The gut microbiome of a pre-Columbian Andean mummy looks much different than our own

A photo of the mummy whose microbiome was studied

The study of ancient humans’ microbiomes is a topic of growing interest, because it is believed that these microbiomes more closely resemble native or ‘natural’ microbiomes than the ones we have today.  There have been a few studies on humans’ microbiomes at different periods of history, and another data point was added to the list last week.  Researchers from Italy and California were able to measure the microbiome of a pre-Columbian human (11th century to be exact) that was mummified naturally after he died in the cold, harsh, and high elevations of the Andes Mountains in Chile.  The researchers published their findings in the journal PLoS ONE.

The researchers sequenced the bacteria that were in the mummy’s colon, as well as the mummy’s feces.  Strikingly, around 99% of the bacteria belonged to the Firmicutes genus, mainly dominated by Clostridia, and Turicibacter.  In addition, the human appeared to have many bacteria associated with modern day diseases.  For example the mummy’s microbiome contained Clostridium difficile (the cause of C. difficile infection), Trypansoma cruzi (the cause of Chagas’ disease), and many types of human papilloma virus (HPV).  Finally, the researchers noted that many genes associated with antibiotic resistance were found in the mummy’s microbiome, long before these antibiotics were introduced.

This paper revealed many fascinating aspects about our ancient microbiomes.  First, it is interesting to see that Firmicutes dominated our ancient flora, especially because Bacteroidetes, which are much more common in our guts today, are broadly associated with health.  Also, it appears that many of the pathogens that afflict all sorts of diseases today have prehistoric counterparts, and may have been more abundant, or even more tolerable long ago.  Finally, the revelation about antibiotic resistance genes show that the mutations that cause them appear common enough that they occurred naturally in thousand year old colons.

Microbiome Innovation: Roadmap to the Future – Report from the White House

Last week the American Microbiome Institute was invited to the White House to attend the Microbiome Innovation: Roadmap to the Future conference. The conference was hosted by the Office of Science and Technology Policy, which is embracing microbiome science and its promise to revolutionize various fields of research, such as health, medicine, agriculture, ecology, and more.  The purpose of the symposium was to bring together representatives from industry, academia, government, foundations, and non-profits in order to come to a consensus and identify the major roadblocks that are obstructing microbiome science, across all disciplines.

Various agencies from the federal government kicked off the conference by discussing how microbiome science was important to their departments, such as the NSF, USAID, and NIH.  These talks prompted a lively discussion regarding C. difficile treatment and fecal microbiota transplants, and how the FDA should regulate them.  After, working groups were formed to debate and discuss important issues to the field.  For example, groups were tasked with defining a healthy microbiome, but the consensus was that this was difficult because of its dependency on the host.  In addition, groups discussed ways in which interdisciplinary microbiome research could be encouraged.  Two approaches that were recommended to incentivize this were to require grants to include an interdisciplinary component, and to have academic promotion and tenure reward PIs that perform this type of research. 

We at the AMI would like to thank the folks at OSTP for inviting us to the conference.  We actively participated in the discussions to let people know the areas that we have identified as needs, and the things that we are trying to do at the AMI to solve them.  As a non-profit devoted to the microbiome we have a unique perspective on the field, and a mandate to advance it.  

Different diets can affect C. diff infection and survival

We’ve covered the topic of Clostridium difficile infection extensively on this blog. We know that infection of this bacteria (CDI) can be nasty, sometimes even leading to death. A lot of research has been done to find ways to treat the effects of C. diff infection or to find out how the infection is acquired, but few papers have investigated dietary interventions to help treat CDI.  A new study published by PLoS One examined this, studying how different diets, and specifically how protein content of those diets, affected the severity of CDI.

          7-8 week old male mice were weighed and separated into five groups, each given a different diet. One group was fed a protein-deficient 2% protein diet, and a counterpart group was fed a 20% protein diet. Another group was given a Research Diets regional basic malnutrition diet, while its counterpart was fed a matched control. A fifth group was fed a traditional (corn, wheat, soybean) diet, and acted as the positive control. Mice were fed the diets 12-14 days before being given antibiotics and then infected by C. difficile.  After infection, the mice were housed individually to prevent being affected by other mice. Stool and colon samples were collected from the mice up to two weeks after infection, and the bacterial content was sequenced.

Mice on the 20% protein diet showed delayed onset disease with a 25% survival rate over 2 weeks. Mice on the 2% diet also showed delayed disease onset and had a survival rate of 57.1% over two weeks. A significant statistically difference in survival and weigh loss was seen between the traditional diet and both the 20% and 2% diets, however the survival difference between the 20% and 2% groups was not significant.

In another part of the study done by the researchers, they chose to examine the presence of four gut microbiota groups ( Firmicutes, Bacteroides, Enterobacteriaceae, and total bacteria), after antibiotics or no antibiotics. All aspect of the experiment were the same except for this one factor. In mice not given antibiotics, the total number of bacteria was greater in the colon of mice given traditional diet. In mice given antibiotics, traditional diet-fed mice had lower levels of Bacteroidetes but higher levels of Firmicutes and Enterobacteriaceae. The most significant finding the researchers may have made however, is that traditional diet-fed and antibiotic given mice had the highest levels of C. difficile and therefore C. difficile toxins.

In the end, it can be assumed that diet does influence rates of C. diff infection. The presence of antibiotics also alters the bacterial compositions of the colon, with lower protein diets seeming to protect against or prevent full potential C. difficile infection.

Proton pump inhibitors increase risk of C. diff in children

Alka seltzer treats acid reflux without proton pump inhibitors

Acid reflux is a common problem among adults, and is often treated with acid suppression medication such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). Acid suppression medication is also given to children over long periods of time. While there is a recognized connection between proton pump inhibition in adults and Clostridium difficile infection (CDI), a link between the drug intake by children and CDI has not been studied. As we’ve discussed on the blog before, infection by the bacteria C. difficile can cause serious harm to the intestinal tract and immune system. An article published by Clinical Infectious Diseases looks further into the relationship between acid suppression and CDI in children.

          Researchers at Columbia University Medical Center conducted a study using data from the Health Improvement Network, a medical records database. Data from 1995 to 2014 was used, and subjects were selected if they were aged 0-17 at the time of CDI diagnosis. The patients also needed the following requirements:  3 follow-up visits for patients younger than 1 year, and  1 follow-up visit for patients older than 1 year. Children with prior chronic conditions that may be linked to long-term acid suppression, such as neurological disorders and chronic gastrointestinal mucosal diseases, were excluded.

In the end, 650 cases were selected, with 68 of them being infants younger than 1 year. 3200 control cases were selected as well. After statistical analysis, it was found that there was no significant evidence of  age (1 year or 1-17 years) having an effect on the acid suppression-CDI relationship. It was found that the use of stronger proton pump inhibitors, rather than less-strong H2RAs, causes a significantly increased risk for CDI. Additionally, when the acid suppressant was used more recently (8-90 days) than distantly, the likely-hood of CDI was increased.

The researchers point out a potential error diagnosing CDI that could be causing the increase in children with the disease. In children, they say, symptoms of acid-related disorders may be very nonspecific, such as abdominal pain. Physicians then treat this with acid suppression medications, which, as discussed above, would then increase possibility of C. difficile colonization and growth.  However, the original abdominal pains may actually be symptoms of CDI. As a result, treating the CDI with acid suppressants is worsening the infection. With this new research, physicians might want to reconsider their options before treating what they think is an acid-related issue. 

New info on fecal microbiota transplants for C. difficile and ulcerative colitis

"Fecal bacterial communities of recurrent [C. diff]  patients shift towards [healthy] fecal bacterial communities after FMT. Pre-FMT patient samples (red circle); post-FMT patient samples (green circles); trajectory of patient fecal communities after FMT (blue line)."
Image and caption from the C. diff paper: Weingarden et al. Microbiome 2015 3:10   doi:10.1186/s40168-015-0070-0

Two important papers regarding fecal microbiota transplants (FMTs) were published last week.  The first was an examination of a patient’s microbiome over time after he or she undergoes an FMT to treat C. difficile.  The second showed the results of clinical trials that used FMTs in an attempt to treat ulcerative colitis.   The FMT papers, which are described below, improve our understanding of this procedure, which holds promise to treat various microbiome-based diseases.

The C. diff paper, published in the journal Microbiome, attempted to answer the question: Do the microbiome changes that occur after FMT remain long after the procedure?  We know that FMTs are highly effective in treating C. diff because they install a healthy microbiome that can crowd out the infection.  However, it is unknown if these new bugs that take hold are transient, or if they become permanent members of the gut.  The researchers sampled the microbiomes of FMT donors and recipient patients before and up to 84 days after an FMT procedure to treat C. diff.  They discovered that the recipients’ dysbiotic microbiomes stabilized quickly, and after just one day they closely resembled the donors’ microbiomes.  Continued measurements showed that the microbiomes deviated over the next few weeks, but that they remained healthy.

The colitis clinical trial, published in the journal Gastroenterology, attempted to discover if FMTs could treat ulcerative colitis.  Ulcerative colitis is widely considered to somehow be related to a dysbiosis in the microbiome, so can FMTs from healthy donors treat this disease?  The study was a double blind randomized clinical in which 48 people suffering from ulcerative colitis either received stool from healthy donors (treatment) or just an FMT of their own stool (control).  7/23 patients who received stool from a healthy donor were in remission after 12 weeks, while 5/25 patients who received their own stool were in remission at that time.  Unfortunately, this is not a clinically significant result based on the number of patients involved.  The researchers measured the bacterial abundance in all of the patients microbiomes before and after treatment.  Before treatment the microbiomes all had some baseline similarity.  After treatment, though, the patients who responded to treatment from a healthy donor all had an increase in certain Clostridia, and the patients who responded to treatment from their own stool all had in increase in certain Bacilli, Proteobacteria and Bacteriodetes.  The researchers feel that this information warrants further study.

FMTs are an exciting new therapy that may be important in treating some really nasty diseases.  We do want to remind people, though, that it is still an unproven technique that should only be performed under the guidance of a doctor.  As we have written about before, the promise of the microbiome is what makes FMTs both attractive, but potentially dangerous at the same time.

Antibiotic resistant bacteria at UCLA and how the microbiome can prevent similar infections

Endoscopes (the instrument that resulted in infections at UCLA) in sterilization equipment

Over the past few weeks at Ronald Reagan UCLA Medical Center in Los Angeles, California, 179 patients were exposed to Carbapenem-resistant enterobacteriaceae or CRE, resulting in seven patients being infected and two deaths.  This is a lethal bacterium that is very resistant to antibiotics and has resulted in significant discussion in the press. Hospital patients with compromised immune systems are susceptible to infections passed on from other patients and hospital equipment and in the current case of CRE at UCLA, a contaminated endoscope.

Another prominent cause of infection is the bacteria enterococci, specifically vancomycin-resistant enterococci (VRE), which, as the name states, are resistant to the antibiotic vancomycin. In healthy individuals, the bacteria are not a threat and are usually killed by the immune system. In cancer patients, the elderly, transplant recipients, and other patients on antibiotics, the weakened immune system and microbiome colonization cannot fight the colonization of VRE in the gut. The result is an infection of the intestines, and possibly of the urinary tract, blood stream, and heart.

In an article published in FEMS Microbiology Letters in early February, the authors summarize research that is being done to overcome the issue of VRE infection. Infection by enterococci often occurs in patients who have taken antibiotics that deplete beneficial bacteria in the gut. One possible fix for this problem could be the administration of probiotics, live microorganisms that provide a health benefit. Unfortunately, limited research has been done in this area. In one inconclusive study, Lactobacillus rhamnosus appeared to eliminate or at least decrease the presence of VRE in the gut. Other studies suggest that it is easier to prevent infection of, rather than eradicate already present VRE.  

Another area of investigation is the use of commensal bacteria to prevent infection, or the administration of normal gut-colonizing bacteria. A popular topic in microbiome research, and one that often, and recently, appears on our blog is the treatment of infection of Clostridium difficile. One method of treatment that we frequently discuss is fecal microbiota transplant (FMT). The authors of this article suggest the use of FMTs may be able to be applied for the treatment of enterococci infection. 

Many hospital patients get sick from infections passed within the hospital, as their compromised immune systems cannot stave off infection. Hospitals are supposed be a place for getting healthier, yet we know that hospital-acquired infections are a major issue in today’s hospital systems as we have seen over the past few weeks at UCLA. New strategies for overcoming these issues are being pursued and are very important for the prevention of deaths resulting in bacterial infections passed within hospitals.