Compromised Gut Microbiota Networks in Children With Anti-islet Cell Autoimmunity
Compromised Gut Microbiota Networks in Children With Anti-islet Cell Autoimmunity
The gut microbiome is suggested to play a role in the pathogenesis of autoimmune disorders such as type 1 diabetes. Evidence of anti-islet cell autoimmunity in type 1 diabetes appears in the first years of life; however, little is known regarding the establishment of the gut microbiome in early infancy. Here, we sought to determine whether differences were present in early composition of the gut microbiome in children in whom anti-islet cell autoimmunity developed. We investigated the microbiome of 298 stool samples prospectively taken up to age 3 years from 22 case children in whom anti-islet cell autoantibodies developed, and 22 matched control children who remained islet cell autoantibody–negative in follow-up. The microbiome changed markedly during the first year of life, and was further affected by breast-feeding, food introduction, and birth delivery mode. No differences between anti-islet cell autoantibody–positive and –negative children were found in bacterial diversity, microbial composition, or single-genus abundances. However, substantial alterations in microbial interaction networks were observed at age 0.5 and 2 years in the children in whom anti-islet cell autoantibodies developed. The findings underscore a role of the microbiome in the pathogenesis of anti-islet cell autoimmunity and type 1 diabetes.
Type 1 diabetes is the result of a complex interplay of genetic susceptibility and environmental determinants leading to anti-islet cell autoimmunity against pancreatic islet β-cells and autoimmune β-cell destruction. Anti-islet cell autoimmunity precedes the clinical onset of type 1 diabetes and often develops within the first years of life. This suggests that early shaping of the immune system in children is critical for the initiation of autoimmunity. There is increasing evidence that the immune response is shaped by factors that include how the host establishes a stable ecosystem with a large cohort of accompanying bacteria. With this, the role of microbiota in type 1 diabetes pathogenesis has become an important subject of investigation. The largest community of bacteria is established in the gastrointestinal tract where beneficial host-bacteria interactions have been demonstrated for food degradation or pathogen defense.
Relatively few studies of the human gut microbiome have been performed in children <5 years old. These studies suggest that the phylogenetic composition of the bacterial communities evolves toward an adult-like configuration within the 3-year period after birth. Hence, it is conceivable that the evolution of the microbiome in infancy could influence the risk of anti-islet cell autoimmunity in susceptible children. Indeed, studies from Finland have provided evidence for this hypothesis. The aim of our study was to investigate gut bacterial community structures during the early period from birth to the age of 3 years from the perspective of complex interaction networks. We estimated interaction on the basis of covariation of bacterial abundances to compare children in whom anti-islet cell autoantibodies developed with children in whom such autoantibodies did not develop. We took advantage of the prospective BABYDIET study, where infants at increased risk of type 1 diabetes were monitored from birth for the development of anti-islet cell autoantibodies and type 1 diabetes. The gut microbiome composition was estimated based on measurements of 16S rRNA gene sequences from fecal samples that were obtained at 3-month intervals up to the age of 3 years. Analyses were focused on bacterial diversity, community composition, individual bacterial species, and microbial interaction networks. Results show that complex bacterial interaction networks, rather than single genera, appear to be relevant to early preclinical type 1 diabetes.
Abstract and Introduction
Abstract
The gut microbiome is suggested to play a role in the pathogenesis of autoimmune disorders such as type 1 diabetes. Evidence of anti-islet cell autoimmunity in type 1 diabetes appears in the first years of life; however, little is known regarding the establishment of the gut microbiome in early infancy. Here, we sought to determine whether differences were present in early composition of the gut microbiome in children in whom anti-islet cell autoimmunity developed. We investigated the microbiome of 298 stool samples prospectively taken up to age 3 years from 22 case children in whom anti-islet cell autoantibodies developed, and 22 matched control children who remained islet cell autoantibody–negative in follow-up. The microbiome changed markedly during the first year of life, and was further affected by breast-feeding, food introduction, and birth delivery mode. No differences between anti-islet cell autoantibody–positive and –negative children were found in bacterial diversity, microbial composition, or single-genus abundances. However, substantial alterations in microbial interaction networks were observed at age 0.5 and 2 years in the children in whom anti-islet cell autoantibodies developed. The findings underscore a role of the microbiome in the pathogenesis of anti-islet cell autoimmunity and type 1 diabetes.
Introduction
Type 1 diabetes is the result of a complex interplay of genetic susceptibility and environmental determinants leading to anti-islet cell autoimmunity against pancreatic islet β-cells and autoimmune β-cell destruction. Anti-islet cell autoimmunity precedes the clinical onset of type 1 diabetes and often develops within the first years of life. This suggests that early shaping of the immune system in children is critical for the initiation of autoimmunity. There is increasing evidence that the immune response is shaped by factors that include how the host establishes a stable ecosystem with a large cohort of accompanying bacteria. With this, the role of microbiota in type 1 diabetes pathogenesis has become an important subject of investigation. The largest community of bacteria is established in the gastrointestinal tract where beneficial host-bacteria interactions have been demonstrated for food degradation or pathogen defense.
Relatively few studies of the human gut microbiome have been performed in children <5 years old. These studies suggest that the phylogenetic composition of the bacterial communities evolves toward an adult-like configuration within the 3-year period after birth. Hence, it is conceivable that the evolution of the microbiome in infancy could influence the risk of anti-islet cell autoimmunity in susceptible children. Indeed, studies from Finland have provided evidence for this hypothesis. The aim of our study was to investigate gut bacterial community structures during the early period from birth to the age of 3 years from the perspective of complex interaction networks. We estimated interaction on the basis of covariation of bacterial abundances to compare children in whom anti-islet cell autoantibodies developed with children in whom such autoantibodies did not develop. We took advantage of the prospective BABYDIET study, where infants at increased risk of type 1 diabetes were monitored from birth for the development of anti-islet cell autoantibodies and type 1 diabetes. The gut microbiome composition was estimated based on measurements of 16S rRNA gene sequences from fecal samples that were obtained at 3-month intervals up to the age of 3 years. Analyses were focused on bacterial diversity, community composition, individual bacterial species, and microbial interaction networks. Results show that complex bacterial interaction networks, rather than single genera, appear to be relevant to early preclinical type 1 diabetes.