Treating C. difficile without antibiotics

Scanning electron micgrograph of individual C. difficile bacilli cultured from a stool sample of an infected individual.

I recently had the pleasure of hearing a talk by Professor Xinhua Chen from the Beth Israel Deaconess Medical Center about various ways to treat C. difficile infections without antibiotics.  As we know, antibiotics are often successful in treating C. diff infections. However, 30% of all treated infections result in a relapse, likely due to the fact that these antibiotics kill commensal  bacteria which are needed to keep C. diff populations low.  In addition, Dr. Chen discussed how other bacteria can act as a 'sink' for the C. diff. toxins, which, when they bind to other bacteria, do not harm humans.  Therefore Dr. Chen is investigating methods that can prevent acute infection to buy time for commensal bacteria to reestablish themselves in the host.

Host inflammatory response is often the danger in C. Diff infections, and his lab has shown two drugs that help mitigate this response.  The first is a molecule called vascular endothelial growth factor (VEGF) that prevents the toxins from entering the vasculature, which is a cause of inflammation.  The second is by increasing the amount of lipotechoic acid (LTA) in the gut.  LTA is a major component of gram-positive bacteria that can bind to the toxins, much like commensal bacteria can, to prevent infection.  

In addition, Dr. Chen discussed an experiment based on fecal microbiota transfers (FMT).  His group bought two groups of mice, one which had high gut microbiome diversity and one with low gut microbiome diversity.  The mice with high microbiome diversity survived C. Diff infections while those with low microbiome diversity were killed by C. Diff.  When these mice were co-housed their microbiome diversity converged to a diversity that was somewhere between the two.  These mice all died with C. Diff. infection.  Dr. Chen though, was able to isolate one bacteria from the mice with high microbiome diversity, that when given to the mice with low microbiome diversity prevented C. Diff. infection.  His studies are still underway.

On a final note, Dr. Chen was against FMTs.  He thought there was too much 'hype' surrounding them, and that clinicians 'need to be cautious'.  He also discussed the work of Seres Health that has made an oral microbiome drug for C. Diff that includes only spore forming bacteria.   Some of the work came from a PLoS ONE article authored by Chen, but most of what he discussed has yet to be published.

Microbiome and breast cancer

A recent study out of the University of Maryland suggests that post-menopausal women with a more diverse microbiome have a lower risk of getting breast cancer.  The study investigated the fecal microbiomes of 60 healthy women between the ages of 55 and 69 while also testing the estrogen and estrogen metabolites from their urine.  The results showed a correlation between increased urinary metabolites with increased gut microbiome diversity, independent of other variables.

This is important because estrogen that circulates through the body, that isn't broken down and removed by the body, is correlated with an increased risk for breast cancer.  Therefore, decreasing the amount of circulating estrogen, and increasing the rate at which estrogen is removed from the body may result in a lower risk of breast cancer for post-menopausal women.

It is known that as estrogen and its byproducts are naturally processed, they are circulated in and around the gut, which has led scientists to speculate that the gut microbiome may be important to estrogen cycling and removal in the body.  The authors of this paper help support this hypothesis by showing that microbiome diversity effects estrogen removal.

This paper opens the door to some very interesting questions.  Can microbiome diversity be used as a diagnostic for breast cancer risk?  Can the gut microbiome be adjusted to decrease breast cancer risk?  A nice summary of the findings with quotes from the authors was also published by Science Daily.

Microbiome possibly a rich source of new drugs

antibiotic inhibiting growth of S. Aureus.

There has been a bit of popular press recently about an article published in Cell by a group of scientists at UCSF.  The research team that published this article had previously developed an algorithm to look at microbial genetic data and identify genes that were coding for natural products (small molecules that have some, usually unknown, purpose).  Natural products are generally produced in low amounts, or only produced under certain conditions, so they are difficult to discover and isolate.  Throughout pharmaceutical industry history, natural products have been a great source for antibiotic and other pharmaceutical development, because several of their functions mediate microbe to microbe interactions.

When the researchers tested the microbiome genes in the Human Microbiome Project's database using this algorithm, they discovered tens of thousands of new, natural products, including over 3000 that are found in the average individual's microbiome.  Of these 3000 they even found a vaginal microbe from a bacteria, Lactobacillus gasseri, that created a molecule that was similar to an antibiotic that is currently in clinical trials.  When the molecule's antibiotic efficacy was tested in the laboratory, the scientists discovered that it was a potent antibiotic towards common gram-positive pathogens.

The microbiome is an extraordinarily complex system which is one of the primary reasons it has taken so long to properly investigate.  This complexity however, could lead to a gold mine of new compounds and molecules to discover, especially in a system where competition, cooperation, and communication between bugs is so high.  Based on this research, I don't think it will be long before a molecule originally discovered in the microbiome is commercialized.

Are artificial sweeteners hurting our ability to regulate blood sugar levels? Let's ask our microbiome

What if artificial sweeteners and sugar-free snacks and drinks are actually causing our bodies to lose control of the ability to regulate blood sugar levels? What if these sweeteners are a part of the cause of our societal obesity epidemic and not part of the solution?

That is exactly what is being suggested in a landmark study published yesterday in Nature. Researchers at the Weizmann Institute in Israel demonstrated that giving mice water laced with the chemicals in Sweet’N Low, Splenda, or Equal caused the mice to become glucose intolerant, resulting in the inability to metabolize sugars, due to alterations to the gut microbiomes.

People often consume these sweeteners with the rationale that the fewer calories consumed, the more successful they will be in losing weight. This study has shown that these chemicals may be doing more harm than good by altering the composition of our microbiomes.

After the mice receiving artificial sweeteners became glucose intolerant, which is often seen as a precursor to adult onset diabetes and obesity among other metabolic diseases, the researchers treated the mice with antibiotics to eliminate their gut bacteria.  The scientists found that with antibiotic treatment, the glucose intolerance was reversed showing the sweeteners caused the glucose intolerance. The researchers went one step further and transplanted bacteria from the mice treated with sweeteners into germ-free mice. Shortly after receiving the bacteria, the previously healthy mice became glucose intolerant, again telling us that the gut bacteria caused the glucose intolerance. 

As this work was done in mice, the team of scientists conducted a smaller study with human subjects to learn whether if the mouse studies would translate to humans.  Seven individuals who did not usually consume artificially sweetened food and drinks were given a week-long diet consisting of high levels of artificial sweeteners.  In that short amount of time, four of the seven individuals began to develop glucose intolerance. They then took fecal samples from the four individuals whose blood sugar levels were disrupted and put them into healthy mice. The healthy mice after receiving the human's gut bacteria also became glucose intolerant. 

While the sample size of the human experiment was small, the overall study is quite compelling and demonstrates the important impact that diet has on our microbiome. This is not a call for the general public to stop using artificial sweeteners as further research needs to be conducted.

With that said, it will be very interesting to see how the general public reacts to this paper.  Numerous studies have shown correlations between the microbiome and disease, but few studies have shown how such a small change in one's dietary habits could potentially have a major impact on an individual's future health outcomes. This is a story that we look forward to reading more about. 

Type 2 diabetes and the microbiome. iHMP blog #4

Universal symbol for diabetes

Nearly 10% of individuals in the United States suffer from type 2 diabetes, and the associated costs are hundreds of billions of dollars.  Several studies have correlated microbiome alterations with the presence of diabetes, and studies in mice have shown that changes in the microbiome can lower glucose levels, putting the mice at risk for diabetes.  The iHMP plans on studying diabetes and its associations with the microbiome through a longitudinal study. 

Specifically the iHMP will be testing the following hypotheses:
1) "Environmental stress causes dynamic changes in specific biological pathways in the human body, and these changes lead to alteration of the human microbiome...including glucose."
2) "Some of the changes may affect the [hosts' gene regulation] leading to...biological alteraions that extend well beyond the time of the stress period"
3) "Different physiological stresses, such as respiratory viral infections and diet changes, may have common effects in both the host and microbiome"
Source

The iHMP will investigate these hypotheses by enrolling a cohort of 60 adults at risk for diabetes.  The study will last 3 years and during these years the researchers expect at least 10 individuals to become diabetic.  They will sample the patients' stool, nasal, urine, skin, tongue, and blood microbiomes every 2-3 months, which will measure a full suite of biologics that include bacteria, lipid content, metabolites, and proteins.  Sampling will also occur during periods of 'stress' that include mental stress as well as illnesses and physical trauma.

As always the results of the study will be made available, and we will be checking in on their progress.

This blog post concludes our series on the iHMP (HMP2).  We hope that anyone reading this will continue to check in on the iHMP progress, as we hope the role of the microbiome in pregnancy, IBD, and diabetes continues to unfold. 

Inflammatory bowel disease (IBD) and the microbiome. iHMP blog #3

Micrograph of inflammation of the large intestine with IBD

Inflammatory bowel disease (IBD) encompasses a group of diseases that include Crohn's disease and ulcerative colitis, among others.  Thus far, IBD has proven to be a very complex disease, with no straight-forward microbial causes.  Instead, it has been linked to the overall health of the microbiome, which includes disproportionate populations of healthy and unhealthy associated bacteria and their metabolites.

The iHMP is tackling the connection between IBD and the microbiome through a longitudinal IBD study.  The study will recruit 90 patients who are: adults recently diagnosed with IBD, children recently diagnosed with IBD, people with established cases of IBD, and people with no IBD who will serve as controls.  Each person in the study will sample his/her own stool once every 2 weeks for 1 year. The stool will be sampled for its entire microbial community, including bacteria and viruses, as well as proteins, and metabolites.  In addition, biopsies will be performed on the patients' guts periodically over the year.  Finally, blood samples will also be taken.

The overall goal of the study is threefold:
1) "identifying the molecular mechanisms by which the intestinal microbiome may trigger...IBD"
2) "determining if microbial composition predicts subsequent risk of flareups in [IBD]"
3) "testing whether successful response to therapy can be predicted from the stool microbiota"
(source)

This study will be completed within the year and all the data will be made available at ibdmdb.org.  Check back with this blog throughout the year for updates.

I also want to draw attention to the great work being supported by the Crohn's and Colitis Foundation of America's (CCFA) microbiome initiative.  The CCFA is entering the later stages of their own research projects and I encourage any interested people to check out the CCFA website.