Effects of Antibiotics on Microbiome-Associated Diseases
- 1. Graduate Student Researcher, Master’s in Microbiology and Immunology, Vijayawada, Andhra Pradesh, India
ABSTRACT
The gut microbiome is crucial for drug action, bioavailability, and toxicity, affecting host physiology and health, including brain health. Dysbiosis, or disruptions in the gut microbiome, is linked to various diseases, such as inflammatory bowel diseases, obesity, and metabolic syndrome. Antibiotics, used to treat bacterial infections, can disrupt the gut microbiome, leading to antibiotic-resistant organisms and overgrowth of opportunistic pathogens. This disruption can result in toxins invasion and life-threatening infections. The gut microbiome is essential for maintaining intestinal epithelium integrity, modulating metabolic and immunological processes, and protecting against colonization by invasive pathogens. Understanding the complex interplay between the gut microbiome, antibiotics, and environmental factors is essential for developing targeted interventions to prevent and manage microbiome-associated diseases. This review aims to understand the effects of multiple antibiotics on human microbiota, including gut, oral, respiratory, skin, and vaginal microbiota.
KEYWORDS
Dysbiosis; Gut Microbiome; Antibiotics; Proteobacteria; Bacteroidetes; Firmicutes.
INTRODUCTION
The gut microbiome plays a critical role in modulating drug action, bioavailability, and toxicity, affecting host physiology in health and disease, including brain health and related conditions [1]. R. Goodacre suggests that the human microbiota, a complex network of microbes and viruses, is a superorganism in a symbiotic relationship with its host [2]. Its health status can indicate human health [3-5]. However, it is constantly influenced by dynamic factors, and the degree of changes depends on the nature, strength, and duration of the perturbing factor [6]. Dysbiosis refers to an imbalance in the microbiota's taxonomic composition. The human gut microbiome is a complex and dynamic ecosystem composed of trillions of microorganisms, including bacteria, viruses, fungi, and archaea, that reside within the gastrointestinal tract. This diverse microbial community plays a crucial role in maintaining host health, contributing to metabolic, defensive, and trophic functions [7]. Exposure to toxic environmental pollutants, such as heavy metals, has also been found to trigger unique responses from the gut microbiota, potentially contributing to the development of various health issues [8]. Disruptions in the delicate balance of the gut microbiome, often referred to as "dysbiosis," have been linked to a variety of disease states, including inflammatory bowel diseases, obesity, and metabolic syndrome [9]. Moreover, dysbiosis in the gut microbiota post-radiotherapy can lead to chronic diarrhoea and abdominal pain in cancer survivors, highlighting the importance of maintaining a healthy microbial balance for overall well-being [10].
Antibiotics, classified into natural, semisynthetic, and synthetic forms, are used to kill pathogens by influencing bacterial growth curves. Natural antibiotics enhance organisms' survival, while modern antibiotics are semisynthetic modifications of natural compounds [11]. Penicillins produced by Penicillium fungi form the basis for current beta-lactam antibiotics [12]. Antibiotics, which are widely used to treat bacterial infections, can have a profound impact on the gut microbiome, leading to the emergence of antibiotic-resistant organisms and the overgrowth of opportunistic pathogens. The use of antibiotics has been shown to disrupt the protective bacterial flora of the gastrointestinal tract, which can result in the invasion and translocation of toxins, as well as life-threatening infections. This disruption of the gut microbiome can have far-reaching consequences, as the bacterial flora plays a crucial role in maintaining the integrity of the intestinal epithelium, modulating metabolic and immunological processes, and protecting against colonization by invasive pathogens [13].
In conclusion, the gut microbiome plays a critical role in maintaining overall health, and disruptions to this delicate ecosystem can have far-reaching consequences. Understanding the complex interplay between the gut microbiome, antibiotics, and environmental factors is essential for developing targeted interventions to prevent and manage microbiome-associated diseases. This review aims to understand the effects of multiple antibiotics on human microbiota, including gut, oral, respiratory, skin, and vaginal microbiota. The scope covers research related to human microbiota analysis.
ANTIBIOTICS AND MICROBIOME
Damage to the microbiome has been linked to conditions like asthma [14-17], allergies [18], arthritis [19,20], diabetes [21], obesity [22-26], celiac disease [27], mental illness [28], Crohn's disease [29], and impaired neurocognitive outcomes [30]. Antibiotics, commonly prescribed in individuals, disrupt the normal maturation of the microbiome, altering basic physiological equilibrium and affecting gene expression, protein activity, and overall gut microbiota metabolism, potentially influencing organ development and immune functioning [31]. Antibiotics are widely used globally and are a crucial part of medicine. However, the prescription of antibiotics is increasing and antibiotic resistance is escalating, while the number of new antibiotics on the market is decreasing [32-35]. Antibiotic treatment involves considering the dose of the antibiotic, with the Minimal Inhibitory Concentration (MIC) being a key parameter [36]. However, antibiotics can also have co-lateral effects on the microbiota, affecting early gut [37], skin [38], respiratory [39], vaginal [40], and urinary health [41].
Antibiotic use has been linked to a decrease in beneficial gut bacteria, such as Bifidobacteria and Lactobacilli, which produce short-chain fatty acids that positively affect energy metabolism and form probiotic supplements [42]. However, most studies do not report changes in these genera at the species level, limiting our understanding of the specific species associated with antibiotics. The studies examined various antibiotics, with macrolides and penicillins being the most commonly studied. While no specific changes in antibiotic class were found, macrolides were found to cause more microbiome changes and have longer-lasting effects [43, 44]. In different studies, B-lactam antibiotics were found to significantly affect the differential abundance of specific genera in phenotype matched case-control analyses, with two species from the genus Bifidobacterium strongly associated with the use of these antibiotics out of 1649 detected taxonomicclades [45]. Antibiotics, including those not containing b-lactams, can significantly impact our microbiota.
Additionally, antibiotic use has been associated with changes in other beneficial bacteria, such as Clostridium clusters IV and XIVa, which induce regulatory immune cells [46], and Akkermansia Mucinophilia, which has anti-inflammatory and immunostimulant properties [47]. Antibiotics have been linked to an increase in Bacteroidetes and Proteobacteria, which can cause serious infections. While Bacteroides may provide protection, they can also cause bloodstream infections and abscess formation [48]. However, higher levels of Bacteroides in the gut may not be the cause of these infections. E. coli, a Proteobacteria, is a common cause of urinary tract infections and sepsis [49]. Understanding the effects of different antibiotic therapies is crucial as broad-spectrum antibiotics can negatively impact health [50]. This information can help design pathogen-selective antibiotics to minimize disturbance to the microbiome, as short-term treatments can shift the microbiota to long-term dysbiotic states, potentially promoting disease development [51]. Understanding the effects of different antibiotics is practical, as microbiota modulation, such as rifaximin, is a therapeutic option for patients with irritable bowel syndrome and potentially affects intestinal homeostasis [52].
Post-antibiotic dysbiosis reduces bacteria and microbiota diversity, leading to reduced functional diversity and colonization resistance against pathogens. This suggests the danger of antimicrobial resistance and could have future health consequences, as demonstrated by culturomics and next-generation sequencing [53-58]. Different antibiotic treatments have diverse effects on the total microbiota and specific microbial taxons [54]. These collateral effects may not be solely due to the antibiotic itself, but also include the type of administration, pharmacokinetics of the original compounds, and resistance and degradation mechanisms of each microbe [59,60]. Drugs and phytochemicals can transform into bioactive, bioinactive, and toxic metabolites, affecting microbial communities [60], and potentially shielding other microbiota from antibiotics [61].
The following (Table 1) reveals that antibiotic treatments affect Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria, with Bifidobacterium, Bacteroides, Faecalibacterium, and Escherichia as main genera, and Fusobacteria, Planctomycetes, and Verrucomicrobia as other affected phyla. Studies emphasize the need for antibiotic-based treatment strategies that don't harm or unbalance our microbiota, particularly beneficial bacteria. Selective antibiotics can inhibit pathogens while neutralizing beneficial bacteria. However, antibiotics can affect both susceptible and untargeted beneficial bacteria, leading to the proliferation of resistant pathogens like C. difficile [88]. Antibiotic treatment can influence phage-bacteria interactions, leading to horizontal gene transfer. Cocktails of b-lactams, sulfonamides, glycopeptides, cyclic lipopeptides, lycopeptides, rifamycins, and glycopeptides can also influence virus composition, particularly in gut and oral microbiota [89].
Effecting Antibiotic class |
||
Bactria Phyla |
Antibiotic |
References |
Proteobacteria |
Cyclic lipopeptides |
[62] |
Proteobacteria |
Nitroimidazoles |
[63-66] |
Proteobacteria |
Rifamycins |
[67-69] |
Firmicutes |
Aminosalicylates |
[70] |
Firmicutes |
Azolidines |
[71] |
Bacteroidetes and Firmicutes |
Polymyxins |
[72,73] |
|
Polyenes |
[72] |
|
Sulfonamides |
[63] |
Actinobacteria and Firmicutes |
Nitrofurantoins |
[63,65] |
|
Azoles |
[63,65] |
|
Novel class of respiratory tract infection antibiotics |
[63,65] |
Proteobacteria and Firmicutes |
Quinolones |
[74] |
Fusobacteria |
Beta-lactams [amoxicillin] |
[74-76] |
|
Lincosamides [clindamycin] |
[77-82] |
|
Phosphoglycolipids [flavomycin] |
[73] |
Planctomycetes [Gemmata] |
Beta-lactams [cefprozil and cephalosporin] |
[79,83] |
Verrucomicrobia [Akkermansia] |
Beta-lactams [ceftriaxone and cephalosporin] |
[74] |
|
Lincosamides |
[84,85] |
Bifidobacterium and Faecalibacterium |
nitrofurantoins [nr. 12] and azoles |
[63] |
Clostridium and Faecalibacterium |
azolidines |
[71] |
Staphylococcus and Escherichia |
quinolones |
[74] |
Lactobacillus and Bifidobacterium |
respiratory tract infection antibiotics |
[65] |
Bacteroides and Faecalibacterium |
sulfonamides |
[63] |
Bacillus, Klebsiella, Salmonella and Streptococcus |
Ampicillin |
[86,87] |
Antibiotic-induced dysbiosis is often analyzed at the taxonomic level, but fewer studies focus on alterations in molecular agents like genes, proteins, and metabolites [90]. Quantifying microbial activity and diversity, expression, and production levels of genes, proteins, and metabolites is crucial for understanding antibiotic-induced dysbiosis effects on microbiome and host function [91]. However, few studies report such datasets, and all are limited to the gut microbiota. Antibiotics can damage or destroy bacterial cells, causing decreased enzymatic activity 130. This can be seen in membrane integrity, polarity, and nucleic acid content. Antibiotic-susceptible bacteria are replaced by resistant bacteria, maintaining the entire microbiota's metabolic functions. This is called redundancy, where functions conferred by multiple bacteria can be shared between related and unrelated species [5]. However, alterations in specific enzymatic activities, such as the hydrolysis of dietary polysaccharides, have been observed. Treatments with cefazolin, ampicillin, and sulbactam can lead to rapid and unbalanced assimilation of carbohydrates, linked to obesity and diabetes type 2 [92]. A novel bacterial community may be established after antibiotic treatment, with similar metabolic functions.
High-throughput DNA and cDNA sequencing and protein expression analyses have been used to investigate antibiotic-mediated dysbiosis, focusing on the impact of antibiotics on the expression level of metabolically important microbial genes and proteins [93]. Recent studies have shown that antibiotics affect the community composition from the initial stages of treatment, most likely after just 3 days of treatment with a cocktail of cefazolin, ampicillin, and sulbactam [75]. However, these changes are reversed when treatment ends, revealing that the alpha diversity index of the bacterial population returns to that before the intervention. When antibiotic treatment is discontinued, the number and abundance level of genes and proteins being expressed and synthesized are significantly lower compared to those before initiating the treatment. This suggests that antibiotic-induced alterations of a few bacterial groups can cause major changes in gene and protein fluxes, regardless of similarities in alpha diversity index [31-75].
Another study found that the number and expression of genes encoding dietary polysaccharide-degrading enzymes changed significantly in patients receiving b-lactam therapy of a cocktail of cefazolin, ampicillin, and sulbactam [35]. The utilization of amoxicillin, ciprofloxacin, vancomycin, chloramphenicol, and erythromycin have also been linked to the differential expression level of genes involved in tRNA biosynthesis, translation, vitamin transport, phosphate transport, stress response, and proton motive force. The fact that different antibiotics cause similar alterations in microbial products suggests that it is possible to identify a set of core functions associated with antibiotic treatments.
CONCLUSION
The gut microbiota, the densest and most complex bacterial community in the human body, is essential for homeostasis and host health. It performs functions such as nutrition, metabolism, and protection, as well as trophic functions for intestinal epithelium proliferation and differentiation. However, our skin, respiratory system, oral cavity, and vaginal/urinary cavity also contain diverse microbial communities. Antibiotic use has been associated with alteration in the microbiota balance, leading to changes in microbial composition and function during and after antibiotic treatment. OMICS research has become attractive to fully define the compositional changes and metabolic status of the microbiota when confronted with antibiotics. Antibiotics reduce the amount and diversity of our microbes, causing losses in functional diversity and colonization resistance against invading pathogens. This review discusses the effects of 68 different antibiotics on human microbiota composition and microbiome function. Data revealed that antibiotics produce changes in specific sets of bacteria, fungi, archaea, and viruses, with microbes identified as most vulnerable. Establishing new drug-based therapeutic strategies requires multi-variable analysis, considering the type of drug, administration method, pharmacokinetics of the original compound, and resistance mechanisms of the microbiota. This information will help us understand changes in overall microbiome function.
REFERENCES
- Foster J, Clarke G. Microbiota Brain Axis. In Microbiota Brain Axis: A Neuroscience Primer. 2024.
- Goodacre R. Metabolomics of a superorganism. J Nutr. 2007; 137: 259S-266S. doi: 10.1093/jn/137.1.259S. PMID: 17182837.
- Moran NA, Sloan DB. The Hologenome Concept: Helpful or Hollow? PLoS Biol. 2015; 13: e1002311. doi: 10.1371/journal.pbio.1002311. PMID: 26636661; PMCID: PMC4670207.
- Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature. 2014; 509: 357-60. doi: 10.1038/nature13178. Epub 2014 Apr 16. PMID: 24739969; PMCID: PMC4139711.
- Moya A, Ferrer M. Functional Redundancy-Induced Stability of Gut Microbiota Subjected to Disturbance. Trends Microbiol. 2016; 24: 402-413. doi: 10.1016/j.tim.2016.02.002. Epub 2016 Mar 17. PMID: 26996765.
- Shin NR, Whon TW, Bae JW. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. 2015; 33: 496-503. doi: 10.1016/j.tibtech.2015.06.011. Epub 2015 Jul 22. PMID: 26210164.
- Mohajeri MH, Brummer RJM, Rastall RA, Weersma RK, Harmsen HJM, Faas M, et al. The role of the microbiome for human health: from basic science to clinical applications. Eur J Nutr. 2018; 57: 1-14. doi: 10.1007/s00394-018-1703-4. PMID: 29748817; PMCID: PMC5962619.
- Richardson JB, Dancy BCR, Horton CL, Lee YS, Madejczyk MS, Xu ZZ, et al. Exposure to toxic metals triggers unique responses from the rat gut microbiota. Sci Rep. 2018; 8: 6578. doi: 10.1038/s41598-018-24931-w. PMID: 29700420; PMCID: PMC5919903.
- Avrahami S, Jia Z, Neufeld JD, Murrell JC, Conrad R, Küsel K. Active autotrophic ammonia-oxidizing bacteria in biofilm enrichments from simulated creek ecosystems at two ammonium concentrations respond to temperature manipulation. Appl Environ Microbiol. 2011; 77: 7329-7338. doi: 10.1128/AEM.05864-11. Epub 2011 Sep 2. PMID: 21890674; PMCID: PMC3194856.
- Giridhar P, Pradhan S, Dokania S, Venkatesulu B, Sarode R, Welsh JS. Microbiome and Abdominopelvic Radiotherapy Related Chronic Enteritis: A Microbiome-based Mechanistic Role of Probiotics and Antibiotics. Am J Clin Oncol. 2024; 47: 246-252. doi: 10.1097/COC.0000000000001082. Epub 2024 Jan 9. PMID: 38193365.
- Bérdy J. Bioactive microbial metabolites. J Antibiot (Tokyo). 2005; 58: 1-26. doi: 10.1038/ja.2005.1. Erratum in: J Antibiot (Tokyo). 2005 Apr;58(4):C-1. PMID: 15813176.
- von Nussbaum F, Brands M, Hinzen B, Weigand S, Häbich D. Antibacterial natural products in medicinal chemistry--exodus or revival? Angew Chem Int Ed Engl. 2006; 45: 5072-5129. doi: 10.1002/anie.200600350. PMID: 16881035.
- Levy R, Smith SD, Chandler K, Sadovsky Y, Nelson DM. Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor. Am J Physiol Cell Physiol. 2000; 278: C982-C988. doi: 10.1152/ajpcell.2000.278.5.C982. PMID: 10794672.
- Marra F, Marra CA, Richardson K, Lynd LD, Kozyrskyj A, Patrick DM, et al. Antibiotic use in children is associated with increased risk of asthma. Pediatrics. 2009; 123: 1003-1010. doi: 10.1542/peds.2008-1146. PMID: 19255032.
- Strömberg Celind F, Wennergren G, Vasileiadou S, Alm B, Goksör E. Antibiotics in the first week of life were associated with atopic asthma at 12 years of age. Acta Paediatr. 2018; 107: 1798-1804. doi: 10.1111/apa.14332. Epub 2018 Apr 16. PMID: 29577417; PMCID: PMC6175332.
- Yamamoto-Hanada K, Yang L, Narita M, Saito H, Ohya Y. Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5. Ann Allergy Asthma Immunol. 2017; 119: 54-58. doi: 10.1016/j.anai.2017.05.013. PMID: 28668240.
- Ahmadizar F, Vijverberg SJH, Arets HGM, de Boer A, Turner S, Devereux G, et al. Early life antibiotic use and the risk of asthma and asthma exacerbations in children. Pediatr Allergy Immunol. 2017; 28: 430-437. doi: 10.1111/pai.12725. Epub 2017 Jun 8. PMID: 28423467.
- Kim DH, Han K, Kim SW. Effects of Antibiotics on the Development of Asthma and Other Allergic Diseases in Children and Adolescents. Allergy Asthma Immunol Res. 2018; 10: 457-465. doi: 10.4168/aair.2018.10.5.457. PMID: 30088366; PMCID: PMC6082825.
- Horton DB, Scott FI, Haynes K, Putt ME, Rose CD, Lewis JD, et al. Antibiotic Exposure and Juvenile Idiopathic Arthritis: A Case-Control Study. Pediatrics. 2015; 136: e333-e343. doi: 10.1542/peds.2015-0036. Epub 2015 Jul 20. PMID: 26195533; PMCID: PMC4516942.
- Arvonen M, Virta LJ, Pokka T, Kröger L, Vähäsalo P. Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group's greater susceptibility to infections? J Rheumatol. 2015; 42: 521-526. doi: 10.3899/jrheum.140348. Epub 2014 Oct 15. PMID: 25320218.
- Clausen TD, Bergholt T, Bouaziz O, Arpi M, Eriksson F, Rasmussen S, et al. Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes: A Nationwide Danish Cohort Study. PLoS One. 2016; 11: e0161654. doi: 10.1371/journal.pone.0161654. PMID: 27560963; PMCID: PMC4999141.
- Kelly D, Kelly A, O'Dowd T, Hayes CB. Antibiotic use in early childhood and risk of obesity: longitudinal analysis of a national cohort. World J Pediatr. 2019; 15: 390-397. doi: 10.1007/s12519-018-00223-1. Epub 2019 Jan 12. PMID: 30635840.
- Block JP, Bailey LC, Gillman MW, Lunsford D, Daley MF, Eneli I, et al. Early Antibiotic Exposure and Weight Outcomes in Young Children. Pediatrics. 2018; 142: e20180290. doi: 10.1542/peds.2018-0290. Epub 2018 Oct 31. Erratum in: Pediatrics. 2019 Feb;143(2):e20183555. doi: 10.1542/peds.2018-3555. PMID: 30381474; PMCID: PMC6317759.
- Miller SA, Wu RKS, Oremus M. The association between antibiotic use in infancy and childhood overweight or obesity: a systematic review and meta-analysis. Obes Rev. 2018; 19: 1463-1475. doi: 10.1111/obr.12717. Epub 2018 Jul 23. PMID: 30035851.
- Korpela K, Zijlmans MA, Kuitunen M, Kukkonen K, Savilahti E, Salonen A, et al. Childhood BMI in relation to microbiota in infancy and lifetime antibiotic use. Microbiome. 2017; 5: 26. doi: 10.1186/s40168-017-0245-y. PMID: 28253911; PMCID: PMC5335838.
- Scott FI, Horton DB, Mamtani R, Haynes K, Goldberg DS, Lee DY, et al. Administration of Antibiotics to Children Before Age 2 Years Increases Risk for Childhood Obesity. Gastroenterology. 2016; 151: 120-129.e5. doi: 10.1053/j.gastro.2016.03.006. Epub 2016 Mar 18. PMID: 27003602; PMCID: PMC4924569.
- Dydensborg Sander S, Nybo Andersen AM, Murray JA, Karlstad Ø, Husby S, Størdal K. Association Between Antibiotics in the First Year of Life and Celiac Disease. Gastroenterology. 2019; 156: 2217-2229. doi: 10.1053/j.gastro.2019.02.039. Epub 2019 Mar 2. PMID: 30836095.
- Köhler-Forsberg O, Petersen L, Gasse C, Mortensen PB, Dalsgaard S, Yolken RH, et al. A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents. JAMA Psychiatry. 2019; 76: 271-279. doi: 10.1001/jamapsychiatry.2018.3428. PMID: 30516814; PMCID: PMC6439826.
- Hviid A, Svanström H, Frisch M. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011; 60: 49-54. doi: 10.1136/gut.2010.219683. Epub 2010 Oct 21. PMID: 20966024.
- Slykerman RF, Coomarasamy C, Wickens K, Thompson JMD, Stanley TV, Barthow C, et al. Exposure to antibiotics in the first 24 months of life and neurocognitive outcomes at 11 years of age. Psychopharmacology (Berl). 2019; 236: 1573-1582. doi: 10.1007/s00213-019-05216-0. Epub 2019 Apr 30. PMID: 31041458.
- Pérez-Cobas AE, Gosalbes MJ, Friedrichs A, Knecht H, Artacho A, Eismann K, et al. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut. 2013; 62: 1591-601. doi: 10.1136/gutjnl-2012-303184. Epub 2012 Dec 12. PMID: 23236009; PMCID: PMC3812899.
- Zhang L, Huang Y, Zhou Y, Buckley T, Wang HH. Antibiotic administration routes significantly influence the levels of antibiotic resistance in gut microbiota. Antimicrob Agents Chemother. 2013; 57: 3659-3666. doi: 10.1128/AAC.00670-13. Epub 2013 May 20. PMID: 23689712; PMCID: PMC3719697.
- Committee EW. Public Health England. English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) 2010 to 2014. Report 2015.
- Center for Disease Dynamics, E. & P. State of the World’s Antibiotics, 2015. 2015.
- Langdon A, Crook N, Dantas G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 2016; 8: 39. doi: 10.1186/s13073-016-0294-z. PMID: 27074706; PMCID: PMC4831151.
- Andrews JM. Determination of minimum inhibitory concentrations. J. Antimicrob. Chemother. 2001; 48: 5–16.
- Munyaka PM, Khafipour E, Ghia JE. External influence of early childhood establishment of gut microbiota and subsequent health implications. Front Pediatr. 2014; 2: 109. doi: 10.3389/fped.2014.00109. PMID: 25346925; PMCID: PMC4190989.
- Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol. 2011; 9: 244-253. doi: 10.1038/nrmicro2537. Erratum in: Nat Rev Microbiol. 2011; 9(8): 626. PMID: 21407241; PMCID: PMC3535073.
- Biesbroek G, Tsivtsivadze E, Sanders EA, Montijn R, Veenhoven RH, Keijser BJ, et al. Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. Am J Respir Crit Care Med. 2014; 190: 1283-1292. doi: 10.1164/rccm.201407-1240OC. PMID: 25329446.
- Martin DH. The microbiota of the vagina and its influence on women's health and disease. Am J Med Sci. 2012; 343: 2-9. doi: 10.1097/MAJ.0b013e31823ea228. PMID: 22143133; PMCID: PMC3248621.
- Whiteside SA, Razvi H, Dave S, Reid G, Burton JP. The microbiome of the urinary tract--a role beyond infection. Nat Rev Urol. 2015; 12: 81-90. doi: 10.1038/nrurol.2014.361. Epub 2015 Jan 20. PMID: 25600098.
- King S, Tancredi D, Lenoir-Wijnkoop I, Gould K, Vann H, Connors G, et al. Does probiotic consumption reduce antibiotic utilization for common acute infections? A systematic review and meta-analysis. Eur J Public Health. 2019; 29: 494-499. doi: 10.1093/eurpub/cky185. PMID: 30219897; PMCID: PMC6532828.
- Oldenburg CE, Sié A, Coulibaly B, Ouermi L, Dah C, Tapsoba C, et al. Effect of Commonly Used Pediatric Antibiotics on Gut Microbial Diversity in Preschool Children in Burkina Faso: A Randomized Clinical Trial. Open Forum Infect Dis. 2018; 5: ofy289. doi: 10.1093/ofid/ofy289. Erratum in: Open Forum Infect Dis. 2023 Oct 06;10(10):ofad489. doi: 10.1093/ofid/ofad489. PMID: 30515431; PMCID: PMC6262116.
- Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016; 7: 10410. doi: 10.1038/ncomms10410. PMID: 26811868; PMCID: PMC4737757.
- Falony G, Joossens M, Vieira-Silva S, Wang J, Darzi Y, Faust K, et al, Raes J. Population-level analysis of gut microbiome variation. Science. 2016; 352: 560-564. doi: 10.1126/science.aad3503. Epub 2016 Apr 28. PMID: 27126039.
- Yassour M, Vatanen T, Siljander H, Hämäläinen AM, Härkönen T, Ryhänen SJ, et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med. 2016; 8: 343ra81. doi: 10.1126/scitranslmed.aad0917. PMID: 27306663; PMCID: PMC5032909.
- Parker EPK, Praharaj I, John J, Kaliappan SP, Kampmann B, Kang G, et al. Changes in the intestinal microbiota following the administration of azithromycin in a randomised placebo-controlled trial among infants in south India. Sci Rep. 2017; 7: 9168. doi: 10.1038/s41598-017-06862-0. PMID: 28835659; PMCID: PMC5569098.
- Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev. 2007; 20: 593-621. doi: 10.1128/CMR.00008-07. PMID: 17934076; PMCID: PMC2176045.
- Vihta KD, Stoesser N, Llewelyn MJ, Quan TP, Davies T, Fawcett NJ, et al. Trends over time in Escherichia coli bloodstream infections, urinary tract infections, and antibiotic susceptibilities in Oxfordshire, UK, 1998-2016: a study of electronic health records. Lancet Infect Dis. 2018; 18: 1138-1149. doi: 10.1016/S1473-3099(18)30353-0. Epub 2018 Aug 17. PMID: 30126643; PMCID: PMC7612540.
- Yao J, Carter RA, Vuagniaux G, Barbier M, Rosch JW, Rock CO. A Pathogen-Selective Antibiotic Minimizes Disturbance to the Microbiome. Antimicrob Agents Chemother. 2016; 60: 4264-4273. doi: 10.1128/AAC.00535-16. PMID: 27161626; PMCID: PMC4914625.
- Ponziani FR, Pecere S, Lopetuso L, Scaldaferri F, Cammarota G, Gasbarrini A. Rifaximin for the treatment of irritable bowel syndrome - a drug safety evaluation. Expert Opin Drug Saf. 2016; 15: 983-991. doi: 10.1080/14740338.2016.1186639. Epub 2016 May 23. PMID: 27149541.
- Lopetuso LR, Petito V, Scaldaferri F, Gasbarrini A. Gut Microbiota Modulation and Mucosal Immunity: Focus on Rifaximin. Mini Rev Med Chem. 2015; 16: 179-185. doi: 10.2174/138955751603151126121633. PMID: 26643042.
- Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, et al. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010; 3: 148-158. doi: 10.1038/mi.2009.132. Epub 2009 Nov 25. PMID: 19940845; PMCID: PMC2824244.
- Koning CJ, Jonkers D, Smidt H, Rombouts F, Pennings HJ, Wouters E, et al. The effect of a multispecies probiotic on the composition of the faecal microbiota and bowel habits in chronic obstructive pulmonary disease patients treated with antibiotics. Br J Nutr. 2010; 103: 1452-1460. doi: 10.1017/S0007114509993497. Epub 2009 Dec 21. PMID: 20021703.
- Dubourg G, Lagier JC, Robert C, Armougom F, Hugon P, Metidji S, et al. Culturomics and pyrosequencing evidence of the reduction in gut microbiota diversity in patients with broad-spectrum antibiotics. Int J Antimicrob Agents. 2014; 44: 117-124. doi: 10.1016/j.ijantimicag.2014.04.020. Epub 2014 Jun 14. PMID: 25063078.
- Becattini S, Taur Y, Pamer EG. Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. Trends Mol Med. 2016; 22: 458-478. doi: 10.1016/j.molmed.2016.04.003. Epub 2016 May 10. PMID: 27178527; PMCID: PMC4885777.
- Caballero S, Carter R, Ke X, Sušac B, Leiner IM, Kim GJ, et al. Distinct but Spatially Overlapping Intestinal Niches for Vancomycin-Resistant Enterococcus faecium and Carbapenem-Resistant Klebsiella pneumoniae. PLoS Pathog. 2015; 11: e1005132. doi: 10.1371/journal.ppat.1005132. PMID: 26334306; PMCID: PMC4559429.
- Lange K, Buerger M, Stallmach A, Bruns T. Effects of Antibiotics on Gut Microbiota. Dig Dis. 2016; 34 :260-268. doi: 10.1159/000443360. Epub 2016 Mar 30. PMID: 27028893.
- Tanaka S, Kobayashi T, Songjinda P, Tateyama A, Tsubouchi M, Kiyohara C, et al. Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota. FEMS Immunol Med Microbiol. 2009; 56: 80-87. doi: 10.1111/j.1574-695X.2009.00553.x. Epub 2009 Apr 6. PMID: 19385995.
- Kim DH. Gut Microbiota-Mediated Drug-Antibiotic Interactions. Drug Metab Dispos. 2015; 43: 1581-1589. doi: 10.1124/dmd.115.063867. Epub 2015 Apr 29. PMID: 25926432.
- Stiefel U, Tima MA, Nerandzic MM. Metallo-β-lactamase-producing bacteroides species can shield other members of the gut microbiota from antibiotics. Antimicrob Agents Chemother. 2015; 59: 650-653. doi: 10.1128/AAC.03719-14. Epub 2014 Oct 6. PMID: 25288080; PMCID: PMC4291410.
- Citron DM, Tyrrell KL, Dale SE, Chesnel L, Goldstein EJ. Impact of Surotomycin on the Gut Microbiota of Healthy Volunteers in a Phase 1 Clinical Trial. Antimicrob Agents Chemother. 2016; 60: 2069-2074. doi: 10.1128/AAC.02531-15. PMID: 26787687; PMCID: PMC4808227.
- O'Sullivan O, Coakley M, Lakshminarayanan B, Conde S, Claesson MJ, Cusack S, et al. Alterations in intestinal microbiota of elderly Irish subjects post-antibiotic therapy. J Antimicrob Chemother. 2013; 68: 214-221. doi: 10.1093/jac/dks348. Epub 2012 Sep 4. PMID: 22949626.
- Soares GM, Teles F, Starr JR, Feres M, Patel M, Martin L, et al. Effects of azithromycin, metronidazole, amoxicillin, and metronidazole plus amoxicillin on an in vitro polymicrobial subgingival biofilm model. Antimicrob Agents Chemother. 2015; 59: 2791-2798. doi: 10.1128/AAC.04974-14. Epub 2015 Mar 2. PMID: 25733510; PMCID: PMC4394767.
- Mayer BT, Srinivasan S, Fiedler TL, Marrazzo JM, Fredricks DN, Schiffer JT. Rapid and Profound Shifts in the Vaginal Microbiota Following Antibiotic Treatment for Bacterial Vaginosis. J Infect Dis. 2015; 212: 793-802. doi: 10.1093/infdis/jiv079. Epub 2015 Feb 12. PMID: 25676470; PMCID: PMC4539900.
- Macklaim JM, Clemente JC, Knight R, Gloor GB, Reid G. Changes in vaginal microbiota following antimicrobial and probiotic therapy. Microb Ecol Health Dis. 2015; 26: 27799. doi: 10.3402/mehd.v26.27799. PMID: 26282697; PMCID: PMC4539393.
- Ponziani FR, Scaldaferri F, Petito V, Paroni Sterbini F, Pecere S, Lopetuso LR, et al. The Role of Antibiotics in Gut Microbiota Modulation: The Eubiotic Effects of Rifaximin. Dig Dis. 2016; 34: 269-278. doi: 10.1159/000443361. Epub 2016 Mar 30. PMID: 27027301.
- Maccaferri S, Vitali B, Klinder A, Kolida S, Ndagijimana M, Laghi L, Calanni F, et al. Rifaximin modulates the colonic microbiota of patients with Crohn's disease: an in vitro approach using a continuous culture colonic model system. J Antimicrob Chemother. 2010; 65: 2556-2565. doi: 10.1093/jac/dkq345. Epub 2010 Sep 18. PMID: 20852272.
- DuPont HL. Review article: the antimicrobial effects of rifaximin on the gut microbiota. Aliment Pharmacol Ther. 2016; 43: 3-10. doi: 10.1111/apt.13434. PMID: 26618921.
- Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 2012; 13: R79. doi: 10.1186/gb-2012-13-9-r79. PMID: 23013615; PMCID: PMC3506950.
- Stewardson AJ, Gaïa N, François P, Malhotra-Kumar S, Delémont C, Martinez de Tejada B, et al. Collateral damage from oral ciprofloxacin versus nitrofurantoin in outpatients with urinary tract infections: a culture-free analysis of gut microbiota. Clin Microbiol Infect. 2015; 21: 344.e1-e11. doi: 10.1016/j.cmi.2014.11.016. Epub 2014 Nov 25. PMID: 25658522.
- Iapichino G, Callegari ML, Marzorati S, Cigada M, Corbella D, Ferrari S, et al. Impact of antibiotics on the gut microbiota of critically ill patients. J Med Microbiol. 2008; 57: 1007-1014. doi: 10.1099/jmm.0.47387-0. PMID: 18628503.
- Jeong SH, Song YK, Cho JH. Risk assessment of ciprofloxacin, flavomycin, olaquindox and colistin sulfate based on microbiological impact on human gut biota. Regul Toxicol Pharmacol. 2009; 53: 209-216. doi: 10.1016/j.yrtph.2009.01.004. Epub 2009 Jan 24. PMID: 19545513.
- Panda S, El khader I, Casellas F, López Vivancos J, García Cors M, Santiago A, et al. Short-term effect of antibiotics on human gut microbiota. PLoS One. 2014; 9: e95476. doi: 10.1371/journal.pone.0095476. PMID: 24748167; PMCID: PMC3991704.
- Pérez-Cobas AE, Artacho A, Knecht H, Ferrús ML, Friedrichs A, Ott SJ, et al. Differential effects of antibiotic therapy on the structure and function of human gut microbiota. PLoS One. 2013; 8: e80201. doi: 10.1371/journal.pone.0080201. PMID: 24282523; PMCID: PMC3839934.
- Lazarevic V, Manzano S, Gaïa N, Girard M, Whiteson K, Hibbs J, et al. Effects of amoxicillin treatment on the salivary microbiota in children with acute otitis media. Clin Microbiol Infect. 2013; 19: E335-E342. doi: 10.1111/1469-0691.12213. Epub 2013 Apr 9. PMID: 23565884.
- Ladirat SE, Schols HA, Nauta A, Schoterman MH, Keijser BJ, Montijn RC, et al. High-throughput analysis of the impact of antibiotics on the human intestinal microbiota composition. J Microbiol Methods. 2013; 92: 387-397. doi: 10.1016/j.mimet.2012.12.011. Epub 2012 Dec 22. PMID: 23266580.
- Rashid MU, Weintraub A, Nord CE. Development of antimicrobial resistance in the normal anaerobic microbiota during one year after administration of clindamycin or ciprofloxacin. Anaerobe. 2015; 31:72-77. doi: 10.1016/j.anaerobe.2014.10.004. Epub 2014 Oct 15. PMID: 25445201.
- Johnning A, Kristiansson E, Angelin M, Marathe N, Shouche YS, Johansson A, et al. Quinolone resistance mutations in the faecal microbiota of Swedish travellers to India. BMC Microbiol. 2015; 15: 235. doi: 10.1186/s12866-015-0574-6. PMID: 26498929; PMCID: PMC4619388.
- Rashid MU, Zaura E, Buijs MJ, Keijser BJ, Crielaard W, Nord CE, et al. Determining the Long-term Effect of Antibiotic Administration on the Human Normal Intestinal Microbiota Using Culture and Pyrosequencing Methods. Clin Infect Dis. 2015; 60: S77-S84. doi: 10.1093/cid/civ137. PMID: 25922405.
- Lindgren M, Lofmark S, Edlund C, Huovinen P, Jalava J. Prolonged impact of a one-week course of clindamycin on Enterococcus spp. in human normal microbiota. Scand J Infect Dis. 2009; 41: 215-219. doi: 10.1080/00365540802651897. PMID: 19107676.
- Nyberg SD, Osterblad M, Hakanen AJ, Löfmark S, Edlund C, Huovinen P, et al. Long-term antimicrobial resistance in Escherichia coli from human intestinal microbiota after administration of clindamycin. Scand J Infect Dis. 2007; 39: 514-520. doi: 10.1080/00365540701199790. PMID: 17577812.
- Raymond F, Ouameur AA, Déraspe M, Iqbal N, Gingras H, Dridi B, et al. The initial state of the human gut microbiome determines its reshaping by antibiotics. ISME J. 2016; 10: 707-720. doi: 10.1038/ismej.2015.148. Epub 2015 Sep 11. PMID: 26359913; PMCID: PMC4817689.
- Chen T, Li S, Wei H. Antibiotic resistance capability of cultured human colonic microbiota growing in a chemostat model. Appl Biochem Biotechnol. 2014; 173: 765-774. doi: 10.1007/s12010-014-0882-6. Epub 2014 Apr 9. PMID: 24715638.
- Kim BS, Kim JN, Yoon SH, Chun J, Cerniglia CE. Impact of enrofloxacin on the human intestinal microbiota revealed by comparative molecular analysis. Anaerobe. 2012; 18: 310-320. doi: 10.1016/j.anaerobe.2012.01.003. Epub 2012 Feb 3. PMID: 22321759.
- Aloisio I, Quagliariello A, De Fanti S, Luiselli D, De Filippo C, Albanese D, et al. Evaluation of the effects of intrapartum antibiotic prophylaxis on newborn intestinal microbiota using a sequencing approach targeted to multi hypervariable 16S rDNA regions. Appl Microbiol Biotechnol. 2016; 100: 5537-5546. doi: 10.1007/s00253-016-7410-2. Epub 2016 Mar 14. PMID: 26971496.
- Arboleya S, Sánchez B, Solís G, Fernández N, Suárez M, Hernández-Barranco AM, et al. Impact of Prematurity and Perinatal Antibiotics on the Developing Intestinal Microbiota: A Functional Inference Study. Int J Mol Sci. 2016; 17: 649. doi: 10.3390/ijms17050649. PMID: 27136545; PMCID: PMC4881475.
- Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol. 2009; 7: 526-536. doi: 10.1038/nrmicro2164. PMID: 19528959.
- Abeles SR, Ly M, Santiago-Rodriguez TM, Pride DT. Effects of Long Term Antibiotic Therapy on Human Oral and Fecal Viromes. PLoS One. 2015; 10: e0134941. doi: 10.1371/journal.pone.0134941. PMID: 26309137; PMCID: PMC4550281.
- Lepage P, Leclerc MC, Joossens M, Mondot S, Blottière HM, Raes J, et al. A metagenomic insight into our gut's microbiome. Gut. 2013; 62: 146-158. doi: 10.1136/gutjnl-2011-301805. Epub 2012 Apr 23. PMID: 22525886.
- Rojo D, Gosalbes MJ, Ferrari R, Pérez-Cobas AE, Hernández E, Oltra R, et al. Clostridium difficile heterogeneously impacts intestinal community architecture but drives stable metabolome responses. ISME J. 2015; 9: 2206-2220. doi: 10.1038/ismej.2015.32. Epub 2015 Mar 10. PMID: 25756679; PMCID: PMC4579473.
- Hernández E, Bargiela R, Diez MS, Friedrichs A, Pérez-Cobas AE, Gosalbes MJ, et al. Functional consequences of microbial shifts in the human gastrointestinal tract linked to antibiotic treatment and obesity. Gut Microbes. 2013; 4: 306-315. doi: 10.4161/gmic.25321. Epub 2013 Jun 12. PMID: 23782552; PMCID: PMC3744515.
- Suzuki S, Horinouchi T, Furusawa C. Prediction of antibiotic resistance by gene expression profiles. Nat Commun. 2014; 5: 5792. doi: 10.1038/ncomms6792. PMID: 25517437; PMCID: PMC4351646.