ReviewThe effect of antibiotics on the composition of the intestinal microbiota - a systematic review
Introduction
The human intestine is the habitat for a rich and diverse community of microbes consisting of archaea, bacteria, eukaryota (fungi, helminths, and protozoans) and viruses. So far, more than 1000 bacterial species have been identified,1 but it has been suggested that there might be up to 36,000 different species of bacteria living in the intestine.2 Even though it was previously thought that 80% of the intestinal microbiota cannot be cultured,3 the main genera (such as Bacteroides spp., Bifidobacterium spp., Clostridium spp., Enterobacteriaceae, Enterococcus spp., Lactobacillus spp. and Veillonella spp.) are regularly identified in bacterial cultures. More recently, novel methods using selective culture media have enabled the majority of species within the microbiota to be cultured.4,5 Metagenomic shotgun sequencing provides a more in-depth analysis of the intestinal microbiota, including identification of bacterial species, resistance genes, as well as the identification of eukaroytes and viruses. Apart from being involved in various metabolic functions, the intestinal microbes are also crucial for the development of the immune system and regulation of immune responses. The complex interplay between a ‘healthy’ and ‘dysbiotic’ intestinal microbiota, which influences many health outcomes, remains incompletely understood.6, 7, 8
Antibiotics are among the most commonly prescribed drugs. Despite their benefits, their use has been associated with both short- and long-term adverse health outcomes, including increased risk of necrotising enterocolitis,9,10 bronchial hypersensitivity and asthma,11 obesity12 and autoimmune diseases.13 Antibiotic administration leads to perturbations in the intestinal microbiota through which some of these adverse health outcomes are likely mediated. This ‘collateral damage’ to the micobiota includes changes in abundance of certain taxa, a decrease in ‘colonisation resistance’ (protection against colonisation with potentially pathogenic (e.g. Enterobacteriaceae) or opportunistic (e.g. Clostridium difficile, Candida spp.)) organisms, and the development of antibiotic resistance.14 The human intestine has the highest density of microbes of all known environments. Bacteria living in the human intestine have a 25-fold higher rate of gene transfer than bacteria in other settings,15 and antibiotic exposure further increases horizontal gene transfer.16, 17, 18, 19, 20
The effect of antibiotics on the intestinal microbiota likely depends on the spectrum of activity (narrow vs broad spectrum), formulation, route of administration, pharmacokinetics and pharmacodynamics (e.g. biliary secretion), as well as dose and duration of administration. The extent of the effect of antibiotics on the composition of microbiota and whether the effects are only short-term or persist long-term remain uncertain. Additionally, it is uncertain whether antibiotic-resistant strains persist in the absence of selective pressure through antibiotics.
In this review, we summarise studies that have investigated the effect of antibiotics on the composition of the human intestinal microbiota. Understanding these effects will help tailor antibiotic treatment to minimise this ‘collateral damage’.
Section snippets
Systematic review methods
In January 2019, MEDLINE (1946 to present) was searched using the Ovid interface with the following search terms: (anti-bacterial agents OR anti-infective agents OR anti-microbial agents OR antibiotics OR antitubercular agents OR penicillins OR amoxicillin OR carbapenems OR cephalosporins OR macrolides OR quinolones OR glycopeptides OR aminoglycosides OR tetracyclines OR tigecycline OR daptomycin OR streptogramin OR linezolid OR colistin OR trimethoprim OR sulphonamides OR nitrofurantoin OR
Systematic review results
Our search identified 24,718 studies. Of these, 100 fulfilled the inclusion criteria. Hand-searching references identified 29 further relevant studies. The 129 studies included in this review investigated 2076 participants and 301 controls. The results of these studies are summarised in Table 1 and supplementary Tables 1 and 2.22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64
Discussion
This review shows that antibiotics have profound effects on the intestinal microbiota. Amoxicillin/clavulante, ciprofloxacin, minocycline, clindamycin, paromomycin and clarithromycin plus metronidazol were associated with decreased bacterial diversity,26,38,73,82,109,110,144 while amoxcillin and rifaximin did not influence bacterial diversity.26,138,139 Penicillin only had minor effects on the abundance of different taxa in the intestinal microbiota and did not increase resistance.22, 23, 24
CRediT authorship contribution statement
Petra Zimmermann: Writing - original draft. Nigel Curtis: Writing - review & editing.
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgment
PZ is supported by a Fellowship from the European Society of Paediatric Infectious Diseases (ESPID).
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