Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease that results from destruction of pancreatic β-cells. T1D subjects were recently shown to harbor distinct intestinal microbiome profiles. Based on these findings, the role of gut bacteria in T1D is being intensively investigated. The mechanism connecting intestinal microbial homeostasis with the development of T1D is unknown. Specific gut bacteria such as Bacteroides dorei (BD) and Ruminococcus gnavus (RG) show markedly increased abundance prior to the development of autoimmunity. One hypothesis is that these bacteria might traverse the damaged gut barrier, and their constituents elicit a response from human islets that causes metabolic abnormalities and inflammation. We have tested this hypothesis by exposing human islets to BD and RG in vitro, after which RNA-Seq analysis was performed. The bacteria altered expression of many islet genes. The commonly upregulated genes by these bacteria were cytokines, chemokines and enzymes, suggesting a significant effect of gut bacteria on islet antimicrobial and biosynthetic pathways. Additionally, each bacteria displayed a unique set of differentially expressed genes (DEGs). Ingenuity pathway analysis of DEGs revealed that top activated pathways and diseases included TREM1 signaling and inflammatory response, illustrating the ability of bacteria to induce islet inflammation. The increased levels of selected factors were confirmed using immunoblotting and ELISA methods. Our data demonstrate that islets produce a complex anti-bacterial response. The response includes both symbiotic and pathogenic aspects. Both oxidative damage and leukocyte recruitment factors were prominent, which could induce beta cell damage and subsequent autoimmunity.
Highlights
Type 1 diabetes (T1D) is a life-threatening disease with a rapidly increasing incidence in children and adolescents [1]
Among the three tested bacteria, Escherichia coli (EC) was associated with the highest number of Differentially expressed genes (DEGs) at 6 and 24 h [459, 310], followed by Ruminococcus gnavus (RG) [305, 225], and Bacteroides dorei (BD) [157, 151]
Ruminococcus gnavus (RG), a Gram-positive bacterium and a pathobiont-like species, showed a spike in relative abundance in T1Dsusceptible children concomitant with decreased diversity of gut microbiome [15] was investigated in our study
Summary
Type 1 diabetes (T1D) is a life-threatening disease with a rapidly increasing incidence in children and adolescents [1]. Increased expression of inflammatory cytokines in the duodenal mucosa of T1D patients was associated with altered composition of the gut microbiome (dysbiosis) [8] In this regard, several recent studies have reported intestinal dysbiosis in individuals with newly diagnosed T1D [9,10,11,12,13]. Costa et al [18] noted translocation of gut bacteria to pancreatic lymph nodes (PLNs) of streptozotocin (STZ)-injected mice, an experimental model of T1D, by both morphological and molecular approaches Such translocation was thought to contribute to the pathogenesis of T1D by activating pathogenic T helper 1 (Th1) and Th17 cells that expanded in the PLNs and pancreas. The intrinsic response of human islets to specific bacteria, especially those of the gut in T1D subjects remains unknown
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