<i>Lactobacillus plantarum</i> induces innate cytokine responses that potentially provide a protective benefit against COVID‑19: A single‑arm, double‑blind, prospective trial combined with an <i>in vitro</i> cytokine response assay
Yasunari Kageyama, Yasuhiro Nishizaki, Koichi Aida, Katsuyuki Yayama, Tomoka Ebisui, Tetsu Akiyama, Tsutomu Nakamura
Abstract
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 <em>in vitro</em> 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 <em>Lactobacillus plantarum</em> (<em>L. plantarum</em>), <em>Bifidobacterium longum</em> and <em>Lactococcus lactis</em> ssp. <em>lactis</em>, 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‑1β, 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‑1β) 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. <em>L. plantarum</em> demonstrated a strikingly high innate cytokine index in all subjects in the <em>in vitro</em> cytokine response assay. In the subsequent trial, oral intake of <em>L. plantarum</em> 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, <em>L. plantarum</em> ingestion significantly enhanced the activity of natural killer cells. By contrast, oral <em>B. longum</em> 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, <em>L. plantarum</em> demonstrated superior QFPD‑like immunomodulatory ability and mimicked the blood cytokine environment produced by early immune responses to viral infection. Daily consumption of <em>L. plantarum</em> 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).