Top

Published in:

Open Access 01-12-2015 | Study protocol

Intestinal microbiota composition after antibiotic treatment in early life: the INCA study

Authors: N. B. M. M. Rutten, G. T. Rijkers, C. B. Meijssen, C. E. Crijns, J. H. Oudshoorn, C. K. van der Ent, A. M. Vlieger

Published in: BMC Pediatrics | Issue 1/2015

Abstract

Background

The acquisition and development of infant gut microbiota can be influenced by numerous factors, of which early antibiotic treatment is an important one. However, studies on the effects of antibiotic treatment in early life on clinical outcomes and establishment and development of the gut microbiota of term infants are limited. Disturbed microbiota composition is hypothesized to be an underlying mechanism of an aberrant development of the immune system. This study aims to investigate the potential clinical and microbial consequences of empiric antibiotic use in early life.

Methods/Design

450 term born infants, of whom 150 are exposed to antibiotic treatment in early life and 300 are not (control group), are included in this observational cohort study with a one-year follow-up. Clinical outcomes, including coughing, wheezing, fever >38 °C, runny nose, glue ear, rash, diarrhea and >3 crying hours a day, are recorded daily by parents and examined by previously defined doctor’s diagnosis. A blood sample is taken at closure to investigate the infant’s vaccination response and sensitization for food and inhalant allergens. Fecal samples are obtained at eight time points during the first year of life. Potential differences in microbial profiles of infants treated with antibiotics versus healthy controls will be determined by use of 16S-23S rRNA gene analysis (IS-pro). Microbiota composition will be described by means of abundance, diversity and (dis)similarity. Diversity is calculated using the Shannon index. Dissimilarities between samples are calculated as the cosine distance between each pair of samples and analyzed with principal coordinate analysis. Clinical variables and possible associations are assessed by appropriate statistics.

Discussion

Both clinical quantitative and qualitative microbial effects of antibiotic treatment in early life may be demonstrated. These findings can be important, since there is evidence that manipulation of the infant microbiota by using pre- or probiotics can restore the ecological balance of the microbiota and may mitigate potential negative effects on the developing immune system, when use of antibiotics cannot be avoided.

Trial registration

ClinicalTrials.gov NCT02536560. Registered 28 August 2015.

Adlerberth I. Factors influencing the establishment of the intestinal microbiota in infancy. Nestle Nutr Workshop Ser Pediatr Program. 2008;62:13–29. discussion 29–33.CrossRefPubMed

Makino H, Kushiro A, Ishikawa E, Kubota H, Gawad A, Sakai T, et al. Mother-to-infant transmission of intestinal bifidobacterial strains has an impact on the early development of vaginally delivered infant’s microbiota. PLoS One. 2013;8:e78331.CrossRefPubMedPubMedCentral

Fraher MH, O’Toole PW, Quigley EMM. Techniques used to characterize the gut microbiota: a guide for the clinician. Nat Rev Gastroenterol Hepatol. 2012;9:312–22.CrossRefPubMed

Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915–20.CrossRefPubMed

Schaible UE, Kaufmann SHE. A nutritive view on the host-pathogen interplay. Trends Microbiol. 2005;13:373–80.CrossRefPubMed

Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292:1115–8.CrossRefPubMed

Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr. 2002;22:283–307.CrossRefPubMed

Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol. 2004;4:478–85.CrossRefPubMed

Sjögren YM, Tomicic S, Lundberg A, Böttcher MF, Björkstén B, Sverremark-Ekström E, et al. Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses. Clin Exp Allergy. 2009;39:1842–51.CrossRefPubMed

10.

Grönlund MM, Arvilommi H, Kero P, Lehtonen OP, Isolauri E. Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months. Arch Dis Child Fetal Neonatal Ed. 2000;83:F186–92.CrossRefPubMedPubMedCentral

11.

Alm B, Erdes L, Möllborg P, Pettersson R, Norvenius SG, Aberg N, et al. Neonatal antibiotic treatment is a risk factor for early wheezing. Pediatrics. 2008;121:697–702.CrossRefPubMed

12.

Bisgaard H, Li N, Bonnelykke K, Chawes BLK, Skov T, Paludan-Müller G, et al. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J Allergy Clin Immunol. 2011;128:646–52. e1–5.CrossRefPubMed

13.

Li M, Wang M, Donovan SM. Early development of the gut microbiome and immune-mediated childhood disorders. Semin Reprod Med. 2014;32:74–86.CrossRefPubMed

14.

Ringel-Kulka T, Cheng J, Ringel Y, Salojärvi J, Carroll I, Palva A, et al. Intestinal microbiota in healthy U.S. young children and adults--a high throughput microarray analysis. PLoS One. 2013;8:e64315.CrossRefPubMedPubMedCentral

15.

Bedford Russell a R, Murch SH. Could peripartum antibiotics have delayed health consequences for the infant? BJOG. 2006;113:758–65.CrossRefPubMed

16.

Caramia G, Atzei A, Fanos V. Probiotics and the skin. Clin Dermatol. 2008;26:4–11.CrossRefPubMed

17.

Verhulst SL, Vael C, Beunckens C, Nelen V, Goossens H, Desager K. A longitudinal analysis on the association between antibiotic use, intestinal microflora, and wheezing during the first year of life. J Asthma. 2008;45:828–32.CrossRefPubMed

18.

Penders J, Stobberingh EE, Thijs C, Adams H, Vink C, van Ree R, et al. Molecular fingerprinting of the intestinal microbiota of infants in whom atopic eczema was or was not developing. Clin Exp Allergy. 2006;36:1602–8.CrossRefPubMed

19.

Kalliomäki M, Collado MC, Salminen S, Isolauri E. Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr. 2008;87:534–8.PubMed

20.

Reinhardt C, Reigstad CS, Bäckhed F. Intestinal microbiota during infancy and its implications for obesity. J Pediatr Gastroenterol Nutr. 2009;48:249–56.CrossRefPubMed

21.

Marra F, Lynd L, Coombes M, Richardson K, Legal M, Fitzgerald JM, et al. Does antibiotic exposure during infancy lead to development of asthma?: a systematic review and metaanalysis. Chest. 2006;129:610–8.CrossRefPubMed

22.

Musso G, Gambino R, Cassader M. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med. 2011;62:361–80.CrossRefPubMed

23.

Abraham C, Medzhitov R. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology. 2011;140:1729–37.CrossRefPubMedPubMedCentral

24.

Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the Intestinal Microbiota during a Critical Developmental Window Has Lasting Metabolic Consequences. Cell. 2014;158:705–21.CrossRefPubMedPubMedCentral

25.

Saulnier DM, Riehle K, Mistretta T-A, Diaz M-A, Mandal D, Raza S, et al. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology. 2011;141:1782–91.CrossRefPubMedPubMedCentral

26.

Savino F, Cordisco L, Tarasco V, Calabrese R, Palumeri E, Matteuzzi D. Molecular identification of coliform bacteria from colicky breastfed infants. Acta Paediatr. 2009;98:1582–8.CrossRefPubMed

27.

Adlerberth I, Wold a E. Establishment of the gut microbiota in Western infants. Acta Paediatr. 2009;98:229–38.CrossRefPubMed

28.

Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006;118:511–21.CrossRefPubMed

29.

Arrieta M-C, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The Intestinal Microbiome in Early Life: Health and Disease. Front Immunol. 2014;5:427.CrossRefPubMedPubMedCentral

30.

Penders J, Kummeling I, Thijs C. Infant antibiotic use and wheeze and asthma risk: a systematic review and meta-analysis. Eur Respir J. 2011;38:295–302.CrossRefPubMed

31.

Azad MB, Bridgman SL, Becker AB, Kozyrskyj AL. Infant antibiotic exposure and the development of childhood overweight and central adiposity. Int J Obes (Lond). 2014;38:1290–8.CrossRef

32.

Gough EK, Moodie EEM, Prendergast AJ, Johnson SMA, Humphrey JH, Stoltzfus RJ, et al. The impact of antibiotics on growth in children in low and middle income countries: systematic review and meta-analysis of randomised controlled trials. BMJ. 2014;348:g2267.CrossRefPubMedPubMedCentral

33.

Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ. Infant antibiotic exposures and early-life body mass. Int J Obes (Lond). 2013;37:16–23.CrossRef

34.

Tanaka S, Kobayashi T, Songjinda P, Tateyama A, Tsubouchi M, Kiyohara C, et al. Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota. FEMS Immunol Med Microbiol. 2009;56:80–7.CrossRefPubMed

35.

Hussey S, Wall R, Gruffman E, O’Sullivan L, Ryan CA, Murphy B, et al. Parenteral antibiotics reduce bifidobacteria colonization and diversity in neonates. Int J Microbiol. 2011;2011.

36.

Bennet R, Eriksson M, Nord CE. The fecal microflora of 1-3-month-old infants during treatment with eight oral antibiotics. Infection. 2002;30:158–60.CrossRefPubMed

37.

Chang JY, Shin SM, Chun J, Lee J-H, Seo J-K. Pyrosequencing-based molecular monitoring of the intestinal bacterial colonization in preterm infants. J Pediatr Gastroenterol Nutr. 2011;53:512–9.PubMed

38.

Rougé C, Goldenberg O, Ferraris L, Berger B, Rochat F, Legrand A, et al. Investigation of the intestinal microbiota in preterm infants using different methods. Anaerobe. 2010;16:362–70.CrossRefPubMed

39.

Mai X-M, Kull I, Wickman M. Bergström a: Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation. Clin Exp Allergy. 2010;40:1230–7.CrossRefPubMed

40.

Bentsen BG. International classification of primary care. Scand J Prim Health Care. 1986;4:43–50.CrossRefPubMed

41.

Budding a E, Grasman ME, Lin F, Bogaards J a, Soeltan-Kaersenhout DJ, Vandenbroucke-Grauls CMJE, et al. IS-pro: high-throughput molecular fingerprinting of the intestinal microbiota. FASEB J. 2010;24:4556–64.CrossRefPubMed

42.

Haegeman B, Hamelin J, Moriarty J, Neal P, Dushoff J, Weitz JS. Robust estimation of microbial diversity in theory and in practice. ISME J. 2013;7:1092–101.CrossRefPubMedPubMedCentral

43.

Boyle RJ, Bath-Hextall FJ, Leonardi-Bee J, Murrell DF, Tang ML: Probiotics for treating eczema. Cochrane database Syst Rev 2008:(4):CD006135. doi:10.1002/14651858.CD006135.

44.

Niers L, Martín R, Rijkers G, Sengers F, Timmerman H, van Uden N, et al. The effects of selected probiotic strains on the development of eczema (the PandA study). Allergy. 2009;64:1349–58.CrossRefPubMed

45.

Lucassen P. Colic in infants. BMJ Clin Evid. 2010;2010.

46.

Matricardi PM, Illi S, Grüber C, Keil T, Nickel R, Wahn U, et al. Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence. Eur Respir J. 2008;32:585–92.CrossRefPubMed

47.

Kummeling I, Stelma FF, Dagnelie PC, Snijders BEP, Penders J, Huber M, et al. Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study. Pediatrics. 2007;119:e225–31.CrossRefPubMed

48.

Celedón JC, Litonjua A a, Ryan L, Weiss ST, Gold DR. Lack of association between antibiotic use in the first year of life and asthma, allergic rhinitis, or eczema at age 5 years. Am J Respir Crit Care Med. 2002;166:72–5.CrossRefPubMed

49.

Savino F, Roana J, Mandras N, Tarasco V, Locatelli E, Tullio V. Faecal microbiota in breast-fed infants after antibiotic therapy. Acta Paediatr. 2011;100:75–8.CrossRefPubMed

50.

Maukonen J, Simões C, Saarela M. The currently used commercial DNA-extraction methods give different results of clostridial and actinobacterial populations derived from human fecal samples. FEMS Microbiol Ecol. 2012;79:697–708.CrossRefPubMed

51.

Bahl MI, Bergström A, Licht TR. Freezing fecal samples prior to DNA extraction affects the Firmicutes to Bacteroidetes ratio determined by downstream quantitative PCR analysis. FEMS Microbiol Lett. 2012;329:193–7.CrossRefPubMed

52.

Echarri PP, Graciá CM, Berruezo GR, Vives I, Ballesta M, Solís G, et al. Assessment of intestinal microbiota of full-term breast-fed infants from two different geographical locations. Early Hum Dev. 2011;87:511–3.CrossRefPubMed

53.

Marques TM, Wall R, Ross RP, Fitzgerald GF, Ryan CA, Stanton C. Programming infant gut microbiota: influence of dietary and environmental factors. Curr Opin Biotechnol. 2010;21:149–56.CrossRefPubMed

Title: Intestinal microbiota composition after antibiotic treatment in early life: the INCA study
Authors: N. B. M. M. Rutten
G. T. Rijkers
C. B. Meijssen
C. E. Crijns
J. H. Oudshoorn
C. K. van der Ent
A. M. Vlieger
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Pediatrics / Issue 1/2015
Electronic ISSN: 1471-2431
DOI: https://doi.org/10.1186/s12887-015-0519-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Intestinal microbiota composition after antibiotic treatment in early life: the INCA study

Abstract

Background

Methods/Design

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods/Design

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2015

Parent/caregiver health literacy among children with special health care needs: a systematic review of the literature

Optimising nutrition to improve growth and reduce neurodisabilities in neonates at risk of neurological impairment, and children with suspected or confirmed cerebral palsy

The socio-economic determinants of infant mortality in Nepal: analysis of Nepal Demographic Health Survey, 2011

Evaluation of the Family Integrated Care model of neonatal intensive care: a cluster randomized controlled trial in Canada and Australia

Fever phobia: a comparison survey between caregivers in the inpatient ward and caregivers at the outpatient department in a children’s hospital in China

Scoping review of patient- and family-oriented outcomes and measures for chronic pediatric disease