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The Effect of Antibiotics on the Gut Microbiota

The gut microbiota (also referred to as gut flora) is the population of bacteria that colonizes the human gut. There have been 50 bacterial species that have been described, but the human gut microbiota is dominated by 2 particular species: Bacteroidetes and Firmicutes. Other species such as Proteobacteria, Verrucomicrobia, Actinobacteria, Fusobacteria, and Cyanobacteria are much smaller in number (1). The gut microbiota aids the absorption of nutrients in the gut, produces various vitamins and chemicals (for example vitamins B and K, and competes with harmful bacteria which enters the gut from outside sources. The gut bacteria is associated with various human diseases such as inflammatory bowel diseases –  for example enterotoxigenic B. fragilis (ETBF) (a strain of Bacteroides fragilis– a normal, common form of gut bacteria) is thought to cause colitis (inflammation of the colon) (2); diabetes – it is understood that the composition of gut bacteria affects nutrient (notably carbohydrate) absorption in the small intestine (3) , and even certain neurological disorders – gut bacteria manufacture neurochemicals such as dopamine and serotonin which are involved in brain signalling (4).

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As the importance of the gut microbiota is becoming increasingly evident, studies have been carried out with the aim of gaining a more comprehensive understanding of the potentially harmful effects of antibiotics on this essential ecosystem. Clearly antibiotics have bactericidal and bacteriostatic properties against pathogenic bacteria. However, does this necessarily mean these properties will extend to encompass the non-pathogenic bacteria? Although there have been studies investigating the effect of these drugs on strains of bacteria commonly found in the gut, the studies have been limited to the effects on a particular bacteria strain or species in isolation from the vast array of other bacteria strains and species that are indigenous to the human gut. This may be partly because of the challenges involved in successfully cultivating a large number of different strains and species of bacteria using cultivation-based techniques. Only relatively recently have there been investigations into the effects of antibiotics on the overall bacterial community that would typically live in the gut.

Antibiotics have been proved to kill the body’s health-promoting ‘good’ bacteria in the gut, while having little effect on resistant pathogenic bacteria strains such as Salmonella typhimurium and Clostridium difficile. Consequently, this results in a loss of resistance to pathogen colonization in the gut due to the reduction in resource competition between the invading pathogenic bacteria and the indigenous bacteria (5), therefore making an individual more susceptible to infection from these disease-causing bacteria (for example C.difficile causes diarrhoea). This is therefore clearly a case against antibiotic treatment, because in taking antibiotics, we hope to kill invading pathogens in the body; however there is evidence to suggest that through antibiotic use, we are in fact encouraging the colonisation of pathogenic bacteria in the gut. Furthermore, with further use of antibiotics, the number of pathogens which develop resistance to certain antibiotics will increase, due to the fact that the antibiotics introduce strong selective pressures and so promote the development of resistance in bacteria which arises from the spontaneous mutation of bacterial genomes, and from the transfer/exchange of bacterial genetic information (a process by which resistant genes such as the ermB resistance gene can be transferred from one bacterium to another) (5). The results of several studies have supported the idea that pathogen resistance to antibiotics is increased by their use, for example a study investigating the resistance to the antibacterial drugs Chloramphenicol, Doxycycline and Trimethoprim found that over a 20-day period after antibiotic treatment with each of these drugs, resistance levels of the bacterium Escherichia coli (E.coli) to these drugs increased dramatically (6).

An undated file picture taken with electronic microscope shows EHEC bacteria (enterohaemorrhagic Escherichia coli) in Helmholtz Centre for Infection Research in Brunswick. German health authorities on May 25, 2011 have warned consumers to be careful with raw salad vegetables, especially those originating from northern Germany, after reporting about 140 cases and at least four deaths. REUTERS/Manfred Rohde/Helmholtz-Zentrum für Infektionsforschung (HZI) (GERMANY - Tags: SCI TECH HEALTH) THIS IMAGE HAS BEEN SUPPLIED BY A THIRD PARTY. IT IS DISTRIBUTED, EXACTLY AS RECEIVED BY REUTERS, AS A SERVICE TO CLIENTS. FOR EDITORIAL USE ONLY. NOT FOR SALE FOR MARKETING OR ADVERTISING CAMPAIGNS - RTR2MWXS

A recent study used pyrosequencing technology to obtain full-length rRNA sequences (of the 16s rRNA gene) which indicate the diversity, richness and evenness of the bacterial community. This sequencing was carried out to analyse stool samples from 3 healthy adult individuals before and after treatment with the antibiotic Ciprofloxacin. It was found that the antibiotic treatment affected a third of the total bacterial population that was sequenced, hence lowering the diversity, richness and evenness of the bacteria. The composition of the community of bacteria largely recovered to its original pre-antibiotic treatment state after four weeks, however a few species of bacteria did not return to their original numbers within six months of the antibiotic treatment (7). When the subjects took a second course of Ciprofloxacin, although the indigenous bacteria population became stable again, it was found that the composition of these bacteria was different to that of the original gut microbiota before the antibiotic was ingested, suggesting that the extent of the antibiotic usage affects the extent of the negative impact on the gut bacteria (8).

It has also been made evident that different antibacterial drugs have different effects on the gut microbiota in terms of the duration of significant effects. One study investigated the long-term effects on the gut microbiota after a 7-day treatment with the antibacterial drug, Clindamycin. The results showed that after 2 years, there were still significant differences in the bacteria population, especially in the diversity (decreased) of the Bacteroides (a genus of anaerobic bacteria present in the gut), and in the presence of highly resistant strains. The population never returned to its original composition over the 2-year monitoring period (9). While the investigation using the pyrosequencing technology investigating the drug ciprofloxacin showed that the community largely recovered after 6 months of treatment, the results of this study seems to suggest that the drug Clindamycin has more long-term effects.

A common theme in all of the studies mentioned above is that the subjects are adults. Although there are so few studies into the effects of antibiotics on the whole gut microbiota, a study in 2012 focused solely on the negative impact on newly born babies’ gut bacteria. It was previously thought that the environment in which a foetus develops is sterile, meaning that the baby’s first encounter with bacteria is in the birth canal. However new evidence shows the presence of bacteria in the amniotic fluid and in the blood in the umbilical cord. Since these infants were healthy, this implies that the bacteria present were not harmful pathogenic bacteria, rather just bacteria that are normal to the baby’s development (10). However, it is still agreed that the human gut microbiota undergoes rapid development in the early stages of an infant’s life. The development of a healthy intestinal gut is linked to the mode of deliver of the baby and to the quality of the breast milk and has a profound effect on the health of the individual (even much later in life). As microbiologist Giulia Enders writes in her bestselling book ‘Gut’, she was delivered by caesarean section, and was unable to be breastfed; details to which she holds account for her intolerance to lactose (11). Knowing the importance of a healthy development of the intestinal gut microbiota in newborns, this study in 2012 was carried out on 9 newborns that had been treated with the antibiotics Ampicillin and Gentamicin within 48 hours of birth and a control group of 9 untreated individuals. After 4 weeks, the bacterial population of antibiotic-treated individuals was dominated by Proteobacteria, whereas that of the control group was not. Less than half of the antibiotic-treated individuals were populated by Bacteroidetes, and in the individuals who were populated by these, the population size was lower than in the untreated individuals. Furthermore, Actinobacteria levels were also lower in antibiotic-treated individuals. After 8 weeks, in most of the antibiotic-treated individuals, levels of Proteobacteria had decreased – now much more similar to the levels present in the control group. An increase in the levels of Bacteroidetes meant their population sizes were also similar to those of the control group after 8 weeks. However, a more biodiverse bacterial ecosystem was detected in the control group than in the treated individuals after 8 weeks. Therefore, this study demonstrated the potentially negative impact that antibiotic treatment has on the gut microbiota while it is in its developing stage (12).

In summary, although there are relatively few studies, the ones that do exist seem to show similar results – that treatment with a variety of different antibiotics poses a threat to the health of an individual by potentially damaging the intestinal bacterial population. However, it would be widely acknowledged that the results from these studies should be viewed cautiously due to the very small number of participants. Studies involving 3 or 18 people are in no way representative of the entire human population. You would expect that there would be larger-scale studies to be carried out in the near future, so watch the space!

Sources:

(1) http://physrev.physiology.org/content/90/3/859.short

(2) http://www.nature.com/ajgsup/journal/v1/n1/full/ajgsup20124a.html

(3) http://care.diabetesjournals.org/content/diacare/33/10/2277.full.pdf

(4) http://articles.mercola.com/sites/articles/archive/2015/05/17/gut-bacteria-brain-health.aspx

(5) https://www.jci.org/articles/view/72333

(6) http://www.nature.com/ng/journal/v44/n1/abs/ng.1034.html

(7) http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060280

(8) http://www.pnas.org/content/108/Supplement_1/4554.full

(9) http://www.ncbi.nlm.nih.gov/pubmed/18043614

(10) https://www.sciencenews.org/blog/growth-curve/baby%E2%80%99s-first-bacteria-arrive-sooner-we-thought

(11) ‘Gut’, Giulia Enders, Scribe Publications 2015, ISBN 978-1-925228-60-1

(12) http://aac.asm.org/content/56/11/5811.full

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