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Infant gut microbiota, immune responses and allergic disease during childhood
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The early-life microbiota is important for postnatal immune maturation and implied in immune mediated diseases. The aim of this work was to study specific species of bacteria in the gut microbiota and relate them to immune function and allergic disease during childhood.

In paper I we investigated gut bacteria in feces from infants included in a prospective allergy cohort. We found that children with non-allergic parents were more likely to be colonized with a group of lactobacilli. Further, lactobacilli colonization was more prevalent in children remaining non-allergic, regardless of allergic heredity. In paper II we related the infant gut bacteria to immune function at two years of age. Infant Staphylococcus (S.) aureus colonization associated with increased immune responsiveness, whereas co-colonization with S. aureus and lactobacilli associated with reduced responses. In paper III we investigated T regulatory (Treg) cell phenotype and cytokine production during childhood, and related S. aureus and lactobacilli colonization to Treg phenotype at the age of two. The Treg population matured with age, regarding phenotype and cytokine production. Furthermore, infant S. aureus colonization associated with Treg phenotype at the age of two. In paper IV we investigated the in vitro peripheral blood mononuclear cells responses to soluble factors produced by lactobacilli and S. aureus. Both T- and natural killer cells responded with cytokine production, degranulation and proliferation after S. aureus and simultaneous culture with lactobacilli could dampen the S. aureus-induced responses.

Taken together this thesis shows that the gut microbiota is altered in children who develop allergies, and that early life bacteria associate with immune function. Our in vitro findings support that lactobacilli modulate immune maturation and responses, and that early lactobacilli-colonization may be important for a properly regulated maturation of the immune system.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2014. , 82 p.
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-108425ISBN: 978-91-7649-036-5 (print)OAI: oai:DiVA.org:su-108425DiVA: diva2:757843
Public defence
2014-11-28, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2014-11-06 Created: 2014-10-23 Last updated: 2016-09-27Bibliographically approved
List of papers
1. Early colonization with a group of Lactobacilli decreases the risk for allergy at five years of age despite allergic heredity.
Open this publication in new window or tab >>Early colonization with a group of Lactobacilli decreases the risk for allergy at five years of age despite allergic heredity.
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, e23031- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Microbial deprivation early in life can potentially influence immune mediated disease development such as allergy. The aims of this study were to investigate the influence of parental allergy on the infant gut colonization and associations between infant gut microbiota and allergic disease at five years of age.

METHODS AND FINDINGS: Fecal samples were collected from 58 infants, with allergic or non-allergic parents respectively, at one and two weeks as well as at one, two and twelve months of life. DNA was extracted from the fecal samples and Real time PCR, using species-specific primers, was used for detection of Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, Clostridium (C.) difficile, a group of Lactobacilli (Lactobacillus (L.) casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus. Infants with non-allergic parents were more frequently colonized by Lactobacilli compared to infants with allergic parents (p = 0.014). However, non-allergic five-year olds acquired Lactobacilli more frequently during their first weeks of life, than their allergic counterparts, irrespectively of parental allergy (p = 0.009, p = 0.028). Further the non-allergic children were colonized with Lactobacilli on more occasions during the first two months of life (p = 0.038). Also, significantly more non-allergic children were colonized with B. bifidum at one week of age than the children allergic at five years (p = 0.048).

CONCLUSION: In this study we show that heredity for allergy has an impact on the gut microbiota in infants but also that early Lactobacilli (L. casei, L. paracasei, L. rhamnosus) colonization seems to decrease the risk for allergy at five years of age despite allergic heredity.

National Category
Immunology Biological Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-65650 (URN)10.1371/journal.pone.0023031 (DOI)000293511200031 ()21829685 (PubMedID)
Note

authorCount :5

Available from: 2011-12-13 Created: 2011-12-13 Last updated: 2017-12-08Bibliographically approved
2. Early-Life Gut Bacteria Associate with IL-4-, IL-10- and IFN-γ Production at Two Years of Age
Open this publication in new window or tab >>Early-Life Gut Bacteria Associate with IL-4-, IL-10- and IFN-γ Production at Two Years of Age
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, e49315-(9 pp) p.Article in journal (Refereed) Published
Abstract [en]

Microbial exposure early in life influences immune maturation and potentially also the development of immune-mediated disease. Here we studied early-life gut colonization in relation to cytokine responses at two years of age. Fecal samples were collected from infants during the first two months of life. DNA was extracted from the fecal samples and Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, a group of lactobacilli (L. casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus were detected with real time PCR. Peripheral mononuclear cells were stimulated with phytohaemagglutinin (PHA) and numbers of IL-4-, IL-10- and IFN-γ secreting cells were evaluated using ELISpot. We further stimulated peripheral blood mononuclear cells with bacterial supernatants in vitro and assessed the IL-4-, IL-10- and IFN-γ inducing capacity by flow cytometry and ELISA. Early S. aureus colonization associated with higher numbers of IL-4- (p = 0.022) and IL-10 (p = 0.016) producing cells at two years of age. In contrast to colonization with S. aureus alone, co-colonization with lactobacilli associated with suppression of IL-4- (p = 0.004), IL-10- (p = 0.004) and IFN-γ (p = 0.034) secreting cells. In vitro stimulations of mononuclear cells with bacterial supernatants supported a suppressive role of L. rhamnosus GG on S. aureus-induced cytokine responses. We demonstrate that the early gut colonization pattern associates with the PHA-induced cytokine profile at two years of age and our in vitro findings support that specific bacterial species influence the T helper cell subsets. This suggests that dysbiosis in the early microbiota may modulate the risk of developing inflammatory conditions like allergy.

National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-86260 (URN)10.1371/journal.pone.0049315 (DOI)000311535700028 ()23185315 (PubMedID)
Available from: 2013-01-11 Created: 2013-01-11 Last updated: 2017-12-06Bibliographically approved
3. FOXP3+ CD4 T-cell maturity and responses to microbial stimulation alter with age and associate with early-life gut colonization
Open this publication in new window or tab >>FOXP3+ CD4 T-cell maturity and responses to microbial stimulation alter with age and associate with early-life gut colonization
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2016 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 138, no 3, 905-908 p.Article in journal, Letter (Refereed) Published
National Category
Immunology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-133987 (URN)10.1016/j.jaci.2016.04.027 (DOI)000385496000031 ()
Available from: 2016-09-26 Created: 2016-09-26 Last updated: 2017-04-21Bibliographically approved
4. Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells
Open this publication in new window or tab >>Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells
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2016 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, 273Article in journal (Refereed) Published
Abstract [en]

Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human mucosal-associated invariant T cells (MAIT cells), gamma delta T cells, NK cells, as well as of conventional CD4(+) and CD8(+) T cells in vitro. Further, we investigated if lactobacilli-derived factors could modulate their activation. PBMC were cultured with S. aureus 161: 2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-gamma and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation.

Keyword
cell-free supernatant, immune modulation, lactobacilli, NK cells, probiotic, T cells, Staphylococcus aureus, superantigens
National Category
Biological Sciences Immunology in the medical area
Identifiers
urn:nbn:se:su:diva-132953 (URN)10.3389/fimmu.2016.00273 (DOI)000379401800001 ()27462316 (PubMedID)
Available from: 2016-08-30 Created: 2016-08-26 Last updated: 2017-11-21Bibliographically approved

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