Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of means for monitoring immune responsiveness to experimental therapies. The LEW1.WR1 rat develops autoimmunity following infection with the parvovirus Kilham rat virus (KRV) via mechanisms linked with activation of proinflammatory pathways and alterations in the gut bacterial composition. We used this animal to test the hypothesis that intervention with agents that block innate immunity and diabetes is associated with a shift in the gut microbiota. We observed that infection with KRV results in the induction of proinflammatory gene activation in both the spleen and pancreatic lymph nodes. Furthermore, administering animals the histone deacetylase inhibitor ITF-2357 and IL-1 receptor antagonist (Anakinra) induced differential STAT-1 and the p40 unit of IL-12/IL-23 gene expression. Sequencing of bacterial 16S rRNA genes demonstrated that both ITF-2357 and Anakinra alter microbial diversity. ITF-2357 and Anakinra modulated the abundance of 23 and 8 bacterial taxa in KRV-infected animals, respectively, of which 5 overlapped between the two agents. Lastly, principal component analysis implied that ITF-2357 and Anakinra induce distinct gut microbiomes compared with those from untreated animals or rats provided KRV only. Together, the data suggest that ITF-2357 and Anakinra differentially influence the innate immune system and the intestinal microbiota and highlight the potential use of the gut microbiome as a surrogate means of assessing anti-inflammatory immune effects in type 1 diabetes.

Green Tea Liquid Consumption Alters the Human Intestinal and Oral Microbiome

“…Dimensional reduction of the Bray–Curtis distance between microbiome samples using PCoA ordination method (PAST software) was done and significant differences among groups at all the taxonomic levels were tested with permutational multivariate analysis of variance (PERMANOVA), a multivariate non‐parametric one‐way ANOVA, which utilizes the sample‐to‐sample Bray–Curtis distance matrix directly. Differential abundance (non‐parametric ANOVA with Benjamini‐Hochberg false discovery rate [FDR] correction for multiple comparisons; p < 0.05) of taxon were identified using XLSTAT (Addinsoft, USA) software program, those with p < 0.05 were grouped, their relative abundance were shown by heat‐map with hierarchical clustering (HCN) analysis and their contribution to groups (between and within groups) were analyzed using PCA (variance‐covariance type) ordination method . To compare the RA of taxa between any two time points, a non‐parametric paired t ‐test was used.…”

The gut microbiota in type 1 diabetes: friend or foe?

“…IL-2 treatment expanded Tregs within the intestine, increased goblet cell mucous production and reduced intestinal immune infiltration as well as altering the gut microbiota composition [23 & ]. Likewise, inhibiting innate immune activation either with IL-1R blockade or a histone deacetylase inhibitor in a rat model of T1D also induced potent alterations in the gut microbiota [46]. Modulation of the gut microbiota by immunotherapy may be a surrogate marker of response to therapy, without contributing itself to disease protection.…”