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Early-life gut microbiota and breast milk oligosaccharides in relation to childhood immune maturation and allergy
Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atopic allergy is the most common chronic disease among children in the developed world. This high prevalence could be associated with low microbial exposure. The early gut microbiota appears to be important for immune maturation. Immunomodulatory components in human milk might differ between mothers and could therefore explain the contradictory results seen regarding breastfeeding and allergy development. The aim of this thesis was to investigate whether early colonization with certain gut microbiota species influences childhood immune responses and allergy development up to age five. Also, as human milk oligosaccharides (HMOs) might stimulate the growth of certain gut microbiota species, the consumption of neutral colostrum HMOs was investigated for their role in allergy development up to 18 months.

The concentrations of neutral colostrum HMOs varied considerably between women; however this variation could not be explained by their allergic status. Neither was the consumption of neutral colostrum HMOs related to allergy development in their children up to 18 months.

Infants who harboured lactobacilli group I and Bifidobacterium adolescentis one week after birth developed allergic disease less frequently during their first five years than infants who did not harbour these bacteria at the same time. Also, colonization with several Bifidobacterium species was associated with higher levels of house dust endotoxin and larger family size.

The early Bifidobacterium flora influenced levels of salivary secretory IgA at six and 12 months but not during later childhood. Moreover, the intensity of early Bacteroides fragilis colonization was inversely associated with spontaneous Toll-like receptor 4 mRNA expression in peripheral blood cells collected 12 months after birth.

In conclusion, these results indicate that the early infant gut microbiota influences systemic and mucosal immune maturation during infancy, and that it might be altered in infants developing allergic disease.

Place, publisher, year, edition, pages
Stockholm: Wenner-Gren Institute for Experimental Biology, Stockholm University , 2009. , 92 p.
Keyword [en]
allergy, infant, gut microbiota, human milk oligosaccharides, Bifidobacterium, Lactobacillus, Bacteroides fragilis, Clostridium difficile, family size, secretory IgA, toll like receptor
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-26781ISBN: 978-91-7155-854-1 (print)OAI: oai:DiVA.org:su-26781DiVA: diva2:211364
Public defence
2009-05-15, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2009-04-24 Created: 2009-04-14 Last updated: 2009-04-15Bibliographically approved
List of papers
1. Neutral oligosaccharides in colostrum in relation to maternal allergy and allergy development in children up to 18 months of age
Open this publication in new window or tab >>Neutral oligosaccharides in colostrum in relation to maternal allergy and allergy development in children up to 18 months of age
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2007 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 18, no 1, 20-26 p.Article in journal (Refereed) Published
Keyword
Colostrum/chemistry/*immunology, Female, Humans, Hypersensitivity/*etiology/*immunology/microbiology, Infant, Infant; Newborn, Intestines/microbiology, Male, Oligosaccharides/analysis/*immunology, Pregnancy, Prospective Studies
Identifiers
urn:nbn:se:su:diva-21025 (URN)10.1111/j.1399-3038.2006.00486.x (DOI)000244060400004 ()17295795 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-13Bibliographically approved
2. Altered early infant gut microbiota in children developing allergy up to 5 years of age
Open this publication in new window or tab >>Altered early infant gut microbiota in children developing allergy up to 5 years of age
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2009 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 39, 518-526 p.Article in journal (Refereed) Published
Abstract [en]

Background: Early colonization with bifidobacteria and lactobacilli is postulated to protect children from allergy, while Clostridium difficile colonization might be associated with allergic disease. Previous studies of the infant gut microbiota in relation to subsequent allergy development have mostly employed culture dependent techniques, studied genera of bacteria and the follow up period was limited to two years.

Objective: To relate gut microbiota in early infancy, notably bifidobacteria and lactobacilli at species level, to allergy development during the first five years of life and study if environmental factors influence the early infant gut microbiota.

Methods: Faecal samples were collected at one week, one month and two months after birth from 47 Swedish infants, followed prospectively to five years of age. Bacterial DNA was analysed with Real-time PCR and related to allergy development, family size as well as endotoxin and Fel d 1 levels in house dust samples. Primers binding to Clostridium difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis were used. Children regarded as allergic manifested allergic symptoms and were skin prick test positive during their first five years while non-allergic children were neither.

Results: Children who developed allergy were significantly less often colonized with lactobacilli group I (Lactobacillus (L.) rhamnosus, L. casei, L. paracasei), Bifidobacterium adolescentis and Clostridium difficile during their first two months. Infants colonized with several Bifidobacterium species had been exposed to higher amounts of endotoxin and grew up in larger families than infants harbouring few species.

Conclusion: A more diverse gut microbiota early in life might prevent allergy development and may be related to the previously suggested inverse relationship between allergy, family size and endotoxin exposure.

Keyword
allergy, infant, gut microbiota, bifidobacteria, lactobacilli, Clostridium difficile, siblings, endotoxin, Fel d 1
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-26788 (URN)10.1111/j.1365-2222.2008.03156.x (DOI)000264184800010 ()
Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2017-12-13Bibliographically approved
3. Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses
Open this publication in new window or tab >>Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses
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(English)Manuscript (Other academic)
Abstract [en]

Introduction: Among sensitized infants those with high, as compared with low levels, of salivary secretory IgA (SIgA) are less likely to develop allergic symptoms. Also, early colonization with certain gut microbiota, e.g. Lactobacilli and Bifidobacterium species, might be associated with less allergy development. Although animal and in vitro studies emphasize the role of the commensal gut microbiota in the development of the immune system, the influence of the gut microbiota on immune development in infants is unclear.

Objective: To assess whether early colonization with certain gut microbiota species associates with mucosal and systemic immune responses i.e. salivary SIgA and the spontaneous toll like receptor (TLR) 2 and TLR4 mRNA expression and LPS-induced cytokine/chemokine responses in peripheral blood mononuclear cells (PBMC).

Methods: Faecal samples were collected at one week, one month and two months after birth from 64 Swedish infants, followed prospectively to five years of age. Bacterial DNA was analyzed with real-time PCR using primers binding to Clostridium difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis. Saliva was collected at age six and twelve months and at two and five years and SIgA was measured with ELISA. The PBMC, collected twelve months after birth, were analyzed for TLR2 and TLR4 mRNA expression with real-time PCR. Further, the PBMC were stimulated with LPS and cytokine/chemokine responses were measured with Luminex.

Results: The number of Bifidobacterium species in the early faecal samples correlated significantly with the total salivary SIgA levels at six months. Early colonization with Bifidobacterium species, lactobacilli groups or C. difficile did not influence TLR2 and TLR4 expression in PBMC. However, PBMC from infants colonized early with high amounts of Bacteroides fragilis expressed lower levels of TLR4 mRNA spontaneously. Furthermore, LPS-induced production of inflammatory cytokines and chemokines, e.g. IL-6 and CCL4 (MIP-1β), were inversely correlated to the relative amounts of Bacteroides fragilis in the early faecal samples.

Conclusion: Bifidobacterial diversity may enhance the maturation of the mucosal SIgA system and early high colonization with Bacteroides fragilis might down-regulate LPS responsiveness in infancy.

Keyword
Gut microbiota, lactobacilli, bifidobacteria, Clostridium difficile, Bacteroides fragilis, SIgA, TLR2, TLR4, infant
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-26790 (URN)
Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2010-01-14Bibliographically approved

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