Abstract
The aim of this study was to map the microbiota distribution along the gut and establish whether colon/faecal samples from diabetic rats adequately reflect the diabetic alterations in the microbiome. Streptozotocin-treated rats were used to model type 1 diabetes mellitus (T1D). Segments of the duodenum, ileum and colon were dissected, and the microbiome of the lumen material was analysed by using next-generation DNA sequencing, from phylum to genus level. The intestinal luminal contents were compared between diabetic, insulin-treated diabetic and healthy control rats. No significant differences in bacterial composition were found in the luminal contents from the duodenum of the experimental animal groups, whereas distinct patterns were seen in the ileum and colon, depending on the history of the luminal samples. Ileal samples from diabetic rats exhibited particularly striking alterations, while the richness and diversity obscured some of the modifications in the colon. Characteristic rearrangements in microbiome composition and diversity were detected after insulin treatment, though the normal gut flora was not restored. The Proteobacteria displayed more pronounced shifts than those of the predominant phyla (Firmicutes and Bacteroidetes) in the rat model of T1D. Diabetes and insulin replacement affect the composition of the gut microbiota in different, gut region-specific manners. The luminal samples from the ileum appear more suitable for diagnostic purposes than the colon/faeces. The Proteobacteria should be at the focus of diagnosis and potential therapy. Klebsiella are recommended as biomarkers of T1D.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease that results from the T cellmediated destruction of insulin-producing beta cells [1]
In order to explore the possible correlation between the diabetes-related gut region-dependent nitrergic myenteric neuropathy and the altered mesenteric capillaries [10,11] and the spatiallyrestricted distribution of the gut microbiota, we carried out a metagenomic analysis of the luminal contents of the duodenum, ileum and colon of rats with STZ-induced diabetes and insulin-treated diabetes in comparison with control rats
The regionally distinct alterations in the microbiome along the GI tract of rats with STZ-induced diabetes or insulin-treated diabetes correlated well with the regional manifestations of the diabetes-related enteric neuropathy and mesenteric capillary damage. This suggests that the myenteric neurones in a distinct gut segment are not targets of T1D, but rather active participants in the pathogenic pathways initiated by the regionally altered microbiota, a common environmental trigger for autoimmune diabetes and enteric neuropathy
Summary
Type 1 diabetes (T1D) is an autoimmune disease that results from the T cellmediated destruction of insulin-producing beta cells [1]. We earlier demonstrated [10,11] that myenteric neurones and microvessels adjacent to the myenteric ganglia are direct targets of diabetes, and the rate and extent of their damage depend strictly on the intestinal segment in which the particular neurones or capillaries are located Their responsiveness to insulin replacement is gut region-dependent. Several studies have indicated that, in addition to being targets of inflammation, the peptidergic enteric neurones modulate the immune cell function and can stimulate pro-inflammatory cytokine production and result in neurodegeneration [13,14,15] These data suggest that the pathogenic cascade which leads to the development of autoimmune diabetes through secreted lymphokines might result in altered neuro-immune interactions and provoke myenteric neuropathy. Of the potential environmental triggers implicated in the development of diabetes-related myenteric neuropathy, the intestinal microbiome is regarded as primary candidate
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