The human gut microbiome in early-onset type 1 diabetes from the TEDDY study

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors 1 , including complex genetic elements 2 , patient exposures 3 and the gut microbiome 4 . Viral infections 5 and broader gut dysbioses 6 have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species ( B. bifidum , B. breve or B. longum ) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts 7 , 8 and a T1D mouse model 9 , these data support the protective effects of short-chain fatty acids in early-onset human T1D.

The Environmental Determinants of Diabetes in the Young (TEDDY) Study: 2018 Update

“…These phases correlated with diet, especially with breast-feeding which was the most significant factor associated with the microbiome structure. While a number of factors were identified to determine the development of gut bacteriome in early childhood, no association was found with IA [62, 63]. However, genes mapping to bacterial fermentation pathways, including the production of short-chain fatty acids (SCFA), were decreased in cases of IA, supporting previously postulated protective effects of SCFA on early-onset human T1D.…”

Current understanding of the role of gut dysbiosis in type 1 diabetes

“…Feeding NOD mice on specialized diets resulted in the production of high amounts of SCFAs that were associated with the protection of these mice against the development of T1D . Indeed, the abundance of SCFA‐producing bacteria is decreased in infants with islet autoimmunity and T1D compared with control children . Cathelicidin antimicrobial peptide (CAMP) is a novel peptide expressed specifically by pancreatic β‐cells of rats, mice, and humans, and has been found to be associated with diabetes protection .…”

“…103 Indeed, the abundance of SCFA-producing bacteria is decreased in infants with islet autoimmunity and T1D compared with control children. 104 Cathelicidin antimicrobial peptide (CAMP) is a novel peptide expressed specifically by pancreatic β-cells of rats, mice, and humans, and has been found to be associated with diabetes protection. 105,106 Interestingly, CAMP production by pancreatic β-cells was found to be governed by SCFAs.…”

Genome Sequence of Segmented Filamentous Bacteria Present in the Human Intestine

“…However, this gene catalogue is mainly derived from samples from adults, while SFB in most animals peak in young individuals during weaning 32 . Therefore, we instead scanned a large recent metagenomic study consisting of a time-series of faecal samples from children 0 -3 years born in Russia, Estonia and Finland 33 . The reads from the metagenome samples were first mapped against SFB-human-IMAG using standard settings.…”

“…Matching of the ORFs in IGC v9.9 (db.cngb.org/microbiome) against SFB-human-IMAG was performed with blastn v2.7.1+ 55 requiring at least 80% identity over at least 70% of the query sequence. To assess the presence of SFB-human-IMAG and of SFBs from mouse, rat and turkey in the faeces of young children, we used the recent work of Vatanen et al 33 , one of the datasets that we used for the binning. Mapping of the preprocessed reads against the SFB genomes was run in 'strict' mode, where only alignments without mismatches were reported ('-score-min C,0,0' in bowtie2).…”