Advertisement

Antibiotic effects on gut microbiota, metabolism, and beyond

  • Chunlong Mu
  • Weiyun ZhuEmail author
Mini-Review

Abstract

Current advances on gut microbiota have broadened our view on host-microbiota interactions. As a microbiota-targeted approach, the use of antibiotics has been widely adopted to explore the role of gut microbiota in vivo. Antibiotics can change the microbial composition, resulting in varied effects, depending on the antibiotic class, dosage, and duration. Antibiotic intervention in early life leads to life-long phenotype alterations, including obesity. Antibiotic-induced changes in gut microbiota affect the epithelial utilization of both macronutrients (e.g., amino acids) and micronutrients (e.g., copper, vitamin E) and the redox homeostasis. Of particular interest is the regulation of gut anaerobiosis and aerobiosis by oxygen availability, which is closely related to epithelial metabolism. Additionally, antibiotic interventions enable to identify novel roles of gut microbiota in gut-liver axis and gut-brain axis. Indigenous antimicrobial molecules are produced by certain microbes, and they have the potential to affect function through eliciting changes in the gut microbiota. This review discusses at length these findings to gain a better and novel insight into microbiota-host interactions and the mechanisms involved.

Keywords

Microbial composition Nutrient utilization Redox potential Gut-liver axis Gut-brain axis Indigenous antimicrobial molecules 

Notes

Funding information

This work was funded by the Natural Science Foundation of China (31430082) and National Key Basic Research Program of China (2013CB127300).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. Azevedo AC, Bento CB, Ruiz JC, Queiroz MV, Mantovani HC (2015) Distribution and genetic diversity of bacteriocin gene clusters in rumen microbial genomes. Appl Environ Microbiol 81:7290–7304PubMedPubMedCentralCrossRefGoogle Scholar
  2. Becattini S, Taur Y, Pamer EG (2016) Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med 22:458–478PubMedPubMedCentralCrossRefGoogle Scholar
  3. Behr C, Slopianka M, Haake V, Strauss V, Sperber S, Kamp H, Walk T, Beekmann K, Rietjens I, van Ravenzwaay B (2019) Analysis of metabolome changes in the bile acid pool in feces and plasma of antibiotic-treated rats. Toxicol Appl Pharmacol 363:79–87PubMedCrossRefGoogle Scholar
  4. Brussow H (2015) Growth promotion and gut microbiota: insights from antibiotic use. Environ Microbiol 17:2216–2227PubMedCrossRefGoogle Scholar
  5. Byndloss MX, Olsan EE, Rivera-Chávez F, Tiffany CR, Cevallos SA, Lokken KL, Torres TP, Byndloss AJ, Faber F, Gao Y (2017) Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357:570–575PubMedPubMedCentralCrossRefGoogle Scholar
  6. Caputi V, Marsilio I, Filpa V, Cerantola S, Orso G, Bistoletti M, Paccagnella N, De Martin S, Montopoli M, Dall'Acqua S, Crema F, Di Gangi IM, Galuppini F, Lante I, Bogialli S, Rugge M, Debetto P, Giaroni C, Giron MC (2017) Antibiotic-induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice. Br J Pharmacol 174:3623–3639PubMedPubMedCentralCrossRefGoogle Scholar
  7. Champagne-Jorgensen K, Kunze WA, Forsythe P, Bienenstock J, McVey Neufeld KA (2019) Antibiotics and the nervous system: more than just the microbes? Brain Behav Immun 77:7–15PubMedCrossRefGoogle Scholar
  8. Chatzispyrou IA, Held NM, Mouchiroud L, Auwerx J, Houtkooper RH (2015) Tetracycline antibiotics impair mitochondrial function and its experimental use confounds research. Cancer Res 75:4446–4449PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chevalier C, Stojanovic O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, Rigo D, Fabbiano S, Stevanovic A, Hagemann S, Montet X, Seimbille Y, Zamboni N, Hapfelmeier S, Trajkovski M (2015) Gut microbiota orchestrates energy homeostasis during cold. Cell 163:1360–1374PubMedCrossRefGoogle Scholar
  10. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, Khiabanian H, Adeyemi A, Bataller R, Lefkowitch JH, Bower M, Friedman R, Sartor RB, Rabadan R, Schwabe RF (2012) Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21:504–516PubMedPubMedCentralCrossRefGoogle Scholar
  11. Desbonnet L, Clarke G, Traplin A, O’Sullivan O, Crispie F, Moloney RD, Cotter PD, Dinan TG, Cryan JF (2015) Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav Immun 48:165–173PubMedCrossRefGoogle Scholar
  12. Djaldetti M, Nachmias N, Bessler H (2016) The effect of antibiotics on cytokine production by mononuclear cells and the cross-talk with colon cancer cells. J Pharm Pharmacog Res 4:134–143Google Scholar
  13. Espey MG (2013) Role of oxygen gradients in shaping redox relationships between the human intestine and its microbiota. Free Radic Biol Med 55:130–140PubMedCrossRefGoogle Scholar
  14. Gao K, Pi Y, Mu CL, Peng Y, Huang Z, Zhu WY (2018) Antibiotics-induced modulation of large intestinal microbiota altered aromatic amino acid profile and expression of neurotransmitters in the hypothalamus of piglets. J Neurochem 146:219–234PubMedCrossRefGoogle Scholar
  15. Gao K, Pi Y, Mu CL, Farzi A, Liu Z, Zhu WY (2019) Increasing carbohydrate availability in the hindgut promotes hypothalamic neurotransmitter synthesis: aromatic amino acids linking the microbiota-brain axis. J Neurochem 149:641–659PubMedCrossRefGoogle Scholar
  16. Garcia-Gutierrez E, Mayer MJ, Cotter PD, Narbad A (2019) Gut microbiota as a source of novel antimicrobials. Gut Microbes 10:1–21PubMedCrossRefGoogle Scholar
  17. Guida F, Turco F, Iannotta M, De Gregorio D, Palumbo I, Sarnelli G, Furiano A, Napolitano F, Boccella S, Luongo L, Mazzitelli M, Usiello A, De Filippis F, Iannotti FA, Piscitelli F, Ercolini D, de Novellis V, Di Marzo V, Cuomo R, Maione S (2018) Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. Brain Behav Immun 67:230–245PubMedCrossRefGoogle Scholar
  18. Hildebrand F, Moitinho-Silva L, Blasche S, Jahn MT, Gossmann TI, Heuerta-Cepas J, Hercog R, Luetge M, Bahram M, Pryszlak A, Alves RJ, Waszak SM, Zhu A, Ye L, Costea PI, Aalvink S, Belzer C, Forslund SK, Sunagawa S, Hentschel U, Merten C, Patil KR, Benes V, Bork P (2019) Antibiotics-induced monodominance of a novel gut bacterial order. Gut 68:1781–1790PubMedCrossRefGoogle Scholar
  19. Hoban AE, Stilling RM, Moloney GM, Moloney RD, Shanahan F, Dinan TG, Cryan JF, Clarke G (2017) Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. Microbiome 5:102PubMedPubMedCentralCrossRefGoogle Scholar
  20. Ianiro G, Tilg H, Gasbarrini A (2016) Antibiotics as deep modulators of gut microbiota: between good and evil. Gut 65:1906–1915PubMedCrossRefGoogle Scholar
  21. Inoue Y, Fukui H, Xu X, Kondo T, Kono T, Tozawa K, Ohda Y, Tomita T, Oshima T, Watari J (2018) Sa1592-Antibiotics treatment prolongs gastrointestinal transit time accompanied by increase of colonic Glp-1/Gpr43 expression. Gastroenterology 154:S-324CrossRefGoogle Scholar
  22. Johnson TA, Looft T, Severin AJ, Bayles DO, Nasko DJ, Wommack KE, Howe A,Allen HK (2017) The in-feed antibiotic carbadox induces phage gene transcription in the swine gut microbiome. MBio 8:e00709-17Google Scholar
  23. Kang JD, Myers CJ, Harris SC, Kakiyama G, Lee I-K, Yun B-S, Matsuzaki K, Furukawa M, Min H-K, Bajaj JS (2019) Bile acid 7α-dehydroxylating gut bacteria secrete antibiotics that inhibit Clostridium difficile: Role of secondary bile acids. Cell Chem Biol 26:27–34 e24PubMedCrossRefGoogle Scholar
  24. Kuno T, Hirayama-Kurogi M, Ito S, Ohtsuki S (2019) Proteomic analysis of small intestinal epithelial cells in antibiotic-treated mice: changes in drug transporters and metabolizing enzymes. Drug Metab Pharmacokinet 34(2):159–162PubMedCrossRefGoogle Scholar
  25. Leclercq S, Mian FM, Stanisz AM, Bindels LB, Cambier E, Ben-Amram H, Koren O, Forsythe P, Bienenstock J (2017) Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat Commun 8:15062PubMedPubMedCentralCrossRefGoogle Scholar
  26. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517:455–459PubMedCrossRefGoogle Scholar
  27. Litvak Y, Byndloss MX, Tsolis RM, Baumler AJ (2017) Dysbiotic Proteobacteria expansion: a microbial signature of epithelial dysfunction. Curr Opin Microbiol 39:1–6PubMedCrossRefGoogle Scholar
  28. Litvak Y, Byndloss MX, Baumler AJ (2018) Colonocyte metabolism shapes the gut microbiota. Science 362(6418):eaat9076PubMedPubMedCentralCrossRefGoogle Scholar
  29. Liu J, Wu M, He J, Xiao C, Xue Y, Fu T, Lin C, Dong D, Li Z (2018) Antibiotic-induced dysbiosis of gut microbiota impairs corneal nerve regeneration by affecting CCR2-negative macrophage distribution. Am J Pathol 188:2786–2799PubMedCrossRefGoogle Scholar
  30. Livanos AE, Greiner TU, Vangay P, Pathmasiri W, Stewart D, McRitchie S, Li H, Chung J, Sohn J, Kim S, Gao Z, Barber C, Kim J, Ng S, Rogers AB, Sumner S, Zhang XS, Cadwell K, Knights D, Alekseyenko A, Backhed F, Blaser MJ (2016) Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol 1:16140PubMedPubMedCentralCrossRefGoogle Scholar
  31. Looft T, Johnson TA, Allen HK, Bayles DO, Alt DP, Stedtfeld RD, Sul WJ, Stedtfeld TM, Chai B, Cole JR, Hashsham SA, Tiedje JM, Stanton TB (2012) In-feed antibiotic effects on the swine intestinal microbiome. Proc Natl Acad Sci U S A 109:1691–1696PubMedPubMedCentralCrossRefGoogle Scholar
  32. Looft T, Allen HK, Cantarel BL, Levine UY, Bayles DO, Alt DP, Henrissat B, Stanton TB (2014) Bacteria, phages and pigs: the effects of in-feed antibiotics on the microbiome at different gut locations. ISME J 8:1566PubMedPubMedCentralCrossRefGoogle Scholar
  33. Lowe PP, Gyongyosi B, Satishchandran A, Iracheta-Vellve A, Cho Y, Ambade A, Szabo G (2018) Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression. J Neuroinflammation 15:298PubMedPubMedCentralCrossRefGoogle Scholar
  34. Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, Agdashian D, Terabe M, Berzofsky JA, Fako V, Ritz T, Longerich T, Theriot CM, McCulloch JA, Roy S, Yuan W, Thovarai V, Sen SK, Ruchirawat M, Korangy F, Wang XW, Trinchieri G,Greten TF (2018) Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360:eaan5931PubMedPubMedCentralCrossRefGoogle Scholar
  35. Manrique P, Bolduc B, Walk ST, van der Oost J, de Vos WM, Young MJ (2016) Healthy human gut phageome. Proc Natl Acad Sci U S A 113:10400–10405PubMedPubMedCentralCrossRefGoogle Scholar
  36. Miller KA, Vicentini FA, Hirota SA, Sharkey KA, Wieser ME (2019) Antibiotic treatment affects the expression levels of copper transporters and the isotopic composition of copper in the colon of mice. Proc Natl Acad Sci U S A 116:5955–5960PubMedPubMedCentralCrossRefGoogle Scholar
  37. Modi SR, Lee HH, Spina CS, Collins JJ (2013) Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499:219–222PubMedPubMedCentralCrossRefGoogle Scholar
  38. Mu C, Yang Y, Zhu W (2016) Gut microbiota: the brain peacekeeper. Front Microbiol 7:345PubMedPubMedCentralGoogle Scholar
  39. Mu C, Yang Y, Su Y, Zoetendal EG, Zhu W (2017a) Differences in microbiota membership along the gastrointestinal tract of piglets and their differential alterations following an early-life antibiotic intervention. Front Microbiol 8:797PubMedPubMedCentralCrossRefGoogle Scholar
  40. Mu C, Yang Y, Yu K, Yu M, Zhang C, Su Y, Zhu W (2017b) Alteration of metabolomic markers of amino-acid metabolism in piglets with in-feed antibiotics. Amino Acids 49:771–781PubMedCrossRefGoogle Scholar
  41. Nogacka AM, Salazar N, Arboleya S, Suarez M, Fernandez N, Solis G, de Los Reyes-Gavilan CG, Gueimonde M (2018) Early microbiota, antibiotics and health. Cell Mol Life Sci 75:83–91PubMedCrossRefGoogle Scholar
  42. Olishevska S, Nickzad A, Deziel E (2019) Bacillus and Paenibacillus secreted polyketides and peptides involved in controlling human and plant pathogens. Appl Microbiol Biotechnol 103:1189–1215PubMedCrossRefGoogle Scholar
  43. Ooijevaar RE, Terveer EM, Verspaget HW, Kuijper EJ, Keller JJ (2019) Clinical application and potential of fecal microbiota transplantation. Annu Rev Med 70:335–351PubMedCrossRefGoogle Scholar
  44. Palleja A, Mikkelsen KH, Forslund SK, Kashani A, Allin KH, Nielsen T, Hansen TH, Liang S, Feng Q, Zhang C, Pyl PT, Coelho LP, Yang H, Wang J, Typas A, Nielsen MF, Nielsen HB, Bork P, Wang J, Vilsboll T, Hansen T, Knop FK, Arumugam M, Pedersen O (2018) Recovery of gut microbiota of healthy adults following antibiotic exposure. Nat Microbiol 3:1255–1265PubMedCrossRefGoogle Scholar
  45. Pi Y, Gao K, Peng Y, Mu CL, Zhu WY (2019) Antibiotic-induced alterations of the gut microbiota and microbial fermentation in protein parallel the changes in host nitrogen metabolism of growing pigs. Animal 13:262–272PubMedCrossRefGoogle Scholar
  46. Ran L, Liu AB, Lee MJ, Xie P, Lin Y, Yang CS (2019) Effects of antibiotics on degradation and bioavailability of different vitamin E forms in mice. Biofactors 45:450–462PubMedCrossRefGoogle Scholar
  47. Reese AT, Cho EH, Klitzman B, Nichols SP, Wisniewski NA, Villa MM, Durand HK, Jiang S, Midani FS, Nimmagadda SN, O’Connell TM, Wright JP, Deshusses MA,David LA (2018) Antibiotic-induced changes in the microbiota disrupt redox dynamics in the gut. Elife 7:e35987Google Scholar
  48. Rivera-Chavez F, Zhang LF, Faber F, Lopez CA, Byndloss MX, Olsan EE, Xu G, Velazquez EM, Lebrilla CB, Winter SE, Baumler AJ (2016) Depletion of butyrate-producing Clostridia from the gut microbiota drives an aerobic luminal expansion of Salmonella. Cell Host Microbe 19:443–454PubMedPubMedCentralCrossRefGoogle Scholar
  49. Rizzatti G, Ianiro G, Gasbarrini A (2018) Antibiotic and modulation of microbiota: a new paradigm? J Clin Gastroenterol 52:S74–S77PubMedCrossRefGoogle Scholar
  50. Roychowdhury S, Cadnum J, Glueck B, Obrenovich M, Donskey C, Cresci GAM (2018) Faecalibacterium prausnitzii and a prebiotic protect intestinal health in a mouse model of antibiotic and Clostridium difficile exposure. JPEN J Parenter Enteral Nutr 42:1156–1167PubMedPubMedCentralCrossRefGoogle Scholar
  51. Schulfer AF, Battaglia T, Alvarez Y, Bijnens L, Ruiz VE, Ho M, Robinson S, Ward T, Cox LM, Rogers AB, Knights D, Sartor RB, Blaser MJ (2018) Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat Microbiol 3:234–242PubMedCrossRefGoogle Scholar
  52. Schulfer AF, Schluter J, Zhang Y, Brown Q, Pathmasiri W, McRitchie S, Sumner S, Li H, Xavier JB, Blaser MJ (2019) The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes. ISME J 13(5):1280–1292PubMedPubMedCentralCrossRefGoogle Scholar
  53. Sherwin E, Dinan TG, Cryan JF (2018) Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann N Y Acad Sci 1420:5–25PubMedCrossRefGoogle Scholar
  54. Soto M, Herzog C, Pacheco JA, Fujisaka S, Bullock K, Clish CB, Kahn CR (2018) Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism. Mol Psychiatry 23:2287PubMedPubMedCentralCrossRefGoogle Scholar
  55. Sprockett D, Fukami T, Relman DA (2018) Role of priority effects in the early-life assembly of the gut microbiota. Nat Rev Gastroenterol Hepatol 15:197–205PubMedPubMedCentralCrossRefGoogle Scholar
  56. Stanisavljevic S, Cepic A, Bojic S, Veljovic K, Mihajlovic S, Dedovic N, Jevtic B, Momcilovic M, Lazarevic M, Mostarica Stojkovic M, Miljkovic D, Golic N (2019) Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats. Sci Rep 9:918PubMedPubMedCentralCrossRefGoogle Scholar
  57. Stark CM, Susi A, Emerick J, Nylund CM (2019) Antibiotic and acid-suppression medications during early childhood are associated with obesity. Gut 68:62–69PubMedCrossRefGoogle Scholar
  58. Suter PM, Golner BB, Goldin BR, Morrow FD, Russell RM (1991) Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. Gastroenterology 101:1039–1045PubMedCrossRefGoogle Scholar
  59. Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, Holmes E (2011) Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A 108(Suppl 1):4523–4530PubMedCrossRefGoogle Scholar
  60. Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R (2018) The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 15:397–411PubMedPubMedCentralCrossRefGoogle Scholar
  61. Ubeda C, Pamer EG (2012) Antibiotics, microbiota, and immune defense. Trends Immunol 33:459–466PubMedPubMedCentralCrossRefGoogle Scholar
  62. Vrieze A, Out C, Fuentes S, Jonker L, Reuling I, Kootte RS, van Nood E, Holleman F, Knaapen M, Romijn JA, Soeters MR, Blaak EE, Dallinga-Thie GM, Reijnders D, Ackermans MT, Serlie MJ, Knop FK, Holst JJ, van der Ley C, Kema IP, Zoetendal EG, de Vos WM, Hoekstra JB, Stroes ES, Groen AK, Nieuwdorp M (2014) Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol 60:824–831PubMedCrossRefGoogle Scholar
  63. Xiao H, Shao F, Wu M, Ren W, Xiong X, Tan B, Yin Y (2015) The application of antimicrobial peptides as growth and health promoters for swine. J Anim Sci Biotechnol 6:19PubMedPubMedCentralCrossRefGoogle Scholar
  64. Yu M, Mu C, Yang Y, Zhang C, Su Y, Huang Z, Yu K, Zhu W (2017a) Increases in circulating amino acids with in-feed antibiotics correlated with gene expression of intestinal amino acid transporters in piglets. Amino Acids 49:1587–1599PubMedCrossRefGoogle Scholar
  65. Yu M, Zhang C, Yang Y, Mu C, Su Y, Yu K, Zhu W (2017b) Long-term effects of early antibiotic intervention on blood parameters, apparent nutrient digestibility, and fecal microbial fermentation profile in pigs with different dietary protein levels. J Anim Sci Biotechnol 8:60PubMedPubMedCentralCrossRefGoogle Scholar
  66. Zarrinpar A, Chaix A, Xu ZZ, Chang MW, Marotz CA, Saghatelian A, Knight R, Panda S (2018) Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism. Nat Commun 9:2872PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and TechnologyNanjing Agricultural UniversityNanjingChina
  2. 2.National Center for International Research on Animal Gut NutritionNanjing Agricultural UniversityNanjingChina

Personalised recommendations