Gut microbioma and antibiotic resistance

Gut microbiota

Although the phenomenon of AMR can be attributed to many factors, there is a well-established relationship between antibiotic prescribing practices and the emergence of antibiotic-resistant pathogens. After they have emerged, resistant pathogens may be transmitted from one individual to another. While, the indigenous intestinal microbiota provides an important host-defense mechanism by preventing colonization of potentially pathogenic microorganisms, the intestinal tract is also an important reservoir for antibiotic-resistant bacteria.

Recently, the rapid development of high-throughput sequencing technology, including metagenomics, metatranscriptomics, and metaproteomics approaches, has provided with powerful tools to study the composition and function of gut microbiota. It is estimated that approximately 100 trillion microbes from over 1000 species and more than 7000 strains reside in the gut. Although enormous gut microbes in addition to bacteria have recently been identified (including helminths, protozoa, archaea, viruses, phages, yeast, and fungi), bacteria are still the main participants in gut and host homeostasis. The five major bacterial phyla in the gut are Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia, accounting for more than 90% of the total bacterial population that inhabit the gut. However, the relative proportions of each taxa vary between individuals and even within individuals over their lifetime. The composition of an individual’s microbiota is influenced by many factors such as  age, geographical provenance and environment, dietary habits, co-morbidities and use of and antibiotics. Human immune homeostasis, modulation of gastrointestinal development and metabolism of nutrients all benefit from the intestinal commensal microbiota. These microbial communities reside with varied density in different segments of the gut and play a crucial role in many aspects of physiological processes, including facilitating food digestion and energy utilization, synthesizing vitamins and essential amino acids, promoting the development of the immune system, maintaining the integrity of the gut mucosal barrier, and protecting against enterogenous pathogens.

Moreover, the host is endowed by the intestinal microbiota with resistance against a wide range of pathogens, a mechanism known as colonisation resistance. Colonisation resistance results from:

 (1) indirect mechanisms, i.e., the activation of innate immune defences in the mucosa and the production of protective metabolites such as secondary biliary acids, antimicrobial peptides and short-chain fatty acids, and

(2) direct mechanisms, through direct competition, secretion of bacteriocins, and nutrient depletion.

The perturbation of the normally stable gut microbiota, named as dysbiosis, may adversely affect the health status of an individual and cause the loss of protection against colonisation. Reservoirs of MDR bacteria are ubiquitous, and they can merge with the gut microbiome via two mechanisms: firstly, exogenous MDR bacteria can be acquired by the host and colonise the intestinal epithelium; secondly, previously susceptible bacteria may become resistant through selection or induction of antibiotic-resistant mutants mediated by the presence of antibiotics or by gene transfer events. Currently, there is substantial evidence that the composition of the gut microbiota may fluctuate in response to external factors such as antibiotics. The administration of antibiotics may contribute to or cause dysbiosis by directly eliminating the bacterial populations that confer colonisation resistance to the intestinal microbiome. Then, antibiotic-resistance genes can be horizontally spread among bacteria through three kinds of mechanisms: conjugation, transduction, and transformation.  Antibiotic-resistance genes are more readily transmitted across bacterial species, which may lead to a rapid dissemination of antibiotic resistance in other members of the gut microbiota. Several data attempt to unify all the literature regarding the effect of the different groups of antibiotics in the intestinal microbiota. However, it is difficult to obtain conclusive evidence from these studies due to the small sample sizes and heterogeneity of the data, namely co-administration of other antibiotics or other drugs, previous antibiotic exposure or hospitalization, age groups, dosing regimens and method of microbiome analysis. The best clinical example to illustrate the potential impact of antibiotics on the intestinal microbiome is the infection by Clostridium difficile. This microorganism primarily causes infections in hospitalised patients and residents of long-term health care facilities following the use of broad-spectrum antibiotics. C. difficile is the most common cause of nosocomial diarrhoea, with a clinical presentation that ranges from mild diarrhoea to pseudomembranous colitis and toxic megacolon. Although most antibiotics increase the risk of developing C. difficile infection, this condition is generally associated with the use of fluoroquinolones, cephalosporins and primarily, clindamycin. Clindamycin is excreted in bile and thus reaches high concentration in faeces. In experimental models, a single dose of clindamycin markedly reduces the diversity of the intestinal microbiota.

Treatment of multidrug-resistant organism infections presents a major clinical challenge, as the increase in antibiotic resistance leads to a greater risk of therapeutic failure, relapses, longer hospitalizations, and worse clinical outcomes. Moreover, the increase in AMR has outpaced the development of new antibiotics. Currently, there are no validated therapeutic strategies for many MDR infections, and preventing the spread of pathogens through hospital infection control procedures and antimicrobial stewardship programs is often the only tool available to healthcare providers.