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Nanovesicles From Lactobacillus johnsonii N6.2 Reduce Apoptosis in Human Beta Cells by Promoting AHR Translocation and IL10 Secretion.

ABSTRACT: L. johnsonii N6.2 releases nano-sized vesicles (NVs) with distinct protein and lipid contents. We hypothesized that these NVs play a central role in the delivery of bioactive molecules that may act as mechanistic effectors in immune modulation. In this report, we observed that addition of NVs to the human pancreatic cell line βlox5 reduced cytokine-induced apoptosis. Through RNAseq analyses, increased expression of CYP1A1, CYP1B1, AHRR, and TIPARP genes in the aryl hydrocarbon receptor (AHR) pathways were found to be significantly induced in presence of NVs. AHR nuclear translocation was confirmed by confocal microscopy. The role of NVs on beta cell function was further evaluated using primary human pancreatic islets. It was found that NVs significantly increased insulin secretion in presence of high glucose concentrations. These increases positively correlated with increased GLUT6 and SREBF1 mRNA and coincided with reduced oxidative stress markers. Furthermore, incubation of NVs with THP-1 macrophages promoted the M2 tolerogenic phenotype through STAT3 activation, expression of AHR-dependent genes and secretion of IL10. Altogether, our findings indicate that bacterial NVs have the potential to modulate glucose homeostasis in the host by directly affecting insulin secretion by islets and through the induction of a tolerogenic immune phenotype.

SUBMITTER: Teixeira LD

PROVIDER: S-EPMC9221839 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lactobacillus johnsonii N6.2 mitigates the onset of type 1 diabetes (T1D) in biobreeding diabetes-prone rats, in part, through changes in kynurenine:tryptophan (K:T) ratios. The goal of this pilot study was to determine the safety, tolerance, and general immunological response of L. johnsonii N6.2 in healthy subjects. A double-blind, randomized clinical trial in 42 healthy individuals with no known risk factors for T1D was undertaken to evaluate subject responses to the consumption of L. johnsonii N6.2. Participants received 1 capsule/day containing 108 colony-forming units of L. johnsonii N6.2 or placebo for 8 weeks. Comprehensive metabolic panel (CMP), leukocyte subpopulations by complete blood count (CBC) and flow cytometry, serum cytokines, and relevant metabolites in the indoleamine-2,3-dioxygenase pathway were assessed. L. johnsonii N6.2 survival and intestinal microbiota was analyzed. Daily and weekly questionnaires were assessed for potential effects of probiotic treatment on general wellness. The administration of L. johnsonii N6.2 did not modify the CMP or CBC of participants suggesting general safety. In fact, L. johnsonii N6.2 administration significantly decreased the occurrence of abdominal pain, indigestion, and cephalic syndromes. As predicted, increased serum tryptophan levels increased resulting in a decreased K:T ratio was observed in the L. johnsonii N6.2 group. Interestingly, immunophenotyping assays revealed that monocytes and natural killer cell numbers were increased significantly after washout (12 weeks). Moreover, an increase of circulating effector Th1 cells (CD45RO+CD183+CD196-) and cytotoxic CD8+ T cells subset was observed in the L. johnsonii N6.2 group. Consumption of L. johnsonii N6.2 is well tolerated in adult control subjects, demonstrates systemic impacts on innate and adaptive immune populations, and results in a decreased K:T ratio. These data provide support for the safety and feasibility of using L. johnsonii N6.2 in prevention trials in subjects at risk for T1D.Trial registrationThis trial was registered at http://clinicaltrials.gov as NCT02349360.

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Nanovesicles From Lactobacillus johnsonii N6.2 Reduce Apoptosis in Human Beta Cells by Promoting AHR Translocation and IL10 Secretion.

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