PracticeUpdate Diabetes Best of 2018

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Differences in Gut Microbiota Composition and Functionality Among Children With Type 1 and MODY2 Diabetes Care Take-home message • This study compared the gut microbiota of children with type 1 diabetes (n=15), maturity-onset diabetes of the young 2 (MODY2; n=15), and healthy children (n=13). Children with type 1 diabetes had lower microbiota diversity; altered bacteria abundance (higher levels of Bacteroides , Veillonella , and Streptococcus and lower abundance of Bifidobacterium and Faecalibacterium ); and increased proinflammatory cytokines, lipopolysaccharides, and gut permeability. • The gut microbiota differ taxonomically and functionally in children with type 1 diabetes compared with their healthy counterparts and with children with MODY2. Long-term studies are needed to determine if the microbiota contributes to disease presentation. Abstract

COMMENT By Li Wen MD, PhD

OBJECTIVE Type 1 diabetes is associated with compositional differences in gut microbiota. To date, no microbiome studies have been per- formed in maturity-onset diabetes of the young 2 (MODY2), a monogenic cause of diabetes. Gut microbiota of type 1 diabetes, MODY2, and healthy control subjects was compared. RESEARCH DESIGN AND METHODS This was a case-control study in 15 children with type 1 dia- betes, 15 children with MODY2, and 13 healthy children. Metabolic control and potential fac- tors modifying gut microbiota were controlled. Microbiome composition was determined by 16S rRNA pyrosequencing. RESULTS Compared with healthy control subjects, type 1 diabetes was associated with a signifi- cantly lower microbiota diversity, a significantly higher relative abundance of Bacteroides, Ruminococcus, Veillonella, Blautia, and Strepto- coccus genera, and a lower relative abundance of Bifidobacterium, Roseburia, Faecalibacterium, and Lachnospira. MODY2 showed a signifi- cantly higher Prevotella abundance and a lower Ruminococcus and Bacteroides abundance. Proinflammatory cytokines and lipopolisaccha- rides were increased in type 1 diabetes, and gut permeability (determined by zonulin levels) was significantly increased in type 1 diabetes and MODY2. The PICRUSt analysis found an increment of genes related to lipid and amino acid metabolism, ABC transport, lipopoly- saccharide biosynthesis, arachidonic acid metabolism, antigen processing and presenta- tion, and chemokine signaling pathways in type 1 diabetes. CONCLUSIONS Gut microbiota in type 1 diabetes differs at taxonomic and functional levels not only in comparison with healthy subjects but fundamentally with regard to a model of nonau- toimmune diabetes. Future longitudinal studies should be aimed at evaluating if the modulation of gut microbiota in patients with a high risk of type 1 diabetes could modify the natural history of this autoimmune disease. Gut Microbiota Differs in Composition and Functionality Between Children With Type 1 Diabetes, MODY2, and Healthy Control Sub- jects: A Case-Control Study. Diabetes Care 2018 Sep 17;[EPub Ahead of Print], I Leiva-Gea, L Sánchez-Alcoholado, B Martín-Tejedor, et al.

I ncreasing evidence suggests that the development of type 1 diabetes (T1D) is asso- ciated with the alteration of gut bacteria, but little about whether gut bacteria are also altered in patients with maturity-onset diabetes of the young 2 (MODY2), a monogenic cause of diabetes accounting for 1% to 2% of all diabetes cases in Europe. Leiva-Gea and colleagues conducted a case-controlled cross-sectional study to inves- tigate the composition of gut bacteria in children with T1D, with MODY2, and healthy children. They thoroughly investigated the composition of gut bacteria, gut permea- bility, and inflammatory biomarkers in the three study groups. When analyzing alpha diversity, a measure of gut bacterial richness, the authors found no significant differ- ences among the three study groups, although the alpha diversity was highest in healthy controls and lowest in T1D, whereas MODY2 was in between. However, the authors found that the beta diversity, a measure of the overall composition of gut bac- teria, was very different in T1D patients compared with healthy controls and MODY2 patients, who showed overall similar beta diversity to that in the healthy controls. The authors further analyzed 16 bacterial families belonging to major bacterial phyla, including Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria. Patients with T1D showed the most significant alteration in many of the families analyzed when com- pared with MODY2 patients and healthy controls, although a few bacterial families were also altered in patients with MODY2. Bacterial gene function analysis revealed that genes for energy and carbohydrate metabolism were significantly depleted in T1D patients. The Firmicutes-to-Bacteroidetes ratio was positively correlated with HbA1c in both T1D and MODY2 patients, but negatively correlated with the abundance of Ruminococcus , a butyrate-producing gut bacterium. Interestingly, the authors found that MODY2 patients have the highest levels of circu- lating zonulin, an indicator of gut permeability, suggesting that the MODY2 patients might have leakier guts than T1D patients. This was attributed to the abundance of Prevotella , mucin-degrading bacteria, which could result in a lack of mucin in the gut lumen in MODY2 patients. However, patients with T1D presented with the highest level of circulating endotoxin, LPS, as well as the inflammatory cytokines IL-1β, IL-6, and TNF-α. In summary, this study not only provides further support for the role of gut bacteria in T1D but also the first evidence that gut bacteria are also altered in patients with MODY2.

Dr. Wen is Senior Research Scientist and Director of Core Laboratory of Yale Center for Clinical Investigation, Yale University School of Medicine in New Haven, Connecticut.

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