Melanoma cancer therapy’s efficacy may depend on the existence of specific gut bacteria

Ipilimumab is a monoclonal antibody (mAb) that binds to, and activates T-cells. (Technically, the drug binds to the CTLA-4 receptor on T-cells, which decreases T-cell suppression)  It is currently an approved therapy for the treatment of metastatic melanoma.  Unfortunately, activation of the immune system can damage the microbiome, and taking iplimumab often results in adverse side effects in the gut, such as diarrhea.  Scientists from France were studying the effect of the drug on the microbiome when they discovered that its efficacy was actually dependent on the presence of certain gut bacteria.  They published their results in the journal Science.

First, the scientists administered the ipilimumab to three groups of mice that had been given cancer through an established model.  One group of mice had a normal microbiome, the second group was germ-free, and the final group had a normal microbiome, but then were given antibiotics.  Surprisingly, the mAb activated much fewer T-cells and was much less effective in destroying the cancer in the mice that were germ free and had been given antibiotics compared to the normal mice.  In addition, the scientists noted that intestinal inflammation occurred in the normal mice, but less so in the others.  Next, the scientists measured the microbiome changes as a result of administration of the mAb, and observed a rapid decrease in Bacteroidales, Burkholderiales, and an increase in Clostridiales.  The scientists then inoculated cancerous mice with specific bacterial species prior to administration of the drug, and then measured the drug’s efficacy.  Remarkably, specific species, such as Bacteroides thetaiotaomicron were able to reestablish the drug’s therapeutic potential and decrease inflammation.

The microbiome’s complex dynamic with the immune system once again presents itself, this time by modulating the efficacy of ipilimumab.  The scientists did do some work on humans, and they noted that not all human patients suffering from melanoma and taking ipilimumab have those beneficial bacteria in their stool.  The scientists did not discuss whether their existence was associated with the cancer’s progression in humans, although it would be interesting to see.  Ipilimumab is just one of many drugs that use the immune system to attack cancer.  Continued research is needed on the microbiome’s impact on these drugs.

New study shows how E. coli and B. theta grow in the gut mucus

The mucosal membrane continues to be one of the most intriguing and vexing components of the gut microbiome.  It is the interface between the body and the environment, it is inhabited many bacteria, and it is a nutritional source that shapes the populations in the gut.  There is still very little known about the specific interactions between gut mucous and bacteria, but this critical system is rapidly being studied.  In the most recent advance, scientists from Switzerland and Germany examined two very different gut bacteria that fill different mucosal niches. They published their results in the journal Nature Communications.  The two bacteria they studied were Bacteroides thetaiotaomicron (B. theta) and Escherichia coli.  B. theta is a slow growing bacteria that has high metabolic flexibility that is capable of directly using gut mucins as an energy source.  E. coli is a fast growing bacteria that is much more limited in its metabolism and can’t directly use the carbohydrates in the gut, but can take hold and rapidly proliferate after a course of antibiotics. 

The researchers meticulously researched gnotobiotic mice and made many discoveries about bacteria in their mucous.  First, they discovered that the mucosal microbiome varies across its thickness, and is sterile closest to the intestines, but rich in life closest to the lumen.  In addition, they noted that the luminal microbiome is distinct from the mucosal microbiome, even though the mucous is constantly being shed into the lumen.  To this end, they confirmed that with regards to E. coli, these bugs replicate faster than they are shed (in about 3 hours in the mucous but 8 hours in the lumen), and that their persistence is due to replication rather than uptake from the lumen.  How though, can E. coli thrive with their limited ability to break down mucins?  The scientists learned that they likely metabolize iron, in addition to atypical carbon sources such as fatty acids and glycerol.  B. theta, on the other hand, has a huge repertoire of genes to break down mucins.  They do, though, have the ability to leave the mucins and form biofilms on bits of food, such as fiber, that pass through the lumen, and this is one way they travel through the gut.  Regardless of whether they are in the lumen or the mucins they proliferate at the same rate.

Each of these bacteria occupy different niches in the gut, and each is important to our health.  The discovery that E. coli can use iron for metabolism is particularly interesting, as chemotrophy is not normally considered as important in the body, and may be important to iron regulation.  As more research is published the mucous appears to be ‘where the rubber meets the road’ in the microbiome, and new discoveries in this area will be crucial to our overall understanding of the microbiome’s interaction with the body.

Algorithms that can analyze the microbiome after diet induced changes

An increasing body of evidence supports that the gut microbiome composition can alter host metabolism, and eventually result in disease.  To date most of these studies have pointed to associations between the microbiota and host metabolism, but little has been able to demonstrate causal relationships between the two.  To address this, researchers from Sweden developed a specialized computational platform called CASINO (Community and System-level Interactive Optimization) to quantify the release and consumption of metabolites from gut microbiota, and pairing this data to dietary intake characteristics and patterns.  CASINO in a multidimensional platform, but ties both species richness/diversity to dietary intake in the gut microbiome.  The algorithms were optimized to distinguish bacteria that consumed carbohydrates/metabolites, and those that produce metabolites instead. 

In an in vitro validation test, the CASINO simulation was able to predict net production of metabolites produced by each community and was even able to distinguish between the syntheses of more essential amino acids as compared to non-essential amino acids.  In the past, researchers have been able to link two to three species to metabolic consumption rates.  Using CASINO, researchers in this study were able to write algorithms that could analyze at least five species.  The analysis quantified the contribution of individual bacteria to the overall microbiome, as it was shown that B. thetaiotaomicron, E. rectale, and F. prausnitzii dominated metabolism. 

CASINO was also used in a clinical experiment.  Data was examined from an experiment in which 45 overweight and obese individuals were given a restricted low-calorie diet for 6 weeks.  The simulation was able to characterize species diversity and composition.  After characterizing the species, CASINO was also used to simulate the effect of diet on the gut microbiome composition at baseline and after diet intervention in the test subjects.  CASINO algorithms were able to predict a decrease in carbohydrate consumption and increase in amino acid consumption (i.e. protein) by analysis of microbiota metabolites of the five select gut bacterial species. 

The CASINO algorithms examined most metabolic functions and allowed several species to be included in a simulation.  Furthermore, the authors propose that the program is scalable to include more than five species.  CASINO could pave the way toward development of quantification methods that could serve as a predictive interaction tool, especially in light of the importance of biomarkers in predicting disease onset.  We discussed biomarkers last week in our blog regarding renal disease, and these types of tools could provide exceptional value for clinical diagnostics.

Episode 5 of The Microbiome Podcast: Diet and its impact on our microbiota and health with Drs. Erica and Justin Sonnenburg

As we read on yesterday's blog post, dietary fibers alter the microbiome. On this week's episode of The Microbiome Podcast we talked in depth with Drs. Erica and Justin Sonnenburg from Stanford University about dietary fibers and their impact on our microbiota and our health.  Erica and Justin wrote a book that was published today called The Good Gut: Taking Control of Your Weight, Your Mood, and Your Long-term Health. You can buy it here on Amazon and it's a highly recommended read for anyone interested in the microbiome. 

Check out the newest episode on iTunes, Stitcher, or listen on our website. 

We will continue answering your questions on the podcast so please call 518-945-8583 with any questions for us or for next week's guest, Dr. Elaine Hsiao.

See below for more detailed show notes from today's episode: 

(1:17) Dr. Rob Knight received a Creative Promise in Biomedical Science Prize from the Vilcek Foundation. Read more.
(3:09) Rob Knight also published a book called Follow Your Gut: The Enormous Impact of Tiny Microbes. Click here to buy it on Amazon. 
(3:33) uBiome recently began a pregnancy microbiome study to better understand how the bacteria in our bodies change during and after pregnancy. Find out more on the uBiome website. 
(4:56) Microbiome Therapeutics performed a clinical study with an investigational drug in type 2 diabetics taking metformin and found that the drug resulted in more tolerability for patients and fewer side effects than metformin without the drug. Read more.  

In the (9:40) conversation with Erica and Justin Sonnenburg (read more about their research), we talked about several topics pertaining to diet and dietary fiber and its impact on our microbiota and health. We also discussed: 

(11:49) Why they decided to write the book.
(16:05) Their personal experiences having children and the importance of nurturing their health and its impact on their lives.
(17:55) Dietary fibers and differences among various types of fibers in our diets.
(26:15) How fast does diet change the microbiota?
(32:05) Bacteroides thetaiotaomicron and why it is Erica and Justin's favorite microbe and a study Justin published in 2005 while he was in Jeff Gordon's lab. Read the paper here.  
(37:35) How microbiome therapies are going to look in the future. 
(41:00) How eating better can make an impact now on our overall health. Read the seminal obesity and microbiome paper Erica mentions from the Gordon laboratory. 

We also answered two other (44:00) listener questions about phage therapy and organic vs. non-organic baby and adult foods. 

Next week we will be talking with Dr. Elaine Hsiao from Cal Tech so please call 518-945-8583 with your questions about autism and the microbiome as well as the microbiome's ability to regulate serotonin levels.