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Do antibiotics ‘wipe out’ your gut bacteria?

By Dr. Karen Scott, University of Aberdeen, UK

Antibiotics have been an important tool in medicine to kill pathogenic bacteria and treat infectious diseases for many decades. But for most of those decades, scientists had limited awareness of the community of ‘good’ microbes that reside in our guts and other parts of the body. Now that we have ample evidence of the beneficial functions of these abundant resident microbial communities, we need to be aware of the potential impact antibiotics may have on them – and whether antibiotics might wipe them out, creating a different health problem.

Antibiotics act against basic cellular functions of microbes – targeting cell wall synthesis, DNA/RNA synthesis, protein synthesis and folate synthesis. In order to avoid the effects of the antibiotics, bacteria can either alter their own target molecule so that the antibiotic is ineffective, actively pump the antibiotic out of the cell, or inactivate the antibiotic. With bacteria constantly trying to survive in the face of antibiotics, we are in a continuous race to ensure that the disease-causing bacteria we are trying to eliminate remain susceptible to the antibiotics used to treat them.

The action of antibiotics against bacteria can be classified according to:

  • Bacteriostatic (inhibiting growth of the target microorganism) vs. bactericidal (killing cells)
  • Narrow spectrum (acting against a few specific bacteria) vs. broad spectrum (acting indiscriminately against many bacteria).

Clearly an ‘ideal’ antibiotic would be narrow spectrum and bactericidal, rapidly killing only the target bacteria. In contrast a broad spectrum, bacteriostatic antibiotic may only inhibit growth of the target bacterium and at the same time may be bactericidal to others.

And here we come to the basic problem of antibiotic use in general medicine. When a patient attends the doctor’s office with a complaint such as a sore throat or an ear infection, most likely due to a viral infection, the doctor has a few choices:

  1. The doctor can inform the patient that antibiotics would be ineffective, and that the infection will go away by itself in a few days, and that the patient go home, rest and take other remedies to target symptoms such as pain, fever, or congestion in the meantime.
  2. The doctor can succumb to pressure from the patient demanding a prescription ‘remedy’ and prescribe an unnecessary and useless course of antibiotics. While this was common in the past, in many countries doctors now stand firm, maintaining antibiotics would be ineffective and are not required.
  3. The doctor can offer a delayed antibiotic prescription – sending the patient away with a prescription but advising the patient to wait for a couple of days to see if symptoms resolve before deciding if the prescription is required. This approach is becoming more common and does reduce unnecessary antibiotic use.
  4. Finally, the doctor can determine that even if the original illness was caused by a virus, there is now a secondary bacterial infection and that a course of antibiotics is now required. The problem here is that without a laboratory test the doctor cannot be sure which bacterium is causing the disease so in order to be sure that the antibiotic will be effective, a broad spectrum antibiotic is often prescribed.

Any antibiotic prescription that the patient collects from the chemist (pharmacist) and starts taking, immediately causes collateral damage to their own resident microbiota. It is now well-established that a short course of antibiotics disrupts the gut bacterial community, killing many important resident bacteria. This can be observed by a reduction in diversity (see articles here and here, and figure here), meaning that fewer different bacterial groups can be detected. Normally once the patient stops taking the antibiotic the diversity of the community increases within a month, almost returning to the starting composition. Almost. Some bacterial species are particularly sensitive to certain antibiotics and may never recover. Oxalobacter formigenes, the bacterium that protects against kidney stone formation, is one example.

The other hidden effect of antibiotic treatment is that although all members of the microbial community may re-establish, they may not be the same as before. The levels of antibiotic resistance amongst bacteria isolated from samples from patients after seven days of antibiotic treatment were much higher than those from controls without any treatment, even four years later (see here). The selection pressure exerted on bacteria during short courses of antibiotic treatment results in transfer of antibiotic resistance genes, and the spread of resistance to many other members of the microbial community, increasing the overall resistance profile. Whilst this may not be immediately damaging to the health of the person, this change in baseline resistance does mean that a subsequent course of antibiotic treatment could be less successful because more bacteria will be able to withstand being affected by the antibiotic, and more bacteria will contain resistance genes that could be transferred to disease-causing bacterium.

Historically, as soon as we started using purified antimicrobials therapeutically, we started seeing rise of resistance to those antibiotics. The first recognised tetracycline resistance gene, otrA, was identified in Streptomyces, a genus of Gram-positive bacteria now known to produce many antimicrobial agents as secondary metabolites (see figure here).

The indiscriminate effects of antibiotics can be even more severe in hospitalised patients. Recurring Clostridioides difficile-associated diarrhoea (CDAD) is a direct consequence of antibiotic treatment. The microbial diversity decreases in patients receiving antibiotics for legitimate therapeutic reasons, and the Clostridioides difficile population expands to occupy empty niches. Overgrowth of C. difficile results in toxin production, abdominal pain, fever and ultimately CDAD. Treatment is difficult because some C. difficile strains are antibiotic resistant and C. difficile forms non-growing spores that persist during the antibiotic treatment. This means that even if the initial infection is successfully treated, once the antibiotic treatment ceases the spores can germinate and cause recurring C. difficile infections. Although initial treatment with antibiotics works for 75% of patients, the remaining 25% end up with recurring CDAD infections. A more effective treatment may be faecal microbial transplant (FMT) therapy (see blog post here).

Scientists have spent the last 20 years investigating the many ‘good microbes’ that inhabit our intestinal tracts leading to a much greater understanding of what they do, and the potential repercussions when we destroy them. This means we are now very aware of the collateral damage a course of antibiotics can have. A new era of developing the ‘good microbes’ themselves as therapeutic agents, using them to treat disease, or to recolonise damaged intestinal ecosystems, beckons. New drugs may take the form of next generation probiotics or whole microbial community faecal transplants, or even postbiotics, but the common feature is that they are derived from the abundance of our important natural gut inhabitants.

 

ISAPP board members look back in time to respond to Benjamin Franklin’s suggestion on how to improve “natural discharges of wind from our bodies”

Benjamin Franklin, born in 1706, was a multi-talented politician and scientist best known for his discoveries related to electricity. Historians say he was scientifically pragmatic—aiming not just to advance theories, but to solve the most vexing problems of the day.

In 1780, when Franklin read about the intellectual contests being held by The Royal Academy of Brussels (today known as the Royal Flemish Academy of Belgium for Science and the Arts – KVAB), he took it upon himself to write an amusing letter that contained a suggestion for an important scientific challenge: “To discover some Drug wholesome & not disagreable, to be mix’d with our common Food, or Sauces, that shall render the natural Discharges of Wind from our Bodies, not only inoffensive, but agreable as Perfumes.”

Over two centuries later, the organization was prompted for a reply. Writer Brian Van Hooker wrote to the KVAB: ‘I am a writer at MEL Magazine and I am working on a piece about a letter that Benjamin Franklin sent to your organization’s predecessor, the Royal Academy of Brussels, 240 years ago. The letter was entitled “Fart Proudly,” and I’m reaching out to see if anyone at your organization might like to issue a reply to Mr. Franklin’s letter’.

Since ISAPP board member Prof. Sarah Lebeer (University of Antwerp, Belgium) is a KVAB Belgian Young Academy alumna with microbiome knowledge, Bert Seghers from the Academy asked her to help draft a reply. However, since the gut microbiome is not her main area of expertise, she consulted her fellow ISAPP board members. For example, Bob Hutkins, author of a popular ISAPP blog post on intestinal gas, immediately sent her a paper entitled Identification of gases responsible for the odour of human flatus and evaluation of a device purported to reduce this odour with the comment: “The next time a graduate student complains about their project, refer them to this paper and the 5th paragraph of the methods”—a paragraph that describes how scientists in the experiment were tasked with rating the odor of flatus and differentiating between the different smells of sulphur-containing gases.

But it was the answer of Prof. Glenn Gibson (University of Reading, UK) that was incorporated into the ‘formal’ reply to Franklin’s suggestion. “Your suggested topic on improving flatulence odour is amusing, but indeed also very relevant. An outstanding answer to the contest as you formulate it would be ground-breaking,” wrote Profs. Lebeer and Gibson. They noted that gases in the intestine are mainly released by the bacteria living there—but especially the sulphate reducing bacteria contribute to the “traditional” smell due to their production of noxious H2S —and that advances in probiotic and prebiotic science could one day lead to reduced (and “nicer smelling”) gas production by switching hydrogen gas production to methane or even acetate and away from H2S.

Brian Van Hooker summarized: “In other words, Mr. Franklin, they’re working on it and, perhaps sometime within the next 240 years, your dream of non-smelly farts might just come true.”

The KVAB response to Benjamin Franklin concluded: “Your letter is a ripple through time. It may not surprise you that scientific questions can have effects across decades and even centuries. This idea remains the tacit hope of many scientists working together for the progress of humanity. We have not yet invented a reverse time machine, but we send our answer along with your question forward in time, hoping that it may inspire future scientists as your question inspired us.”

Read the MEL Magazine article here.

Read more about gut microbiota & intestinal gas here.

stool sample for lab

Microbiome Analysis – Hype or Helpful?

September 2017. By Karen Scott, PhD, Rowett Institute, University of Aberdeen, Scotland.

Since we have realized that we carry around more microbial than human cells, and that these microbial inhabitants are important to maintain our health, searching for the bacterial species that are implicated in causing disease has become the holy grail of microbiology. However, to understand which bacteria are unnaturally present or absent in a disease state, we first have to understand what constitutes normal. This is hampered by the fact that we are all different – and our microbial communities are also all different. In fact, the faecal bacterial community in samples taken months apart from one person will be identifiable as coming from that specific healthy adult, but the community will be quite distinct from samples from any other healthy adult. In the same way, the microbial community of two individuals suffering from the same disease will be different.

Despite these differences, scientists have managed to establish some facts over the past 15 years. Too many Proteobacteria, which includes Enterobacteria and E.coli, in your large intestine is not generally good news. Firstly, it means that conditions in the large intestine are probably not as anaerobic as they should be. Secondly, an expansion in these populations usually means a decline in something else – after all food and places to live are finite resources. Bacterial diversity in the adult intestine is also important. The main factor that has been found across many different diseases is that bacterial diversity is lower in diseased individuals than their healthy counterparts. This does not necessarily mean that a low diversity is causing the disease, as various features of the disease (including any antibiotic therapy, inflammation, decreased or increased transit time) may all themselves affect the diversity of the microbiota.

Although scientists have not succeeded in defining a ‘healthy microbiota,’ there is an increasing trend to get your microbiome tested. Entrepreneurial microbiome companies are bombarding us with offers to “send in a small sample and find out about your gut microbiota”. All of course, for a ‘reasonable’ price. So, should you?

This really depends why you want to know, and what level of detail of analysis is being offered. Remember the orders of taxonomy? Kingdom, phylum, class, order, family, genus, and species.  Some companies identify the bacteria in your faeces only to the phylum level. This is a taxonomic level above the level needed to differentiate mammals and fish (these are ‘classes’). If you told someone that there were more fish in the Indian Ocean than mammals would this be a surprise? It would be such an expected fact it would be meaningless. This is similar to describing the microbiota at a phylum level – Bacteroidetes numbers versus Firmicutes numbers. Such numbers are meaningless. However, continuing the fish analogy, if you said that there were more mackerel than tuna in the North Atlantic Ocean this becomes a bit more meaningful. The fisherman immediately knows what type of fish he is more likely to catch, and perhaps even which net to use. The same is true of the microbiome. Telling someone that he/she has a lot of Enterobacteria and few Roseburia is actually useful as we know from studies that this represents an abnormal balance of bacteria and something should be done to redress this. Yet the bottom line health consequence of this abnormal balance of bacteria remains to be determined. So getting your gut microbiome sequenced could be useful – depending on what level of information you will receive, and what you are prepared to do about it.

And so we come to the next problem. Having established what your gut microbiota is, how are you going to make it better? And will that make YOU better? At the moment scientists don’t really have a good answer to these questions. Specific prebiotics can certainly be useful to increase the numbers of some bacteria generally assumed to be beneficial – such as Bifidobacterium, Faecalibacterium prausnitzii and even Roseburia species. But it is not really clear what the exact health benefits of such an increase in bacterial numbers would be. Health claims on prebiotics are currently limited to ‘improve intestinal transit’ and ‘lower the glycaemic response’. If you found out that your microbiota had a low diversity, increasing the variety of foods in your diet, in particular the fibre component, could certainly improve this. Our gut microbiota basically relies on our undigested food to survive, so providing a greater amount and more types of food containing fibre and prebiotics will definitely encourage populations of diverse bacteria to expand. In addition to improving digestive health, fibre fermentation by gut bacteria also results in the production of microbial products that have been shown to have health benefits.

So by all means get your gut microbiome analyzed if you want to, but perhaps instead, save your money and just increase your prebiotic and fibre consumption, which will increase levels of the potentially beneficial bacteria that are already there in your gut.