Osamu Kanauchi

The rising health threat to healthcare workers (HCWs) demands innovative preventive solutions that are affordable, scalable, and easy to deploy, especially in resource-limited settings. This present study investigated the effects of Lactococcus lactis strain Plasma (LC-Plasma) intake on upper respiratory infection (URI)-like symptoms in a healthy healthcare-associated population in Vietnam. A randomized, placebo-controlled, double-blind, parallel-group clinical trial was conducted, integrating clinical symptom analysis with ex vivo immune response analysis of peripheral blood mononuclear cells (PBMCs). The study found that after 4 weeks of continuous oral LC-Plasma intake, participants in the LC-Plasma group had significantly fewer cumulative days of fever and fatigue than those in the Control group. Increased expression of interferon-stimulated genes (ISGs), particularly MxA, was observed in PBMC cultures from the LC-Plasma intake group. In PBMCs from LC-Plasma recipients classified as low IFN-α responders, the addition of CpG ODN 2216, a mild TLR9 agonist, significantly enhanced interferon-α production. Humoral factors derived from LC-Plasma-primed PBMCs demonstrated inhibitory effects on dengue virus replication in Huh-7 cells. These results suggest that LC-Plasma consumption by the healthcare-associated population reduces the severity of viral infection symptoms, notably fever and fatigue. Elevation of systemic antiviral immunity through activation of plasmacytoid dendritic cells (pDCs) to produce IFN-α and upregulation of ISG expression could be the mechanisms of action. Lactococcus lactis LC-Plasma supplementation, hence, presents a promising adjunctive approach to alleviate the burden of URI-like symptoms in low-resourced vulnerable populations.

Viruses, like influenza and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remain major causes of upper respiratory tract infections worldwide, with symptoms ranging from asymptomatic to lethal outcomes. While antivirals and vaccines have helped ameliorate disease morbidity and mortality, these infections still pose significant challenges. Probiotics, including Lactococcus lactis strain plasma (LC-Plasma), have recently shown antiviral effects by activating plasmacytoid dendritic cells (pDCs), though their detailed mechanism remains unclear. In this study, we stimulated peripheral blood mononuclear cells (PBMCs) collected from healthy participants with LC-Plasma and conducted immunological analyses to investigate the immunomodulatory mechanisms of LC-Plasma. The supernatant derived from LC-Plasma-stimulated PBMCs (LCP Sup) exhibited dose-dependent inhibition of replication in Influenza A virus subtype H1N1 (H1N1) and SARS-CoV-2. LCP Sup significantly reduced the SARS-CoV-2 viral load in Huh-7 cells. However, in the H1N1 antiviral assay using A549 cells, LCP Sup was required at a higher concentration against H1N1 in A549 cells compared with SARS-CoV-2 in Huh-7 cells. Treatment with LCP Sup significantly upregulated interferon-stimulated genes (ISG) expression, particularly MxA, in A549 cells. While MxA showed the most notable increase, other ISGs also exhibited elevated expression levels compared with the negative control. Other cytokines, chemokines, and growth factors were also induced by LC-Plasma and CpG-DNA stimulation, and the effects of LC-Plasma were much higher than those of CpG-DNA. These results provide in vitro evidence of the antiviral mechanisms of LC-Plasma via upregulation of interferon-α (IFN-α) and related ISGs for host defense against respiratory viruses.

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.

(1) Background: Lactococcus lactis strain Plasma (LC-Plasma) is a unique strain which directly activates plasmacytoid dendritic cells, resulting in the prevention against broad spectrum of viral infection. Additionally, we found that LC-Plasma intake stimulated skin immunity and prevents Staphylococcus aureus epicutaneous infection. The aim of this study was to investigate the effect of LC-Plasma dietary supplementation on skin microbiome, gene expression in the skin, and skin conditions in healthy subjects. (2) Method: A randomized, double-blind, placebo-controlled, parallel-group trial was conducted. Seventy healthy volunteers were enrolled and assigned into two groups receiving either placebo or LC-Plasma capsules (approximately 1 × 10¹¹ cells/day) for 8 weeks. The skin microbiome was analyzed by NGS and qPCR. Gene expression was analyzed by qPCR and skin conditions were diagnosed by dermatologists before and after intervention. (3) Result: LC-Plasma supplementation prevented the decrease of Staphylococcus epidermidis and Staphylococcus pasteuri and overgrowth of Propionibacterium acnes. In addition, LC-Plasma supplementation suggested to increase the expression of antimicrobial peptide genes but not tight junction genes. Furthermore, the clinical scores of skin conditions were ameliorated by LC-Plasma supplementation. (4) Conclusions: Our findings provided the insights that the dietary supplementation of LC-Plasma might have stabilizing effects on seasonal change of skin microbiome and skin conditions in healthy subjects.

Age-related macular degeneration and retinitis pigmentosa are leading causes of blindness and share a pathological feature, which is photoreceptor degeneration. To date, the lack of a potential treatment to prevent such diseases has raised great concern. Photoreceptor degeneration can be accelerated by excessive light exposure via an inflammatory response; therefore, anti-inflammatory agents would be candidates to prevent the progress of photoreceptor degeneration. We previously reported that a lactic acid bacterium, Lactobacillus paracasei KW3110 (L. paracasei KW3110), activated macrophages suppressing inflammation in mice and humans. Recently, we also showed that intake of L. paracasei KW3110 could mitigate visual display terminal (VDT) load-induced ocular disorders in humans. However, the biological mechanism of L. paracasei KW3110 to retain visual function remains unclear. In this study, we found that L. paracasei KW3110 activated M2 macrophages inducing anti-inflammatory cytokine interleukin-10 (IL-10) production in vitro using bone marrow-derived M2 macrophages. We also show that IL-10 gene expression was significantly increased in the intestinal immune tissues 6 h after oral administration of L. paracasei KW3110 in vivo. Furthermore, we demonstrated that intake of L. paracasei KW3110 suppressed inflammation and photoreceptor degeneration in a murine model of light-induced retinopathy. These results suggest that L. paracasei KW3110 may have a preventive effect against degrative retinal diseases.

Background: Visual display terminals (VDTs) emitting blue light can cause ocular disorders including eye fatigue. Some dietary constituents have been reported to be effective in improving ocular disorders while few clinical studies have been performed. We evaluated the effects of heat-killed Lactobacillus paracasei KW 3110 on improving ocular disorders and symptoms of eye fatigue among healthy human subjects with VDT loads. Methods: In vitro, the effect of L. paracasei KW3110 on blue light-induced human retinal pigment epithelial (ARPE-19) cell damage. For clinical studies, 62 healthy Japanese volunteers of 35 to 45 years of age who had experienced eye fatigue were randomized into two groups and given a placebo or L. paracasei KW3110-containing supplements for eight weeks. The primary endpoint was changes in VDT load-induced eye fatigue as determined by critical flicker frequency four and eight weeks after the start of supplementation. Results: In vitro, blue light-induced human retinal cell death was suppressed with the culture supernatants of cells treated with L. paracasei KW3110. In clinical study, the VDT load-induced reduction of critical flicker frequency tended to be milder in the L. paracasei KW3110 group when compared with the placebo group during the fourth week. Subgroup analysis classified by the degree of eye fatigue showed that the VDT load-induced reduction of critical flicker frequency was significantly better in the high-level eye fatigue subjects from the L. paracasei KW3110 group when compared with the placebo group during the fourth week (p = 0.020). Conclusions: L. paracasei KW3110 suppressed blue light-induced retinal pigment epithelial cell death. In the clinical study, ingestion of L. paracasei KW3110 had a potential to improve eye fatigue induced by VDT loads especially high levels of eye fatigue. However, further studies should be required to show more dependable clinical efficacy of L. paracasei KW3110.

Recently, the risk of viral infection has dramatically increased owing to changes in human ecology such as global warming and an increased geographical movement of people and goods. However, the efficacy of vaccines and remedies for infectious diseases is limited by the high mutation rates of viruses, especially, RNA viruses. Here, we comprehensively review the effectiveness of several probiotics and paraprobiotics (sterilized probiotics) for the prevention or treatment of virally-induced infectious diseases. We discuss the unique roles of these agents in modulating the cross-talk between commensal bacteria and the mucosal immune system. In addition, we provide an overview of the unique mechanism by which viruses are eliminated through the stimulation of type 1 interferon production by probiotics and paraprobiotics via the activation of dendritic cells. Although further detailed research is necessary in the future, probiotics and/or paraprobiotics are expected to be among the rational adjunctive options for the treatment of various viral diseases.

The gastrointestinal tract harbors a tremendous number and variety of commensal microbiota. The intestinal mucosa simultaneously absorbs essential nutrients and protects against detrimental antigens or pathogenic microbiota as the first line of defense. Beneficial interactions between the host and microbiota are key requirements for host health. Although the gut microbiota has been previously studied in the context of inflammatory diseases, it has recently become clear that this microbial environment has a beneficial role during normal homeostasis, by modulating the immune system or bowel motor function. Recent studies revealed that microbiota, including their metabolites, modulate key signaling pathways involved in the inflammation of the mucosa or the neurotransmitter system in the gut–brain axis. The underlying molecular mechanisms of host–microbiota interactions are still unclear; however, manipulation of microbiota by probiotics or prebiotics is becoming increasingly recognized as an important therapeutic option, especially for the treatment of the dysfunction or inflammation of the intestinal tract.

Background and Aim:  Germinated barley foodstuff (GBF) is a prebiotic product that reduces colonic mucosal inflammation and the clinical symptoms observed in ulcerative colitis (UC). The risk of contracting colorectal cancer is higher in patients with UC than in that of the general population. The aim of this study is to apply this prebiotic approach to control chronic colitis and to reduce the incidence of colitic cancer.Methods:  Repeated and intermitted dextran sulfate sodium administration to male Sprague–Dawley rats was used for the chronic and subacute colitis models. GBF was added as the diet (10% w/v). The incidence of adenomatous high‐grade dysplasia, and pathophysiological observations, including the proliferative cell nuclear antigen (PCNA) labeling index, and clinical score, cecal organic acid profile, and the accompanying β‐glucosidase activity were determined.Results:  In the chronic phase, the incidence of adenomatous dysplasia was only confirmed in the control group, and the GBF group had no dysplasia in the entire colon; the stratified squamous epithelium area of GBF was significantly lower than that of the controls. GBF treatment significantly lowered the cecal succinate content and significantly increased β‐glucosidase activity compared to the controls. In addition, colonic mucosal inflammatory damage was comparable between the two groups, while the PCNA labeling index of the colonic mucosa in the GBF group was significantly lower than that of the control group. However, in the subacute phase, the mucosal damage score of GBF was significantly attenuated, and the PCNA labeling index of the colonic mucosa in the GBF group was significantly higher than that of the control group.Conclusion:  This preliminary study demonstrated that GBF effectively prevents colitis‐related dysplasia and inflammatory change in chronic and subacute colitis models by modulating the intestinal environment as a prebiotic. This prebiotic might contribute to the prevention of mucosal damage, to show different proliferative effects on the epithelium in the regeneration and steady states.

Germinated barley foodstuff contains prebiotics which are reported to have anti-cancerous effects in colorectal cancer model, but the detailed mechanism remains unclear. Recent studies revealed that the role of microbiota was strongly related to the regulation of incidence and progression of colorectal cancer. The aim of this study was to examine the anti-neoplastic mechanism by prebiotics. Azoxymethane treated F344 rats were used as the sporadic cancerous model. After azoxymethane injection, either a control or germinated barley foodstuff diet was administered to the rats for another 5 weeks, and the number of abberant crypt foci, toll like receptor 4, Kirsten rat sarcoma viral oncogene homolog, adenomatous polyposis coli tumor suppressor gene and cyclooxygenase 2 mRNA expression of colonic mucosa and cecal short chain fatty acids were examined. The germinated barley food stuff significantly attenuated the number of abberant crypt focis and the expression of toll like receptor 4 and cyclooxygenase 2 mRNA, compared to the control group. In addition, the cecal butyrate production in the germinated barley foodstuff group was significantly higher than that in the control. In conclusion, this prebiotic treatment for colorectal cancer may be useful without causing the adverse effects seen in either anti-cancer drugs or anti-inflammatory drugs.