Lactobacillus johnsonii N6.2 Modulates the Host Immune Responses: A Double-Blind, Randomized Trial in Healthy Adults

Guillermo E Marcial, Amanda L Ford, Michael J Haller, Salvador A Gezan, Natalie A Harrison, Dan Cai, Julie L Meyer, Daniel J Perry, Mark A Atkinson, Clive H Wasserfall, Timothy Garrett, Claudio F Gonzalez, Todd M Brusko, Wendy J Dahl, Graciela L Lorca, Guillermo E Marcial, Amanda L Ford, Michael J Haller, Salvador A Gezan, Natalie A Harrison, Dan Cai, Julie L Meyer, Daniel J Perry, Mark A Atkinson, Clive H Wasserfall, Timothy Garrett, Claudio F Gonzalez, Todd M Brusko, Wendy J Dahl, Graciela L Lorca

Abstract

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 registration: This trial was registered at https://ichgcp.net/clinical-trials-registry/NCT02349360" title="See in ClinicalTrials.gov">NCT02349360.

Keywords: Lactobacillus johnsonii; T cell; diabetes type I; gastrointestinal symptom; immunological response; indoleamine-2,3-dioxygenase; microbiome; probiotic.

Figures

Figure 1
Figure 1
Study flow diagram to illustrate the number of subjects that were screened, consented, and randomized. Code 090115-A was used for the placebo, whereas Code 090115-B was used for Lactobacillus johnsonii N6.2.
Figure 2
Figure 2
Determination of total lactic acid bacteria (LAB) and L. johnsonii N6.2 (Ljo) in stool samples. In placebo and Ljo groups, it was determined: (A) total number of LAB (Log CFU/g). Based on the numbers of LAB obtained, three subgroups were defined: (a) high LAB, (b) low to high LAB, and (c) low LAB. (B) Relative change in LAB for Ljo. (C) Relative change in LAB for placebo. (D) The presence of Ljo was confirmed by performing qRT-PCR of the T285_00345 gene and expressed as genomic equivalents. These data were further stratified based on the determination of total LAB numbers for the Ljo (E) and placebo (F) treatment groups. * indicates statistical differences (p < 0.05) between the groups and time points shown in panels (E,F) using analysis of variance. Comparison of the treatment combinations was performed by least significance difference with a significance level of 5%.
Figure 3
Figure 3
Peripheral tryptophan and kynurenine concentration in plasma of healthy subjects. The concentrations of kynurenine (A) and tryptophan (B) were determined by LC-HRMS/HRMS after 8 or 12 weeks in the placebo or L. johnsonii N6.2 (Ljo) treatment groups. Panel (C) is shown the kynurenine:tryptophan (K:T) ratio. The concentration of the metabolites shown has been normalized to the concentration found at time 0 for each subject. The results obtained were further stratified based on the number of LAB present as described in the Section “Results.” (a) High LAB; (b) low to high LAB, and (c) low LAB.
Figure 4
Figure 4
Monocytes and natural killer (NK) cells in healthy subjects. (A) Mononuclear cells (CD3−CD19−) were stained with specific antibodies to define monocytes (CD14+) and NK cells (CD14−) in the placebo and in the L. johnsonii N6.2 (Ljo) groups. (B) Expression of HLA-DR (mfi) in different NK cells subset: CD16−CD56hi, CD16+CD56lo/−, and CD16+CD56hi after 8 weeks of treatment or 12 weeks (4 weeks into the washout). The concentration of cells shown has been normalized to the concentration found at time 0 for each subject.
Figure 5
Figure 5
T cell subset. CD4+(A) or CD8+(B) T cells populations subsets [Naïve, Tem, activated (CD38+HLA-DR+)] were quantified after 8 or 12 weeks of treatment in the placebo and L. johnsonii N6.2 (Ljo) groups. Naïve (CD197+CD45RA+), Tem (CD197−CD45RA−), Tcm (CD197+CD45RA−), and Temra (CD197−CD45RA+) by labeling with specific antibodies (C). The concentration of cells shown has been normalized to the concentration found at time 0 for each subject.
Figure 6
Figure 6
Expression of CD185+ and CD279+ on T cells subset. Expression of CD279+(A) or CD185+(B) on Naïve, Tem, Tcm, and Temra CD4+ T cells. Expression of CD279+(C) or CD185+(D) on Naïve, Tem, Tcm, and Temra CD8+ T cells. The number of cells in each population was evaluated for the placebo (white bars) and the L. johnsonii N6.2 (Ljo, blue bars) group at 8 and 12 weeks. The concentration of cells shown has been normalized to the concentration found at time 0 for each subject.
Figure 7
Figure 7
T effector cells subset (CD3+CD4+CD45RO+). (A) Th1 (CD183+CD196−), Th2 (CD183−CD196−), Th17 (CD183−CD196+), and Th1/Th17 (CD183+CD196+) were labeled with specific antibodies and quantified in the placebo (white bars) and L. johnsonii N6.2 (Ljo, blue bars) group at 8 and 12 weeks of treatment. (B) HLA-DR+ and (C) HLA-DR+CD38+ are shown for the Th1 and Th1/Th17 effector T cells. The concentration of cells shown has been normalized to the concentration found at time 0 for each subject.
Figure 8
Figure 8
Determination of soluble markers. The concentrations of IFNγ, IgA, and TNFα were quantified in the placebo (white bars) and L. johnsonii N6.2 (Ljo, blue bars) group at time 0 and after 8 weeks of treatment or after the washout (12 weeks).

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