Abstract
Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48–0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.
Similar content being viewed by others
Change history
30 November 2017
Please see accompanying Corrigendum (http://doi.org/10.1038/nature25006). In this Article, the statement ‘There were 88 culture-positive and 94 culture-negative cases’ has been corrected to ‘Apart from 88 cases of suspect sepsis that included both culture-negative and culture-positive infants, there were an additional 94 culture-negative cases’.
References
Thaver, D. & Zaidi, A. K. Burden of neonatal infections in developing countries: a review of evidence from community-based studies. Pediatr. Infect. Dis. J. 28 (suppl. 1), S3–S9 (2009)
Liu, L. et al. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 385, 430–440 (2015)
United Nations Inter-agency Group for Child Mortality Estimation. Levels and Trends in Child Mortality ; https://www.unicef.org/media/files/Levels_and_Trends_in_Child_Mortality_2014.pdf (UNICEF, WHO, The World Bank, UNDP, 2014)
Seale, A. C. et al. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect. Dis. 14, 731–741 (2014)
Blencowe, H. et al. Estimates of neonatal morbidities and disabilities at regional and global levels for 2010: introduction, methods overview, and relevant findings from the Global Burden of Disease study. Pediatr. Res. 74 (suppl. 1), 4–16 (2013)
Lawn, J. E. et al. Every Newborn: progress, priorities, and potential beyond survival. Lancet 384, 189–205 (2014)
Oza, S., Lawn, J. E., Hogan, D. R., Mathers, C. & Cousens, S. N. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000–2013. Bull. World Health Organ. 93, 19–28 (2015)
Boghossian, N. S. et al. Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J. Pediatr. 162, 1120–1124.e1 (2013)
Marshall, J. C. Why have clinical trials in sepsis failed? Trends Mol. Med. 20, 195–203 (2014)
The INIS Collaborative Group. Treatment of neonatal sepsis with intravenous immune globulin. N. Engl. J. Med. 365, 1201–1211 (2011)
Mullany, L. C., Darmstadt, G. L. & Tielsch, J. M. Safety and impact of chlorhexidine antisepsis interventions for improving neonatal health in developing countries. Pediatr. Infect. Dis. J. 25, 665–675 (2006)
Gewolb, I. H., Schwalbe, R. S., Taciak, V. L., Harrison, T. S. & Panigrahi, P. Stool microflora in extremely low birthweight infants. Arch. Dis. Child. Fetal Neonatal Ed. 80, F167–F173 (1999)
AlFaleh, K. & Anabrees, J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst. Rev. http://dx.doi.org/10.1002/14651858.CD005496.pub4 (2014)
Dilli, D. et al. Treatment outcomes of infants with cyanotic congenital heart disease treated with synbiotics. Pediatrics 132, e932–e938 (2013)
Dilli, D. et al. The ProPre-Save study: effects of probiotics and prebiotics alone or combined on necrotizing enterocolitis in very low birth weight infants. J. Pediatr. 166, 545–51.e1 (2015)
Nandhini, L. et al. Synbiotics for decreasing incidence of necrotizing enterocolitis among preterm neonates—a randomized controlled trial. J. Matern. Fetal Neonatal Med. 29, 821–825 (2016)
Jacobs, S. E. et al. Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics 132, 1055–1062 (2013)
Costeloe, K. et al. Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial. Lancet 387, 649–660 (2016)
Agarwal, R. et al. Effects of oral Lactobacillus GG on enteric microflora in low-birth-weight neonates. J. Pediatr. Gastroenterol. Nutr. 36, 397–402 (2003)
Panigrahi, P. et al. Long-term colonization of a Lactobacillus plantarum synbiotic preparation in the neonatal gut. J. Pediatr. Gastroenterol. Nutr. 47, 45–53 (2008)
National Health Mission. Health Statistics; http://www.nrhmorissa.gov.in/frmhealthstatistics.aspx (2011)
Sinha, A. et al. Role of probiotics VSL#3 in prevention of suspected sepsis in low birthweight infants in India: a randomised controlled trial. BMJ Open 5, e006564 (2015)
Waters, D. et al. Aetiology of community-acquired neonatal sepsis in low and middle income countries. J. Glob. Health 1, 154–170 (2011)
Panigrahi, P., Gupta, S., Gewolb, I. H. & Morris, J. G. Jr. Occurrence of necrotizing enterocolitis may be dependent on patterns of bacterial adherence and intestinal colonization: studies in Caco-2 tissue culture and weanling rabbit models. Pediatr. Res. 36, 115–121 (1994)
Panigrahi, P., Bamford, P., Horvath, K., Morris, J. G. Jr & Gewolb, I. H. Escherichia coli transcytosis in a Caco-2 cell model: implications in neonatal necrotizing enterocolitis. Pediatr. Res. 40, 415–421 (1996)
Khailova, L., Baird, C. H., Rush, A. A., McNamee, E. N. & Wischmeyer, P. E. Lactobacillus rhamnosus GG improves outcome in experimental pseudomonas aeruginosa pneumonia: potential role of regulatory T cells. Shock 40, 496–503 (2013)
Chu, H. & Mazmanian, S. K. Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat. Immunol. 14, 668–675 (2013)
Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat. Rev. Immunol. 12, 9–23 (2011)
Arrieta, M. C., Stiemsma, L. T., Amenyogbe, N., Brown, E. M. & Finlay, B. The intestinal microbiome in early life: health and disease. Front. Immunol. 5, 427 (2014)
Deshmukh, H. S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–530 (2014)
Kiso, M. et al. Protective efficacy of orally administered, heat-killed Lactobacillus pentosus b240 against influenza A virus. Sci. Rep. 3, 1563 (2013)
Tanaka, A. et al. Lactobacillus pentosus strain b240 suppresses pneumonia induced by Streptococcus pneumoniae in mice. Lett. Appl. Microbiol. 53, 35–43 (2011)
Moles, L. et al. Bacterial diversity in meconium of preterm neonates and evolution of their fecal microbiota during the first month of life. PLoS One 8, e66986 (2013)
Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra65 (2014)
Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152 (2015)
Khosravi, A. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15, 374–381 (2014)
Hensey, O. J., Hart, C. A. & Cooke, R. W. Serious infection in a neonatal intensive care unit: a two-year survey. J. Hyg. (Lond.) 95, 289–297 (1985)
Spigelblatt, L., Saintonge, J., Chicoine, R. & Laverdière, M. Changing pattern of neonatal streptococcal septicemia. Pediatr. Infect. Dis. 4, 56–58 (1985)
West, P. W. et al. Speciation of presumptive viridans streptococci from early onset neonatal sepsis. J. Med. Microbiol. 47, 923–928 (1998)
Schrag, S. J. et al. Epidemiology of invasive early-onset neonatal sepsis, 2005 to 2014. Pediatrics 138, e20162013 (2016)
Jalilsood, T. et al. Characterization of pR18, a novel rolling-circle replication plasmid from Lactobacillus plantarum. Plasmid 73, 1–9 (2014)
Jacobsen, L. et al. Horizontal transfer of tet(M) and erm(B) resistance plasmids from food strains of Lactobacillus plantarum to Enterococcus faecalis JH2-2 in the gastrointestinal tract of gnotobiotic rats. FEMS Microbiol. Ecol. 59, 158–166 (2007)
Feld, L. et al. Selective pressure affects transfer and establishment of a Lactobacillus plantarum resistance plasmid in the gastrointestinal environment. J. Antimicrob. Chemother. 61, 845–852 (2008)
Toomey, N., Bolton, D. & Fanning, S. Characterisation and transferability of antibiotic resistance genes from lactic acid bacteria isolated from Irish pork and beef abattoirs. Res. Microbiol. 161, 127–135 (2010)
Bujalance, C., Jiménez-Valera, M., Moreno, E. & Ruiz-Bravo, A. A selective differential medium for Lactobacillus plantarum. J. Microbiol. Methods 66, 572–575 (2006)
Lai, E. M., Nathan, A. M., de Bruyne, J. A. & Chan, L. L. Should all children admitted with community acquired pneumonia have blood cultures taken? Indian J. Pediatr. 82, 439–444 (2015)
McCulloh, R. J. et al. Evaluating the use of blood cultures in the management of children hospitalized for community-acquired pneumonia. PLoS One 10, e0117462 (2015)
Das, A., Patgiri, S. J., Saikia, L., Dowerah, P. & Nath, R. Bacterial pathogens associated with community-acquired pneumonia in children aged below five years. Indian Pediatr. 53, 225–227 (2016)
Young Infants Clinical Signs Study Group. Clinical signs that predict severe illness in children under age 2 months: a multicentre study. Lancet 371, 135–142 (2008)
Carlo, W. A. et al. Newborn-care training and perinatal mortality in developing countries. N. Engl. J. Med. 362, 614–623 (2010)
Panigrahi, P. et al. Neonatal sepsis in rural India: timing, microbiology and antibiotic resistance in a population-based prospective study in the community setting. J. Perinatal. http://dx.doi.org/10.1038/jp.2017.67 (2017)
Acknowledgements
We are thankful to the Indian Council of Medical Research and the Ministry of Health and Family Welfare Government of India for their review and timely clearance. The Government of Odisha, Department of Health and Family Welfare provided necessary approvals and directives at the block level for implementation of the project in the hospitals and the community setting. We are grateful to the Director of Capital Hospital, Bhubaneswar, and Ispat General Hospital for providing dedicated clinical research space and laboratory space to set up the Bactec blood culture, microbiology, and data management facilities. Our gratitude to Dayananda Das (now deceased) of Jana Sikshan Sansthan for his management skills and each of the >200 members in the three-tier community intervention team. K. Pradhan and K. Mishra deserve thanks for managing the study in the two districts. Our thanks to the DSMB members for reviewing all serious adverse events and convening yearly in person for further review of compiled data and providing valuable insights. This study could not have been possible without the unconditional support of the parents of the newborns born in the study districts and the physicians, nurse-midwives, and Anganwadi workers of the government system who provided assistance throughout the conduct of the study. This study was funded by grants U01 HD 40574 and R01 HD 53719 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, USA.
Author information
Authors and Affiliations
Contributions
P.P. and I.G. conceived the study and P.P. wrote the first draft. P.P., S.N.P., I.G., N.P. and J.G.M. designed the study with help from the other authors. N.N., R.S., L.P. and A.M. were responsible for clinical operations. S.S.M. managed the field activities. J.J. and R.C. were in charge of developing microbiology protocols and standard operating procedures. R.C. was in charge of the reference laboratory and supervised the final strain designation of blood isolates. H.C. and L.B. conducted the data management and statistical analyses. D.C. managed the protocol from the principal investigator’s laboratory and handled data acquisition, microbiology quality assurance, and institutional review board matters. All authors contributed in writing different sections of the manuscripts.
Corresponding author
Ethics declarations
Competing interests
Following institutional procedures for federally funded grants, a new invention disclosure on the use of a combination of L. plantarum and fructooligosaccharides against infection and inflammation was made to the UNMC office of technology transfer (UNeMed). UNeMed, upon its decision not to pursue the invention, has released the rights to the inventor (P.P.). A PCT patent application has been filed (pending examination) and assigned to the Asian Institute of Public Health. None of the authors, including P.P., has any financial or management interest with any commercial entity.
Additional information
Reviewer Information Nature thanks R. Feng, T. Kollmann, D. J. Tancredi and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Figure 1 Site maps.
Location of study sites in Odisha, India. Source: India and Odisha state maps, redrawn to show the geographic location of study sites. Reproduced with permission from ref. 51.
Extended Data Figure 2 Site structure.
Three-tier structure for field operations and implementation of the clinical trial in the community. Reproduced with permission from ref. 51.
Supplementary information
Supplementary Information
This file contains supplementary information 1 (A-C), 2 and 3 (Consort checklist). (PDF 1754 kb)
PowerPoint slides
Rights and permissions
About this article
Cite this article
Panigrahi, P., Parida, S., Nanda, N. et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature 548, 407–412 (2017). https://doi.org/10.1038/nature23480
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature23480
- Springer Nature Limited
This article is cited by
-
Impact of hyperoxia on the gut during critical illnesses
Critical Care (2024)
-
Short-chain fatty acids: linking diet, the microbiome and immunity
Nature Reviews Immunology (2024)
-
Role of the microbiota in response to and recovery from cancer therapy
Nature Reviews Immunology (2024)
-
Synbiotics as potent functional food: recent updates on therapeutic potential and mechanistic insight
Journal of Food Science and Technology (2024)
-
Relationship between gut microbiota dysbiosis and immune indicator in children with sepsis
BMC Pediatrics (2023)