Collateral damage: antibiotics disrupt the balance in the gut

Break submission by Katri Korpela, PhD student, Department of Bacteriology and Immunology, Immunobiology Research Program, University of Helsinki, Finland

Bacteria are present everywhere, also on our body surfaces. The intestine provides optimal living conditions to a diverse microbial ecosystem, termed the gut microbiota. In the intestine, the microbes live in very close connection and constant interaction with the host, us. The connection between bacteria and humans has a long evolutionary history and the microbes and their activities have become an integral part of how our bodies work. Microbial products act directly on the cells in the intestine, for example by providing energy to the cells lining the intestine and by stimulating the intestinal immune system. Many microbial products enter the bloodstream and influence different organ systems and tissues. It is becoming increasingly recognised that these microbes are part of us, and have a role in the maintenance of human health.

As we begin to understand that microbes living in our intestines can affect how our bodies work, it is becoming evident that disturbing the natural balance in their microbial community may have negative consequences on us. Antibiotics taken orally kill not only the pathogens that they are supposed to target, but also innocent bystanders in the intestine. Antibiotic use is known to change the composition of the gut bacterial community, killing susceptible organisms, and thus allowing resistant ones to bloom. Bacterial species differ in their ability to tolerate change, and often it is the potentially pathogenic species that have the ability to opportunistically repopulate a new ecological space when it becomes available; for example when antibiotics have reduced the number of normally dominant species. Antibiotics are among the most common prescription drugs given to children. It has been assumed that gut microbiota recovers within weeks or a few months after an antibiotic treatment. However, studies which used mice as model organism, suggest that early-life antibiotic treatments could have long-term effects on the host, showing in particular that antibiotic treatments in early life alter the microbiota in a way which predisposes the host to be overweight. Indeed, many studies in human children have shown that antibiotic use in early life is associated with increased weight (measured by the BMI) later in childhood. These observations led to the question of how the microbiota change in healthy children after antibiotic treatments.

To answer this question, we analysed the fecal bacterial composition in a group of 142 healthy daycare-attending 2-7 year olds in Finland. The bacterial composition was analysed using DNA-sequencing: we extracted DNA from the frozen fecal samples, and read the DNA sequence of a gene region that differs between bacterial species. The DNA sequences allowed us to identify which bacteria were in the fecal samples and how abundant they were. We collected antibiotic purchase information for the children from the national drug purchase registry, which allowed us link the composition of the microbiota to the children’s antibiotic use history.

We found that antibiotic use was the main factor affecting the children’s microbiota composition. Specifically, the time since the child had their last macrolide-antibiotic treatment was strongly associated with the composition and diversity of the microbiota: macrolide treatments appeared to cause a decline in gut bacterial diversity, and particularly a dramatic reduction in the abundance of one gorup, the bifidobacteria. Bifidobacteria are generally considered beneficial to the health of children and they may even protect against obesity. In general, the microbial changes that we observed after a macrolide treatment have all been previously associated with obesity or related disorders. The full recovery of the children’s gut microbiota was estimated to take up to two years after their last macrolide treatment. The associations between gut microbial diversity and the other common antibiotic types, penicillin or amoxicillin, were somewhat weaker and the recovery of the bacterial diversity slightly faster. All of these antibiotic types are often prescribed to treat the same infections, so the differences were not caused by different types of infections. These results suggest that antibiotics, and macrolides in particular, cause potentially obesity-promoting changes in children’s gut microbiota, which could explain why the use of these antibiotics in childhood is associated with an increased risk of being overweight.

EDITED BY:
Carlos Rivera-Rivera, Scientific Editor — TheScienceBreaker

ORIGINAL PAPER:
Korpela K, Salonen A, Virta L et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nature Communications. 2016;7:10410. doi:10.1038/ncomms10410.

Fighting back antibiotic resistance: a new hope from the soil

Break submission by Dan Kramer, PhD student in Molecular and Cellular Biology, University of Berkley, California

Bacteria live in a hectic world. They need to find food and a happy place to live all while dividing every 20 or so minutes. To complicate things further, they must also outcompete the other bacteria they share a space with. In the human gut, for example, there may be up to 1,000 different species of bacteria⁵. That’s a lot of competition! In order to outcompete each other for nutrients, some bacteria produce molecules that seek out and destroy other species of bacteria. This is one of the ways that antibiotics are created. Most of the antibiotics that humans use are derived from different bacterial strains, or other small organisms like fungi.

Because bacteria grow and divide very fast, they can quickly adapt to new surroundings. When we use an antibiotic to get rid of disease-causing bacteria, we eliminate all the bacteria in that colony that are susceptible to the antibiotic. However, there will be a small portion immune to the antibiotic that will survive and continue to grow. This leaves us with a new colony of the same disease-carrying bacteria that are now resistant to the antibiotic. Antibiotic resistance is a major issue^2,3 and doesn’t appear to be going away any time soon. This means we are in a constant need of new antibiotics.

To combat antibiotic resistance, scientists search for new bacteria that naturally produce antibiotics, as synthesizing new antibiotics from scratch is a costly and extremely difficult task. In order to find new antibiotics, researchers need to keep the bacteria growing in a lab, in a controlled environment, to test each for their ability to produce antibiotics. There is a problem with this, however – the majority (nearly 99%) of bacteria scientists find won’t grow successfully in the lab using the usual, artificial techniques¹. This leaves us with a small percentage of bacteria that we can successfully grow. But, we have been drawing from this well for so long that the pool of untested bacteria is rapidly shrinking.

To combat this, about 5 years ago, scientists developed a new technique that allows us to grow strains of bacteria that we were unable to culture before – expanding our pool of testable bacteria. The technique involves a tool named iChip that has thousands of tiny wells which allow researchers to cultivate individual colonies of rare bacteria directly in the soil they call home. In this way, they can grow up to 10,000 unique strains of bacteria in their natural environment. This was a breakthrough in our ability to grow bacteria in the lab. It increased the amount of bacteria that we could cultivate by about 50 fold.

Recently, a team of researchers used this technique to search for new antibiotics⁴. In a new strain of bacteria that couldn’t be grown before the iChip, they discovered a new antibiotic they named teixobactin. This drug has a unique mechanism, as it attacks a molecule that is vital for bacteria to build its membrane. The process that teixobactin disrupts is so basic and essential, it makes it nearly impossible for susceptible bacteria to mutate and develop a resistance. Their research showed that, compared to other popular antibiotics, bacteria aren’t developing a resistance. In an experiment where they measure the amount of antibiotic it takes to kill a colony of bacteria in successive generations (usually each successive generation will be more resistant), the same amount of antibiotic was as effective in the first generation as it was to the 25^th. This is amazing especially compared to other antibiotics that required 256 times the normal dose to kill the same amount of bacteria at the 25^th generation. They then tested teixobactin in several different disease models in mice, including pneumonia, to find it was more efficient in eradicating the disease-causing bacteria than other effective antibiotics. So, not only is this antibiotic difficult to build a resistance to, but it is also more efficient at eradicating bacteria. A real win win!

This discovery represents a major breakthrough in the field, and our lives in general. It shows that the iChip method is successful in growing difficult-to-culture strains of bacteria. It has vastly increased the pool of bacteria we can search through to find new antibiotics. This research also shows that some of the antibiotics we find could be extremely useful, with potentially new targets that make building a resistance nearly impossible. It may be too soon to tell, but hopefully these findings are just the prologue to many more future discoveries.

1. Lewis K. (2013), Nature Reviews Drug Discovery 12(5):371-387
2. http://www.who.int/mediacentre/factsheets/fs194/en/ (antibiotic resistance)
3. Spellberg B et al. (2014) Clin Pharmacol Ther. 96(2):151-153
4. Ling L. et al.  (2015) Nature 517(7535):455-459
5. Sears C. (2005) Anaerobe 11(5):247-251. doi:10.1016/j.anaerobe.2005.05.001.

EDITED BY:
Tobias Preuten, Managing Editor — TheScienceBreaker

ORIGINAL PAPER:
Ling L, Schneider T, Peoples A et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015;517(7535):455-459. doi:10.1038/nature14098.