet.

Bifidobacterium can be found in many probiotics available online such as this one from Tisso. For the other two I do not have yet a source, so if you find one please let me know. Note, most of the commercial probiotics may not end up being active (Ref.1 Ref.2) so you probably want to focus on the natural probiotics sources such as sauerkraut, and next to that add some of the commercial ones anyway.

I am convinced that immune system is essential in cancer and the gut bacteria has a main responsibility for how our immune system looks like. So whenever something is wrong with your immune system think of gut bacteria too. Is that balanced in the right way? If not, what probiotcis and what food should we eat in order to induce the balance? Here is an article that gives some answers to these questions. For example the article suggests that: ” …. It was previously noted that diets rich in fats and red meats result in dysbiosis, favoring the growth of Proteobacteria phylum (species such as E. coli, Klebsiella, Enterobacter, and Citrobacter) andFusobacterium nucleatum [103, 104] and impacting in a negative way certain species of Firmicutes and Bacteroidetes [73]. Notably, Fusobacterium nucleatum species are able to kill maturing lymphocytes via M cells in the Peyer’s patches via direct contact, lowering the number of circulating systemic lymphocytes [92,105] (Figure 2). An intestinal microbiome that destroys lymphocytes may influence the outcomes of cancer.” So here is an open question: does this mean that (restricted) Ketogenic Diet, promoted as a solution for cancer, may actually lower our immune system? If that is true, it makes much sense to add serious amount of probiotics when on Ketogenic Diet.

My conclusions after reading about gut bacteria and cancer:

  1. Avoid antibiotics (when possible – note that some antibiotics have anti cancer effects too)
  2. Use probiotics and prebiotics
  3. Watch your diet – too much fats may be detrimental while fiber is supportive to good gut bacteria

Other relevant references:

In vitro Th1 cytokine-independent Th2 suppressive effects of bifidobacteria http://www.ncbi.nlm.nih.gov/pubmed/17641467

A comparison between 17 strains of lactic acid bacteria and 15 strains of bifidobacteria indicated that bifidobacteria induced significantly lower levels of interleukin-12 (IL-12) in murine splenic cells. The present study aims to evaluate the effect and mechanism of Bifidobacterium longum BB536, a probiotic strain, in suppressing antigen-induced Th2 immune response in vitro. BB536 suppressed immunoglobulin (Ig) E and IL-4 production by ovalbumin-sensitized splenic cells, but induction of Th1-inducing cytokine production, such as IL-12 and gamma interferon (IFN-gamma) tended to be lower compared with lactic acid bacteria. Neutralization with antibodies to IL-12, IFN-gamma, IL-10 and transforming growth factor beta indicated negative involvement of Th1-inducing cytokines and regulatory cytokines in the suppression of Th2 immune response by BB536, especially when treated at higher doses of BB536 (>10 microg cells/ml). Furthermore, BB536 induced the maturation of immature bone marrow-derived dendritic cells (BM-DCs), and suppressed antigen-induced IL-4 production mediated by BM-DCs. These results suggested that BB536 suppressed Th2 immune responses, partially independent of Th1-inducing cytokines and independent of regulatory cytokines, mediated by antigen-presenting cells such as dendritic cells.

Evolving concepts: how diet and the intestinal microbiome act as modulators of breast malignancy http://www.ncbi.nlm.nih.gov/pubmed/24187630

The intestinal microbiome plays an important role in human physiology. Next-generation sequencing technologies, knockout and gnotobiotic mouse models, fecal transplant data and epidemiologic studies have accelerated our understanding of microbiome abnormalities seen in immune diseases and malignancies. Dysbiosis is the disturbed microbiome ecology secondary to external pressures such as host diseases, medications, diet and genetic conditions often leading to abnormalities of the host immune system. Specifically dysbiosis has been shown to lower circulating lymphocytes, and increase neutrophil to lymphocyte ratio, a finding which has been associated with a decreased survival in women with breast cancers. Dysbiosis also plays a role in the recycling of estrogens via the entero-hepatic circulation, increasing estrogenic potency in the host, which is another leading cause of breast malignancy. Non-modifiable factors such as age and genetic mutations disrupt the microbiome, but modifiable factors such as diet may also lead to profound disruptions as well. A better understanding of dietary factors and how they disrupt the microbiome may lead to beneficial nutritional interventions for breast cancer patients.

The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of €œpathogenic€ T helper 17 (pTH17) cells and memory TH1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pTH17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pTH17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.

New research sheds light on how popular probiotic benefits the gut

The gut bacteria Lactobacillus rhamnosus GG has a reputation as a helpful microbe. Now, researchers have come up with an explanation for why. It appears that the bacteria may boost the activity of other gut microbes

Fish oil-diet benefits may be mediated by gut microbes

Diets rich in fish oil versus diets rich in lard (e.g., bacon) produce very different bacteria in the guts of mice, reports a new study. The researchers transferred these microbes into other mice to see how they affected health. The results suggest that gut bacteria share some of the responsibility for the beneficial effects of fish oil and the harmful effects of lard.

Do gut bacteria rule our minds? In an ecosystem within us, microbes evolved to sway food choices

It sounds like science fiction, but it seems that bacteria within us — which outnumber our own cells about 100-fold — may very well be affecting both our cravings and moods to get us to eat what they want, and often are driving us toward obesity.

Understanding Probiotics: Health Benefits, Types of Probiotics

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10 thoughts on “Gut bacteria amplifies immunotherapy: the power of Probiotics

      1. If i may….
        i’m fairly convinced that a hot drink from time to time may also help boost immunity trough gut bacteria and not only, most likely not to cure cancer, but hey… whatever helps right?

  1. Commercially available probiotics that I use myself and for my cats are:
    Bifidobacterium longum
    Bifidobacterium infantis
    Lactobacillus acidophilus
    Lactobacillus casei,
    these 4 from Urobiotic (20 capsules in a bottle, which once opened they are good for some 2 weeks).
    Bifidobacterium BB-12
    Lactobacillus paracasei 431
    Streptococcus Thermophillus TH-4
    these 3 from EuBiotic baby (small satchels, I mix bit in my cats’ food and the rest take myself).
    But I must warn again that large amounts of these lead to liver and pancreas damage.

  2. I believe this should be updated as probiotics are now a NO NO with immunotherapy. They should not be taken as the article that I link suggests . Important is to have rich microbiome. Probiotics mostly promote only certain types of bacteria and therefore the microbiome is not so rich and has less variety after probiotics.
    https://www.healthline.com/health-news/probiotics-linked-to-poorer-response-to-cancer-immunotherapy-in-skin-cancer-patients#Probiotics-worsen-response-to-immunotherapy
    It seems to be important to consume a lot of fiber.

    1. Hi Michal,

      Thank you for your comment. The article you linked contains very useful information but also some misleading one. Specifically, the statements related to the probiotics being detrimental is a missing one since it refers to results that have not been published in a peer review journal yet. So from scientific point of view, those results are non-existing. In contrast to that, the article linked above addressing the benefits of Bifidobacterium were published in on of the best scientific journal, Science.

      One example why the anecdotal reports mentioned in the article could be highly misleading of the readers: typically, the patients taking probiotics in a conventional hospital, they are doing that because they are also taking antibiotics. And it is well known that patients using anti-biotics prior to chemo are not doing well with chemo https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964118/ So I would say that antibiotics and not probiotics should be avoided with immonotherapy, and based on the published evidence so far, probiotics such as Bifidobacterium are a strong YES.

      Again, thanks a lot for bringing such a relevant subject into the discussion. I actually want to write an article on this subject (antibiotics and probiotics). Btw, I think Antibiotics have also a major role in cancer treatment, a positive one, but should not be combined with immunotherapy. It’s just that we have to make choices on how we want to fight cancer and avoid using antagonist while doing that.

      Kind regards,
      Daniel

  3. Hi Daniel,
    Thank you for your response. This topic is really important to me as I want my mother (with EGFR positive NSCLC) to start low-dose immunotherapy treatment in 1-2 weeks. I have been getting information in Cancer Immunotherapy facebook group (admin is Jason Williams) where there seemed to be some kind of consensus that probiotics should be avoided based on the research I linked. But you are right that the study is preliminary and also based on questionnaires. Anyway I guess it should be considered too. The study with Bifidobacterium was done in mice? If so then it might have limitations too as mice microbiome is different from human. So it seems to be difficult to say. To stay on the safe side then maybe people before immunotherapy should eat high fibre diet, could take prebiotics, and maybe include food probiotics such as kefir … Over the counter probiotic pills maybe should be avoided, what do you think ? .
    There is probably no question on antibiotics and immunotherapy.
    I wanted to ask you for your recommendations to enhance the effect of low-dose immunotherapy for my mum. We need to pay for the treatment and low-dose Nivolumab seems to be a thing that we could try. But the response rates for immunotherapy are still rather low, so enhancements are needed.

    1. Dear Michal,

      I am sorry your mom has to deal with this and hope everything will be better and better.
      I did not know Jason has his own Facebook group. Very interesting to hear that.
      We need to realise that in this world we can find whatever answer we like. We just have to search enough for that. The same happens in science. And so everything can be debated. In this context, I prefer to look at where the most evidence is, and combine that with what seems logical to me. So far, most science indicates probiotics such as Bifidobacterium as one that promotes health. Here is an example of a review addressing that https://pubmed.ncbi.nlm.nih.gov/29212851-omics-of-bifidobacteria-research-and-insights-into-their-health-promoting-activities/ I totally agree, that the best way to build our health is via fibre reach diets. However, that takes time and sometimes we may need to act faster since conventional therapies often negatively affect the gut bacteria, and they do it fast and frequently. That is when we need to use the probiotics. And personally, I would use them. One of the best probiotic to my knowledge is sauerkraut juice. That can be easily made at home. Others like kefir and in general fermented food should be very helpful too. I think that in general we need to introduce fermented food in our diet regardless if we have or not health challenges. But I also think that some probiotics known to be beneficial and are not present in e.g. sauerkraut or kefir, should be supplemented with good quality probiotics.
      I actually think that the ultimate, best approach may be via faecal transplant. I know someone who’s like was saved by that (not a cancer patient).
      Beyond probiotics, there are various ways to help the immune system. Some have been discussed here, including Cimetidine https://www.cancertreatmentsresearch.com/case-report-stage-iv-sarcoma-good-news-from-jg/
      This will also help to reduce acidity around the tumor and increase the chance foe effectiveness
      https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/
      I think Dr. Dana Flavin had a good strategy in place to support immunotherapy but I think it is not cheap to get her support http://collmed.org
      Using mushroom supplements including Coriolus and AHCC could help too!

      Kind regards,
      Daniel

  4. I have melanoma of the scalp which is not a good thing to have. it has spread all over my scalp and down forehead. I believe it is in some of my lymph nodes now. go back to Dr. Tuesday for those results. I just heard about the dog dewormer and other vitamins. I am in immunotherapy. just wondering if safe for me to take.

    1. Hi Drusilla,

      I am so sorry to hear about the challenges and I hope you will be soon better. Immunotheraphy is indeed a good option for melanoma. Adding DC vaccines may further help. I do not expect any major interaction or side effect from Fenbendazole.
      You may also want to have a look at this:
      https://www.cancertreatmentsresearch.com/unlocking-zincs-potential-to-fight-cancer/
      – Inositol: Inositol hexaphosphate plus inositol induced complete remission in stage IV melanoma: a case report https://www.supersupps.com/downloads/product_files/917/Inositol_hexaphosphate_plus_inositol_induced.99190.pdf
      – Thymus vulgaris Long-term complete remission of cutaneous melanoma metastases in association with a folk remedy https://www.jaad.org/article/S0190-9622(04)03675-8/fulltext
      – Complete Remission of Widely Metastatic Melanoma: A Case Report https://genechanger.com/complete-remission-widely-metastatic-melanoma-case-report/

      Kind regards,
      Daniel

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