%0 Journal Article %J Nat Med %D 2019 %T Prospective virome analyses in young children at increased genetic risk for type 1 diabetes. %A Vehik, Kendra %A Lynch, Kristian F %A Wong, Matthew C %A Tian, Xiangjun %A Ross, Matthew C %A Richard A Gibbs %A Ajami, Nadim J %A Petrosino, Joseph F %A Rewers, Marian %A Toppari, Jorma %A Ziegler, Anette G %A She, Jin-Xiong %A Lernmark, Ake %A Akolkar, Beena %A Hagopian, William A %A Schatz, Desmond A %A Krischer, Jeffrey P %A Hyoty, Heikki %A Lloyd, Richard E %K Adolescent %K Autoimmunity %K Child %K Child, Preschool %K Diabetes Mellitus, Type 1 %K Enterovirus %K Feces %K Female %K Humans %K Infant %K Insulin %K Insulin-Secreting Cells %K Islets of Langerhans %K Male %K Pancreas %K RNA, Viral %X

Viruses are implicated in autoimmune destruction of pancreatic islet β cells, which results in insulin deficiency and type 1 diabetes (T1D). Certain enteroviruses can infect β cells in vitro, have been detected in the pancreatic islets of patients with T1D and have shown an association with T1D in meta-analyses. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses and the selection of variants with altered pathogenicity and ability to spread in populations. β cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to β cells between serotypes and within the same serotype. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.

%B Nat Med %V 25 %P 1865-1872 %8 2019 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/31792456?dopt=Abstract %R 10.1038/s41591-019-0667-0 %0 Journal Article %J Nature %D 2018 %T Temporal development of the gut microbiome in early childhood from the TEDDY study. %A Stewart, Christopher J %A Ajami, Nadim J %A O'Brien, Jacqueline L %A Hutchinson, Diane S %A Smith, Daniel P %A Wong, Matthew C %A Ross, Matthew C %A Lloyd, Richard E %A Harshavardhan Doddapaneni %A Ginger A Metcalf %A Donna M Muzny %A Richard A Gibbs %A Vatanen, Tommi %A Huttenhower, Curtis %A Xavier, Ramnik J %A Rewers, Marian %A Hagopian, William %A Toppari, Jorma %A Ziegler, Anette-G %A She, Jin-Xiong %A Akolkar, Beena %A Lernmark, Ake %A Hyoty, Heikki %A Vehik, Kendra %A Krischer, Jeffrey P %A Petrosino, Joseph F %K Adolescent %K Animals %K Bifidobacterium %K Breast Feeding %K Case-Control Studies %K Child %K Child, Preschool %K Cluster Analysis %K Datasets as Topic %K Diabetes Mellitus, Type 1 %K Female %K Firmicutes %K Gastrointestinal Microbiome %K Humans %K Infant %K Male %K Milk, Human %K Pets %K RNA, Ribosomal, 16S %K Siblings %K Surveys and Questionnaires %K Time Factors %X

The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases such as persistent islet autoimmunity and type 1 diabetes. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.

%B Nature %V 562 %P 583-588 %8 2018 Oct %G eng %N 7728 %1 https://www.ncbi.nlm.nih.gov/pubmed/30356187?dopt=Abstract %R 10.1038/s41586-018-0617-x