Such changes would likely have the greatest impact on those with an inherited hyper-responsiveness to innate stimuli. Together, these changes are hypothesized to contribute to higher gut permeability, greater microbial antigen exposure, and increased systemic inflammation 17. Notably, the gut microbiota of modern urban humans has been found distinct from that of West African hunter-gatherers, ancient humans, and great apes 18, 19, 20, 21, exhibiting lower community diversity and lower abundances of potentially beneficial taxa, including short-chain fatty acid (SCFA) producers. Over this same time frame, there has been greater use of antibiotics and more widespread consumption of the low-fiber and highly processed Western diet 15, 16, 17. These rapid changes cannot be explained by genetic shifts and suggest the presence of greater environmental pressure. The increasing incidence of T1D in recent decades has been accompanied by a reduction in the age of onset and a lower percentage of individuals possessing high-risk HLA haplotypes 12, 13, 14. This heightened responsiveness likely contributes to an elevated baseline inflammatory state and more robust inflammatory excursions during infections that together may foster breaks in immune tolerance. Finally, independent of high-risk HLA (human leukocyte antigen) haplotypes or autoantibody status, peripheral blood mononuclear cells of T1D patients and their healthy first-degree relatives hyper-secrete cytokines (IL-1α, IFN-1, TNF-α) after stimulation with Toll-like receptor (TLR) ligands, including endotoxin and CpG oligodeoxynucleotides 9, 10, 11. Further, ex vivo whole blood stimulation with IFN-β or polyinosinic:polycytidylic acid, a synthetic dsRNA analog and activator of Toll-like receptor 3 (TLR3), has revealed an IFN-1 hyper-responsiveness in T1D patients compared to healthy controls 8. Transcriptomic studies of unstimulated peripheral blood mononuclear cells (PBMC) drawn from individuals at high genetic risk of developing T1D have identified a type I interferon (IFN-1) signature prior to the development of islet autoantibodies 6, 7. Monocytes isolated from T1D patients spontaneously secrete IL-1β and IL-6 and induce more IL-17-secreting memory T-cells, suggesting that innate immune activity may drive adaptive responses during T1D pathogenesis by expanding the effector Th17 cell population 5. While less understood, many studies have also suggested a role for altered innate immune activity in T1D pathogenesis (reviewed in Refs. Adaptive immune responses are involved in T1D pathogenesis, as T-cells comprise a significant proportion of the islet infiltrate 1, and T-cell targeted therapies delay disease progression 2. Type 1 diabetes (T1D) arises through the immune-mediated destruction of insulin-producing pancreatic β-cells and results in dependence on life-long exogenous insulin replacement therapy. Probiotic supplementation may modify T1D susceptibility and progression and warrants further study. Post-supplement IL-12p40, IL-13, IL-15, IL-18, CCL2, and CCL24 plasma levels were significantly reduced, while post-supplement butyrate levels trended 1.4-fold higher. com exhibited significantly lower CD4+ CD45RO+ (memory):CD4+ CD45RA+ (naïve) T-cell ratios after supplementation. Subjects with the greatest post-supplement reduction in I.I. com was significantly reduced and pathway analysis predicted inhibition of numerous inflammatory mediators and activation of IL10RA. Systemic inflammation was measured by plasma-induced transcription and quantified with a gene ontology-based composite inflammatory index ( I.I. However, LEfSe analyses identified post-supplement enrichment of the family Lachnospiraceae, producers of the anti-inflammatory short chain fatty acid butyrate. Community alpha and beta diversity were not altered between the pre- and post-supplement stool samplings. Probiotic supplementation was well-tolerated as reflected by high participant adherence and no adverse events. A 6-week, single-arm, open-label pilot trial was conducted to investigate whether daily multi-strain probiotic supplementation could reduce this familial inflammation in 25 unaffected siblings of T1D patients. Dysbiosis, gut barrier dysfunction, and elevated systemic inflammation consistent with microbial antigen exposure, have been associated with T1D susceptibility and progression. The incidence of type 1 diabetes (T1D) has increased, coinciding with lifestyle changes that have likely altered the gut microbiota.
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