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. 2011;6(10):e25792.
doi: 10.1371/journal.pone.0025792. Epub 2011 Oct 17.

Gut Microbiome Metagenomics Analysis Suggests a Functional Model for the Development of Autoimmunity for Type 1 Diabetes

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Free PMC article

Gut Microbiome Metagenomics Analysis Suggests a Functional Model for the Development of Autoimmunity for Type 1 Diabetes

Christopher T Brown et al. PLoS One. .
Free PMC article

Abstract

Recent studies have suggested a bacterial role in the development of autoimmune disorders including type 1 diabetes (T1D). Over 30 billion nucleotide bases of Illumina shotgun metagenomic data were analyzed from stool samples collected from four pairs of matched T1D case-control subjects collected at the time of the development of T1D associated autoimmunity (i.e., autoantibodies). From these, approximately one million open reading frames were predicted and compared to the SEED protein database. Of the 3,849 functions identified in these samples, 144 and 797 were statistically more prevalent in cases and controls, respectively. Genes involved in carbohydrate metabolism, adhesions, motility, phages, prophages, sulfur metabolism, and stress responses were more abundant in cases while genes with roles in DNA and protein metabolism, aerobic respiration, and amino acid synthesis were more common in controls. These data suggest that increased adhesion and flagella synthesis in autoimmune subjects may be involved in triggering a T1D associated autoimmune response. Extensive differences in metabolic potential indicate that autoimmune subjects have a functionally aberrant microbiome. Mining 16S rRNA data from these datasets showed a higher proportion of butyrate-producing and mucin-degrading bacteria in controls compared to cases, while those bacteria that produce short chain fatty acids other than butyrate were higher in cases. Thus, a key rate-limiting step in butyrate synthesis is more abundant in controls. These data suggest that a consortium of lactate- and butyrate-producing bacteria in a healthy gut induce a sufficient amount of mucin synthesis to maintain gut integrity. In contrast, non-butyrate-producing lactate-utilizing bacteria prevent optimal mucin synthesis, as identified in autoimmune subjects.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. The pipeline of metagenome sequence analysis used in this work.
Figure 2
Figure 2. Statistically significant metabolic steps in controls (blue) and cases (red).
Figure 3
Figure 3. Mean proportion of the 11 most abundant genera that differ significantly between cases and controls (p value≤0.01).
Figure 4
Figure 4. Mean proportion of four functional groups that differ significantly between cases and controls (p value≤0.01).
Depicted is the abundance of 16S rRNA reads that are assigned to genera known to produce butyrate, lactate, or other short chain fatty acids (SCFA) such as propionate, acetate, or succinate. Also shown is the proportion of bacteria that degrade mucin.
Figure 5
Figure 5. Forty known functions that differ significantly between cases and controls (p value≤0.01) as determined by the log of the ration between cases and controls.
Twenty of these functions are the highest in cases relative to controls while the other twenty are the highest in controls relative to cases.
Figure 6
Figure 6. Model for a bacterial role in gut integrity leading to either a healthy state or autoimmunity for type 1 diabetes.
In this model, the fate of lactate is crucial in determining gut health. Conversion to butyrate results in more mucin synthesis and tighter junctions. Conversion to other short chain fatty acids (SCHAs) reduces mucin synthesis and tight junctions. Bacterial genera listed are examples of a given phenotype. Other bacteria may also be involved in these characteristics.

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