Lactobacillus plantarum induces innate cytokine responses that potentially provide a protective benefit against COVID-19: A single-arm, double-blind, prospective trial combined with an in vitro cytokine response assay.

Intestinal microbiota can indirectly modulate airway physiology and immunity through the gut-lung axis. Recent microbiome studies indicate that patients with coronavirus disease 2019 (COVID-19) exhibit a specific intestinal dysbiosis that is closely associated with the disease pathophysiology. Therefore, rebalancing the intestinal microbiome using probiotics may be effective for controlling COVID-19. However, the rationale for using probiotics in COVID-19 remains unclear. In the present study, an in vitro cytokine response assay was conducted, followed by a single-arm, double-blind, prospective trial to evaluate the immunological efficacy of probiotic lactic acid bacteria against COVID-19. The present study focused on Lactobacillus plantarum (L. plantarum), Bifidobacterium longum and Lactococcus lactis ssp. lactis, which exhibit robust protective effects against infection with respiratory RNA viruses. Considering the feasibility of long-term daily intake for prophylactic purposes, healthy uninfected individuals were enrolled as subjects. Our previous pilot trial demonstrated that oral Qingfei Paidu decoction (QFPD), a Chinese herbal medicine formulated specifically against COVID-19, upregulates plasma TNF-α, IL-1ß, IL-18 and IL-8. Therefore, the present study utilized the cytokine changes induced by QFPD to define the innate cytokine index QICI [=(TNF-α) x (IL-1ß) x (IL-18) x (IL-8)/(IL-6)] as an indicator of the anti-COVID-19 immunomodulatory potential of the lactic acid bacteria. A total of 20 eligible volunteers were enrolled, 18 of whom completed the intervention. L. plantarum demonstrated a strikingly high innate cytokine index in all subjects in the in vitro cytokine response assay. In the subsequent trial, oral intake of L. plantarum significantly increased the innate cytokine index (mean fold change, 17-fold; P=0.0138) and decreased the plasma level of IL-6 (P=0.0128), a key driver of complex immune dysregulation in COVID-19, as compared with the baseline. The cytokine index increased in 16 of 18 subjects (88.9%) with considerable individual differences in the fold change (1- to 128-fold). In line with these innate cytokine changes, L. plantarum ingestion significantly enhanced the activity of natural killer cells. By contrast, oral B. longum failed to induce a significant increase in the innate cytokine index (mean fold change, 2-fold; P=0.474) as compared with the baseline. In conclusion, L. plantarum demonstrated superior QFPD-like immunomodulatory ability and mimicked the blood cytokine environment produced by early immune responses to viral infection. Daily consumption of L. plantarum as an anti-COVID-19 probiotic may be a possible option for preventing COVID-19 during the pandemic. The present study was prospectively registered in the University Hospital Medical Information Network-Clinical Trials Registry under the trial number UMIN000040479 on 22 May 2020 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046202).

[Investigating the relationship between higher life functions, overall mortality, and incidence of care needs in long-term follow-up study of the local population: The Kamogawa Cohort Study].

Objectives　In addition to physical independence such as ADLs, higher-level functional capacity ("instrumental self-maintenance," "intellectual activity," and "social role") are necessary to lead the final stage of life as independently and for as long as possible. Accordingly, in a long-term follow-up study of the local population, we examined the association of health status (total mortality and incidence of care needs) with instrumental independence, intellectual activity, and social role.Methods　We used participant data from the Kamogawa cohort study, which included surveyed use of health service, health status, disease prevalence, and use of long-term care insurance service for Kamogawa citizens in Chiba prefecture from 2003 to 2013. We compared the differences in lifestyle and higher-level functional capacity, by status of death and using the Long-term Care Insurance service. Higher-level functional capacity was assessed with the Tokyo Metropolitan Institute of Gerontology-Index of Competence (TMIG-IC); answer to each question, each domain score, and total score were examined.Results　During the follow-up period to the end of March 2013, 810 deaths and 917 care needs were observed among the 6,503 people who consented to be followed up. The adjusted HR of higher-level functional capacity for all-cause mortality was "instrumental self-maintenance," score 4 or 5 to less than 3: 2.03 (95%CI: 1.59-2.60), "intellectual activity," score 4 to less than 3: 1.39 (95%CI: 1.09-1.77), and "social role," score 4 to less than 3: 1.28 (95%CI: 1.03-1.59). In subgroup analyses by sex, "instrumental self-maintenance" was associated with both men and women, but "intellectual activity" and "social roles" were associated with women only. The adjusted HRs for the incidence of care needs were 1.93 (95%CI: 1.55-2.40) for "instrumental self-maintenance" and 1.30 (95%CI: 1.07-1.58) for "social role." In subgroup analyses by sex, "instrumental self-maintenance" was associated with both genders, but "social role" was observed only for women.Conclusion　Higher-level functional capacity ("instrumental self-maintenance," "intellectual activity," and "social role") was significantly associated with total mortality and incidence of care needs.

Dysbiosis of Oral Microbiota Associated with Palmoplantar Pustulosis.

BACKGROUND: Dysbiosis of oral microbiota is implicated not only in oral inflammatory lesions, but also in a variety of extraoral diseases. The etiology of palmoplantar pustulosis (PPP) remains unclear; however, it has been suggested that chronic inflammation caused by periodontopathic bacterial infection may play a role. OBJECTIVES/METHODS: To determine whether patients with PPP have altered diversity and composition of oral microbiota, we conducted the 16S rDNA analysis using saliva samples collected from 21 outpatients with PPP and 10 healthy individuals. RESULTS: We found that the proportion of bacteria in the phylum Proteobacteria was significantly lower in PPP patients (p = 0.025). At the genus level, patients with PPP had a significantly lower abundance of Neisseria (p = 0.014), which best accounted for the observed decrease in Proteobacteria. We also identified multiple minor genera and species that were represented at a significantly higher level in the PPP group, several of which have been associated with periodontal diseases. CONCLUSION: Our results suggest a possible link between PPP and dysbiosis of oral microbiota, particularly the lower abundance of Neisseria, the most predominant genus of Proteobacteria in healthy oral microbiota. Probiotics that improves oral dysbiosis may be beneficial for patients with PPP as an adjunctive therapy.

Higher Prevalence of Nickel and Palladium Hypersensitivity in Patients with Ulcerative Colitis.

BACKGROUND: The etiology of ulcerative colitis (UC) remains elusive even though many genetic and environmental pathogenic factors have been reported. Aberrant inflammatory responses mediated by specific subsets of T cells have been observed in ulcerative lesions of UC patients. OBJECTIVES: To elucidate the involvement of a delayed-type hypersensitivity reaction in UC, we focused on dental metal hypersensitivity, a T cell-mediated, delayed-type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation. METHOD: We recruited 65 Japanese UC patients and 22 healthy controls (HC) and used the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium - the metals that have been widely used in dentistry. All subjects were users of metallic dental implants and/or prostheses containing zinc, gold, nickel, and/or palladium as major constituents. RESULTS: Sixty percent of the UC patients were hypersensitive to at least one metal species, whereas 32% of the HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for UC patients than for HC. Furthermore, a significantly greater proportion of UC patients were hypersensitive to nickel or palladium. The severity of the sensitivity to nickel and palladium was also significantly greater for UC patients than for HC. CONCLUSIONS: This pilot study demonstrates that UC patients have a significantly higher incidence of hypersensitivity to nickel and palladium, suggesting the possible involvement of dental metal hypersensitivity in UC pathogenesis.

Higher incidence of zinc and nickel hypersensitivity in patients with irritable bowel syndrome.

INTRODUCTION: The etiology of irritable bowel syndrome (IBS) remains elusive even though several genetic and environmental pathogenic factors have been reported. IBS is considered to be a functional disorder without any detectable lesions in the patient's bowel. However, many studies have demonstrated that a subset of IBS patients have low-grade inflammation and aberrant T-cell activation in their intestinal mucosa. To elucidate the immune mechanism underlying the mucosal inflammation in IBS, we focused on dental metal hypersensitivity, a T cell-mediated, delayed-type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation. METHODS: We recruited 147 Japanese IBS patients and 22 healthy controls (HCs). The subjects underwent the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium, the metals that have been commonly used in dentistry. RESULTS: A total of 56.5% of the IBS patients were hypersensitive to at least one metal species, whereas 31.8% of HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for IBS patients than for HC. Furthermore, a significantly higher proportion of IBS patients were hypersensitive to zinc and/or nickel. The severity of the sensitivity to zinc and nickel was also significantly greater for IBS patients than for HC. There was no significant difference in the sensitization rates and the sensitivity among the IBS subtypes. CONCLUSIONS: This pilot study demonstrates that IBS patients have a significantly higher prevalence of hypersensitivity to zinc and nickel, suggesting the possible involvement of dental metal hypersensitivity in IBS pathogenesis in a subset of patients.