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Fermentable dietary fiber promotes insulin sensitivity thus mitigating type 2 diabetes. Here we report such protection extended to the streptozotocin (STZ)-induced model of type 1 diabetes. Specifically, low-fiber diets exacerbated STZ-induced diabetes while diets enriched with fermentable fiber strongly protected against, or treated, it. Fermentable fiber, inulin, but not insoluble fiber, cellulose, restored glycemic control and prevented loss of adipose depots, while reducing food and water consumption. Inulin normalized pancreatic function and markedly enhanced insulin sensitivity. Such amelioration of diabetes was associated with alterations in gut microbiota composition and was eliminated by antibiotic administration. Pharmacologic blockade of fermentation reduced inulin’s glycemic control benefits indicating a role for short-chain fatty acids in its beneficial action. Furthermore, inulin’s microbiota-dependent anti-diabetic impact correlated with restoration of IL-22, which was necessary and sufficient to ameliorate STZ-induced diabetes. Thus, fermentable fiber, SCFA, and/or IL-22 may have use in prevention and/or treatment of type 1 diabetes.

Emerging evidence indicates a central role for the microbiome in immunity. However, causal evidence in humans is sparse. Here, we administered broad-spectrum antibiotics to healthy adults prior and subsequent to seasonal influenza vaccination. Despite a 10,000-fold reduction in gut bacterial load and long-lasting diminution in bacterial diversity, antibody responses were not significantly affected. However, in a second trial of subjects with low pre-existing antibody titers, there was significant impairment in H1N1-specific neutralization and binding IgG1 and IgA responses. In addition, in both studies antibiotics treatment resulted in (1) enhanced inflammatory signatures (including AP-1/NR4A expression), observed previously in the elderly, and increased dendritic cell activation; (2) divergent metabolic trajectories, with a 1,000-fold reduction in serum secondary bile acids, which was highly correlated with AP-1/NR4A signaling and inflammasome activation. Multi-omics integration revealed significant associations between bacterial species and metabolic phenotypes, highlighting a key role for the microbiome in modulating human immunity.

Background: Fecal microbiota transplant (FMT) is fast emerging as a promising therapy for recurrent clostridium difficile colitis in patients not responding to antibiotic therapy. However all patients for FMT need a fecal sample from a healthy donor. However the effect of age on the fecal microbiome of the healthy donor and its clinical efficacy, has not been examined previously. Aim: To examine fecal samples of healthy human subjects of various ages, volunteering to donate their samples for FMT by genomic analysis and clinical outcom. Methods: All healthy subjects who were rigorously screened for infectious disease and selected as donors for FMT were included in the study. Fecal samples were processed and analyzed using 16S rRNA gene amplicon sequencing. Microbiota compositions were studied using standard 16S rRNA analysis tools (CloVR-16S). Differences in bacterial phylum abundance and diversity (Shannon index) of the donor fecal microbiota were analyzed using three different cutoff for age of 50 years, 60 years and 70 years. Effect of fecal microbiota from donors of different age groups on efficacy of FMT in patients with RCDI was monitored in the GI clinic. Results: Fecal microbiota of 30 healthy donors was analyzed. The mean age of the donors was 50±15.3 years and ranged between 20 years to 82 years. Of these 30 donors, 18 (60%) were males and 26 (87%) were related to the recipients. The Shannon index did demonstrate significant increase in the fecal microbiome diversity in 70+ year old donors, as demonstrated in Figure 1. Althoughmicrobiome dissimilarity between the younger donors groups was relatively larger than the older donors groups on weighted UniFrac metric analysis, the association was not statistically significant. At phylum level, while the relative abundance of Firmicutes was higher in older groups (p

G A A b st ra ct s unknown. Hence, we investigated here whether the gut microbiota can affect colonic miRNAs secretion and profile. Results: High throughput technology screening the expression levels of 752 known mouse miRNAs revealed that miRNA profiles were different in the feces of GF mice compared to conventionalized mice, with 13 miRNAs deregulated in the absence of a microbiota. In order to investigate if the microbiota composition play a role in fecal miRNA profiles, germ-free C57/Bl6 mice were "conventionalized" with microbiota of WT mice, non colitic IL10-/mice or colitic IL10-/mice, and fecal miRNAs profiles were analyzed. Microbiota composition analysis confirmed that we successfully transferred the difference in composition, with clear clustering according to the microbiota transferred. Mice receiving microbiota from colitic IL10-/mice harbor a proinflammatory microbiota 49 days post conventionalization, as assayed by fecal LPS and flagellin loads, and proinflammatory potential of mice receiving microbiota from non-colitic IL10-/mice were found to be moderately elevated compare to mice receiving microbiota from WT mice. Intestinal inflammatory status of mice from the three groups was unchanged, as assessed by MPO. However, mice colonized with colitic IL10-/microbiota displayed a slight but significant increase in blood glucose level, as well as other parameters of low-grade intestinal inflammation, such as fecal Lcn-2. miRNA profile was analyzed and Principal component analysis showed a clear clustering between the 3 groups at 49 days post conventionalization, that was not observed at day 0 (before conventionalization). Interestingly, the level of some miRNAs correlate with the level of some members of the gut microbiota found to drive the difference in the microbiota composition previously observed. Conclusion: Altogether, these data showed that the microbiota composition induces drastic changes in the dynamic of fecal miRNA. Fecal miRNA signature could be used as tools for assessing the gut microbiota composition and its inflammatory potential.