How do antibiotics affect the gut microbiota?

ANTIBIOTICS The introduction of antibiotics into medicine revolutionised the way infectious diseases are treated and led to an eight-year jump in life expectancy between 1945 and 1972 by treating infections that were previously likely to kill patients. Today, antibiotics are one of the most commonly prescribed medications worldwide and made many complex surgery’s possible that have now become routine throughout the world(1,2). Antibiotics are classed as an antimicrobial substance designed to target bacterial infections within or on the body(2). Antibiotics should only be used to treat or prevent certain types of bacterial infections that are unlikely to clear up without antibiotics, could infect others, take too long to clear without treatment or carry the risk for more serious complications(3). Additionally, they cannot be used for fungal and viral infections(2). Some antibiotics are highly specialised and are only effective against certain bacteria, whilst others (known as broad-spectrum antibiotics) can attack a wide range of bacteria, including the beneficial bacteria that are found naturally in our gut(2). There are two main mechanisms in which antibiotics target bacteria; either by preventing the replication of bacteria or by killing the bacteria (e.g. by stopping the mechanism responsible for building their cell walls)(2). Antibiotics can disrupt the balance in the gut microbiota (dysbiosis) which can lead to several unpleasant side effects(1). The most common side effects of antibiotics affect the digestive system and can affect 1 in 10 people. Common side effects include; vomiting, nausea, diarrhoea, bloating and indigestion, abdominal pain and loss of appetite(3).

HOW DO ANTIBIOTICS AFFECT THE GUT MICROBIOTA? Antibiotics distrust intestinal flora balance by killing susceptible intestinal flora bacteria(4). Broad spectrum antibiotics can affect the abundance of the bacteria in the gut microbiome, causing rapid and significant drops in taxonomic richness, diversity and eveness(5). These changes can affect the capacity of the resident microbiota to resist invasion of pathogenic microorganisms(6) or the overgrowth of opportunistic pathogen species that are endogenously present in the microbiota(5,7).

The impact of antibiotics on the gut microbiota has more recently been investigated through the variety of “omic” techniques(5). These “omic” techniques have shown that, beyond altering the composition of taxa, antibiotics also affect the gene expression, protein activity and overall metabolism of the gut microbiota. These changes can occur at a much faster pace than those involving replacement of microbiota community(8). Once the antibiotic treatment has stopped, the microbiota may present a certain degree of resilience and may be capable of returning to a composition similar to the original one. However, this initial state is often not totally recovered and there can often be long-lasting effects on the balance of the gut microbiota which can span for several months to years. Consequently, the patient may be left more susceptible to further infections and diseases(5,9,10). Experimental approaches have also confirmed that antibiotics rapidly alter the physiological state and activity of the gut microbiota. In ex vivo incubations of faecal samples with different antibiotics, there was in increase in the proportion of gut microbiota cells with damaged membranes, the active populations of the microbiota had changed and the genes involved in antibiotic resistance, stress response and phage induction was greater in expression(11). ANTIBIOTIC ASSOCIATED DIARRHOEA One of the most imminent threats of gut microbiota alterations is the increased susceptibility to intestinal infections, which can stem from newly acquired pathogens or from the sudden overgrowth of pathogenic bacteria and opportunistic organisms already present in the microbiota. In particular, antibiotic associated diarrhoea (AAD) due to nosocomial pathogens occurs in 1-44% of antibiotic users and one in five people stop taking their antibiotics due to diarrhoea(5,16).Various mechanisms of AAD have been proposed including overgrowth of toxigenic bacteria leading to infectious diarrhoea and/or the loss of beneficial metabolic activities of intestinal microbes leading to excessive carbohydrates in the colonic lumen and osmotic diarrhoea(12-14). Adults over the age of 65 years are more susceptible to AAD and broad spectrum antibiotics (clindamycin, cephalosporin and fluroquinolones) are more likely to cause AAD compared to narrow spectrum antibiotics(15). AAD is often associated with organisms such as Klebsiella pneumoniae, Staphylococcus aureus and, of most concern, Clostridium difficile which can cause intractable, long-term recurrent infections and even potentially lethal pseudomembranous colitis(5,16). C.difficile associated diarrhoea (CDAD) accounts for 10-20% of cases, leaving the majority of AAD cases resulting from other enteric pathogens or non-infectious mechanisms(13). When the gut microbiota has not been compromised, a healthy adult will generally be resistant to C. difficile colonisation(17,18). However, when the gut microbiota becomes altered due to antibiotic usage, the risk of C. difficile colonisation increases.19 C. difficile is a bacteria that causes gastrointestinal infections in humans which can range in severity from asymptotic colonisation to severe diarrhoea, pseudomembranous colitis, toxic megacolon, colonic perforation and can be related to considerable morbidity and mortality(20,21). Typical clinical features of C. difficile infection include watery diarrheic, lower abdominal pain and systemic symptoms such as fever, anorexia, nausea and malaise(21). The onset of symptoms of C. difficile infection can be seen from the first day of taking antibiotics(22,23). The first line treatment for CDAD in adults is discontinuation of antibiotic, when possible. For mild disease, this is often sufficient for recovery(21). Beyond AAD, microbiota alterations caused by antibiotics can also affect basic immune homeostatic with body-wide and long-term repercussions. Atopic, inflammatory and autoimmune diseases have been linked to gut microbiota dysbiosis and in some cases significant associations have been established between these diseases and intake of antibiotics during early life(5) Secondly, antibiotics have recently been implicated in increased the risk of type 1 diabetes, insulin-dependent diabetes, an autoimmune disease. In an epidemiological study involving a large UK population, the repeated use of penicillin, cephalosporins, macrolides, or quinolones was associated with increase in diabetic risk(24). Several metabolic disorders have been linked with microbiota dysbiosis. In particular, obesity has been associated with phylum levels changes in the gut microbiota, reduced bacterial diversity and an altered representation of bacterial genes and metabolic pathogens. This can result in an increased capacity of the gut microbiomes to harvest energy from the diet which is associated with obesity. This is in line with the fact that long term exposure to antibiotics is associated with increased body mass index in humans. Antibiotic usage is therefore emerging as an important risk factor for the development of obesity even with a normal dietary intake and may also contribute to the development of metabolic syndrome in obese individuals(5). Dysbiosis of the gut microbiota caused by antibiotics can negatively affect health in numerous ways and may affect an individual for long periods of time. In light of this knowledge and given that bacterial infections remain a public health concern, strategies are needed help prevent and minimise dysbiosis when antibiotics are required. Therefore, probiotics aimed at inhibiting dysbiosis or at re-establishing the gut microbiota during and after antibiotic treatment is a promising approach(5). THE USE OF PROBIOTICS Probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host”(25). Probiotics have many ways in which they can prevent infection within the gut microbiota. They are able to compete with pathogens for nutrients and adhesion sites on the gastrointestinal mucosa(26,27) in the process of competitive exclusion(28). They can also prevent pathogenicity by interfering with signalling between pathogens by degrading quorum sensing molecules(29). In addition, direct antagonisms can occur through the production of bacteriocins or metabolites with antimicrobial activity against pathogenic microorganisms(30,31). Finally, probiotics are able to modulate and stimulate local and systemic immune responses in the patient(32). Therefore, probiotic supplementation can be used to reduce the risk of commonly seen sides effects of antibiotic therapy(4). A recent Cochrane review set about to determine whether probiotics prevent CDAD in adults and children receiving antibiotic therapy and whether probiotics cause any side effects. Randomised controlled trials investigating probiotics for prevention of CDAD were considered for inclusion. The analysis (23 trials) suggested that probiotics significantly reduce the risk of CDAD by 64%. The incidence of CDAD was 2.0% in the probiotic group compared to 5.5% in the placebo or no treatment control groups. Adverse events were assessed in 26 studies (3964 participants) and showed that probiotics reduce the risk of adverse events by 20%. The authors conclude there is moderate quality evidence that probiotics are both safe and effective for preventing CDAD. A review carried out in The Netherlands reviewed the efficacy of probiotics in reducing the incidence of AAD in patients treated with antibiotics(32). Trials were included in the meta-analysis. Probiotics were associated with lower incidence of AAD compared to the control. For trials using probiotic dairy products, the incidence of AAD in the probiotic group was 15.2% compared to 27.5% in the control group. For trials using probiotic supplements (i.e. non-dairy products) the incidence of diarrhoea in the probiotic group was 12.2% compared to 16.3% in the control group. Furthermore, the authors stated that the strain L. rhamnosus GG is strongly recommended for the prevention of AAD and has been repeatedly proven to be effective in reducing the incidence of diarrhoea in antibiotic-treated patients.(33) Lactobacillus has been shown to produce an antimicrobial agent that is effective against a variety of potentially pathogenic bacteria species such as Clostridium, Bacteroides, Enterobacteriaceae, Pseudomonas, Staphylococcus and Streptococcus spp. that commonly infect the intestinal system which may explain why it is effective for reducing the risk of AAD(34). Shen et al,. carried out a systematic review to provide evidence on the use of probiotics in preventing C. difficile infection (CDI). 19 randomised controlled trials which evaluated the use of probiotics and CDI in hospitalised adults taking antibiotics were included. The incidence of CDI was lower in the probiotic group than the control group (1.6% and 3.9% respectively). The authors also demonstrated that probiotics were significantly more effective if given closer to the first antibiotic dose, with a decrease in efficacy for every day of delay in starting probiotics. Probiotics given within 2 days of antibiotic initiation produced a greater reduction in risk for CDI than later administration; the efficacy of probiotics at preventing CDI was cut in half if probiotics when begun more than 2 days after antibiotics were started(35). A study conducted by Madden et al.(36) showed that in patients receiving multiple forms of antibiotics, probiotics are effective in restoring intestinal flora removed by antibiotic therapy. This study also showed that potentially pathogenic bacteria such as Enterobacteriaceae and Staphylococci increase in numbers after 14 days of antibiotic treatment, compared to other species of naturally occurring intestinal flora and therefore, the microbiome is still susceptible to infections once the antibiotic course has finished.

A benefit analysis was conducted in the United Kingston to evaluate the cost impact of AAD in hospitalised patients on antibiotics when ingesting fermented milk containing probiotic Lactobacillus paracasei ssp paracasei CNCM I-1518. The probiotic intervention to prevent AAD generated an estimated mean cost saving of £339 per hospitalised patient over 65 years, compared to no preventive probiotic(15).

It is suggested to take probiotics 2-6 hours after the antibiotic dose throughout the antibiotic treatment, this is due to the antibiotics having passed through the body by this stage, so they will not destroy the supplement. It is then suggested to continue with the probiotic 7-10 days after ending the antibiotic regime. Additionally, if possible, it has been suggested to begin taking probiotics before beginning antibiotic therapy to established the gut micrbiota(16). Taking a high strength dosage of probiotics (100 billion cfu/day) during antibiotic treatment will encourage the colonisation of friendly bacteria in the gut whilst a lower dose (10 billion cfu/day) after treatment will help maintain the growth of the beneficial bacteria, reduce infection by beneficial bacteria and prevent any permeant changes to the gut bacteria composition. BIBLIOGRAPHY

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