Probiotic Lactobacillus reuteri DSM 17938: what is known about it today?

The review is devoted to the analysis of data on the effects of Lactobacillus reuteri DSM 17938, confirmed in clinical trials. Thanks to their antimicrobial activity, L. reuteri is able to inhibit colonization by pathogenic microorganisms and restore the composition of compensatory intestinal microbiota. Another study showed a positive protective effect of intestinal microbiota when administered L. reuteri simultaneously with antibiotics. In addition, L. reuteri supports the immune system of the human body. For example, some strains of L. reuteri may reduce the production of pro-inflammatory cytokines while stimulating the development and proliferation of regulatory T-lymphocytes. Adding L. reuteri to the diet may be attractive in terms of preventing the development of inflammatory bowel disease. The results of a recent meta-analysis confirmed the efficacy of L. reuteri in the treatment of infantile colic. Further research is aimed at finding evidence of the efficacy of L. reuteri use in children who are artificially fed, with infant colic and in children born by caesarean section.

1. World Gastroenterology Organisation Global Guidelines: Celiac Disease February 2017. doi: 10.1097/MCG.0000000000000919.

2. Oh P.L., Benson A.K., Peterson D.A., Patil P.B., Moriyama E.N., Roos S., Walter J. Diversification of the gut symbiont Lactobacillus reuteri as a result of host-driven evolution. ISME J. 2010;4:377–387. doi: 10.1038/ismej.2009.123.

3. Walter J., Britton R.A., Roos S. Host-microbial symbiosis in the vertebrate gastrointestinal tract and the Lactobacillus reuteri paradigm. Proc. Natl. Acad. Sci. U.S.A. 2011;108 (Suppl. 1):4645–4652. doi. 10.1073/pnas.1000099107.

4. Valeur N., Engel P. Carbajal N., Connolly E., Ladefoged K. Colonization and immunomodulation by Lactobacillus reuteri ATCC 55730 in the human gastrointestinal tract. Appl Environ Microbiol. 2004;70;1176–1181. doi: 10.1128/aem.70.2.1176-1181.2004.

5. Bjorkman P. Colonization of the human gastrointestinal tract by the lactic acid bacteria Lactobacillus reuteri. M.Sc. thesis, Dept. of Food Technology, University of Helsinki, Finland. 1999. Available at: https://www.biogaia.com/study/colonization-of-the-human-gastrointestinaltractby-lactobacillus-reuteri/.

6. Sinkiewicz G., Nordstrom E.A. Occurrence of Lactobacillus reuteri, lactobacilli and bifidobacteria in human breast milk. Pediatric Research. 2005;58:415. doi. 10.1080/0891060080234100.

7. Krumbeck J.A., Marsteller N.L., Frese S.A., Peterson D.A., Ramer-Tait A.E., Hutkins R.W., Walter J. Characterization of the ecological role of genes mediating acid resistance in Lactobacillus reuteri during colonization of the gastrointestinal tract. Environ Microbiol. 2016;18:2172–2184. doi: 10.1111/1462-2920.13108.

8. Seo B. J., Mun M. R., J RK., Kim C. J., Lee I., Chang Y. H., Park Y.H. Bile tolerant Lactobacillus reuteri isolated from pig feces inhibits enteric bacterial pathogens and porcine rotavirus. Vet. Res. Commun. 2010;34:323–333. doi: 10.1007/s11259-010-9357-6.

9. Sarxelin M., Tynkkynen S., Mattila-sandholm T., Vos W.M. Probiotic and other functional microbes: From markets to mechanisms. Curr. Opin. Microbiol. 2005;16:204–211. doi: 10.1016/j.copbio.2005.02.003.

10. Lewis K. Riddle of biofilm resistance. Antimicrob. Agents Chemother. 2001;45:999– 1007. doi: 10.1128/AAC.45.4.999-1007.2001.

11. Roos S., Jonsson H. A high-molecular-mass cellsurface protein from Lactobacillus reuteri 1063 adheres to mucus components. Microbiology. 2002;148(Pt 2):433–442. doi: 10.1099/00221287148-2-433.

12. Kleerebezem M., Hols P., Bernard E., Rolain T., Zhou M., Siezen R. J., P.A. Bron. The extracellular biology of the lactobacilli. FEMS Microbiol. Rev. 2010;34:199–230. doi: 10.1111/j.1574-6976.2009.00208.x.

13. Gunning A.P., Kavanaugh D., Thursby E., Etzold S., MacKenzie D.A., Juge N. Use of atomic force microscopy to study the multi-modular interaction of bacterial adhesins to mucins. Int. J. Mol. Sci. 2016;17:1854. doi: 10.3390/ijms17111854.

14. Mackenzie D. A., Jeffers F., Parker M. L., VibertVallet A., Bongaerts R. J., Roos S., Walter J., Juge N. Strain-specific diversity of mucus-binding proteins in the adhesion and aggregation properties of Lactobacillus reuteri. Microbiology. 2010;156(11):3368–3378. doi: 10.1099/mic.0.043265-0.

15. Mu Q., Tavella V.J., Luo X.M. Role of Lactobacillus reuteri in Human Health and Diseases. Front. Microbiol. 2018. doi. 10.3389/fmicb.2018.00757.

16. Navarro J.B., Mashburn-Warren L., Bakaletz L.O., Bailey M.T., Goodman S.D. Enhanced probiotic potential of Lactobacillus reuteri when delivered as a biofilm on dextranomer microspheres that contain beneficial cargo. Front. Microbiol. 2017;8:489. doi: 10.3389/fmicb.2017.00489.

17. Dobrogosz W.J., Casas I.A., Pagano G.A., Talarico T.L., Sjoberg B-M., Karlsson M. Lactobacillus reuteri and the enteric microbiota. In: The Regulatory and Protective Role of the Normal Microflora. 1989;283–292. Eds.: Grubb R., Midtvedt T., Norin E.Macmillian LTD, London.

18. Cadieux P., Wind A., Sommer P., Schaefer L., Crowley K., Britton R. A., G. Reid. Evaluation of reuterin production in urogenital probiotic Lactobacillus reuteri RC-14. Appl. Environ. Microbiol. 2008;74:4645–4649. doi: 10.1128/AEM.00139-08.

19. Wu R.Y. Lactobacillus: A probiotic modulator of gastrointestinal motility. Meducator. 2011;19:16-18.

20. Casas I.A., Dobrogosz W.J. Validation of the probiotic concept: Lactobacillus reuteri confers broad-spectrum protection against disease in humans and animals. Microbial Ecol Health Dis. 2000;12(4):247– 285. doi: 10.1080/08910600050216246-1.

21. Reuter G. The Lactobacillus and Bifidobacterium microflora of the human intestine: composition and succession. Curr Issues Intest Microbiol. 2001;2:43-53. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11721280.

22. Axelsson L., Chung T.C., Dobrogosz W., Lindgren S.E. Production of a broad spectrum antimicrobial substance by Lactobacillus reuteri. Microb Ecol health Dis. 1989;2:131–136. doi: 10.3109/08910608909140210.

23. Luo H., Zhou D., Liu X., Nie Z., Quiroga-Sanchez D.L., Chang Y. Production of 3-Hydroxypropionic Acid via the Propionyl-CoA Pathway Using Recombinant Escherichia coli Strains. PLOS ONE. 2016;1-13. doi: 10.1371/journal.pone.0156286.

24. Sebastianes F.L.S., Cabedo N., El Aouad N., Valente A.M.M. P., Lacava P.T., Azevedo J.L., Pizzirani-Kleiner A.A., Cortes D. 3-Hydroxypropionic acid as an antibacterial agent from endophytic fungi Diaporthe phaseolorum. Curr. Microbiol. 2012;65:622–632. doi: 10.1007/s00284-012-0206-4.

25. Stevens J. F., Maier C. S. Acrolein: sources, metabolism, and biomolecular interactions relevant to human health and disease. Mol. Nutr. Food Res. 2008;52:7–25. doi: 10.1002/mnfr.200700412.

26. Engels C., Schwab C., Zhang J., Stevens M. J., Bieri C., Ebert M. O., McNeill K., Sturla S.J., Lacroix C. Acrolein contributes strongly to antimicrobial and heterocyclic amine transformation activities of reuterin. Sci. Rep. 2016;6:36246. doi: 10.1038/srep36246.

27. Mishra S. K., Malik R. K., Manju G., Pandey N., Singroha G., Behare P. et al. Characterization of a reuterin-producing Lactobacillus reuteri BPL-36 strain isolated from human infant fecal sample. Probiotics Antimicrob Proteins. 2012;4:154–161. doi: 10.1007/s12602-012-9103-1.

28. Ganzle M. G., Vogel R. F. Studies on the mode of action of reutericyclin. Appl. Environ. Microbiol. 2003;69:1305–1307. doi: 10.1128/AEM.69.2.1305-1307.2003.

29. Burge G., Saulou-Berion C., Moussa M., Pollet B., Flourat A., Allais F. et al. Diversity of Lactobacillus reuteri strains in converting glycerol into 3-hydroxypropionic acid. Appl. Biochem. Biotechnol. 2015;177:923–939. doi: 10.1007/s12010-015-1787-8.

30. Gopi G.R., Ganesh N., Pandiaraj S., Sowmiya B., Brajesh R.G., Ramalingam S. A study on enhanced expression of 3-hydroxypropionic acid pathway genes and impact on its production in Lactobacillus reuteri. Food Technol. Biotechnol. 2015;53:331–336. doi: 10.17113/ftb.53.03.15.3976.

31. Jiang X., Meng X., Xian M. Biosynthetic pathways for 3-hydroxypropionic acid production. Applied Microbiology and Biotechnology. 2009;82(6):995– 1003. doi: 10.1007/s00253-009-1898-7.

32. Zhang D., Hillmyer M. A., Tolman W. B. A new synthetic route to poly [3-hydroxypropionic acid] (P[3-HP]): ring-opening polymerization of 3-HP macrocyclic esters. Macromol. 2004;37:8198–8200. doi: 10.1021/ma048092q.

33. Sardari R. R. R., Dishisha T., Pyo S. H., Hatti-Kaul R. Improved production of 3-hydroxypropionaldehyde by complex formation with bisulfite during bio-transformation of glycerol. Biotechnol. Bioeng. 2013;110:1243–1248. doi: 10.1002/bit.24787.

34. Sardari R.R.R., Dishisha T., Pyo S.H., Hatti-Kaul R. Biotransformation of glycerol to 3-hydroxypropionaldehyde: Improved production by in situ complexation with bisulfate in a fed-batch mode and separation on anion exchanger. J. Biotechnol. 2013;168:534–542. doi: 10.1016/j.jbiotec.2013.09.009.

35. Cherian P.T., Wu X., Yang L., Scarborough J.S., Singh A.P., Alam Z.A. et al. Gastrointestinal localization of metronidazole by a lactobacilliinspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection. J. Antimicrob. Chemother. 2015;70:3061–3069. doi: 10.1093/jac/dkv231.

36. Abhisingha M., Dumnil J., Pitaksutheepong C. Selection of potential probiotic Lactobacillus with inhibitory activity against Salmonella and fecal coliform bacteria. Probiotics Antimicrob. Proteins. 2018;10(2):218-227. doi: 10.1007/s12602-017-9304-8.

37. Genis S., Sanchez-Chardi A., Bach A., Fabregas F., Aris A. A combination of lactic acid bacteria regulates Escherichia coli infection and inflammation of the bovine endometrium. J. Dairy Sci. 2017;100:479–492. doi: 10.3168/jds.2016-11671.

38. Shornikova A.V., Casas I.A., Isolauri E., Mykkanen H., Vesikari T. Lactobacillus reuteri as a therapeutic agent in acute diarrhea in young children. J. Pediatr. Gastroenterol. Nutr. 1997;24:399– 404. doi: 10.1097/00005176-199704000-00008.

39. Preidis G.A., Saulnier D.M., Blutt S.E., Mistretta T.A., Riehle, K.P., Major, A.M. et al. Host response to probiotics determined by nutritional status of rotavirus-infected neonatal mice. J. Pediatr. Gastroenterol. Nutr. 2012;55:299–307. doi: 10.1097/MPG.0b013e31824d2548.

40. Ang L.Y., Too H.K., Tan E.L., Chow T.K., Shek P.C., Tham E. et al. Antiviral activity of Lactobacillus reuteri Protectis against Coxsackievirus A and Enterovirus 71 infection in human skeletal muscle and colon cell lines. Virol. J. 2016;13:111. doi: 10.1186/s12985-016-0567-6.

41. Diaz M., Ladero V., del Rio B., Redruello B., Fernandez M., Martin M.C. et al. Biofilm-forming capacity in biogenic amine-producing bacteria isolated from dairy products. Front. Microbiol. 2016;7:591. doi: 10.3389/fmicb.2016.00591.

42. Greifova G., Majekova H., Greif G., Body P., Greifova M., Dubnickova M. Analysis of antimicrobial and immunomodulatory substances produced by heterofermentative Lactobacillus reuteri. Folia Microbiol. 2017;62:515–524. doi: 10.1007/s12223-017-0524-9.

43. Thomas C. M., Hong T., van Pijkeren J. P., Hemarajata P., Trinh D.V., Hu W. et al. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One. 2012;7:31951. doi: 10.1371/journal.pone.0031951.

44. Rossi F., Gardini F., Rizzotti L., La Gioia F., Tabanelli G., and Torriani S. Quantitative analysis of histidine decarboxylase gene (hdcA) transcription and histamine production by Streptococcus thermophilus PRI60 under conditions relevant to cheese making. Appl. Environ. Microbiol. 2011;77:2817–2822. doi: 10.1128/AEM.02531-10.

45. Gao C., Major A., Rendon D., Lugo M., Jackson V., Shi Z. et al. Histamine H2 Receptor-Mediated Suppression of Intestinal Inflammation by Probiotic Lactobacillus reuteri. mBio. 2015;6:01358-15. doi: 10.1128/mBio.01358-15.

46. Thomas C.M., Saulnier D.M., Spinler J.K., Hemarajata P., Gao C., Jones S.E. et al. FolC2mediated folate metabolism contributes to suppression of inflammation by probiotic Lactobacillus reuteri. Microbiologyopen. 2016;5:802–818. doi: 10.1002/mbo3.371.

47. Hemarajata P., Gao C., Pflughoeft K.J., Thomas C.M., Saulnier D.M., Spinler J.K. et al. Lactobacillus reuteri-specific immunoregulatory gene rsiR modulates histamine production and immunomodulation by Lactobacillus reuteri. J. Bacteriol. 2013;195:5567–5576. doi: 10.1128/JB.00261-13.

48. Linares D.M., Gomez C., Renes E., Fresno J. M., Tornadijo M. E., Ross R.P. et al. Lactic acid bacteria and bifidobacteria with potential to design natural biofunctional health-promoting dairy foods. Front. Microbiol. 2017;8:846. doi: 10.3389/fmicb.2017.00846.

49. Morita H., Toh H., Fukuda S., Horikawa H., Oshima K., Suzuki T. et al. Comparative genome analysis of Lactobacillus reuteri and Lactobacillus fermentum reveal a genomic island for reuterin and cobalamin production. DNA Res. 2008;15:151– 161. doi: 10.1093/dnares/dsn009.

50. Santos F., Spinler J.K., Saulnier D.M., Molenaar D., Teusink B., de Vos W. M. et al. Functional identification in Lactobacillus reuteri of a PocR-like transcription factor regulating glycerol utilization and vitamin B12 synthesis. Microb. Cell Fact. 2011;10:55. doi: 10.1186/1475-2859-10-55.

51. Molina V. C., Medici M., Taranto M. P., Font de Valdez G. Lactobacillus reuteri CRL 1098 prevents side effects produced by a nutritional vitamin B deficiency. J. Appl.Microbiol. 2009;106:467–473. doi: 10.1111/j.1365-2672.2008.04014.x.

52. Santos F., Wegkamp A., de Vos W. M., Smid E. J., Hugenholtz J. High-Level folate production in fermented foods by the B12 producer Lactobacillus reuteri JCM11. Environ. Microbiol. 2008;74:3291– 3294. doi: 10.1128/AEM.02719-07.

53. Inoue K., Shirai T., Ochiai H., Kasao M., Hayakawa K., Kimura M. et al. Blood-pressurelowering effect of a novel fermented milk containing γ-aminobutyric acid (GABA) in mild hypertensives. Eur. J. Clin. Nutr. 2003;57:490– 495. doi: 10.1038/sj.ejcn.1601555.

54. Marques T.M., Patterson E., Wall R., O’Sullivan O., Fitzgerald G.F., Cotter P.D. et al. Influence of GABA and GABA-producing Lactobacillus brevis DPC 6108 on the development of diabetes in a streptozotocin rat model. Benef. Microbes. 2016;7:409–420. doi: 10.3920/BM2015.0154.

55. Foster A.C., Kemp J.A. Glutamateand GABAbased CNS therapeutics. Curr. Opin. Pharmacol. 2006;6:7–17. doi: 10.1016/j.coph.2005.11.005.

56. Chen L., Zhao H., Zhang C., Lu Y., Zhu X., Lu Z. γ-Aminobutyric acid-rich yogurt fermented by Streptococcus salivarius subsp. thermophiles fmb5 appears to have anti-diabetic effect on streptozotocininduced diabetic mice. J. Func. Foods. 2016;20:267–275. doi: 10.1016/j.jff.2015.10.030.

57. Pouliot-Mathieu K., Gardner-Fortier C., Lemieux S., St-Gelais D., Champagne C.P., Vuillemard J.C. Effect of cheese containing gamma-aminobutyric acid-producing lactic acid bacteria on blood pressure in men. PharmaNutrition. 2013;1:141–148. doi: 10.1016/j.phanu.2013.06.003.

58. Romeo M.G., Romeo D.M., Trovato L., Oliveri S., Palermo F., Cota F., Betta P. Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome. Journal of Perinatology. 2011;31:63–69. doi: 10.1038/jp.2010.57.

59. Savino F., Cordisco L., Tarasco V., Palumeri E., Calabrese R., Oggero R., Roos S., Matteuzzi D. Lactobacillus reuteri DSM 17938 in Infantile Colic: A Randomized, Double-Blind, PlaceboControlled Trial. Pediatrics. 2010;126;e526-e533. doi: https://doi.org/10.1542/peds.2010-0433.

60. Savino F., Cordisco L., Tarasco V., Calabrese R., Palumeri E., Matteuzzi D. Molecular identification of coliformbacteria fromcolicky breastfed infants. Acta Paediatr. 2009;98:1582-8. doi: 10.1111/j.1651-2227.2009.01419.x.

61. Rhoads J.M., Fatheree N.Y., Norori J., Liu Y., Lucke J.F., Tyson J.E. et al. Altered fecal microflora and increased fecal calprotectin in infants with colic. J Pediatr. 2009;155:823-8. doi: 10.1016/j.jpeds.2009.05.012.

62. Savino F., Cresi F., Pautasso S., Palumeri E., Tullio V., Roana J. et al. Intestinal microflora in breastfed colicky and non-colicky infants. Acta Paediatr. 2004;93:825-9. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15244234.

63. Sung V., D’Amico F., Cabana M.D., Chau K., Koren G., Savino F., Szajewska H., Deshpande G., Dupont C., Indrio F., Mentula S., Partty A., Tancredi D. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics. 2018;141(1). pii: e20171811. doi: 10.1542/peds.2017-1811.

64. Mai T., Fatheree N.Y., Gleason W., Liu Y., Rhoads J.M. Infantile Colic: New Insights into an Old Problem. Gastroenterology Clinics of North America. 2018;829-844. doi: 10.1016/j.gtc.2018.07.008.

65. Savino F., Garro M., Montanari P., Galliano I., Bergallo M. Crying Time and RORγ/FOXP3 Expression in Lactobacillus reuteri DSM17938Treated Infants with Colic: A Randomized Trial. The journal of pediatrics. 2018;192:171-177.e1. doi: 10.1016/j.jpeds.2017.08.062.

66. Sefik E., Geva-Zatorsky N., Oh S., Konnikova L., Zemmour D., Manson McGuire A., et al. Individual intestinal symbionts induce a distinct population of RORg+ regulatory T cells. Science. 2015;6251:993-7.

67. Wu R.Y., Pasyk M., Wang B., Forsythe P., Bienenstock J., Mao Y.–K., Sharma P., Stanisz A.M., Kunze W.A. Spatiotemporal maps reveal regional differences in the effects on gut motility for Lactobacillus reuteri and rhamnosus strains. Neurogastroenterology& Motility. 2013;25(3):205-14. doi: 10.1111/nmo.12072.

68. Morgun A., Dzutsev A., Dong X., Greer R.L., Sexton D.J., Ravel J., Schuster M., Hsiao W., Matzinger P., Shulzhenko N. Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks. Gut. 2015;64(11):1732–1743. doi: 10.1136/gutjnl-2014-308820.

69. Lionetti E., Castellaneta S., Minielloet V.L., Magista A.M. Lactobacillus reuteri therapy to reduce side-effects during anti-Helicobacter pylori treatment in children: a randomised placebo controlled trial. Aliment Pharmacol Ther. 2006;24:1461-1468. doi: 10.1111/j.1365-2036.2006.03145.x.

70. Cimperman L., Best K., Bayless G., Mordarski B., Smith M. et al. A Randomised, double-blind, placebo-controlled pilot study of Lactobacillus reuteri for the prevention of antibiotic-associated diarrhoea in hospitalise adults. J Clin Gastroenterol. 2011;45(9):785-9. doi: 10.1097/MCG.0b013e3182166a42.

71. Szajewska H., Guarino A., Hojsak I., Indrio F., Kolacek S., Shamir R., Vandenplas Y., Weizman Z. The use of probiotics for the management of acute gastroenteritis: a position paper by the Espghan Working Group for probiotics. J Pediatr Gastroenterol Nutr. 2014;58:531–539. doi: 10.1097/MPG.0000000000000320.