BioProject

BACKGROUND. The incidence of Type 1 Diabetes (T1D) has significantly increased in recent decades and coincides with lifestyle changes that have likely altered the composition of the gut microbiota. Dysbiosis and gut barrier dysfunction are associated with T1D, and notably, our studies have identified an inflammatory state in T1D families that is consistent microbial antigen exposure. METHODS. We conducted a 6-week, single-arm, open-label trial to investigate whether daily multi-strain probiotic (Bifidobacteria, Lactobacillus, and Streptococcus) supplementation could reduce the familial inflammatory state in 25 unaffected siblings of diabetes patients. RESULTS. Probiotic supplementation was found safe and well-tolerated; there were no adverse events and participant adherence was 93%. Bacterial 16S rDNA gene sequencing of stool revealed that community alpha and beta diversity were not altered between the pre- and post-supplement samplings. LEfSe analyses identified post-supplement enrichment of the family Lachnospiraceae, producers of the anti-inflammatory short chain fatty acid butyrate. Systemic inflammation was measured by plasma induced transcription and quantified with a gene ontology-based composite inflammatory index (I.I.com). After supplementation, I.I.com was reduced (p=0.017), and pathway analysis predicted inhibition of IL17A, lipopolysaccharide, NFkB, IL1B, and TNF (Z-score≤-2.0) and activation of IL10RA (Z-score=2.0). Post-supplement plasma levels of IL12p40, IL-13, IL-15, IL-18, CCL2, CCL24 were reduced (p<0.05), while butyrate levels trended 2.4-fold higher (p=0.06). CONCLUSION. There is a substantial need for safe, broadly applicable therapies to reduce T1D susceptibility. This study indicates that investigations of prebiotic and probiotic strategies are warranted as they may be efficacious either alone or in combination with other therapeutic agents. Overall design: UPN119 PBMC cells were stimulated with unaffected siblings of diabetes patients' pre VSL3 probiotic supplement or post VSL3 probiotic supplement (n=25) plasma. Gene expression analysis was perfromed in order to evaluate modulation of the inflammatory state associated with T1D susceptibility.