Background: Plasmacytoid dendritic cells (pDCs) are a type of immune cell that play a crucial role in the defense against viral infection. Multiple randomized controlled trials (RCTs) have reported that oral intake of Lactococcus lactis strain Plasma (LC-Plasma) activates pDCs and reduces cold-like symptoms. This study conducted a meta-analysis to comprehensively evaluate the effects of oral LC-Plasma intake on pDC activation and cold-like symptoms by comparing healthy adults. Method: This study targeted RCTs that examined the effects of oral intake of LC-Plasma or placebo food products on pDC activation or common cold-like symptoms in healthy adult males and females. Data sources included PubMed, Cochrane Library, J-Dream III, UMIN-CTR, and the International Clinical Trials Registry Platform, with searches conducted up to June 21 ^st , 2024. The primary outcome evaluated pDC activation, and the secondary outcome evaluated the subjective evaluation of common cold-like symptoms. A quantitative synthesis was performed by meta-analysis using random-effects models. Two authors independently assessed risk of bias using the revised Cochrane risk of bias tool (RoB2). Results: Among the eight RCTs that met the eligibility criteria for this study, individual participant data (IPD) were obtained from seven. Since we were unable to obtain IPD from the remaining study, we integrated data from this study based on its final report. The meta-analysis in this study, conducted using data from 619 participants, revealed that the expression levels of pDC activation markers, CD86 and HLA-DR, were significantly maintained during LC-Plasma intake when compared to the placebo control group (CD86: SMD = 0.37, 95% CI (confidence interval): 0.17 to 0.57; HLA-DR: SMD = 0.47, 95% CI: 0.21 to 0.73). In addition, LC-Plasma intake significantly reduced the cumulative number of days per 28 days of cough and feverishness compared to the control group, according to the meta-analysis using data from 555 participants (Cough: MD=-0.69, 95%CI: -1.24 to -0.14; Feverishness: MD=-0.26, 95%CI: -0.52 to -0.0038). Conclusion: This study is the first to present, through integrated analyses using identical analytical conditions, that daily intake of LC-Plasma may help sustain pDC activation and could be useful in reducing cough and feverishness, typical cold-like symptoms. Systematic Review Registration: https://www.umin.ac.jp/ , identifier UMIN000054706.

Lactococcus lactis subsp. lactis strain plasma (LC-plasma) is a bacterial strain that activates plasmacytoid dendritic cells and induces viral resistance genes via the TLR9/MyD88 pathway. We recently showed that oral administration of LC-plasma prevents skin infection by Staphylococcus aureus, possibly by activating skin immunity. In this study, we conducted a double-blind clinical trial to investigate the effect of oral administration of heat-killed LC-plasma on the skin microbiome, gene expression in the skin, and the skin condition of healthy volunteers. Seventy healthy volunteers were randomly assigned to receive either heat-killed LC-plasma or a placebo for eight weeks. Analysis of the skin microbiome by next-generation sequencing suggested that the alpha-diversity of the skin microbiome did not change during the test period in either group. However, the proportion of species that changed significantly during the test period was 10-fold smaller in the LC-plasma group than in the placebo group, suggesting that LC-plasma may maintain the skin microbiome. Quantitative PCR analysis indicated that tight-junction genes, such as CLDN1 and CLDN12, and the antimicrobial peptide gene BD3 were significantly up-regulated in the LC-plasma group but not in the placebo group. Our results suggest that administration of LC-plasma helps to maintain the skin microbiome and that it affects homeostasis-related genes.

Upper respiratory tract infections (URTIs) are highly prevalent and impose substantial individual and societal burdens. Plasmacytoid dendritic cells (pDCs) are major producers of type I interferons (IFNs) with antiviral activity. This study investigated whether CpG oligodeoxynucleotide-induced IFN-α production by peripheral blood mononuclear cells (PBMCs), a marker of pDC activity, was associated with subsequent occurrence of the common cold. Data from 41 healthy adults in the placebo arm of a randomized controlled trial were analyzed. CpG-induced IFN-α production was measured before a 4-week observation period, and participants were dichotomized into high and low IFN-α production groups based on the median value. The occurrence of common cold events and cold symptoms was assessed using daily self-reported symptom scores and body temperature records. Seven participants developed the common cold, all in the low group. The crude risk difference between the low and high groups was 0.333 (Miettinen–Nurminen 95% CI, 0.148–0.546; Fisher’s exact p = 0.009). The low group also showed higher risks for fever, plugged nose, and sore throat, while findings for the other symptoms were less conclusive. As a hypothesis-generating pilot study, these findings suggest that low TLR9-mediated IFN-α production may be associated with increased susceptibility to URTIs in healthy adults.