Antibiotics affect the mouth and gut differently

When we discuss antibiotic resistance, it’s not always clear where the resistance is developing or how exactly the resistance develops. A study out of the UK and Sweden looked at two niches, the gut and the mouth, to understand the difference between how the different parts of the body react to antibiotics.

The scientists discovered that these two parts of the body reacted and recovered very differently after a one-week course of antibiotics. They took fecal and saliva samples prior to the antibiotic regime and then gave the study participants a weeklong course of clindamycin, ciprofloxacin, minocycline, amoxicillin, or a placebo and continued taking fecal and saliva samples for a year.

They found that the oral microbiome recovered much faster than the gut microbiome back to its normal state. It took much longer for the gut microbiome to recover and for participants taking ciprofloxacin, diversity was changed even after 12 months. They also found that while participants largely had genes associated with antibiotic resistance in their gut prior to the trial, the amount of antibiotic resistant genes increased after taking the antibiotic. Antibiotic resistant genes in the mouth remained largely stable before and after treatment.  It was also observed that butyrate production, a health associated short-chain fatty acid, was severely affected by ciprofloxacin and clindamycin.

This raises a number of questions like why does the oral microbiome recover so much faster than the gut microbiome? And why isn’t there a similar increase in antibiotic resistant genes in the mouth like we see in the gut? While this study raises many questions, it provides an opportunity to look at the mouth and better understand what is unique about that environment in comparison to the gut. 

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.

Misconceptions about antibiotic use remain prevalent

While today’s post is not specifically about the microbiome, it is about a critical issue that we talk about all the time on this blog, the misuse of antibiotics in today’s society. A group of researchers compared the attitudes of parents with children on Mediciad managed care plans to those on commercial plans about the use of antibiotics and published their results in Pediatrics. They utilized insurance type as a proxy for sociodemographic factors as Medicaid is a government run insurance program for lower-income families.

The researchers surveyed approximately 1,500 families in Massachusetts with a child younger than 6 and asked them about the use of antibiotics for their children. Those insured by Medicaid answered more questions about antibiotics incorrectly than those with commercial plans. Another important finding was that those insured by Medicaid were more likely to request antibiotics be prescribed to their child unnecessarily.

The overuse of antibiotics in children can lead to significant health issues during childhood as well as later in life. Many studies, including many by Dr. Marty Blaser, have shown that antibiotic use has critical impacts on the microbiome with many downstream heath effects. Overusing antibiotics can also lead to antibiotic resistance, a rapidly growing public health concern.

A key takeaway from this study is that education by providers to parents about what antibiotics are useful and not useful for is critical. Pressure from parents of sick children will often lead to the unnecessary and ineffective prescription of antibiotics and it is important that these practices are ended. The authors of the paper state,“Tailored efforts for socioeconomically disadvantaged populations remain warranted to decrease parental drivers of unnecessary antibiotic prescribing.”

Significant bacterial diversity found in the microbiomes of remote Amerindians

A group of Yanomami people in Demini, Brazil © Fiona Watson/Survival

The Yanomami Indians are a native people that reside in remote areas of the Amazon jungle in South America, where they live in a society devoid of westernization and modernization.  They were first contacted in the 1960s, and the Venezuelan government has since preserved isolation among these societies by preventing modern development from expanding into their lands.  From an anthropologic perspective, these people therefore represent a glimpse into the past of a hunter-gatherer subsistence living human society.  Capitalizing on this unique characteristic, researchers from several institutions led by AMI Scientific Advisory Board member Maria Gloria Dominguez Bello, set out to investigate the human microbiomes of these remote communities in a twofold manner.  Bacterial diversity of the Yanomami microbiota was characterized, concomitant to exploring bacterial and gene responses to antibiotics commonly utilized in clinics in Western societies. 

Thirty four Yanomami subjects between 4 and 50 years old were selected for analysis.  Forearm skin, oral mucosa, and fecal samples were collected for bacterial analysis and compared to subjects from the U.S., Guahibo Amerindian, and Malawian tribes (the latter two were selected for comparison, as their cultures are in transition to modernization).  E. coli cultures were examined and genomic libraries were created for further analysis of bacterial expression, functional diversity, and resistome (the collection of antibiotic resistant genes) gene expression in response to antibiotic treatment. 

The Yanomami people displayed extraordinary levels of bacterial diversity as compared to the U.S. subjects, Guahibo Amerindians, and Malawians.  Specifically, the Yanomami fecal samples were characterized by high expression of Prevotella and low expression of Bacteroide bacteria.  With respect to functional bacterial diversity, the Yanomami displayed higher fecal and skin functional diversity among the other Amerindian and U.S. subjects.  Furthermore, over-enrichment in bacteria that interact with pathways involved with protein and carbohydrate metabolism was observed in the Yanomami. 

23 antibiotics were tested on 131 E. coli strains isolated from 11 fecal samples, and sensitivity to all antibiotics was observed.  Interestingly, functional libraries created from these E. coli isolates displayed antibiotic resistant genes targeted against 8 of the 23 antibiotics.  This suggests that antibiotic resistance genes have been maintained despite the lack of apparent antibiotic selection pressure that is characteristic among Western societies. 

Results from this study indicate a greater scope of bacterial diversity in a defined group of people than ever reported before.  Furthermore, the investigation illuminated an important characteristic of the bacterial resistome, as the results indicated that resistant genes were present in a population that had not been exposed to any Westernization.  This suggests that some antibiotic resistant genes are archaic, dating back to pre-westernization times and also that westernization affects microbiome diversity.  Ultimately, this study employed a fascinating approach to investigating human microbiome divergence and evolution, in addition to providing more insight to host-species relationships with respect to pharmacologic therapies.  

Antibiotic use in livestock is increasing and leading to greater antibiotic resistance

We’ve talked extensively about antibiotic resistance on the blog but we haven’t focused much on the impact that antibiotics given to livestock have on humans. Farmers give low doses of antibiotics to farm animals in order to not only prevent illnesses in their animals, but also to promote growth within their livestock. Animals being produced for food account for about 80% of antimicrobial use in the United States and bacteria in the animals become resistant to these antibiotics in the same fashion that they do in humans. As antibiotic use rises, more bacteria are becoming resistant and these bacteria are passed from animals to humans through the environment, consumption, and direct contact. An international research team from Europe, India, Africa, and the United States mapped the global consumption of antimicrobials in livestock.

The results were published in the Proceedings of the National Academies of Science (PNAS) and compared the use of antibiotics in livestock in 2010 to the projected use in 2030. The authors found that the global use of antibiotics in livestock will increase 67% in the 20 years between 2010 and 2030. This is largely a result of an increase in demand for meat by middle class individuals in countries like Brazil, Russia, India, China, and South Africa (BRICS). These BRICS countries have shifted their livestock production systems to be more cost-effective by increasing the use of antimicrobials to ensure the health of their animals and to promote growth.

This increase in antimicrobial use in animals is a compounded annual growth rate of 2.6% annual which is almost three times the annual growth rate of the human population (.98%) during the same time period. The authors found that in 2030, if new regulations are not put into place, approximately 30% of all antimicrobial use will be accounted for in the livestock industry in China.

Many countries, and specifically those in the developing world, do not regulate the use of antimicrobials in livestock production. While directly linking antibiotic use in animals to drug resistant infections in humans is very complex, it can be inferred that increase in antibiotic use leads to antibiotic resistant bacteria, and we have seen evidence of this in practice. In countries like India, where bacterial diseases are very prevalent and a major public health concern, antibiotics are a key factor in fighting these illnesses.  Increased resistance to bacteria by increased use of antibiotics in farm animals will only increasingly prevent the effectiveness of antibiotics in humans.  

The study authors call for global action to decrease the use of antibiotics used in animals that are raised for meat consumption. While the authors do state that this analysis was based on limited available data, largely in developed nations, the global trends of antibiotic use in livestock is concerning. 

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.