Probiotic Lactobacillus kefiri prevents endotoxin-induced preterm birth and stillbirth in mice

in Reproduction
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  • 1 Laboratorio de Inmunologia de la Reproduccion, CEFYBO-UBA-CONICET, Buenos Aires, Argentina
  • 2 YPF Tecnología, Berisso, Buenos Aires, Argentina
  • 3 Cátedra de Microbiología, Facultad de Ciencias Exactas, UNLP, La Plata, Buenos Aires, Argentina
  • 4 Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK.
  • 5 Centro Integrativo de Biología Y Química Aplicada, Universidad Bernardo O’Higgins, 8307993, Santiago, Chile.

Correspondence should be addressed to F Jensen; Email: fedejensen2012@gmail.com
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Preterm birth (PTB), defined as birth occurring before 37 weeks of pregnancy, affects 5–18% of pregnancies and is the leading cause of neonatal morbidity and mortality worldwide. Although PTB is considered a syndrome, infection-induced inflammation accounts for up to 50% of all cases. Despite the effort to reduce the incidence of PTB, it continues to rise worldwide and current approaches for preventing or treating PTB are largely unsatisfactory. Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. It is well known that probiotics can modulate the host immune system exerting a potent anti-inflammatory activity. The main aim of this work was to evaluate the capacity of the probiotic Lactobacillus kefiri (Lk48) to prevent preterm birth in mice. C57BL/6 female mice were treated with Lk48 or vehicle a week before and during pregnancy and were challenged with LPS (10 µg), a dose known to induce PTB on gestational day 16. Percentages of PTB as well as stillbirth were evaluated. We observed that oral administration of Lk48 significantly reduced the occurrence of LPS-induced PTB and stillbirth as well as improved post-natal development. This protective effect was associated with a reduction in leucocyte infiltration and reduced inflammation-induced damage in reproductive tissue. Besides, Lk48 treatment also modulated the diversity of vaginal microbiota. Our results demonstrated that prophylactic consumption of probiotic L. kefiri prevented LPS-induced PTB and still birth in mice and opens new avenues for exploring novel and promising strategies for preventing PTB in humans.

 

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  • Arenas-Hernandez M, Romero R, Xu Y, Panaitescu B, Garcia-Flores V, Miller D, Ahn H, Done B, Hassan SS & Hsu CD et al2019 Effector and activated T cells induce preterm labor and birth that is prevented by treatment with progesterone. Journal of Immunology 202 25852608. (https://doi.org/10.4049/jimmunol.1801350)

    • Search Google Scholar
    • Export Citation
  • Arenas-Hernandez M, Sanchez-Rodriguez EN, Mial TN, Robertson SA & Gomez-Lopez N 2015 Isolation of leukocytes from the murine tissues at the maternal-fetal interface. Journal of Visualized Experiments 99 e52866. (https://doi.org/10.3791/52866)

    • Search Google Scholar
    • Export Citation
  • Ashraf R & Shah NP 2014 Immune system stimulation by probiotic microorganisms. Critical Reviews in Food Science and Nutrition 54 938956. (https://doi.org/10.1080/10408398.2011.619671)

    • Search Google Scholar
    • Export Citation
  • Azad MAK, Sarker M, Li T & Yin J 2018 Probiotic species in the modulation of gut microbiota: an overview. BioMed Research International 2018 9478630. (https://doi.org/10.1155/2018/9478630)

    • Search Google Scholar
    • Export Citation
  • Basavaprabhu HN, Sonu KS & Prabha R 2020 Mechanistic insights into the action of probiotics against bacterial vaginosis and its mediated preterm birth: an overview. Microbial Pathogenesis 141 104029. (https://doi.org/10.1016/j.micpath.2020.104029)

    • Search Google Scholar
    • Export Citation
  • Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn JBorn Too Soon Preterm Birth Action Group 2013 Born too soon: the global epidemiology of 15 million preterm births. Reproductive Health 10 (Supplement 1) S2. (https://doi.org/10.1186/1742-4755-10-S1-S2)

    • Search Google Scholar
    • Export Citation
  • Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S & Say L et al2012 National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 379 21622172. (https://doi.org/10.1016/S0140-6736(12)60820-4)

    • Search Google Scholar
    • Export Citation
  • Blencowe H, Lee ACC, Cousens S, Bahalim A, Narwal R, Zhong N, Chou D, Say L, Modi N & Katz J et al2013 Preterm birth-associated neurodevelopmental impairment estimates at regional and global levels for 2010. Pediatric Research 74 (Supplement 1) 1734. (https://doi.org/10.1038/pr.2013.204)

    • Search Google Scholar
    • Export Citation
  • Bosch A, Golowczyc MA, Abraham AG, Garrote GL, De Antoni GL & Yantorno O 2006 Rapid discrimination of lactobacilli isolated from kefir grains by FT-IR spectroscopy. International Journal of Food Microbiology 111 280287. (https://doi.org/10.1016/j.ijfoodmicro.2006.05.010)

    • Search Google Scholar
    • Export Citation
  • Brocklehurst P, Gordon A, Heatley E & Milan SJ 2013 Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database of Systematic Reviews CD000262. (https://doi.org/10.1002/14651858.CD000262.pub4)

    • Search Google Scholar
    • Export Citation
  • Carasi P, Racedo SM, Jacquot C, Romanin DE, Serradell MA & Urdaci MC 2015 Impact of kefir derived lactobacillus kefiri on the mucosal immune response and gut microbiota. Journal of Immunology Research 2015 361604. (https://doi.org/10.1155/2015/361604)

    • Search Google Scholar
    • Export Citation
  • Carasi P, Trejo FM, Pérez PF, De Antoni GL & Serradell de los Mde L 2012 A. Surface proteins from Lactobacillus kefir antagonize invitro cytotoxic effect of Clostridium difficile toxins. Anaerobe 18 135142. (https://doi.org/10.1016/j.anaerobe.2011.11.002)

    • Search Google Scholar
    • Export Citation
  • Chee WJY, Chew SY & Than LTL 2020 Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health. Microbial Cell Factories 19 203. (https://doi.org/10.1186/s12934-020-01464-4)

    • Search Google Scholar
    • Export Citation
  • Claes IJJ, Segers ME, Verhoeven TLA, Dusselier M, Sels BF, De Keersmaecker SCJ, Vanderleyden J & Lebeer S 2012 Lipoteichoic acid is an important microbe-associated molecular pattern of Lactobacillus rhamnosus GG. Microbial Cell Factories 11 161. (https://doi.org/10.1186/1475-2859-11-161)

    • Search Google Scholar
    • Export Citation
  • Coan PM, Ferguson-Smith AC & Burton GJ 2004 Developmental dynamics of the definitive mouse placenta assessed by Stereology1. Biology of Reproduction 70 18061813. (doi:10.1095/biolreprod.103.024166)

    • Search Google Scholar
    • Export Citation
  • Cocolin L, Alessandria V, Botta C, Gorra R, De Filippis F, Ercolini D & Rantsiou K 2013 NaOH-debittering induces changes in bacterial ecology during table olives fermentation. PLoS ONE 8 e69074. (https://doi.org/10.1371/journal.pone.0069074)

    • Search Google Scholar
    • Export Citation
  • Comeau AM, Douglas GM & Langille MGI 2017 Microbiome helper: a custom and streamlined workflow for microbiome research. mSystems 2. e00127-16(https://doi.org/10.1128/mSystems.00127-16)

    • Search Google Scholar
    • Export Citation
  • Di Renzo GC, Tosto V & Giardina I 2018 The biological basis and prevention of preterm birth. Best Practice and Research: Clinical Obstetrics and Gynaecology 52 1322. (https://doi.org/10.1016/j.bpobgyn.2018.01.022)

    • Search Google Scholar
    • Export Citation
  • Donders GG, Zodzika J & Rezeberga D 2014 Treatment of bacterial vaginosis: what we have and what we miss. Expert Opinion on Pharmacotherapy 15 645657. (https://doi.org/10.1517/14656566.2014.881800)

    • Search Google Scholar
    • Export Citation
  • Douglas GM, Comeau AM & Langille MGI 2018 Processing a 16S rRNA sequencing dataset with the microbiome Helper workflow. Methods in Molecular Biology 1849 131141. (https://doi.org/10.1007/978-1-4939-8728-3_9)

    • Search Google Scholar
    • Export Citation
  • Dowd SE, Sun Y, Wolcott RD, Domingo A & Carroll JA 2008 Bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP) for microbiome studies: bacterial diversity in the ileum of newly weaned Salmonella-infected pigs. Foodborne Pathogens and Disease 5 459472. (https://doi.org/10.1089/fpd.2008.0107)

    • Search Google Scholar
    • Export Citation
  • Dudley DJ, Chen CL, Branch DW, Hammond E & Mitchell MD 1993 A murine model of preterm labor: inflammatory mediators regulate the production of prostaglandin E2 and interleukin-6 by murine decidua. Biology of Reproduction 48 3339. (doi:10.1095/biolreprod48.1.33)

    • Search Google Scholar
    • Export Citation
  • Farr A, Sustr V & Kiss H Rosicky I, Graf A, Makristathis A, Foessleiner P & Petricevic L 2020 Oral probiotics to reduce vaginal group B streptococcal colonization in late pregnancy. Scientific Reports 10 19745.

    • Search Google Scholar
    • Export Citation
  • Faust K, Härtel C, Preuß M, Rabe H, Roll C, Emeis M, Wieg C, Szabo M, Herting E & Göpel W et al. 2015 Short-term outcome of very-low-birthweight infants with arterial hypotension in the first 24 h of life. Archives of Disease in Childhood: Fetal and Neonatal Edition 100 F388F392. (https://doi.org/10.1136/archdischild-2014-306483)

    • Search Google Scholar
    • Export Citation
  • Fricke EM, Elgin TG, Gong H, Reese J, Gibson-Corley KN, Weiss RM, Zimmerman K, Bowdler NC, Kalantera KM & Mills DA et al2018 Lipopolysaccharide-induced maternal inflammation induces direct placental injury without alteration in placental blood flow and induces a secondary fetal intestinal injury that persists into adulthood. American Journal of Reproductive Immunology 79 e12816. (https://doi.org/10.1111/aji.12816)

    • Search Google Scholar
    • Export Citation
  • Furcron A, Romero R, Plazyo O, Unkel R, Xu Y, Hassan SS, Chaemsaithong P, Mahajan A & Gomez-Lopez N 2015 Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface. American Journal of Obstetrics and Gynecology 213 846.e1846.e19. (https://doi.org/10.1016/j.ajog.2015.08.010)

    • Search Google Scholar
    • Export Citation
  • Furcron AE, Romero R, Mial TN, Balancio A, Panaitescu B, Hassan SS, Sahi A, Nord C & Gomez-Lopez N 2016 Human chorionic gonadotropin has anti-inflammatory effects at the maternal-fetal interface and prevents endotoxin-induced preterm birth, but causes dystocia and fetal compromise in mice. Biology of Reproduction 94 136. (https://doi.org/10.1095/biolreprod.116.139345)

    • Search Google Scholar
    • Export Citation
  • Garrote GL, Abraham AG & De Antoni GL 2001 Chemical and microbiological characterisation of kefir grains. Journal of Dairy Research 68 639652. (https://doi.org/10.1017/s0022029901005210)

    • Search Google Scholar
    • Export Citation
  • Garrote GL, Serradell MA, Abraham AG, Añon MC, Fossati CA & De Antoni GL 2005 Development of an immunochemical method to detect Lactobacillus kefir. Food and Agricultural Immunology 16 221233. (https://doi.org/10.1080/09540100500244146)

    • Search Google Scholar
    • Export Citation
  • Goldenberg RL, Culhane JF, Iams JD & Romero R 2008 Epidemiology and causes of preterm birth. Lancet 371 7584. (https://doi.org/10.1016/S0140-6736(08)60074-4)

    • Search Google Scholar
    • Export Citation
  • Goldenberg RL, Hauth JC & Andrews WW 2000 Intrauterine infection and preterm delivery. New England Journal of Medicine 342 15001507. (https://doi.org/10.1056/NEJM200005183422007)

    • Search Google Scholar
    • Export Citation
  • Golowczyc MA, Mobili P, Garrote GL, Abraham AG & De Antoni GL 2007 Protective action of Lactobacillus kefir carrying S-layer protein against Salmonella enterica serovar Enteritidis. International Journal of Food Microbiology 118 264273. (https://doi.org/10.1016/j.ijfoodmicro.2007.07.042)

    • Search Google Scholar
    • Export Citation
  • Gomez-Lopez N, StLouis D, Lehr MA, Sanchez-Rodriguez EN & Arenas-Hernandez M 2014 Immune cells in term and preterm labor. Cellular and Molecular Immunology 11 571581. (https://doi.org/10.1038/cmi.2014.46)

    • Search Google Scholar
    • Export Citation
  • Hamet MF, Londero A, Medrano M, Vercammen E, Van Hoorde K, Garrote GL, Huys G, Vandamme P & Abraham AG 2013 Application of culture-dependent and culture-independent methods for the identification of Lactobacillus kefiranofaciens in microbial consortia present in kefir grains. Food Microbiology 36 327334. (https://doi.org/10.1016/j.fm.2013.06.022)

    • Search Google Scholar
    • Export Citation
  • Harrison MS & Goldenberg RL 2016 Global burden of prematurity. Seminars in Fetal and Neonatal Medicine 21 7479. (https://doi.org/10.1016/j.siny.2015.12.007)

    • Search Google Scholar
    • Export Citation
  • Heyser CJ 2003 Assessment of developmental milestones in rodents. Current Protocols in Neuroscience 25 18.18.18.15. (https://doi.org/10.1002/0471142301.ns0818s25)

    • Search Google Scholar
    • Export Citation
  • Iraporda C, Romanin DE, Bengoa AA, Errea AJ, Cayet D, Foligné B, Sirard JC, Garrote GL, Abraham AG & Rumbo M 2016 Local treatment with lactate prevents intestinal inflammation in the TNBS-induced colitis model. Frontiers in Immunology 7 651. (https://doi.org/10.3389/fimmu.2016.00651)

    • Search Google Scholar
    • Export Citation
  • Janevic T, Zeitlin J, Auger N, Egorova NN, Hebert P, Balbierz A & Howell EA 2018 Association of race/ethnicity with very preterm neonatal morbidities. JAMA Pediatrics 172 10611069. (https://doi.org/10.1001/jamapediatrics.2018.2029)

    • Search Google Scholar
    • Export Citation
  • Jarde A, Lewis-Mikhael AM, Moayyedi P, Stearns JC, Collins SM, Beyene J & McDonald SD 2018 Pregnancy outcomes in women taking probiotics or prebiotics: a systematic review and meta-analysis. BMC Pregnancy and Childbirth 18 14. (https://doi.org/10.1186/s12884-017-1629-5)

    • Search Google Scholar
    • Export Citation
  • Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A & Taylor DJ 2008 Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the Oracle II trial. Lancet 372 13191327. (https://doi.org/10.1016/S0140-6736(08)61203-9)

    • Search Google Scholar
    • Export Citation
  • Kingdom J, Huppertz B, Seaward G & Kaufmann P 2000 Development of the placental villous tree and its consequences for fetal growth. European Journal of Obstetrics, Gynecology, and Reproductive Biology 92 3543. (https://doi.org/10.1016/s0301-2115(00)00423-1)

    • Search Google Scholar
    • Export Citation
  • Lamont RF 2003 The role of infection in preterm labour and birth. Hospital Medicine 64 644647. (https://doi.org/10.12968/hosp.2003.64.11.2343)

    • Search Google Scholar
    • Export Citation
  • Langille MGI, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Vega Thurber RL & Knight R et al2013 Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nature Biotechnology 31 814821. (https://doi.org/10.1038/nbt.2676)

    • Search Google Scholar
    • Export Citation
  • Laptook AR, Bell EF, Shankaran S, Boghossian NS, Wyckoff MH, Kandefer S, Walsh M, Saha S, Higgins R & Polin RA et al2018 Admission temperature and associated mortality and morbidity among moderately and extremely preterm infants. Jurnalul Pediatrului 192 53-59.e2.

    • Search Google Scholar
    • Export Citation
  • Laue C, Papazova E, Liesegang A, Pannenbeckers A, Arendarski P, Linnerth B, Domig KJ, Kneifel W, Petricevic L & Schrezenmeir J 2018 Effect of a yoghurt drink containing Lactobacillus strains on bacterial vaginosis in women - a double-blind, randomised, controlled clinical pilot trial. Beneficial Microbes 9 3550. (https://doi.org/10.3920/BM2017.0018)

    • Search Google Scholar
    • Export Citation
  • Lee AC, Blencowe H & Lawn JE 2019 Small babies, big numbers: global estimates of preterm birth. Lancet: Global Health 7 e2e3. (https://doi.org/10.1016/S2214-109X(18)30484-4)

    • Search Google Scholar
    • Export Citation
  • Lei J, Xie L, Zhao H, Gard C, Clemens JL, McLane MW, Feller MC, Ozen M, Novak C & Alshehri W et al2018 Maternal CD8 + T-cell depletion alleviates intrauterine inflammation-induced perinatal brain injury. American Journal of Reproductive Immunology 79 e12798. (https://doi.org/10.1111/aji.12798)

    • Search Google Scholar
    • Export Citation
  • Li W, Yang S, Kim SO, Reid G, Challis JRG & Bocking AD 2014 Lipopolysaccharide-induced profiles of cytokine, chemokine, and growth factors produced by human decidual cells are altered by lactobacillus rhamnosus gr-1 supernatant. Reproductive Sciences 21 939947. (https://doi.org/10.1177/1933719113519171)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Tran DQ & Rhoads JM 2018 Probiotics in disease prevention and treatment. Journal of Clinical Pharmacology 58 (Supplement 10) S164S179. (https://doi.org/10.1002/jcph.1121)

    • Search Google Scholar
    • Export Citation
  • McMillan A, Rulisa S, Sumarah M, Macklaim JM, Renaud J, Bisanz JE, Gloor GB & Reid G 2015 A multi-platform metabolomics approach identifies highly specific biomarkers of bacterial diversity in the vagina of pregnant and non-pregnant women. Scientific Report 5 14174. (https://doi.org/10.1038/srep14174)

    • Search Google Scholar
    • Export Citation
  • Morelli L & Capurso L 2012 FAO/WHO guidelines on probiotics: 10 years later. Journal of Clinical Gastroenterology 46 S1S2. Available at: (https://journals.lww.com/jcge/Fulltext/2012/10001/FAO_WHO_Guidelines_on_Probiotics__10_Years_Later.2.aspx). (https://doi.org/10.1097/MCG.0b013e318269fdd5https://journals.lww.com/jcge/Fulltext/2012/10001/FAO_WHO_Guidelines_on_Probiotics__10_Years_Later.2.aspx). (https://doi.org/10.1097/MCG.0b013e318269fdd5)

    • Search Google Scholar
    • Export Citation
  • Morgan TK 2016 Role of the placenta in preterm birth: a review. American Journal of Perinatology 33 258266. (https://doi.org/10.1055/s-0035-1570379)

    • Search Google Scholar
    • Export Citation
  • Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Ezzati M, Shibuya K, Salomon JA & Abdalla S et al2012 Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380 21972223. (https://doi.org/10.1016/S0140-6736(12)61689-4)

    • Search Google Scholar
    • Export Citation
  • Mwaniki MK, Atieno M, Lawn JE & Newton CRJC 2012 Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet 379 445452. (https://doi.org/10.1016/S0140-6736(11)61577-8)

    • Search Google Scholar
    • Export Citation
  • Nallasamy S, Akins M, Tetreault B, Luby-Phelps K & Mahendroo M 2018 Distinct reorganization of collagen architecture in lipopolysaccharide-mediated premature cervical remodeling. Biology of Reproduction 98 6374. (https://doi.org/10.1093/biolre/iox155)

    • Search Google Scholar
    • Export Citation
  • Oleszczuk J, Darmochwal-Kolarz D, Leszczynska-Gorzelak B & Rolinski J 2000 Alterations in the immune system of patients with imminent preterm labour. Gynecologic and Obstetric Investigation 49 110113. (https://doi.org/10.1159/000010226)

    • Search Google Scholar
    • Export Citation
  • Oliver RS & Lamont RF 2013 Infection and antibiotics in the aetiology, prediction and prevention of preterm birth. Journal of Obstetrics and Gynaecology 33 768775. (https://doi.org/10.3109/01443615.2013.842963)

    • Search Google Scholar
    • Export Citation
  • Pavel AB & Vasile CI 2012 PyElph - a software tool for gel images analysis and phylogenetics. BMC Bioinformatics 13 9. (https://doi.org/10.1186/1471-2105-13-9)

    • Search Google Scholar
    • Export Citation
  • Pendharkar S, Brandsborg E, Hammarström L, Marcotte H & Larsson PG 2015 Vaginal colonisation by probiotic lactobacilli and clinical outcome in women conventionally treated for bacterial vaginosis and yeast infection. BMC Infectious Diseases 15 255. (https://doi.org/10.1186/s12879-015-0971-3)

    • Search Google Scholar
    • Export Citation
  • Reid G 2001 Probiotic agents to protect the urogenital tract against infection. American Journal of Clinical Nutrition 73 437S443S. (https://doi.org/10.1093/ajcn/73.2.437s)

    • Search Google Scholar
    • Export Citation
  • Reid G 2015 The growth potential for dairy probiotics. International Dairy Journal 49 1622. (https://doi.org/10.1016/j.idairyj.2015.04.004)

    • Search Google Scholar
    • Export Citation
  • Reid G & Bocking A 2003 The potential for probiotics to prevent bacterial vaginosis and preterm labor. American Journal of Obstetrics and Gynecology 189 12021208. (https://doi.org/10.1067/s0002-9378(03)00495-2)

    • Search Google Scholar
    • Export Citation
  • Reid G, Charbonneau D, Erb J, Kochanowski B, Beuerman D, Poehner R & Bruce AW 2003 Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunology and Medical Microbiology 35 131134. (https://doi.org/10.1016/S0928-8244(02)00465-0)

    • Search Google Scholar
    • Export Citation
  • Romanin D, Serradell M, González Maciel D, Lausada N, Garrote GL & Rumbo M 2010 Down-regulation of intestinal epithelial innate response by probiotic yeasts isolated from kefir. International Journal of Food Microbiology 140 102108. (https://doi.org/10.1016/j.ijfoodmicro.2010.04.014)

    • Search Google Scholar
    • Export Citation
  • Romero R, Ceska M, Avila C, Mazor M, Behnke E & Lindley I 1991 Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition. American Journal of Obstetrics and Gynecology 165 813820. (https://doi.org/10.1016/0002-9378(91)90422-n)

    • Search Google Scholar
    • Export Citation
  • Romero R, Dey SK & Fisher SJ 2014 Preterm labor: one syndrome, many causes. Science 345 760765. (https://doi.org/10.1126/science.1251816)

  • Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel LA & Nien JK 2006 Inflammation in preterm and term labour and delivery. Seminars in Fetal and Neonatal Medicine 11 317326. (https://doi.org/10.1016/j.siny.2006.05.001)

    • Search Google Scholar
    • Export Citation
  • Romero R, Mazor M, Wu YK, Sirtori M, Oyarzun E, Mitchell MD & Hobbins JC 1988 Infection in the pathogenesis of preterm labor. Seminars in Perinatology 12 262279.

    • Search Google Scholar
    • Export Citation
  • Romero R, Salafia CM, Athanassiadis AP, Hanaoka S, Mazor M, Sepulveda W & Bracken MB 1992 The relationship between acute inflammatory lesions of the preterm placenta and amniotic fluid microbiology. American Journal of Obstetrics and Gynecology 166 13821388. (https://doi.org/10.1016/0002-9378(92)91609-e)

    • Search Google Scholar
    • Export Citation
  • Romero R, Sibai B, Caritis S, Paul R, Depp R, Rosen M, Klebanoff M, Sabo V, Evans J & Thom E 1993 Antibiotic treatment of preterm labor with intact membranes: A multicenter, randomized, double-blinded, placebo-controlled trial. American Journal of Obstetrics and Gynecology 169 764774. (https://doi.org/10.1016/0002-9378(93)90003-2)

    • Search Google Scholar
    • Export Citation
  • Sabbatini S, Monari C, Ballet N, Mosci P, Decherf AC, Pélerin F, Perito S, Scarpelli P & Vecchiarelli A 2018 Saccharomyces cerevisiae–based probiotic as novel anti-microbial agent for therapy of bacterial vaginosis. Virulence 9 954966. (https://doi.org/10.1080/21505594.2018.1464362)

    • Search Google Scholar
    • Export Citation
  • Schander JA, Aisemberg J, Correa F, Wolfson ML, Juriol L, Cymeryng C, Jensen F & Franchi AM 2020 The enrichment of maternal environment prevents pre-term birth in a mice model. Reproduction 159 479492. (https://doi.org/10.1530/REP-19-0572)

    • Search Google Scholar
    • Export Citation
  • Shennan A, Crawshaw S, Briley A, Hawken J, Seed P, Jones G & Poston L 2006 A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 113 6574. (https://doi.org/10.1111/j.1471-0528.2005.00788.x)

    • Search Google Scholar
    • Export Citation
  • Shynlova O, Nedd-Roderique T, Li Y, Dorogin A & Lye SJ 2013 Myometrial immune cells contribute to term parturition, preterm labour and post-partum involution in mice. Journal of Cellular and Molecular Medicine 17 90102. (https://doi.org/10.1111/j.1582-4934.2012.01650.x)

    • Search Google Scholar
    • Export Citation
  • Slattery MM & Morrison JJ 2002 Preterm delivery. Lancet 360 14891497. Available at: (http://www.sciencedirect.com/science/article/pii/S0140673602114760). (https://doi.org/10.1016/S0140-6736(02)11476-0)

    • Search Google Scholar
    • Export Citation
  • Slutsky R, Romero R, Xu Y, Galaz J, Miller D, Done B, Tarca AL, Gregor S, Hassan SS & Leng Y et al2019 Exhausted and senescent T cells at the maternal-fetal interface in preterm and term labor. Journal of Immunology Research 2019 3128010. (https://doi.org/10.1155/2019/3128010)

    • Search Google Scholar
    • Export Citation
  • Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, Higgins RDNational Institute of Child Health and Human Development Neonatal Research Network 2004 Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 292 23572365. (https://doi.org/10.1001/jama.292.19.2357)

    • Search Google Scholar
    • Export Citation
  • Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, Hale EC, Newman NS, Schibler K & Carlo WA et al2010 Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 126 443456. (https://doi.org/10.1542/peds.2009-2959)

    • Search Google Scholar
    • Export Citation
  • Subramaniam A, Abramovici A, Andrews WW & Tita AT 2012 Antimicrobials for preterm birth prevention: an overview. Infectious Diseases in Obstetrics and Gynecology 2012 157159. (https://doi.org/10.1155/2012/157159)

    • Search Google Scholar
    • Export Citation
  • Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P & Ota E 2015 Antibiotic prophylaxis during the second and third trimester to reduce adverse pregnancy outcomes and morbidity. Cochrane Database of Systematic Reviews 6 CD002250.

    • Search Google Scholar
    • Export Citation
  • Toscano M, De Grandi R, Miniello VL, Mattina R & Drago L 2017 Ability of Lactobacillus kefiri LKF01 (DSM32079) to colonize the intestinal environment and modify the gut microbiota composition of healthy individuals. Digestive and Liver Disease 49 261267. (https://doi.org/10.1016/j.dld.2016.11.011)

    • Search Google Scholar
    • Export Citation
  • Uroić K, Novak J, Hynönen U, Pietilä TE, Leboš Pavunc A, Kant R, Kos B, Palva A & Šušković J 2016 The role of S-layer in adhesive and immunomodulating properties of probiotic starter culture Lactobacillus brevis D6 isolated from artisanal smoked fresh cheese. LWT: Food Science and Technology 69 623632. (https://doi.org/10.1016/j.lwt.2016.02.013)

    • Search Google Scholar
    • Export Citation
  • Valeff N, Juriol L, Quadrana F, Muzzio DO, Zygmunt M, Quiroga MF, Ventimiglia MS & Jensen F 2020 Expression of IL-33 receptor is significantly up-regulated in B cells during pregnancy and in the acute phase of preterm birth in mice. Frontiers in Immunology 11 111.

    • Search Google Scholar
    • Export Citation
  • Vásquez A, Ahrné S, Jeppsson B & Molin G 2005 Oral administration of Lactobacillus and Bifidobacterium strains of intestinal and vaginal origin to healthy human females: re-isolation from faeces and vagina. Microbial Ecology in Health and Disease 17 1520. (https://doi.org/10.3402/mehd.v17i1.7811)

    • Search Google Scholar
    • Export Citation
  • Vogel JP, Chawanpaiboon S, Moller AB, Watananirun K, Bonet M & Lumbiganon P 2018 The global epidemiology of preterm birth. Best Practice and Research: Clinical Obstetrics and Gynaecology 52 312. (https://doi.org/10.1016/j.bpobgyn.2018.04.003)

    • Search Google Scholar
    • Export Citation
  • WHO 2006 Neonatal and perinatal mortality: country region and Global estimates. Available at: (http//:www.who.int).

  • Zubiría MG, Gambaro SE, Rey MA, Carasi P, Serradell de los MLÁ & Giovambattista A 2017 Deleterious metabolic effects of high fructose intake: the preventive effect of Lactobacillus kefiri administration. Nutrients 9. (https://doi.org/10.3390/nu9050470)

    • Search Google Scholar
    • Export Citation