Gut Microbiome Signatures Distinguish Susceptibility from Disease Development in Type 2 Diabetes

Individuals may be prone or resistant to the development of type 2 diabetes. The basis for susceptibility is in part genetic, but environmental factors are likely to come into play. The gut microbiome stands at the interface of genetics and the host microenvironment. Its role in mediating susceptibility to diabetes, however, has not been resolved. Here we investigated whether the gut microbial composition contributes to susceptibility to diabetes, as distinct from disease development. We hypothesized that distinct microbial signatures modulate sensitivity or resistance to a diabetogenic diet (DD) and that separate signatures are linked to disease development. To test this hypothesis, we studied the Cohen diabetic rat model, comprising a diabetes-sensitive strain (CDs/y) and a diabetes-resistant strain (CDr/y). When exposed to DD, diabetes develops in CDs/y but not in CDr/y rats; on a regular diet (RD), both strains remain metabolically normal. To establish the contribution of the gut microbiome to susceptibility, we studied the fecal microbial composition in young, metabolically healthy CDs/y and CDr/y rats, using 16S rRNA gene sequencing, measures of α- and β-diversity, and differential taxonomic abundance. We found distinct, strain-specific gut microbiota profiles that differentiated diabetes-sensitive from -resistant animals, indicating an association between microbial composition and susceptibility. To test causality, we co-housed sensitive and resistant animals to allow passive microbial cross-transfer and fed the animals with DD. Co-housing led to partial convergence of microbial communities and significantly attenuated the diabetic phenotype in CDs/y rats, supporting a contributory and causal role for the gut microbiome in modulating sensitivity to diabetes. The resistance phenotype, on the other hand, remained unchanged. To distinguish between the contribution of the gut microbiome to susceptibility to diabetes as opposed to the development of the disease, we studied the gut microbial profiles across strains after feeding with DD or RD and the development of diabetes in CDs/y but not in CDr/y. We found distinct taxonomic signatures that differentiated diabetic from non-diabetic animals. These findings demonstrate that the gut microbiome contributes to susceptibility to diabetes with separate pathways from those linked to the development of diabetes and may represent an important modifiable determinant of diabetes risk and a target for early intervention.