Alexander Fleming could not have imagined that his discovery of penicillin in 1928 would create the basis for the “antibiotics revolution.”
Though antibiotics saved millions of lives by killing pathogens, new research shows their antibacterial effects also impact beneficial bacteria inhabiting our guts.
With the advent of 16S RNA sequencing technology, the world of microbes is being unraveled in a form without precedents. This knowledge led us into the "microbiome revolution."
Paramount research is deciphering so many different areas of the microbiome and its relationship with antibiotics. For instance, their association with each other, the effects of antibiotics on gut microbes, how their association influences diseases, and some antibiotic alternatives.
Group of antibiotics and their effects on gut microbiota
Consequences of antibiotic abuse
Alternatives to the antibiotic use
Group of antibiotics and their effects on gut microbiota
Thanks to 16S rRNA sequencing technology, where the 16S gene is widely conserved among the bacterial taxa and thus is easy to identify bacteria, it is clear that broad-spectrum antibiotics affect both harmful bacteria and beneficial bacteria.
Depending on the antibiotic group, action mode, dosage, and the route of administration, antibiotics may influence the composition and dynamics of the gut microbiota.
We could classify the antibiotics into five groups: lincosamides, macrolides, β-Lactams, fluoroquinolones, and glycopeptides.
Each group has different effects on the gut microbiome.
Figure 1. Clindamycin structure showing the basic backbones in color of lincosamides.
Lincosamides are antibiotics composed of a pyrrolidine ring linked to a pyranose moiety (figure 1).
Lincomycin, clindamycin, and pirlimycin are all lincosamide antibiotics.
These antibiotics are bacteriostatic, meaning they stop bacterial growth but do not kill the bacteria. Growth is stopped by interference with the protein synthesis in the bacteria. They are used to treat various bacterial infections such as intestinal disorders (colitis, Crohn's disease), allergic skin reactions, and respiratory infections (e.g., asthma).
Clindamycin is a good example of how a lincosamide antibiotic can impact our gut microbiome. Clindamycin is excreted in bile and may increase its concentration in the colon, which causes a shift in bacterial colonization. These conditions allow the overgrowth of Clostridium difficile, a pathogenic bacterium.
Consequently, it can lead to colitis, diarrhea, and gastritis effects and disturb normal bowel function (Yang et al., 2021).
Macrolides are antibiotics that include erythromycin, azithromycin, and clarithromycin. They are commonly used in respiratory, skin, sexually transmitted, and Helicobacter pylori (in gastritis) infections.
Macrolides are natural products with antibiotic properties consisting of a large macrocyclic lactone ring with one or more deoxy sugars added (figure 2).
Figure 2. Erythromycin structure showing the basic backbones in color of macrolides.
A large study with Finnish children determined macrolides induce long-term alterations of microbiota, particularly a reduction of Actinobacteria (e.g., Bifidobacteria) and Firmicutes (e.g., Lactobacilli).
Overall, there was a reduction in the microbial diversity, with an increase of pathogenic-related abundances like Bacteroidetes and Proteobacteria (Korpela et al., 2016).
β-Lactams are antibiotics including penicillin V, amoxicillin, ampicillin/sulbactam, and cephalosporins.
They contain a beta-lactam ring in their chemical structure (figure 3), and their action mechanism is exerted by inhibiting cell wall biosynthesis in the bacteria.
β-Lactams account for 65% of all prescriptions for injectable antibiotics in the United States (Bush and Bradford 2016). They are prescribed to treat many bacterial infections, particularly Streptococcus spp., and respiratory and gastrointestinal disorders.
Figure 3. β-Lactam structure showing the β-Lactam ring.
Contradictory studies are found regarding β-Lactam antibiotics. Some studies indicate penicillins (like penicillin V and amoxicillin) do not cause relevant changes to microbiota. However, other studies suggest that combinations of different β-Lactams (i.e., amoxicillin with cephalosporins) or mixtures with other components (i.e., amoxicillin with clavulanic acid) exert devasting effects on the gut microbiota.
For example, there was a study carried out with amoxicillin plus clavulanic acid. After four days, this combination in humans showed reversible changes to the original microbiota, except for beneficial bacteria Bifidobacterium. This suggests a negative effect on the gut microbiota (De La Cochetière et al. 2005).
Fluoroquinolones are broad-spectrum antibiotics such as ciprofloxacin and levofloxacin.
They are used to treat several infections; however, epidemiological studies show an increased risk of rare adverse effects, including tendon rupture, peripheral neuropathy, and aortic aneurysm (Baggio et al. 202).
They contain a bicyclic core structure related to the compound 4-quinolone and a fluoride group in the central ring, usually at position 6 (Figure 4).
Ciprofloxacin structure showing the basic backbone in color of fluoroquinolones.
Recently, ciprofloxacin was shown to provide long-term changes to the microbiota of healthy individuals, mainly, increasing Gram-positive aerobes, and reduce bacterial diversity (Dethlefsena and Relman, 2011).
Glycopeptides are antibiotics composed of glycosylated cyclic or polycyclic nonribosomal peptides (figure 5).
Antibiotics such as telavancin, ramoplanin, and vancomycin are examples of glycopeptides.
These antibiotics impede the synthesis of cell walls by inhibiting peptidoglycan synthesis (building blocks for bacteria).
For instance, vancomycin is used to treat infections caused by C. dificile and methicillin resistance Staphylococcus areaus (or MRSA). Both infections are involved in causing gastrointestinal disorders, among many other problems.
Vancomycin was shown to decrease the total bacterial diversity, reduce beneficial bacteria like Firmicutes, and increase pathogenic-related Proteobacteria (Ianiro et al., 2016).
Figure 5. Vancomycin structure showing polycyclic nonribosomal peptides in the square.
Consequences of antibiotic abuse
One of the main consequences for the gut microbiota when overusing or improperly using antibiotics is the reduction of the microbial diversity.
Generally, because antibiotics are broad-spectrum, they can kill all bacteria, good and bad. This reduces microbial diversity, and consequently, reduces the beneficial metabolites such as short fatty acids.
Microbiome research allowed a deeper understanding about the mechanisms that benefit human health.
Gut microbes produce metabolites like short fatty acids (SCFAs), phytoestrogens, and vitamins that play positive roles in our digestion, immune systems, organs, and genes.
A logical consequence of antibiotics killing beneficial bacteria is the inhibition of these metabolites. Without these metabolites, our organs can have chemical imbalances, leading to gastrointestinal, respiratory, and even neurological disorders.
While diarrhea is a commonly associated adverse effect of antibiotic consumption, toxic effects on the central nervous system (CNS) and generation of neurological disorders are less recognized. Drug-induced neurotoxicity is mostly observed after beta-lactams
and quinolones intake. Also, penicillin may produce a wide range of neurological dysfunctions, including seizures (Grill and Maganti, 2011).
Despite the above information, I should say that antibiotics have life-saving applications and are still very necessary. The idea with antibiotics is reduce their abuse and promote responsible use.
This research is important because we don’t want antibiotics to be over prescribed. Also, antibiotics consumption matters because in many other countries out of US, antibiotics are found over the counter and taken whenever, promoting antibiotic abuse.
In human diseases
Antibiotics cause dysbiosis, an imbalance of microbiota diversity, by killing harmful and beneficial bacteria. Many human health disorders have been reported as a consequence of gut dysbiosis.
For instance, the common short-term effect of antibiotic is diarrhea (by Clostridium difficile). For long-term, allergic conditions like asthma, food allergies, and obesity become common.
In this sense, human studies show antibiotics, even a tiny dose found in food (mainly livestock fed with antibiotics), cause obese-related effects for the consumers (Yang et al., 2021).
Furthermore, antibiotic exposure may cause the dysregulation of immune responses and atherosclerosis-driven events. Studies have also shown that antibiotics may influence the pathogenesis of neurodegenerative diseases, such as multiple sclerosis and Amyotrophic Lateral Sclerosis (ALS), through gut microbiome dysfunction (Konstantinidis et al., 2020).
In antimicrobial resistance
Maybe one of the main concerns of excessive use of antibiotics is the antimicrobial resistance (AR) prevalence.
Antimicrobial resistance is a worldwide crisis estimated to cause over 50,000 deaths a year in Europe and the USA (Langdon et al., 2016).
As we already know, antibiotics can produce alterations in the host's indigenous microbiota and lead those resistant bacteria to appear as opportunistic pathogens. In other words, gut microbes evolve to defend themselves from the continuous antibiotic charge. Microbes protect themselves from antibiotics by activating "antibiotic-resistant genes."
When these genes are activated within microbes, these microbes may become pathogenic. Ultimately, the antibiotic effect is useless in treating the infection.
Furthermore, another layer of complexity is the fact that new antibiotic production has been decreased over the years.
New alternatives that avoid antibiotic use and therefore the antimicrobial resistance prevalence are being pursued.
Alternatives to the antibiotic use
Alternatives to antibiotics include probiotics, fecal microbiota transplants, and phage therapy strategies.
Probiotics are defined as live microorganisms that confer a health benefit to the host when administered in adequate amounts (Hill et al., 2014).
They improve microbial diversity and have been used in a wide range of gastrointestinal diseases, including C. difficile infection (Johnston et al., 2012).
The good thing is probiotics can be acquired easily throughout the diet in yogurts and edible products labeled as a probiotic food.
The second approach is focused on fecal microbiota transplant. This strategy looks to improve dysbiosis by transferring the stool of a healthy individual into the colon of a sick individual. This therapy has been successful in the treatment of C. difficile infections.
Furthermore, some studies suggest that introducing certain fecal microorganisms into a patient’s colon may help the patient respond to drugs that enhance the immune system’s ability to recognize and kill tumor cells (Davar et al., 2021).
The third strategy is phage therapy. In addition to its bacterial inhabitants, the microbiota is also made up of phage communities.
Phages are natural predators of bacteria and were used in bacterial infections before the antibiotic revolution. Active phages against pathogenic bacteria like Enterococcus faecalis, Bacillus cereus, and Pseudomonas aeruginosa have been identified.
When antibiotics are used properly, they are life-saving and essential. Conditions that enable antibiotic abuse or overuse can contribute to reduced microbial diversity and health in people. New research is allowing us to explore other avenues of treatment, which may help in the long-term to human infections.
Microbiome, antibiotics, antimicrobial resistance, probiotics, fecal transplant, phage therapy.
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