An evolutionarily more recent and much more damaging disruption of our microbiome emerged in the mid 1929’s when Alexander Fleming discovered penicillin [1] and antibiotics began to be used for human medicine. Antibiotics were and remain a miracle drug. Fewer people die now from secondary infections as complications from surgery or due to opportunistic bacterial pathogens. However, there is a cost for this miracle. The antibiotics most frequently used are broad-spectrum, which are indiscriminate killers of all things bacterial.

Alexander Fleming with his many petri dishes of microbial pals. By Calibuon at en.wikibooks, from Wikimedia Commons
Alexander Fleming with his many petri dishes of microbial pals. By Calibuon at en.wikibooks, from Wikimedia Commons

 Which one of these is not like the other?

Antibiotics take advantage of basic differences between humans (and other eukaryotes) and bacteria. Both eukaryotes and bacteria use proteins called ribosomes to make the mRNA for protein synthesis that they need for feeding, reproduction, and other basic, essential functions. However, the ribosomes are very different between eukaryotes and bacteria. So much so that antibiotics that target bacterial ribosomes can’t and don’t recognize the ribosomes of eukaryotes. So humans still have proteins made while the bacterial machinery is shut down. Aminoglycosides like streptomycin and gentamicin are examples of these antibiotics inhibiting protein synthesis.

Another antibiotic target is the bacterial cell wall. Peptidoglycans, a special set of sugars (carbohydrates), linked together form bacterial cell walls. Strands of peptidoglycans are bound together into a sheet by amino acids, the basic building blocks of proteins. The β lactam class of antibiotics, such as penicillins, stop glycosidic linkage formation. This effectively pokes holes in the bacterial wall and causing the cell components to ooze out. In contrast, the human, animal cells are surrounded by a lipid membrane instead of a cell wall and do not have these different linkages. So human cells remain intact.

Tsunamis, tornadoes, and hurricanes: microbial catastrophe

Although these amazing compounds can selectively kill bacteria and not animal cells, they kill all bacteria – the good, the bad, the ugly. Many studies show that taking antibiotics severely and significantly decreases people’s bacterial abundance and diversity [2-4]. This disruption can last for years after one full dose of antibiotics! Just think about what repeated doses with antibiotics of different actions or what happens in infants and young children. Like my garden last summer, when there is open habitat weeds can start growing. Those weedy bacterial species may not provide the same benefits as your native bacteria. They may not be able to digest the same foods or synthesize essential vitamins. Even worse, opportunistic pathogens, bacteria that can cause disease when given the chance, can colonize the disrupted ecosystem and open habitat. This is something that is seen often when people take antibiotics prior to major surgeries.

Though oral prophylactic antibiotics help prevent infections at surgery sites, a side effect is that they kill off members of the digestive system microbiome leaving open habitat. That’s where the trouble really starts! Antibiotic resistant bacteria living in the gut in low numbers and kept in check by the native microbiome now have the space and nutrients to grow. Additionally, any bacterium that can get into the gut and live there now has a chance.

Bad opportunities

Environmentally acquired bacteria can be another source of opportunistic pathogens. Bacteria are everywhere and honestly, trying to get rid of them is futile. See the fabulous work being done at the Microbiology of the Built Environment to understand more about the microbes inhabiting our buildings. Bacteria in the environment range from those that aren’t harmful to people, are helpful, and others that may cause disease. When our microbial ecosystems are intact, there’s no space for new colonizers. With disturbance, pathogens can enter.

 

Gram-positive C. difficile bacteria from a stool sample. From CDC: Janice Carr
Gram-positive C. difficile bacteria from a stool sample. From CDC: Janice Carr

One very nasty example of an opportunistic pathogen is Clostridium difficile, which caused almost half a million infections in 2011[5]. This bacterium forms spores that are dormant in the environment, but start growing in the gut. Some C. difficile produce toxins that kill cells of the digestive system, degrading the gut lining, allowing bacteria to enter the bloodstream, causing sepsis and death [6]. C. difficile also produces spores in the person, allowing reinfection after antibiotics kill active bacteria. C. difficile infection symptoms include severe and chronic diarrhea, as frequent as every 15 minutes, severe abdominal pain, loss of appetite, fever, blood in the stool, and weight loss [6, 7]. If concern about opportunistic pathogens isn’t enough – there’s other reasons to be concerned about antibiotics!

Resistance is not futile

A second issue with antibiotics is that some bacteria can become resistant to these miracle drugs by keeping the antibiotics out, changing the structure that the drugs target, pumping the antibiotics out before the cell is damaged, or degrading the antibiotic. Antibiotic resistant bacteria are increasingly becoming a problem in modern life for several reasons. Stay tuned for future posts on this issue and how pervasive and abundant antibiotics are in U.S. agriculture, toys, personal health care products, and more.

Your microbiome and You: To protect and to serve

You are an ecosystem – like clear cutting a forest, once the native organisms are removed, weedy and non-native organisms can colonize the new habitat. Additionally, components of the environment may not be maintained any longer if the organism they depend on is destroyed. In Alabama, many of our beautiful forests are clear-cut for timber or to build houses. Frequently, the rich top soil the trees held in place washes into nearby creeks and streams. The former forest floor has lost valuable nutrients and the stream is now muddy and has more nutrients disrupting the nutrient cycling of the aquatic ecosystem. Your body’s ecosystems may be similarly disrupted when some organisms are removed – at this point we really don’t know. We have been doing a grand experiment with too many variables and not enough controls. What we are seeing repeatedly is a correlation between low microbiome diversity and chronic conditions that are increasing. These include allergies, asthma, diabetes, autoimmune issues, autism, gastrointestinal diseases, and mental issues like depression and anxiety. Could disturbances in the ecosystem of the digestive tract lead to these conditions or is it just our better ability to screen for these diseases? It’s hard to know. Correlation does not equal causation. Just because we see lower bacterial diversity and these diseases does not mean that one makes the other one occur. However, it is a great place to start doing more testing and experiments with model animals. For now, feed your microbial friends well and try to keep your microbial ecosystem healthy and happy.

REFERENCES

 

  1. Fleming, A. 1929. On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzæ. British Journal of Experimental Pathology 10:226-236.
  2. Dethlefsen, L., and D. A. Relman. 2011. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 108 Suppl 1:4554-61.
  3. Dethlefsen, L., S. Huse, M. Sogin, and D. Relman. 2008. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 6:e280.
  4. Antunes, L. C. M., J. Han, R. B. R. Ferreira, P. Lolić, C. H. Borchers, and B. B. Finlay. 2011. Effect of antibiotic treatment on the intestinal metabolome. Antimicrobial Agents and Chemotherapy 55:1494-1503.
  5. Lessa, F. C., Y. Mu, W. M. Bamberg, Z. G. Beldavs, G. K. Dumyati, J. R. Dunn, M. M. Farley, S. M. Holzbauer, J. I. Meek, E. C. Phipps, et al. 2015. Burden of Clostridium difficile infection in the United States. New England Journal of Medicine 372:825-834.
  6. Martinez, F. J., D. A. Leffler, and C. P. Kelly. 2012. Clostridium difficile outbreaks: prevention and treatment strategies. Risk Management and Healthcare Policy 5:55-64.
  7. Khanna, S., and P. K. Tosh. 2014. A clinician’s primer on the role of the microbiome in human health and disease. Mayo Clinic Proceedings 89:107-114.

 

For an excellent YouTube video from TED-Ed: “Antibiotic resistance and the Microbiome

“Sometimes de escalation may work better than an evolutionary arms race”

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