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On the mechanism of antibiotic resistance and fecal microbiota transplantation

1 School of Mathematical Sciences, Soochow University, Suzhou 215006, P. R. China
2 Center for Systems Biology, Soochow University, Suzhou 215006, P. R. China
3 Mathematics Application Joint Laboratory of Soochow University and Suzhou Jiaoshi Intelligence Technology Co., Ltd, Soochow University, Suzhou 215006, P. R. China

Special Issues: Computational models in life sciences

Antibiotic resistance is a growing threat to human health and is caused by mainly the overuse of antibiotics in clinical medicine. Clinically, drug resistance emerges after a series of antibiotic treatments, implying that each treatment changes the intestinal flora composition and the accumulations of these changes induce the resistance. But mathematically, this cumulative effect cannot be achieved by a general population model, because the system will return to its pre-treatment state (an isolated steady state) after each cure. Based on the fact that sensitive bacteria and resistant bacteria are similar in most respects except their reactions to antibiotics, we developed a mathematical model with a specific phase-space structure: instead of isolated points, the steady states of this system compose one-dimensional manifolds (line segments). This structure explains the fundamental mechanism of antibiotic resistance: after antibiotic treatment, the system cannot return to the pretreatment healthy steady state but rather slightly moves along the manifold to a different steady state. Each use of antibiotics can change the ratio of resistant to susceptible pathogens in the host. The change the ratio can persist and accumulate, and finally promotes the emergence of antimicrobial resistance. We also assessed key factors (such as pathogen composition, the amount and composition of beneficial bacteria, medication duration and bactericidal rates of drugs) influencing the development of drug resistance. In addition, we clarified how fecal microbiota transplantation affects the treatment of antibiotic-resistant infections. The effect is essentially a transfer towards the healthy state in the phase space. Finally, based on the mechanisms revealed by the mathematical models, we suggested some strategies to delay or prevent the emergence of drug resistance. These findings not only provide a solid theoretical basis for the treatment of antimicrobial resistance, but also inspire clues to the phenomenon of drug resistance.
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Keywords drug resistance; fecal microbiota transplant; pathogens; bistability; dynamic model

Citation: Xiaxia Kang, Jie Yan, Fan Huang, Ling Yang. On the mechanism of antibiotic resistance and fecal microbiota transplantation. Mathematical Biosciences and Engineering, 2019, 16(6): 7057-7084. doi: 10.3934/mbe.2019354

References

  • 1. S. Nancey, J. Bienvenu, B. Coffin, et al., Butyrate strongly inhibits in vitro stimulated release of cytokines in blood, Dig. Dis. Sci., 47 (2002), 921–928.
  • 2. S. M. Finegold, S. E. Dowd, V. Gontcharova, et al., Pyrosequencing study of fecal microflora of autistic and control children, Anaerobe, 16 (2010), 444–453.
  • 3. A. C. Ericsson, S. Akter, M. M. Hanson, et al., Differential susceptibility to colorectal cancer due to naturally occurring gut microbiota, Oncotarget, 6 (2015), 33689–33704.
  • 4. H. E. Jakobsson, C. Jernberg, A. F. Andersson, et al., Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome, PLoS One, 5 (2010), e9836.
  • 5. L. Dethlefsen and D. A. Relman, Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation, Proc. Natl. Acad. Sci. U. S. A., 108 (2011), 4554–4561.
  • 6. J. J. Faith, J. L. Guruge, M. Charbonneau, et al., The long-term stability of the human gut microbiota, Science, 341 (2013), 1237439.
  • 7. I. Gustafsson, M. Sjolund, E. Torell, et al., Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage, J. Antimicrob. Chemother., 52 (2003), 645–650.
  • 8. D. Artis, Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut, Nat. Rev. Immunol., 8 (2008), 411–420.
  • 9. V. Bucci, C. D. Nadell and J. B. Xavier, The evolution of bacteriocin production in bacterial biofilms, Am. Nat., 178 (2008), E162–173.
  • 10. J. Zheng, M. G. Ganzle, X. B. Lin, et al., Diversity and dynamics of bacteriocins from human microbiome, Environ Microbiol, 17 (2015), 2133–2143.
  • 11. F. Zhang, B. Cui, X. He, et al., Microbiota transplantation: concept, methodology and strategy for its modernization, Protein. Cell., 9 (2018), 462–473.
  • 12. S. N. Gopalsamy, M. H. Woodworth, T. Wang, et al., The Use of Microbiome Restoration Therapeutics to Eliminate Intestinal Colonization With Multidrug-Resistant Organisms, Am. J. Med. Sci., 356 (2018), 433–440.
  • 13. Y. Wei, J. Gong, W. Zhu, et al., Fecal microbiota transplantation restores dysbiosis in patients with methicillin resistant Staphylococcus aureus enterocolitis, BMC Infect. Dis., 15 (2015), 265.
  • 14. D. Ishikawa, T. Sasaki, T. Osada, et al., Changes in Intestinal Microbiota Following Combination Therapy with Fecal Microbial Transplantation and Antibiotics for Ulcerative Colitis, Inflamm. Bowel. Dis., 23 (2017), 116–125.
  • 15. E. van Nood, A. Vrieze, M. Nieuwdorp, et al., Duodenal infusion of donor feces for recurrent Clostridium difficile, N. Engl. J. Med., 368 (2013), 407–415.
  • 16. C. Ubeda, V. Bucci, S. Caballero, et al., Intestinal microbiota containing Barnesiella species cures vancomycin-resistant Enterococcus faecium colonization, Infect. Immun., 81 (2013), 965–973.
  • 17. L. J. Brandt, American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection, Am. J. Gastroenterol., 108 (2013), 177–185.
  • 18. M. C. Zanella Terrier, M. L. Simonet, P. Bichard, et al., Recurrent Clostridium difficile infections: the importance of the intestinal microbiota, World J. Gastroenterol., 20 (2014), 7416–7423.
  • 19. S. Jamot, V. Raghunathan, K. Patel, et al., Factors Associated with the Use of Fecal Microbiota Transplant in Patients with Recurrent Clostridium difficile Infections, Infect. Control. Hosp. Epidemiol., 39 (2018), 302–306.
  • 20. G. Cammarota, G. Ianiro and A. Gasbarrini, Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review, J. Clin. Gastroenterol., 48 (2014), 693–702.
  • 21. Y. Li, A. Karlin, J. D. Loike, et al., Determination of the critical concentration of neutrophils required to block bacterial growth in tissues, J. Exp. Med., 200 (2004), 613–622.
  • 22. A. Heinken and I. Thiele, Anoxic Conditions Promote Species-Specific Mutualism between Gut Microbes In Silico, Appl. Environ. Microbiol., 81 (2015), 4049–4061.
  • 23. T. J. Wiles, M. Jemielita, R. P. Baker, et al., Host Gut Motility Promotes Competitive Exclusion within a Model Intestinal Microbiota, PLoS Biol., 14 (2016), e1002517.
  • 24. T. E. Gibson, A. Bashan, H. T. Cao, et al., On the Origins and Control of Community Types in the Human Microbiome, PLoS Comput. Biol., 12 (2016), e1004688.
  • 25. D. Gonze, L. Lahti, J. Raes, et al., Multi-stability and the origin of microbial community types, ISME J., 11 (2017), 2159–2166.
  • 26. A. L. Gomes, J. E. Galagan and D. Segre, Resource competition may lead to effective treatment of antibiotic resistant infections, PLoS One, 8 (2013), e80775.
  • 27. E. M. D'Agata, M. Dupont-Rouzeyrol, P. Magal, et al., The impact of different antibiotic regimens on the emergence of antimicrobial-resistant bacteria, PLoS One, 3 (2008), e4036.
  • 28. V. Bucci, S. Bradde, G. Biroli, et al., Social interaction, noise and antibiotic-mediated switches in the intestinal microbiota, PLoS Comput. Biol., 8 (2012), e1002497.
  • 29. S. Estrela and S. P. Brown, Community interactions and spatial structure shape selection on antibiotic resistant lineages, PLoS Comput. Biol., 14 (2018), e1006179.
  • 30. S. W. Wu, H. de Lencastre and A. Tomasz, Recruitment of the mecA gene homologue of Staphylococcus sciuri into a resistance determinant and expression of the resistant phenotype in Staphylococcus aureus, J. Bacteriol., 183 (2001), 2417–2424.
  • 31. S. Gottig, S. Riedel-Christ, A. Saleh, et al., Impact of blaNDM-1 on fitness and pathogenicity of Escherichia coli and Klebsiella pneumoniae, Int. J. Antimicrob. Agents., 47 (2016), 430–435.
  • 32. R. Freter, H. Brickner, J. Fekete, et al., Survival and implantation of Escherichia coli in the intestinal tract, Infect. Immun., 39 (1983), 686–703.
  • 33. M. P. Leatham, S. Banerjee, S. M. Autieri, et al., Precolonized human commensal Escherichia coli strains serve as a barrier to E. coli O157:H7 growth in the streptomycin-treated mouse intestine, Infect. Immun., 77 (2009), 2876–2886.
  • 34. K. Tabita, S. Sakaguchi, S. Kozaki, et al., Comparative studies on Clostridium botulinum type A strains associated with infant botulism in Japan and in California, USA, Jpn. J. Med. Sci. Biol., 43 (1990), 219–231.
  • 35. Y. Yamashiro, Gut Microbiota in Health and Disease, Ann. Nutr. Metab., 71 (2017), 242–246.
  • 36. C. Cordonnier, G. Le Bihan, J. G. Emond-Rheault, et al., Vitamin B12 Uptake by the Gut Commensal Bacteria Bacteroides thetaiotaomicron Limits the Production of Shiga Toxin by Enterohemorrhagic Escherichia coli, Toxins (Basel), 8 (2016), E14.
  • 37. R. A. Sorg, L. Lin, G. S. van Doorn, et al., Collective Resistance in Microbial Communities by Intracellular Antibiotic Deactivation, PLoS Biol., 14 (2016), e2000631.
  • 38. T. Ito, K. Okuma, X. X. Ma, et al., Insights on antibiotic resistance of Staphylococcus aureus from its whole genome: genomic island SCC, Drug Resist Updat., 6 (2003), 41–52.
  • 39. H. Nicoloff and D. I. Andersson, Indirect resistance to several classes of antibiotics in cocultures with resistant bacteria expressing antibiotic-modifying or -degrading enzymes, J. Antimicrob. Chemother., 71 (2016), 100–110.
  • 40. C. A. Lozupone, J. I. Stombaugh, J. I. Gordon, et al., Diversity, stability and resilience of the human gut microbiota, Nature, 489, (2012), 220–230.
  • 41. C. Manichanh, J. Reeder, P. Gibert, et al., Reshaping the gut microbiome with bacterial transplantation and antibiotic intake, Genome. Res., 20 (2010), 1411–1419.
  • 42. E. K. Costello, C. L. Lauber, M. Hamady, et al., Bacterial community variation in human body habitats across space and time, Science, 326 (2009), 1694–1697.
  • 43. P. J. Turnbaugh, M. Hamady, T. Yatsunenko, et al., A core gut microbiome in obese and lean twins, Nature, 457 (2009), 480–484.
  • 44. A. Uygun, K. Ozturk, H. Demirci, et al., Fecal microbiota transplantation is a rescue treatment modality for refractory ulcerative colitis, Medicine (Baltimore), 96 (2017), e6479.
  • 45. B. Cui, Q. Feng, H. Wang, et al., Fecal microbiota transplantation through mid-gut for refractory Crohn's disease: safety, feasibility, and efficacy trial results, J. Gastroenterol. Hepatol., 30 (2015), 51–58.
  • 46. C. R. Kelly, S. Kahn, P. Kashyap, et al., Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook, Gastroenterology, 149 (2015), 223–237.
  • 47. S. Vermeire, M. Joossens, K. Verbeke, et al., Donor Species Richness Determines Faecal Microbiota Transplantation Success in Inflammatory Bowel Disease, J. Crohns. Colitis, 10 (2016), 387–394.
  • 48. H. Seedorf, N. W. Griffin, V. K. Ridaura, et al., Bacteria from diverse habitats colonize and compete in the mouse gut, Cell, 159 (2014), 253–266.
  • 49. S. K. Ji, H. Yan, T. Jiang, et al., Preparing the Gut with Antibiotics Enhances Gut Microbiota Reprogramming Efficiency by Promoting Xenomicrobiota Colonization, Front. Microbiol., 8 (2017), 1208.
  • 50. D. L. Suskind, M. J. Brittnacher, G. Wahbeh, et al., Fecal microbial transplant effect on clinical outcomes and fecal microbiome in active Crohn's disease, Inflamm. Bowel. Dis., 21 (2015), 556–563.
  • 51. A. K. Seth, P. Rawal, R. Bagga, et al., Successful colonoscopic fecal microbiota transplantation for active ulcerative colitis: First report from India, Indian. J. Gastroenterol., 35 (2016), 393–395.
  • 52. S. X. Liu, Y. H. Li, W. K. Dai, et al., Fecal microbiota transplantation induces remission of infantile allergic colitis through gut microbiota re-establishment, World J. Gastroenterol., 23 (2017), 8570–8581.
  • 53. J. Zhang, J. J. Cunningham, J. S. Brown, et al., Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer, Nat. Commun., 8 (2017), 1816.
  • 54. R. B. Montgomery, E. A. Mostaghel, R. Vessella, et al., Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth, Cancer Res., 68 (2008), 4447–4454.
  • 55. J. M. Hyatt, D. E. Nix, C. W. Stratton, et al., In vitro pharmacodynamics of piperacillin, piperacillin-tazobactam, and ciprofloxacin alone and in combination against Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa, Antimicrob. Agents Chemother., 39 (1995), 1711–1716.
  • 56. D. M. Chaput de Saintonge, D. F. Levine, I. T. Savage, et al., Trial of three-day and ten-day courses of amoxycillin in otitis media, Br. Med. J. (Clin. Res. Ed.), 284 (1982), 1078–1081.
  • 57. C. Llor and L. Bjerrum, Antimicrobial resistance: risk associated with antibiotic overuse and initiatives to reduce the problem, Ther. Adv. Drug Saf., 5, (2014), 229–241.
  • 58. I. van Langeveld, R. C. Gagnon, P. F. Conrad, et al., Multiple-Drug Resistance in Burn Patients: A Retrospective Study on the Impact of Antibiotic Resistance on Survival and Length of Stay, J. Burn. Care. Res., 38, (2017), 99–105.

 

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