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Host diabetes status is the major regulator of gut microbiome in the UCD‐T2DM Rat

There is strong evidence in humans and in animal models that the gut microbiome is altered in obesity and/or the insulin resistant condition. Poor metabolic health is often linked to overnutrition and poor‐quality diets, and the gut microbiome is highly dependent on these factors. Less well appreciated is the potential role of host metabolic physiology in modifying gut microbial ecology. To address this question, we have used the UCD‐T2DM Rat model to test whether the gut microbiome is altered during the progression of diabetes when controlling for exogenous factors (sex, strain, age, diet and vivarium housing). Cecal microbial profiles were assessed using amplicon sequencing of 16S rRNA collected from age‐matched lean Sprague‐Dawley rats (LSD, n = 12), pre‐diabetic UCD‐T2DM rats (PD, n = 15), recently‐diabetic UCD‐T2DM rats (RD, n = 10), and 3‐months (D3M n = 11) and 6‐months (D6M n = 7) post‐diabetic UCD‐T2DM rats. LSD rats had significantly greater sample diversity (Shannon Index) at phylum level (P < 0.05, ANOVA), but significantly lower sample richness (Chao1) at genus level (P < 0.05, ANOVA) when compared to all UCD‐T2DM rat groups. β‐diversity was significantly different by group (P < 0.05; PERMANVOA), with LSD rats distinctly clustered from all UCD‐T2DM rat groups in non‐metric dimensional scaling (NMDS) plots. A total of 30 genera were significantly altered between LSD and UCD‐T2DM rat groups, with Lactobacillus being the highest abundance genera that was greater in all UCD‐T2DM rat groups relative to LSD (1.7%, 7.6, 5.7%, 8.5%, and 13.0% in LSD, PD, RD, D3M, and D6M respectively). When only assessing UCD‐T2DM rat groups, there was a significant main effect of diabetes status, starting at bacterial class level and continuing through genus (P < 0.05; PERMANOVA). Only 4 genera were altered between PD and RD groups, while only 3 genera differed between D3M and D6M. NMDS showed that rats from early stages of diabetes (PD plus RD) were discriminated from those in later stages of diabetes (D3M plus D6M). A total of 22 genera were significantly altered when comparing early diabetic groups between later stages. Genus altered with > 1% median relative abundance included Bacteroides (PD: 1.3%, D6M: 0.9%), Lactobacillus (RD: 5.7%, D6M 13.0%), and an unassigned genera in the Clostridiaceae family (PD: 1.1%, D3M: 1.1%). In summary, the cecal gut microbiome in LSD rats was considerably different to UCD‐T2DM rats and may be due to alternative strain backgrounds. A major and novel finding was that significant gut microbe shifts were observed when comparing groups from pre‐ and early‐diabetes stages relative to those in later stages of diabetes, despite controlling for variables that typically confound microbiome studies of type 2 diabetes in humans. This indicates that the metabolic health of the host influences the micro‐ecology of the large intestine.