By Dr. Geoffrey Modest
Well, here is yet another microbiome blog, but this one suggests that the gut microbiome and associated immunologic changes could affect cancer development and therapy. There were 2 articles in an issue of the journal Science which assessed this relationship.
- One study looked at how changes in the microbiome affect host immunity and the natural response to implanted cancer (see Science 2015; 350 (6264): 1084). Prior studies have found a role for the intestinal microbiome in human systemic immune responses.
Details:
- 2 genetically-similar mice from 2 different suppliers (JAX and TAC) with 2 different intestinal microbiomes (257 different bacterial taxa) had different responses to implanted melanoma, with the JAX mice having higher tumor-specific T-cell responses, intratumor CD8 T-cell accumulation, and improved survival
- Cohousing the JAX and TAC mouse eliminated the difference, as did transferring fecal specimens from the JAX mice into the TAC mice (but not if gavage saline or TAC fecal material into TAC mice)
- The clinical effect of having the JAX microbiome was equivalent to using a specific antibody immunotherapy (PD-L1), though the combo of this immunotherapy with the more immunogenic JAX microbiome was even better (human patients with evidence of endogenous T cell response also do better with immunotherapies)
- In assessing the genus-level taxa of the differences in the microbiomes of JAX and TAC mice, the presence of Bifidobacterium species in particular showed the positive association with antitumor T-cell responses (400-fold). And Bifidobacterium species (including B. breve and B. longum) administered to TAC mice led to improved tumor control, which was abrogated in CD-8 depleted mice, suggesting that the effect of this bacterial species was not direct but was mediated through modifying endogenous immunologic responses
- The same basic finding was found with bladder cell implants
- Lactobacillus had no effect on tumor growth
- Further experiments suggested that the antitumor effect of Bifidobacterium was not related to indirect effects of the Bifidobacterium on other bacterial species but was acting on its own. In addition, Bifidobacterium was shown to alter lymphocytic dendritic cell activation and improved tumor-specific CD8 T-cell function.
- Another study (which I will not summarize much) found that antibodies targeting a regulator of T cell activation (ipilimumab, a human monoclonal antibody useful in patients with metastatic melanoma) only worked if the gut microbiome had Bacteroides species present, especially B. fragilis (see Science 2015; 350 (6264): 1079)
So, I am continually amazed at both the extent of the rather profound impacts of the microbiome in preserving many health-related outcomes as well as its remarkable fragility. And, I really do not want to be reductionist — the Bifidobacterium seems to be protective in a few studies, along with other bugs such as Bacteroides. But there are undoubtedly complex interactions between the different species, some known and some not, which are essential for a healthy microbiome. And some of these commensals may be important for some functions and others for other functions. I.e., the answer is not simply to take certain probiotics (which may be helpful), but to do everything we can to preserve the microbiome naturally. As noted in several of themicrobiome blogs, the issue is to emphasize a healthy life style (esp. diet and exercise), eat good foods (e.g. avoid many of the artificial stuff around us, such as artificial sweeteners), and avoid toxins as much as we can (antibiotics, both given unnecessarily in the medical setting, and especially in use in agriculture and in animals). No doubt, the microbiome is often able to regenerate (and we are lucky that many of our natural systems, including the environment are able to repair themselves from natural and human interruptions), but as with all such systems, there may be tipping points beyond which there is no return….
For other blogs on the microbiome:
https://stg-blogs.bmj.com/bmjebmspotlight/2015/12/10/primary-care-corner-with-geoffrey-modest-md-troubling-microbiome-changes/ associates PPI use and C diff infections
https://stg-blogs.bmj.com/bmjebmspotlight/2015/12/03/primary-care-corner-with-geoffrey-modest-md-longterm-microbiome-changes-with-antibiotics/ showing short term salivary and long-term gut microbiome changes after a single dose of antibiotics
https://stg-blogs.bmj.com/bmjebmspotlight/2015/11/09/primary-care-corner-with-geoffrey-modest-md-gi-microbiome-in-little-kids-and-development-of-asthma/ noting increased asthma in kids with early antibiotic exposure, as well as some data on celiac disease (also highlights possible protective effect of Bifidobacterium)
https://stg-blogs.bmj.com/bmjebmspotlight/2015/10/20/primary-care-corner-with-geoffrey-modest-md-international-travel-and-gut-microbiome-changes/ showing microbiome changes with international travel and use of antibiotics
https://stg-blogs.bmj.com/bmjebmspotlight/2015/01/28/primary-care-corner-with-geoffrey-modest-md-heart-failure-microbiome/ looked at the effect of red meat on the microbiome (increasing TMAO levels, which are strongly pro-atherogenic) and showing that metformin induces positive changes in the microbiome which decrease insulin resistance
https://stg-blogs.bmj.com/bmjebmspotlight/2014/12/04/primary-care-corner-with-geoffrey-modest-md-artificial-sweeteners-microbiome-and-glucose-intolerance-in-mice-and-men-and-women/ finding that non-caloric artificial sweeteners induce microbiome changes causing increased insulin resistance and, several additional articles in https://stg-blogs.bmj.com/bmjebmspotlight/category/microbiome/ on recommendations to limit antibiotic use or to use the most targeted and specific antibiotic when necessary in order to inflict the least harm on the microbiome