The gut microbiome AGAIN - as it relates to immunotherapy for melanoma, other cancers, antibiotic use, and fecal transplants!

We have known that the bacteria, good and bad, within our intestines impact our health in ways, good and bad, for far longer than the current run of research and discussion of the microbiome sometimes remembers.  I posted this in 2015 - and it was old news then:  Cooties in our gut keep us skinny, smart and cure cancer!?????   For more on all things microbiome there are these:  The intestinal microbiome

Now, there are these additional reports:  

Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients.  Peters, Wilson, Moran, et al.  Genome Med. 2019 Oct 9.

Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community.

In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression

Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up. Among the species selected in regression, abundance of Bacteroides ovatus, Bacteroides dorei, Bacteroides massiliensis, Ruminococcus gnavus, and Blautia producta were related to shorter PFS, and Faecalibacterium prausnitzii, Coprococcus eutactus, Prevotella stercorea, Streptococcus sanguinis, Streptococcus anginosus, and Lachnospiraceae bacterium 3 1 46FAA to longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways of L-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis.

This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.

NOTE:  While what follows is positive news, many reports have shown that taking probiotics from a bottle do not provide the help our intestinal microbiome really needs, while a diet high in fiber and live cultures like those within yogurt, kefir, sauerkraut, and kimchi does.  Now, this:

Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth.  Li, Elmen, Segota, et al.  Cell Rep.  2020 Feb 11.

Growing evidence supports the importance of gut microbiota in the control of tumor growth and response to therapy. Here, we select prebiotics that can enrich bacterial taxa that promote anti-tumor immunity. Addition of the prebiotics inulin or mucin to the diet of C57BL/6 mice induces anti-tumor immune responses and inhibition of BRAF mutant melanoma growth in a subcutaneously implanted syngeneic mouse model. Mucin fails to inhibit tumor growth in germ-free mice, indicating that the gut microbiota is required for the activation of the anti-tumor immune response. Inulin and mucin drive distinct changes in the microbiota, as inulin, but not mucin, limits tumor growth in syngeneic mouse models of colon cancer and NRAS mutant melanoma and enhances the efficacy of a MEK inhibitor against melanoma while delaying the emergence of drug resistance. We highlight the importance of gut microbiota in anti-tumor immunity and the potential therapeutic role for prebiotics in this process.

When you need your cooties to work for you, it makes sense that killing them off with antibiotics would not serve you well.  Clearly, the development of antibiotics has prolonged and saved untold lives.  However, when they end up in the food chain, are used to treat viruses (for which they do NO GOOD) or are otherwise used inappropriately, real harm can result.  Not the least of which is a poor response in melanoma patients to immunotherapy.  There have been many concerning reports - Antibiotic use may diminish the positive effects of immunotherapy  

Now - there's this:

Antibiotic administration shortly before or after immunotherapy initiation is correlated with poor prognosis in solid cancer patients: An up-to-date systematic review and meta-analysis.  Yang, Wang, Yaun, et al.  Int Immunopharmacol.  2020 Aug.

Objective: Immune checkpoint inhibitors (ICIs) have recently achieved inspiring performance in improving the prognosis of various solid tumors. Gut microbiome plays a crucial modulatory role in the efficacy of ICIs, which can be influenced by antibiotic (ATB) administration. In this meta-analysis, we aimed to clarify the correlations of ATB administration with the prognosis of solid cancer patients receiving ICI treatment.

Method: The eligible literatures were searched using PubMed, Cochrane Library, Web of Science, and Clinical trials.gov databases before 29 February 2020. The correlations of ATB administration with overall survival (OS) and progression-free survival (PFS) were determined using Hazard ratios coupled with 95% confidence intervals.

Results: A total of 33 studies enrolling 5565 solid cancer patients receiving ICI treatment were included in this meta-analysis. As a whole, ATB administration was significantly correlated worse OS  and PFS. This significant association was then observed in the subgroup analysis based on region (except for OS in Europe), sample size, age, therapeutic strategy and ICI type. The similar results were also found in subgroup analysis for lung, renal cell (except for OS) and other cancers (such as melanoma) but not for mixed cancers. In addition, the ICI efficacy was more likely to be diminished by ATB administration within a time frame from 60 days before to 60 days after ICI initiation.

Conclusion: ATBs should be used cautiously in solid cancer patients receiving ICIs. However, further validations are still essential due to existing publication bias.

And this:

Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI).  Creen, Bertrand, Deley, et al.  Oncoimmunology.  2020 Nov.

Background: The gut microbiota has a key role in the regulation of the immune system. Disruption of the gut microbiota's composition by antibiotics might significantly affect the efficacy of immune checkpoint inhibitors. In a study of patients treated with ipilimumab, we sought to assess the relationship between overall survival and in-hospital antibiotic administration. 

Methods: Patients having been treated with ipilimumab between January 2012 and November 2014 were selected from the French National Hospital Discharge Summary Database. Exposure to antibiotics was defined as the presence of a hospital stay with a documented systemic bacterial infection in the 2 months before or the month after initiation of the patient's first ever course of ipilimumab. The primary outcome was overall survival. 

Results: We studied 43,124 hospital stays involving 1585 patients from 97 centers. All patients had received ipilimumab monotherapy for advanced melanoma. Overall, 117 of the 1585 patients (7.4%) were documented as having received systemic antibiotic therapy in hospital during the defined exposure period. The median overall survival time was shorter in patients with infection (6.3 months, vs. 15.4 months in patients without an infection. In a multivariate analysis adjusted for covariates, infection was still significantly associated with overall survival. 

Conclusions: In patients treated with ipilimumab for advanced melanoma, infection, and antibiotic administration in hospital at around the time of the patient's first ever course of ipilimumab appears to be associated with significantly lower clinical benefit.

In 2017 I reported on the positive effects of fecal transplants in poor little cancer affected mice - Back to the cooties in our guts....again!!!  Now, there seems to be a real benefit of same, for melanoma ratties!

Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients.  Davar, Dzutsev, McCulloch, et al.  Science. Feb 2021.

The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy. Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients.

Anti–programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti–PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti–PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti–PD-1 in patients with PD-1–refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti–PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma.

 

Certainly something melanoma peeps who are not responding to anti-PD-1 might wish to discuss with their docs! 

And that brings us up-to-date with the most recent bits and bobs regarding the cooties in our guts!   Kefir smoothie, anyone? - c

More shoo shoo! Or...intestinal flora and melanoma

I've posted on all things dietetic and the flora in our gut in particular for YEARS!!!  Here was my latest round-up just this January:  Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!

I do recommend healthy eating and exercise.  I do take 2000 iu of vitamin D daily.  I do eat lots of foods with active cultures in them - yogurt, kefir, sauerkraut, etc. I eat them because I like them and we have learned that cooties in our gut are important whether they really do anything when we take anti-PD-1 and deal with melanoma or not.  I wish that making immunotherapy effective for everyone who takes it were as simple as a diet change.  However, as I've noted in prior posts...this pendulum continues to swing back and forth and the data is far from conclusive.

Now, there's this ~

The gut microbiota and immune checkpoint inhibitors. Humphries and Daud.Hum Vaccin Immunother. 2018 Mar 1.

Although immunotherapy has been remarkably effective across multiple cancer types, there continues to be a significant number of non-responding patients. A possible factor proposed to influence the efficacy of immunotherapies is the gut microbiome. We discuss the results and implications of recent research on the relationship between the gut microbiome, our immune systems, and immune checkpoint inhibitor therapies including anti-CTLA-4 Ab and anti-PD-1 Ab. While the investigations all exhibit interesting results and conclusions, we find little congruence in the specific bacteria that were found favorable for antitumor responses. It is unclear whether the inconsistencies are due to differential approaches in study design (pre-clinical or clinical subjects, anti-CTLA-4 Ab or anti-PD-1 Ab), experimental methods and measurements (metagenomics sequencing and clustering variations) or subject population dynamics (differential cancer types and baseline characteristics). Moreover, we note studies regarding particular bacterial commensals and autoimmune diseases, which challenge findings from these investigations. We conclude that with the current research, clinical investigators can appreciate the critical role of gut microbiota in mediating immunostimulant response. However, prospective research exploring the biochemical mechanisms which commensal bacteria communicate with each other and the immune system is imperative to understand how they can be adjusted properly for higher immunotherapy response.

For what it's worth.  Hang tough.  Be well. - c

Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!

This past November I posted this:  Back to the cooties in our guts....again!!!

In June, 2017, there was this:  ASCO 2017: Melanoma, anti-PD1 and the microbes in your gut

In February of that year:  Antibiotic use MAY decrease effectiveness of immunotherapy?????

From 2016, there was this:  Intestinal bacteria as a way to determine risk for ipi induced colitis!

And in 2015...with a review of where all this bacterial mess started...there was this:  Cooties in our gut keep us skinny, smart and cure cancer!?????

With all that...now, there's this.....

The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Matsson, Fessler, Bao, et al. Science. 2018 Jan 5.

"Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16S ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients."

And, I present excerpts from:
CANCER THERAPY, Precision medicine using microbiota.  Intestinal microbiota influence cancer patient responses to immunotherapy.  Jobin. Science. 2018 Jan 7.

"…Conceptually, these findings suggest that bacteria-mediated interactions with the immune system are essential for optimal drug efficacy. However, there is limited information regarding the functional impact of the composition of the human microbiome and therapeutic outcomes in cancer patients. ...

...patients can be stratified into responders and nonresponders to immunotherapy on the basis of the composition of their intestinal microbiomes, suggesting that microbiota should be considered when assessing therapeutic intervention....

…Because microbiota have a pronounced modulatory effect on the immune system, they may enhance responses to immune checkpoint therapies...

...They observed that the strongest fecal microbial predictors of anti–PD-1 therapy response were bacterial diversity and abundance of Faecalibacterium and Bacteroidales...

... responding patients had an increased abundance of eight microbial species, including Bifidobacterium longum. The presence of this species in the intestines of tumor-bearing mice was previously found to improve anti–PD-L1 therapy. Interestingly, two species were also associated with nonresponsiveness (Ruminococcus obeum and Roseburia intestinalis). …

…introduction of A. muciniphila to mice receiving human nonresponder FMT reversed the low response to PD-1 blockade, improving antitumor immune cell infiltration and activity in tumors. Overall, these studies report a fascinating interaction between intestinal bacteria and antitumor efficacy of PD-1 blockade in patients, suggesting that precision medicine strategies should include the intestinal microbiota as a potential treatment modifier....

... Therefore, the presence of specific strains of bacteria may be able to modulate cancer progression and therapeutics, raising the possibility that precision medicine directed at the microbiota could inform physicians about prognosis and therapy. ..."

WOW!!!  If that's not a lot of shoo shoo, I don't know what is!!!!  So...let's break it down.  Through all the reports, the good cootie is overwhelmingly Bifidobacterium. That's the doo dad found in yogurt, chocolate, kefir, sauerkraut, spirulina, pickles, kimchi, kombucha!  Now, in addition to the bifidobacterium....the other factor that does a body good is a lot of other shit.  OR, actually...a lot of other STUFF in our boo boo.  A diverse population of cooties...living happily together...improving the lives of one another BECAUSE of their differences and what each "culture" brings to the table!!  (Damn!  Sounds like what the welcoming torch of the Statue of Liberty represented all along!!!!)  At least in little mice, the presence of Ruminococcus obeum and Roseburia intestinalis led to a decreased response to anti-PD-1.  However, by giving those nonresponders a different bacteria (A. muciniphila) the NON responsiveness, was removed.

Okay!  What does all that mean??  Not, sure.  I think a lot of this data meanders back and forth between melanoma peeps and melanoma mice (not to mention koalas in one of the prior reports!!!), so it is hard to know how much we can take as the gospel.  In the end, (HA! HA!  I CRACK myself up!  Poops!  I did it again!!!) I think we've always known that live cultures in foods like kimchi, yogurt, and kefir are good for us.  We also know that, though antibiotics save lives and misery when they are needed, they can also cause harm by killing off microbes that we would actually be better off keeping around.  So....eat the best you can.  Include fiber and culture rich foods in your diet.  Take antibiotics only when you need them.  Keep a sense of humor.  Wipe front to back.  And know that despite all the Latin names...poop...really is...poop!   - c

Cooties in our gut keep us skinny, smart and cure cancer!?????

The cooties in our gut have been the hottest thing in research, and news about research, of late.  It is not as new as some folks would like to have you believe.  We have known for some time now, that a little dirt don't hurt.  Kids have become less immune to disease and more susceptible to various immune problems like asthma and allergies since the world got cleaner around them.  Concomitantly, they do die less from pneumonia and dysentery!!!  Just say'n!  On the other hand, as humans become more willing to take, and docs to prescribe, antibiotics for a cold (That's a virus people!!!  Antibiotics kill bacteria....not a virus!) and allow farmers to feed them in large quantities to animals that end up on our grills, we haven't cured a single virus, but we have killed a lot of important bacteria that should be living in our guts. 

Additionally, the diet most Americans consume...one low in fiber, fruits and vegetables....but filled with processed, "fast" food....does us no favors.  Rats fed more fiber eat less than their fiber-free counterparts, are thinner, faster and live longer.  Studies in real live people show that the fiber does that in an obvious way, but also changes the microbes in our gut as the "good" germs like to eat the fiber!!!  If there's no fiber there for them to eat, they aren't there!!!  So, along with obesity prevention, scientists are now touting the benefit of good germs in our gut to promote brain development, improved cognitive behaviors, and prevent neurologic disorders.  The latest reports also seem to show that good bacteria in our intestines can promote the beneficial effects of immunotherapy....

The Atlantic: 11/2015 - Immunotherapy cancer drugs depend on gut microbes

Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.

Sivan, Corrales, Hubert, et al.  Science. 2015 Nov 5.

"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."

None of this is really surprising.  We already knew how much difference the microbes within our intestines made in the presence of allergies and immunologic based diseases. And, yes, in some medical cases, like the treatment of c. difficile, we have even found that fecal transplants are needed!!! Of course it makes sense that this "background note" would affect drugs and treatments that work by stimulating the immune system!!!  However, once again....it is important to remember that this is not the end all, be all, to cancer and all sorts of diseases.  It goes back to the same old song.  There is no miracle drug or diet.  Doing something extreme or bizarre with your diet is not going to change your world or your cancer.  But....if you will exercise, eat your fruits and veggies....you will set yourself up to be the healthiest you can.  Want to increase the bifidobacterium in your gut?  No problem.  Eat yogurt with live cultures.  Drink kefir or buttermilk.  Enjoy kimchi (Korean fermented cabbage), sauerkraut, miso, and other fermented fruits and veg.  And after that...take a walk...preferably while holding hands with a good friend.
Love and luck - c