Next generation probiotics: an overview of the most promising candidates

1. Ozen M, Dinleyici EC. The history of probiotics: the untold story.  Benef Microbes, 2015;6(2):159–165. doi: 10.3920/BM2014.0103.
2. Sánchez B, Delgado S, Blanco‐Míguez A, et al. Probiotics, gut microbiota, and their influence on host health and disease. Mol Nutr Food Res, 2017;61(1). doi: 10.1002/mnfr.201600240.
3. Plaza-Diaz J, Ruiz-Ojeda FJ, Gil-Campos M, Gil A. Mechanisms of action of probiotics. Adv Nutr, 2019;10(suppl. 1):S49–S66. doi:10.1093/advances/nmy063.
4. De Vos WM, De Vos EAJ. Role of the intestinal microbiome in health and disease: from correlation to causation. Nutr Rev, 2012;70 Suppl 1:S45–S56. doi: 10.1111/j.1753-4887.2012.00505.x.
5. Azad MAK, Sarker M, Li T, Yin J. Probiotic species in the modulation of gut microbiota: An overview. Biomed Res Int, 2018;2018:9478630. doi:10.1155/2018/9478630.
6. Mohajeri MH, Brummer RJM, Rastall RA, et al. The role of the microbiome for human health: from basic science to clinical applications. Eur J Nutr, 2018;57(Suppl 1):1–14. doi:10.1007/s00394-018-1703-4.
7. Almeida D, Machado D, Andrade JC, et al. Evolving trends in next-generation probiotics: a 5W1H perspective. Crit Rev Food Sci Nutr, 2020;60(11):1783–1796. doi:10.1080/10408398.2019.1599812.
8. Hill C, Guarner F, Reid G, et al. Expert consensus document: The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol, 2014;11(8):506–514. doi: 10.1038/nrgastro.2014.66. 

9. Didari T, Mozaffari S, Nikfar S, Abdollahi M. Effectiveness of probiotics  in irritable bowel syndrome: Updated systematic review with meta-analysis. World J Gastroenterol, 2015;21(10):3072–3084. doi: 10.3748/wjg.v21.i10.3072.
10. Alfaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev, 2014;(4):CD005496. doi: 10.1002/14651858.CD005496.pub4.
11. Derwa Y, Gracie DJ, Hamlin PJ, Ford AC. Systematic Review with Meta-Analysis: The efficacy of probiotics in inflammatory bowel disease. Aliment Pharmacol Ther, 2017;46(4):389–400. doi:10.1111/apt.14203.
12. Goldenberg JZ, Yap C., Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev, 2017;12(12):CD006095.doi: 10.1002/14651858.CD006095.pub4.
13. Zhu R, Chen K, Zheng YY, et al. Meta-analysis of the efficacy of probiotics in Helicobacter pylori eradication therapy. World J Gastroenterol, 2014;20(47):18013–18021. doi: 10.3748/wjg.v20.i47.18013.
14. Mansfield J, Bergin SJ, Cooper JR, Olsen CH. Comparative probiotic strain efficacy in the prevention of eczema in infants and children: a systematic review and meta-analysis. Mil Med, 2014;179(6):580–592. doi: 10.7205/MILMED-D-13-00546.
15. Gungor OE, Kirzioglu Z, Kivanc M. Probiotics: can they be used to improve oral health? Benef Microbes, 2015;6(5):647–656. doi:10.3920/BM2014.0167.
16. Ng SC, Hart AL, Kamm MA, Stagg AJ, et al. Mechanisms of action of probiotics: recent advances. Inflamm Bowel Dis,2009;15(2):300–310. doi: 10.1002/ibd.20602.
17. Patel R, Dupont HL. New approaches for bacteriotherapy: prebiotics, new-generation probiotics, and synbiotics. Clin Infect Dis,2015;60 Suppl 2(Suppl 2):S108–121. doi: 10.1093/cid/civ177.
18. Martín R, Langella P. Emerging health concepts in the probiotics field: streamlining the definitions. Front Microbiol, 2019;10:1047.doi: 10.3389/fmicb.2019.01047.
19. Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol, 2004;54(Pt 5):1469–1476. doi: 10.1099/ijs.0.02873-0.
20. Cani PD, Plovier H, Van Hul M, et al. Endocannabinoids – at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol, 2016;12:133–143. doi: 10.1038/nrendo.2015.211.
21. Sun J, Shen X, Li Y, et al. Therapeutic Potential to Modify the Mucus Barrier in Inflammatory Bowel Disease. Nutrients, 2016;8(1):44. doi: 10.3390/nu8010044.
22. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA, 2013;110(22):9066–9071.doi:10.1073/pnas.1219451110.
23. Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut, 2014;63(5):727–735. doi: 10.1136/gutjnl-2012-303839.
24. Corfield AP. The interaction of the gut microbiota with the mucus barrier in health and disease in human. Microorganisms, 2018;6(3):78. doi:10.3390/microorganisms6030078.
25. Lordan C, Thapa D, Ross RP, et al. Potential for enriching next-generation health-promoting gut bacteria through prebiotics and other dietary components. Gut Microbes, 2020;11(1):1–20. doi:10.1080/19490976.2019.1613124.
26. Zhang X, Shen D, Fang Z, et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One, 2013;8(8):e71108. doi:10.1371/journal.pone.0071108.
27. Grander C, Adolph TE, Wieser V, et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut, 2018;67(5):891–901. doi: 10.1136/gutjnl-2016-313432.
28. Yassour M, Lim MY, Yun HS, et al. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med, 2016;8(1):17. doi:10.1186/s13073-016-0271-6.
29. Derrien M, Belzer C, de Vos WM. Akkermansia muciniphila and its role in regulating host functions. Microb Pathog, 2017;106:171–181. doi: 10.1016/j.micpath.2016.02.005.
30. Li J, Zhao F, Wang Y, et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome, 2017;5(1):14. doi:10.1186/s40168-016-0222-x. 

31. Clarke SF, Murphy EF, O’Sullivan O, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut, 2014;63(12):1913–1920. doi: 10.1136/gutjnl-2013-306541.
32. Wu F, Guo X, Zhang M, et al. An Akkermansia muciniphila subtype alleviates high-fat diet-induced metabolic disorders and inhibits the neurodegenerative process in mice. Anaerobe, 2020;61:102138. doi: 10.1016/j.anaerobe.2019.102138.
33. Zhang L, Qin Q, Liu M, et al. Akkermansia muciniphila can reduce the damage of gluco/lipotoxicity, oxidative stress and inflammation, and normalize intestine microbiota in streptozotocin-induced diabetic rats. Pathog Dis, 2018;76(4):fty028. doi:10.1093/femspd/fty028.
34. Yang M, Bose S, Lim S, et al. Beneficial effects of newly isolated Akkermansia muciniphila strains from the human gut on obesity and metabolic dysregulation. Microorganisms, 2020;8(9):1413.doi: 10.3390/microorganisms8091413.
35. Depommier C, Van Hul M, Everard A, et al. Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice. Gut Microbes, 2020;11(5):1231–1245. doi: 10.1080/19490976.2020 1-15.
36. Katiraei S, de Vries MR, Costain AH, et al. Akkermansia muciniphila exerts lipid‐lowering and immunomodulatory effects without affecting neointima formation in hyperlipidemic APOE* 3‐Leiden. CETP mice. Mol Nutr Food Res, 2019;64(15):e1900732. doi: 10.1002/mnfr.201900732.
37. Li J, Lin S, Vanhoutte PM, et al. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe−/− mice. Circulation, 2016;133(24):2434–2446. doi: 10.1161/CIRCULATIONAHA. 115.019645.
38. Bian X, Wu W, Yang L, et al. Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice. Front Microbiol, 2019;10:2259. doi: 10.3389/fmicb.2019.02259.
39. Van Der Lugt B, Van Beek AA, Aalvink S, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1−/Δ7 mice. Immun Ageing, 2019;16(1):6. doi: 10.1186/s12979-019-0145-z.
40. Zhu L, Lu X, Liu L, et al. Akkermansia muciniphila protects intestinal mucosa from damage caused by S. pullorum by initiating proliferation of intestinal epithelium.Vet Res, 2020;51(1):34. doi:10.1186/s13567-020-00755-3.
41. Kim S, Lee Y, Kim Y, et al. Akkermansia muciniphila prevents fatty liver disease, decreases serum triglycerides, and maintains gut homeostasis. Appl Environ Microbiol, 2020;86(7):e03004–19. doi:10.1128/AEM.03004-19.
42. Plovier H, Everard A, Druart C, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med, 2017;23(1):107–113. doi: 10.1038/nm.4236.
43. Wang L, Tang L, Feng Y, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice. Gut, 2020;69(11):1988–1997. doi: 10.1136/gutjnl-2019-320105.
44. Depommier C, Everard A, Druart C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med, 2019;25(7):1096–1103. doi:10.1038/s41591-019-0495-2.
45. Sears CL. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin Microbiol Rev, 2009;22(2):349–369. doi:10.1128/ CMR.00053-08.
46. Zhang W, Zhu B, Xu J, et al. Bacteroides fragilis protects against antibiotic-associated diarrhea in rats by modulating intestinal defenses. Front Immunol, 2018;9:1040. doi:10.3389/fimmu.2018.01040.
47. Wexler AG, Goodman AL. An insider’s perspective: Bacteroides as a window into the microbiome. Nat Microbiol, 2017;2:17026. doi: 10.1038/nmicrobiol.2017.26.
48. Sun F, Zhang Q, Zhao J, et al. A potential species of next-generation probiotics? The dark and light sides of Bacteroides fragilis in health. Food Res Int, 2019;126:108590. doi: 10.1016/j.foodres.2019.108590.
49. Sears CL, Geis AL, Housseau F. Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis. J Clin Invest, 2014;124(10):4166–4172. doi: 10.1172/JCI7233.
50. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature, 2008;453(7195):620–625. doi: 10.1038/nature07008.
51. Krinos CM, Coyne MJ, Weinacht KG, et al. Extensive surface diversity of a commensal microorganism by multiple DNA inversions. Nature, 2001;414(6863):555–558. doi: 10.1038/35107092.
52. Sittipo P, Lobionda S, Lee YK, Maynard CL. Intestinal microbiota and the immune system in metabolic diseases. J Microbiol, 2018;56(3):154–162. doi: 10.1007/s12275-018-7548-y.
53. Blandford LE, Johnston EL, Sanderson JD, et al. Promoter orientation of the immunomodulatory Bacteroides fragilis capsular polysaccharide A (PSA) is off in individuals with inflammatory bowel disease (IBD). Gut Microbes, 2019;10(5):569–577. doi:10.1080/19490976.2018.1560755.
54. Tzianabos AO, Russell PR, Onderdonk AB, et al. IL-2 mediates protection against abscess formation in an experimental model of sepsis. J Immunol, 1999;163(2):893–897.
55. Tzianabos AO, Finberg RW, Wang Y, et al. T cells activated by zwitterionic molecules prevent abscesses induced by pathogenic bacteria. J Biol Chem, 2000;275(10):6733–6740. doi:10.1074/jbc.275.10.6733.
56. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA, 2010;107(27):12204–12209. doi:10.1073/pnas.0909122107.
57. Shen Y, Giardino Torchia ML, et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe, 2012;12(4):509–520. doi:10.1016/j.chom.2012.08.004.
58. Round JL, Lee SM, Li J, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science, 2011;332(6032):974–977. doi:10.1126/science.1206095.
59. Johnson JL, Jones MB, Cobb BA. Bacterial capsular polysaccharide prevents the onset of asthma through T-cell activation. Glycobiology,2015;25(4):368–375. doi: 10.1093/glycob/cwu117.
60. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science,2015;350(6264):1079–1084. doi:10.1126/science.aad1329.
61. Lee YK, Mehrabian P, Boyajian S, et al. The protective role of Bacteroides fragilis in a murine model of colitis-associated colorectal cancer. mSphere, 2018;3(6):e00587–18. doi:10.1128/mSphere.00587-18.
62. Bukina YV, Varynskyi BO, Voitovich AV, et al. The definition of neutrophil extracellular traps and the concentration of shortchain fatty acids in salmonella-induced inflammation of the intestine against the background of vancomycin and Bacteroides fragilis. Pathologia, 2018;1(1):10–17. doi:10.14739/2310-1237.2018.1.128847.
63. Ramakrishna C, Kujawski M, Chu H, et al. Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis. Nat Commun, 2019;10(1):2153. doi:10.1038/s41467-019-09884-6.
64. Deng H, Li Z, Tan Y, et al. A novel strain of Bacteroides fragilis enhances phagocytosis and polarises M1 macrophages. Sci Rep,2016;6:29401. doi: 10.1038/srep29401.
65. Wang Q, McLoughlin RM, Cobb BA, et al. A bacterial carbohydrate links innate and adaptive responses through Toll-like receptor 2.J Exp Med, 2006;203(13):2853–2863. doi:10.1084/jem.20062008.
66. Hecht AL, Casterline BW, Earley ZM, et al. Strain competition restricts colonization of an enteric pathogen and prevents colitis. EMBO Rep, 2016;17(9):1281–1291. doi: 10.15252/embr.201642282.
67. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA, 2008;105(43):16731–16736. doi:10.1073/pnas.0804812105.
68. Rajilić–Stojanović M, Biagi E, Heilig HG, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology, 2011;141(5):1792–1801. doi: 10.1053/j.gastro.2011.07.04. 

69. Schippa S, Iebba V, Santangelo F, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients. PloS One,2013;8(4):e61176. doi: 10.1371/journal.pone.0061176.
70. Miquel S, Martin R, Rossi O, et al. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol, 2013;16(3):255–261. doi: 10.1016/j.mib.2013.06.003.
71. Cao Y, Shen J, Ran ZH. Association between Faecalibacterium prausnitzii reduction and inflammatory bowel disease: A meta-analysis and systematic review of the literature. Gastroenterol Res Pract, 2014;2014:872725. doi:10.1155/2014/872725.
72. Laffin MR, Tayebi Khosroshahi H, Park H, et al. Amylose resistant starch (HAM‐RS2) supplementation increases the proportion of Faecalibacterium bacteria in end‐stage renal disease patients: microbial analysis from a randomized placebo‐controlled trial.Hemodial Int, 2019;23(3):343–347. doi: 10.1111/hdi.12753.
73. Miquel S, Leclerc M, Martin R, et al. Identification of metabolic signatures linked to anti-inflammatory effects of Faecalibacterium prausnitzii. mBio, 2015;6(2):e00300–e00315. doi: 10.1128/mBio.00300-15.
74. Ramirez-Farias C, Slezak K, Fuller Z, et al. Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii. B J Nutr, 2008;101(4):541–550. doi: 10.1017/S0007114508019880.
75. Miquel S, Martín R, Bridonneau C, et al. Ecology and metabolism of the beneficial intestinal commensal bacterium Faecalibacterium prausnitzii. Gut Microb, 2014;357(6351):570–575. doi:10.1126/science.aam9949.
76. Macfarlane GT, Macfarlane S. Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics. J Clin Gastroenterol, 2011;45 Suppl:S120–127. doi: 10.1097/MCG.0b013e31822fecfe.
77. Byndloss MX, Olsan EE, Rivera-Chávez F, et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science, 2017;357(6351):570–575. doi: 10.1126/science.aam9949.
78. Kawade Y, Sakai M, Okamori M, et al. Administration of live, but not inactivated Faecalibacterium prausnitzii has a preventive effect on dextran sodium sulfate-induced colitis in mice. Mol MedRep, 2019;20(1):25–32. doi: 10.3892/mmr.2019.10234.
79. Machiels K, Joossens M, Sabino J, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut, 2014;63(8):1275–1283. doi: 10.1136/gutjnl-2013-304833.
80. Quévrain E, Maubert MA, Michon C, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut, 2016;65(3):415–425. doi: 10.1136/gutjnl-2014-307649.
81. Xu J, Liang R, Zhang W, et al. Faecalibacterium prausnitzii-derived microbial anti-inflammatory molecule regulates intestinal integrity in diabetes mellitus mice via modulating tight junction protein expression. J Diabetes, 2020;12(3):224–236. doi:10.1111/1753-0407.12986. 

82. Min XH, Yu T, Qing Q, et al. Abnormal differentiation of intestinal epithelium and intestinal barrier dysfunction in diabetic mice associated with depressed Notch/NICD transduction in Notch/Hes1 signal pathway. Cell Biol Int, 2014;38(10):1194–1204.
83. Pasini E, Corsetti G, Assanelli D, et al. Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes. Minerva Med, 2019;110(1):3–11. doi: 10.23736/S0026-4806.18.05589-1.
84. Hao Z, Wang W, Guo R, Liu H. Faecalibacterium prausnitzii (ATCC 27766) has preventive and therapeutic effects on chronic unpredictable mild stress-induced depression-like and anxiety-like behaviour in rats. Psychoneuroendocrinology, 2019;104:132–142. doi: 10.1016/j.psyneuen.2019.02.025.
85. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biol Psychiatry, 2013;74:720–726. doi: 10.1016/j.biopsych.2013.05.001.
86. O’Toole PW, Paoli M. The contribution of microbial biotechnology to sustainable development goals: microbiome therapies. Microb Biotechnol, 2017;10(5):1066–1069. doi:10.1111/1751-7915.12752.
87. van der Ark KC, Nugroho ADW, Berton-Carabin C, et al. Encapsulation of the therapeutic microbe Akkermansia muciniphila in a double emulsion enhances survival in simulated gastric conditions. Food Res Int, 2017;102:372–379. doi: 10.1016/j.foodres.2017.09.00.
88. Khan MT, van Dijl JM, Harmsen HJ. Antioxidants keep the potentially probiotic but highly oxygen-sensitive human gut bacterium Faecalibacterium prausnitzii alive at ambient air. PLoS One, 2014;9(5):e96097. doi:10.1371/journal.pone.0096097.
89. Gibson G, Hutkins R, Sanders M, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol, 2017;14(8):491–502. Dostupné na www: https://doi.org/10.1038/nrgastro.2017.75.