Maturation of Gut Microbiota and Circulating Regulatory T Cells and Development of IgE Sensitization in Early Life.

Terhi Ruohtula,Jorma Ilonen,Vallo Tillmann,Marcus C De Goffau,Hermie J Harmsen,Aleksandr Peet,Onni Niemelä,Anu-Maaria Hämäläinen,Gjalt W Welling,Janne K Nieminen,Jarno Honkanen,Heli Siljander,Outi Vaarala,Mikael Knip

doi:10.3389/fimmu.2019.02494

Abstract

Recent studies suggest that the cross-talk between the gut microbiota and human immune system during the first year of life is an important regulator of the later development of atopic diseases. We explored the changes in the gut microbiota, blood regulatory T cells, and atopic sensitization in a birth-cohort of Estonian and Finnish children followed from 3 to 36 months of age. We describe here an infant Treg phenotype characterized by high Treg frequency, the maturation of Treg population characterized by a decrease in their frequency accompanied with an increase in the highly activated Treg cells. These changes in Treg population associated first with the relative abundance of Bifidobacterium longum followed by increasing colonization with butyrate producing bacteria. High bifidobacterial abundance in the neonatal microbiota appeared to be protective, while colonization with Bacteroides and E. coli was associated with later risk of allergy. Estonian children with lower risk of IgE mediated allergic diseases than Finnish children showed an earlier maturation of the gut microbiota, detected as earlier switch to an increasing abundance of butyrate-producing bacteria, combined with an earlier maturation of Treg cell phenotype and total IgE production. The children with established allergic diseases by age 3 showed a decreased abundance of butyrate producing Faecalibacterium. These results suggest that as well as the maintenance of a bifidobacterial dominated gut microbiota is important during the first weeks of life, the overtake by butyrate producing bacteria seems to be a beneficial shift, which should not be postponed.

Highlights

Our understanding of the cross-talk between the gut microbiota and human immune system during the time when allergic sensitization develops is limited, accumulating evidence indicates that the gut microbiome plays a pivotal role in the regulation of allergic immune responses [1,2,3,4,5,6,7,8]
The evidence of the mechanisms of the gut microbiome as a regulator of the immune response is largely based on studies in animal models showing e.g., that the gut microbiome directly or indirectly via metabolites is able to modulate the permeability of the intestinal epithelium [10,11,12], and the differentiation and function of effector and regulatory T cells (Treg cells) [13,14,15,16,17,18,19,20,21], which could further influence the development of immune-mediated diseases, including allergic, inflammatory, and autoimmune diseases
Our study further shows that the maturation of the circulating Treg cells included an increase in the highly activated Treg cells, which was associated with the relative abundance of Bifidobacterium longum and colonization with butyrate producing bacteria, and this maturation process of the gut microbiota and Treg cells was delayed in Finnish children with a higher risk of IgE mediated allergic sensitization and diseases in comparison to Estonian children

Summary

Introduction

Our understanding of the cross-talk between the gut microbiota and human immune system during the time when allergic sensitization develops is limited, accumulating evidence indicates that the gut microbiome plays a pivotal role in the regulation of allergic immune responses [1,2,3,4,5,6,7,8]. The evidence of the mechanisms of the gut microbiome as a regulator of the immune response is largely based on studies in animal models showing e.g., that the gut microbiome directly or indirectly via metabolites is able to modulate the permeability of the intestinal epithelium [10,11,12], and the differentiation and function of effector and regulatory T cells (Treg cells) [13,14,15,16,17,18,19,20,21], which could further influence the development of immune-mediated diseases, including allergic, inflammatory, and autoimmune diseases. The altered gut microbiota composition has been associated with allergic responses in children, the understanding of the mechanisms linking the gut microbiota and altered immune deviation is limited in humans

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Conclusion