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

Yasunari Kageyama, Yasuhiro Nishizaki, Koichi Aida, Katsuyuki Yayama, Tomoka Ebisui, Tetsu Akiyama, Tsutomu Nakamura, 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 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-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. 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).

Keywords: Lactobacillus plantarum; coronavirus disease 2019; cytokines; dysbiosis; gut-lung axis; lactic acid bacteria; microbiota; natural killer cells; probiotics; severe acute respiratory syndrome coronavirus 2.

Conflict of interest statement

YK, KA, KY and TE are employees of Takanawa Clinic. TA and TN serve as research advisors to Takanawa Clinic and receive advisory fees.

Copyright: © Kageyama et al.

Figures

Figure 1
Figure 1
CONSORT flow diagram of participants in the present study. CONSORT; consolidated standards of reporting trials.
Figure 2
Figure 2
Changes in plasma cytokine levels and QICI values before (pre) and after (post) oral intake of (A) Lactobacillus plantarum SNK12 and (B) Bifidobacterium longum BB536. QICI was defined as follows: QICI=(TNF-α) x (IL-1β) x (IL-18) x (IL-8)/(IL-6), where brackets represent the plasma level of the cytokine in pg/ml. Cross marks denote outliers. Each red line represents the change of the medians. The data were statistically analyzed using the Friedman test followed by the Nemenyi post hoc test. QICI, Qingfei Paidu decoction-induced innate cytokine index.
Figure 3
Figure 3
Effects of L. plantarum or B. longum ingestion on the innate immune cell activity. (A) NK cell activity before (pre) and after (post) the L. plantarum or B. longum ingestion. (B) Phagocytic activity of neutrophils. Representative flow cytometry plots are presented in the upper panels. The vertical and horizontal axes are SSC and FSC, respectively. Areas surrounded by black lines represent granulocyte populations characterized as medium FSC/high SSC (granulocyte gating). Histograms of fluorescence intensities of the granulocytes separated by the granulocyte gating are presented in the lower panels. The vertical and horizontal axes demonstrate cell count and fluorescence intensity, respectively. A black vertical line in each histogram indicates the threshold of fluorescence-positive granulocytes (granulocytes that phagocytosed the fluorescent microbeads). The phagocytic activity was calculated as the ratio of fluorescence-positive granulocytes to the total count of granulocytes and presented in the upper right corner of each histogram. (C) Macrophage activity. The serum levels of neopterin, an activation marker of monocytes and macrophages, were determined using reverse-phase high-performance liquid chromatography. Representative chromatograms are presented. The vertical and horizontal axes show the intensity of native fluorescence of neopterin and retention time, respectively. NK, natural killer; L. plantarum, Lactobacillus plantarum; B. longum, Bifidobacterium longum; FSC, forward scatter; SSC, side scatter.

References

    1. Lukassen S, Chua RL, Trefzer T, Kahn NC, Schneider MA, Muley T, Winter H, Meister M, Veith C, Boots AW, et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J. 2020;39(e105114) doi: 10.15252/embj.20105114.
    1. Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, Talavera-López C, Maatz H, Reichart D, Sampaziotis F, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26:681–687. doi: 10.1038/s41591-020-0868-6.
    1. Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;181:1016–1035.e19. doi: 10.1016/j.cell.2020.04.035.
    1. Lee JJ, Kopetz S, Vilar E, Shen JP, Chen K, Maitra A. Relative abundance of SARS-CoV-2 entry genes in the enterocytes of the lower gastrointestinal tract. Genes (Basel) 2020;11(645) doi: 10.3390/genes11060645.
    1. Zang R, Gomez Castro MF, McCune BT, Zeng Q, Rothlauf PW, Sonnek NM, Liu Z, Brulois KF, Wang X, Greenberg HB, et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. 2020;5(eabc3582) doi: 10.1126/sciimmunol.abc3582.
    1. Lamers MM, Beumer J, van der Vaart J, Knoops K, Puschhof J, Breugem TI, Ravelli RBG, Paul van Schayck J, Mykytyn AZ, Duimel HQ, et al. SARS-CoV-2 productively infects human gut enterocytes. Science. 2020;369:50–54. doi: 10.1126/science.abc1669.
    1. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020;158:1831–1833.e3. doi: 10.1053/j.gastro.2020.02.055.
    1. Zhou J, Li C, Liu X, Chiu MC, Zhao X, Wang D, Wei Y, Lee A, Zhang AJ, Chu H, et al. Infection of bat and human intestinal organoids by SARS-CoV-2. Nat Med. 2020;26:1077–1083. doi: 10.1038/s41591-020-0912-6.
    1. Chen Y, Chen L, Deng Q, Zhang G, Wu K, Ni L, Yang Y, Liu B, Wang W, Wei C, et al. The presence of SARS-CoV-2 RNA in the feces of COVID-19 patients. J Med Virol. 2020;92:833–840. doi: 10.1002/jmv.25825.
    1. Kipkorir V, Cheruiyot I, Ngure B, Misiani M, Munguti J. Prolonged SARS-CoV-2 RNA detection in anal/rectal swabs and stool specimens in COVID-19 patients after negative conversion in nasopharyngeal RT-PCR test. J Med Virol. 2020;92:2328–2331. doi: 10.1002/jmv.26007.
    1. Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, Yin H, Xiao Q, Tang Y, Qu X, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020;5:434–435. doi: 10.1016/S2468-1253(20)30083-2.
    1. Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology. 2020;158:1518–1519. doi: 10.1053/j.gastro.2020.02.054.
    1. Wong SH, Lui RN, Sung JJ. Covid-19 and the digestive system. J Gastroenterol Hepatol. 2020;35:744–748. doi: 10.1111/jgh.15047.
    1. Yang L, Tu L. Implications of gastrointestinal manifestations of COVID-19. Lancet Gastroenterol Hepatol. 2020;5:629–630. doi: 10.1016/S2468-1253(20)30132-1.
    1. Budden KF, Gellatly SL, Wood DL, Cooper MA, Morrison M, Hugenholtz P, Hansbro PM. Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol. 2017;15:55–63. doi: 10.1038/nrmicro.2016.142.
    1. Dumas A, Bernard L, Poquet Y, Lugo-Villarino G, Neyrolles O. The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases. Cell Microbiol. 2018;20(e12966) doi: 10.1111/cmi.12966.
    1. Zhang D, Li S, Wang N, Tan HY, Zhang Z, Feng Y. The cross-talk between gut microbiota and lungs in common lung diseases. Front Microbiol. 2020;11(301) doi: 10.3389/fmicb.2020.00301.
    1. Gu S, Chen Y, Wu Z, Chen Y, Gao H, Lv L, Guo F, Zhang X, Luo R, Huang C, et al. Alterations of the gut microbiota in patients with coronavirus disease 2019 or H1N1 influenza. Clin Infect Dis. 2020;71:2669–2678. doi: 10.1093/cid/ciaa709.
    1. Gou W, Fu Y, Yue L, Chen GD, Cai X, Shuai M, Xu F, Yi X, Chen H, Zhu Y, et al. Gut microbiota may underlie the predisposition of healthy individuals to COVID-19. J Genet Genomics. 2021;48:792–802.
    1. Zuo T, Liu Q, Zhang F, Lui GC, Tso EY, Yeoh YK, Chen Z, Boon SS, Chan FK, Chan PK, et al. Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut. 2021;70:276–284. doi: 10.1136/gutjnl-2020-322294.
    1. Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, Wan Y, Chung ACK, Cheung CP, Chen N, et al. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology. 2020;159:944–955.e8. doi: 10.1053/j.gastro.2020.05.048.
    1. Lehtoranta L, Pitkaranta A, Korpela R. Probiotics in respiratory virus infections. Eur J Clin Microbiol Infect Dis. 2014;33:1289–1302. doi: 10.1007/s10096-014-2086-y.
    1. Lei WT, Shih PC, Liu SJ, Lin CY, Yeh TL. Effect of probiotics and prebiotics on immune response to influenza vaccination in adults: A systematic review and meta-analysis of randomized controlled trials. Nutrients. 2017;9(1175) doi: 10.3390/nu9111175.
    1. Luoto R, Ruuskanen O, Waris M, Kalliomaki M, Salminen S, Isolauri E. Prebiotic and probiotic supplementation prevents rhinovirus infections in preterm infants: A randomized, placebo-controlled trial. J Allergy Clin Immunol. 2014;133:405–413. doi: 10.1016/j.jaci.2013.08.020.
    1. Turner RB, Woodfolk JA, Borish L, Steinke JW, Patrie JT, Muehling LM, Lahtinen S, Lehtinen MJ. Effect of probiotic on innate inflammatory response and viral shedding in experimental rhinovirus infection-a randomised controlled trial. Benef Microbes. 2017;8:207–215. doi: 10.3920/BM2016.0160.
    1. Yeh TL, Shih PC, Liu SJ, Lin CH, Liu JM, Lei WT, Lin CY. The influence of prebiotic or probiotic supplementation on antibody titers after influenza vaccination: A systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:217–230. doi: 10.2147/DDDT.S155110.
    1. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181:1036–1045.e9. doi: 10.1016/j.cell.2020.04.026.
    1. Cao X. COVID-19: Immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20:269–270. doi: 10.1038/s41577-020-0308-3.
    1. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, Damoraki G, Gkavogianni T, Adami ME, Katsaounou P, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27:992–1000.e3. doi: 10.1016/j.chom.2020.04.009.
    1. Chong HX, Yusoff NAA, Hor YY, Lew LC, Jaafar MH, Choi SB, Yusoff MSB, Wahid N, Abdullah MFIL, Zakaria N, et al. Lactobacillus plantarum DR7 improved upper respiratory tract infections via enhancing immune and inflammatory parameters: A randomized, double-blind, placebo-controlled study. J Dairy Sci. 2019;102:4783–4797. doi: 10.3168/jds.2018-16103.
    1. Rask C, Adlerberth I, Berggren A, Ahren IL, Wold AE. Differential effect on cell-mediated immunity in human volunteers after intake of different lactobacilli. Clin Exp Immunol. 2013;172:321–332. doi: 10.1111/cei.12055.
    1. Kechaou N, Chain F, Gratadoux JJ, Blugeon S, Bertho N, Chevalier C, Le Goffic R, Courau S, Molimard P, Chatel JM, et al. Identification of one novel candidate probiotic Lactobacillus plantarum strain active against influenza virus infection in mice by a large-scale screening. Appl Environ Microbiol. 2013;79:1491–1499. doi: 10.1128/AEM.03075-12.
    1. Park MK, Ngo V, Kwon YM, Lee YT, Yoo S, Cho YH, Hong SM, Hwang HS, Ko EJ, Jung YJ, et al. Lactobacillus plantarum DK119 as a probiotic confers protection against influenza virus by modulating innate immunity. PLoS One. 2013;8(e75368) doi: 10.1371/journal.pone.0075368.
    1. Kawashima T, Hayashi K, Kosaka A, Kawashima M, Igarashi T, Tsutsui H, Tsuji NM, Nishimura I, Hayashi T, Obata A. Lactobacillus plantarum strain YU from fermented foods activates Th1 and protective immune responses. Int Immunopharmacol. 2011;11:2017–2024. doi: 10.1016/j.intimp.2011.08.013.
    1. Kikuchi Y, Kunitoh-Asari A, Hayakawa K, Imai S, Kasuya K, Abe K, Adachi Y, Fukudome S, Takahashi Y, Hachimura S. Oral administration of Lactobacillus plantarum strain AYA enhances IgA secretion and provides survival protection against influenza virus infection in mice. PLoS One. 2014;9(e86416) doi: 10.1371/journal.pone.0086416.
    1. Kim DH, Chung WC, Chun SH, Han JH, Song MJ, Lee KW. Enhancing the natural killer cell activity and anti-influenza effect of heat-treated Lactobacillus plantarum nF1-fortified yogurt in mice. J Dairy Sci. 2018;101:10675–10684. doi: 10.3168/jds.2018-15137.
    1. Maeda N, Nakamura R, Hirose Y, Murosaki S, Yamamoto Y, Kase T, Yoshikai Y. Oral administration of heat-killed Lactobacillus plantarum L-137 enhances protection against influenza virus infection by stimulation of type I interferon production in mice. Int Immunopharmacol. 2009;9:1122–1125. doi: 10.1016/j.intimp.2009.04.015.
    1. Park S, Kim JI, Bae JY, Yoo K, Kim H, Kim IH, Park MS, Lee I. Effects of heat-killed Lactobacillus plantarum against influenza viruses in mice. J Microbiol. 2018;56:145–149. doi: 10.1007/s12275-018-7411-1.
    1. Takeda S, Takeshita M, Kikuchi Y, Dashnyam B, Kawahara S, Yoshida H, Watanabe W, Muguruma M, Kurokawa M. Efficacy of oral administration of heat-killed probiotics from Mongolian dairy products against influenza infection in mice: Alleviation of influenza infection by its immunomodulatory activity through intestinal immunity. Int Immunopharmacol. 2011;11:1976–1983. doi: 10.1016/j.intimp.2011.08.007.
    1. Kawahara T, Takahashi T, Oishi K, Tanaka H, Masuda M, Takahashi S, Takano M, Kawakami T, Fukushima K, Kanazawa H, Suzuki T. Consecutive oral administration of Bifidobacterium longum MM-2 improves the defense system against influenza virus infection by enhancing natural killer cell activity in a murine model. Microbiol Immunol. 2015;59:1–12. doi: 10.1111/1348-0421.12210.
    1. Namba K, Hatano M, Yaeshima T, Takase M, Suzuki K. Effects of Bifidobacterium longum BB536 administration on influenza infection, influenza vaccine antibody titer, and cell-mediated immunity in the elderly. Biosci Biotechnol Biochem. 2010;74:939–945. doi: 10.1271/bbb.90749.
    1. Sugimura T, Takahashi H, Jounai K, Ohshio K, Kanayama M, Tazumi K, Tanihata Y, Miura Y, Fujiwara D, Yamamoto N. Effects of oral intake of plasmacytoid dendritic cells-stimulative lactic acid bacterial strain on pathogenesis of influenza-like illness and immunological response to influenza virus. Br J Nutr. 2015;114:727–733. doi: 10.1017/S0007114515002408.
    1. Shi HY, Zhu X, Li WL, Mak JWY, Wong SH, Zhu ST, Guo SL, Chan FKL, Zhang ST, Ng SC. Modulation of gut microbiota protects against viral respiratory tract infections: A systematic review of animal and clinical studies. Eur J Nutr: Apr 14, 2021 (Epub ahead of print).
    1. Wang F, Pan B, Xu S, Xu Z, Zhang T, Zhang Q, Bao Y, Wang Y, Zhang J, Xu C, Xue X. A meta-analysis reveals the effectiveness of probiotics and prebiotics against respiratory viral infection. Biosci Rep. 2021;41(BSR20203638) doi: 10.1042/BSR20203638.
    1. Wei PF (ed) Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) Chin Med J (Engl) 2020;133:1087–1095. doi: 10.1097/CM9.0000000000000819.
    1. Cao P, Wu S, Wu T, Deng Y, Zhang Q, Wang K, Zhang Y. The important role of polysaccharides from a traditional Chinese medicine-Lung cleansing and detoxifying decoction against the COVID-19 pandemic. Carbohydr Polym. 2020;240(116346) doi: 10.1016/j.carbpol.2020.116346.
    1. Shi N, Liu B, Liang N, Ma Y, Ge Y, Yi H, Wo H, Gu H, Kuang Y, Tang S, et al. Association between early treatment with Qingfei Paidu decoction and favorable clinical outcomes in patients with COVID-19: A retrospective multicenter cohort study. Pharmacol Res. 2020;161(105290) doi: 10.1016/j.phrs.2020.105290.
    1. Zhao ZH, Zhou Y, Li WH, Huang QS, Tang ZH, Li H. Analysis of traditional Chinese medicine diagnosis and treatment strategies for COVID-19 based on ‘The Diagnosis and Treatment Program for Coronavirus Disease-2019’ from Chinese Authority. Am J Chin Med. 2020;48:1035–1049. doi: 10.1142/S0192415X20500500.
    1. Zhong LLD, Lam WC, Yang W, Chan KW, Sze SCW, Miao J, Yung KKL, Bian Z, Wong VT. Potential targets for treatment of coronavirus disease 2019 (COVID-19): A review of Qing-Fei-Pai-Du-Tang and its major herbs. Am J Chin Med. 2020;48:1051–1071. doi: 10.1142/S0192415X20500512.
    1. Xin S, Cheng X, Zhu B, Liao X, Yang F, Song L, Shi Y, Guan X, Su R, Wang J, et al. Clinical retrospective study on the efficacy of Qingfei Paidu decoction combined with Western medicine for COVID-19 treatment. Biomed Pharmacother. 2020;129(110500) doi: 10.1016/j.biopha.2020.110500.
    1. Kageyama Y, Aida K, Kawauchi K, Morimoto M, Ebisui T, Akiyama T, Nakamura T. Qingfei Paidu decoction, a Chinese herbal medicine against COVID-19, elevates the blood levels of pro-inflammatory cytokines: An open-label, single-arm pilot study. World Acad Sci J. 2021;3(25)
    1. Popkin BM, Du S, Green WD, Beck MA, Algaith T, Herbst CH, Alsukait RF, Alluhidan M, Alazemi N, Shekar M. Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships. Obes Rev. 2020;21(e13128) doi: 10.1111/obr.13128.
    1. Kompaniyets L, Goodman AB, Belay B, Freedman DS, Sucosky MS, Lange SJ, Gundlapalli AV, Boehmer TK, Blanck HM. Body mass index and risk for COVID-19-related hospitalization, intensive care unit admission, invasive mechanical ventilation, and Death-United States, march-december 2020. MMWR Morb Mortal Wkly Rep. 2021;70:355–361. doi: 10.15585/mmwr.mm7010e4.
    1. Elshazli RM, Toraih EA, Elgaml A, El-Mowafy M, El-Mesery M, Amin MN, Hussein MH, Killackey MT, Fawzy MS, Kandil E. Diagnostic and prognostic value of hematological and immunological markers in COVID-19 infection: A meta-analysis of 6320 patients. PLoS One. 2020;15(e0238160) doi: 10.1371/journal.pone.0238160.
    1. Mesas AE, Cavero-Redondo I, Álvarez-Bueno C, Sarriá Cabrera MA, Maffei de Andrade S, Sequí-Dominguez I, Martínez-Vizcaíno V. Predictors of in-hospital COVID-19 mortality: A comprehensive systematic review and meta-analysis exploring differences by age, sex and health conditions. PLoS One. 2020;15(e0241742) doi: 10.1371/journal.pone.0241742.
    1. Zhang X, Tan Y, Ling Y, Lu G, Liu F, Yi Z, Jia X, Wu M, Shi B, Xu S, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature. 2020;583:437–440. doi: 10.1038/s41586-020-2355-0.
    1. Okumura A, Watanabe T, Hayashi K, Yoshida H. Oral administration of distribution-processed Lactobacillus plantarum strain SNK12 protects against influenza virus infection. Jpn Pharmacol Ther. 2019;47:1607–1612.
    1. Watanabe T, Hayashi K, Kan T, Ohwaki M, Kawahara T. Anti-influenza virus effects of Enterococcus faecalis KH2 and Lactobacillus plantarum SNK12 RNA. Biosci Microbiota Food Health. 2021;40:43–49. doi: 10.12938/bmfh.2020-019.
    1. Xiao JZ, Kondo S, Yanagisawa N, Miyaji K, Enomoto K, Sakoda T, Iwatsuki K, Enomoto T. Clinical efficacy of probiotic Bifidobacterium longum for the treatment of symptoms of Japanese cedar pollen allergy in subjects evaluated in an environmental exposure unit. Allergol Int. 2007;56:67–75. doi: 10.2332/allergolint.O-06-455.
    1. Xiao JZ, Kondo S, Yanagisawa N, Takahashi N, Odamaki T, Iwabuchi N, Iwatsuki K, Kokubo S, Togashi H, Enomoto K, Enomoto T. Effect of probiotic Bifidobacterium longum BB536 [corrected] in relieving clinical symptoms and modulating plasma cytokine levels of Japanese cedar pollinosis during the pollen season. A randomized double-blind, placebo-controlled trial. J Investig Allergol Clin Immunol. 2006;16:86–93.
    1. Iwabuchi N, Xiao JZ, Yaeshima T, Iwatsuki K. Oral administration of Bifidobacterium longum ameliorates influenza virus infection in mice. Biol Pharm Bull. 2011;34:1352–1355. doi: 10.1248/bpb.34.1352.
    1. Lau AS, Yanagisawa N, Hor YY, Lew LC, Ong JS, Chuah LO, Lee YY, Choi SB, Rashid F, Wahid N, et al. Bifidobacterium longum BB536 alleviated upper respiratory illnesses and modulated gut microbiota profiles in Malaysian pre-school children. Benef Microbes. 2018;9:61–70. doi: 10.3920/BM2017.0063.
    1. Odamaki T, Sugahara H, Yonezawa S, Yaeshima T, Iwatsuki K, Tanabe S, Tominaga T, Togashi H, Benno Y, Xiao JZ. Effect of the oral intake of yogurt containing Bifidobacterium longum BB536 on the cell numbers of enterotoxigenic Bacteroides fragilis in microbiota. Anaerobe. 2012;18:14–18. doi: 10.1016/j.anaerobe.2011.11.004.
    1. Odamaki T, Xiao JZ, Iwabuchi N, Sakamoto M, Takahashi N, Kondo S, Miyaji K, Iwatsuki K, Togashi H, Enomoto T, Benno Y. Influence of Bifidobacterium longum BB536 intake on faecal microbiota in individuals with Japanese cedar pollinosis during the pollen season. J Med Microbiol. 2007;56:1301–1308. doi: 10.1099/jmm.0.47306-0.
    1. Holvoet S, Zuercher AW, Julien-Javaux F, Perrot M, Mercenier A. Characterization of candidate anti-allergic probiotic strains in a model of th2-skewed human peripheral blood mononuclear cells. Int Arch Allergy Immunol. 2013;161:142–154. doi: 10.1159/000343703.
    1. Medina M, Izquierdo E, Ennahar S, Sanz Y. Differential immunomodulatory properties of Bifidobacterium logum strains: Relevance to probiotic selection and clinical applications. Clin Exp Immunol. 2007;150:531–538. doi: 10.1111/j.1365-2249.2007.03522.x.
    1. Niers LE, Timmerman HM, Rijkers GT, van Bleek GM, van Uden NO, Knol EF, Kapsenberg ML, Kimpen JL, Hoekstra MO. Identification of strong interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines. Clin Exp Allergy. 2005;35:1481–1489. doi: 10.1111/j.1365-2222.2005.02375.x.
    1. Hoffmann G, Wirleitner B, Fuchs D. Potential role of immune system activation-associated production of neopterin derivatives in humans. Inflamm Res. 2003;52:313–321. doi: 10.1007/s00011-003-1181-9.
    1. Gieseg SP, Baxter-Parker G, Lindsay A. Neopterin, inflammation, and Oxidative Stress: What could we be missing? Antioxidants (Basel) 2018;7(80) doi: 10.3390/antiox7070080.
    1. Hausen A, Fuchs D, König K, Wachter H. Determination of neopterine in human urine by reversed-phase high-performance liquid chromatography. J Chromatogr. 1982;227:61–70. doi: 10.1016/s0378-4347(00)80356-4.
    1. Gleiss A, Sanchez-Cabo F, Perco P, Tong D, Heinze G. Adaptive trimmed t-statistics for identifying predominantly high expression in a microarray experiment. Stat Med. 2011;30:52–61. doi: 10.1002/sim.4093.
    1. Krzywinski M, Altman N. Visualizing samples with box plots. Nat Methods. 2014;11:119–120. doi: 10.1038/nmeth.2813.
    1. Domthong U, Parikh CR, Kimmel PL, Chinchilli VM. Assessing the agreement of biomarker data in the presence of left-censoring. BMC Nephrol. 2014;15(144) doi: 10.1186/1471-2369-15-144. Assessment, Serial Evaluation, Subsequent Sequelae of Acute Kidney Injury Consortium.
    1. Yu X, Lakerveld AJ, Imholz S, Hendriks M, Ten Brink SCA, Mulder HL, de Haan K, Schepp RM, Luytjes W, de Jong MD, et al. Antibody and local cytokine response to respiratory syncytial virus infection in community-dwelling older adults. mSphere. 2020;5:e00577–20. doi: 10.1128/mSphere.00577-20.
    1. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–458. doi: 10.1038/bmt.2012.244.
    1. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–191. doi: 10.3758/bf03193146.
    1. Waggoner SN, Reighard SD, Gyurova IE, Cranert SA, Mahl SE, Karmele EP, McNally JP, Moran MT, Brooks TR, Yaqoob F, et al. Roles of natural killer cells in antiviral immunity. Curr Opin Virol. 2016;16:15–23. doi: 10.1016/j.coviro.2015.10.008.
    1. Björkström NK, Strunz B, Ljunggren HG. Natural killer cells in antiviral immunity. Nat Rev Immunol: Jun 11, 2021 (Epub ahead of print).
    1. Berggren A, Lazou Ahren I, Larsson N, Onning G. Randomised, double-blind and placebo-controlled study using new probiotic lactobacilli for strengthening the body immune defence against viral infections. Eur J Nutr. 2011;50:203–210. doi: 10.1007/s00394-010-0127-6.
    1. International Home Medical (IHM): Plant-origin nano-particled (Pro)-Biogenics immunophilus SNK. Plant-origin nano-sized lactic acid bacterium SNK®. IHM Inc., Tolyo, 2021. . Accessed October 14, 2021.
    1. Chen N, Xia P, Li S, Zhang T, Wang TT, Zhu J. RNA sensors of the innate immune system and their detection of pathogens. IUBMB Life. 2017;69:297–304. doi: 10.1002/iub.1625.
    1. Moreno-Eutimio MA, Lopez-Macias C, Pastelin-Palacios R. Bioinformatic analysis and identification of single-stranded RNA sequences recognized by TLR7/8 in the SARS-CoV-2, SARS-CoV, and MERS-CoV genomes. Microbes Infect. 2020;22:226–229. doi: 10.1016/j.micinf.2020.04.009.
    1. Slaats J, Ten Oever J, van de Veerdonk FL, Netea MG. IL-1β/IL-6/CRP and IL-18/ferritin: Distinct inflammatory programs in infections. PLoS Pathog. 2016;12(e1005973) doi: 10.1371/journal.ppat.1005973.
    1. Mick E, Kamm J, Pisco AO, Ratnasiri K, Babik JM, Castañeda G, DeRisi JL, Detweiler AM, Hao SL, Kangelaris KN, et al. Upper airway gene expression reveals suppressed immune responses to SARS-CoV-2 compared with other respiratory viruses. Nat Commun. 2020;11(5854) doi: 10.1038/s41467-020-19587-y.
    1. van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, van Deuren RC, Steehouwer M, van Reijmersdal SV, Jaeger M, et al. Presence of genetic variants among young men with severe COVID-19. JAMA. 2020;324:663–673. doi: 10.1001/jama.2020.13719.
    1. Liu C, Martins AJ, Lau WW, Rachmaninoff N, Chen J, Imberti L, Mostaghimi D, Fink DL, Burbelo PD, Dobbs K, et al. Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19. Cell. 2021;184:1836–1857.e22. doi: 10.1016/j.cell.2021.02.018.
    1. Sahoo D, Katkar GD, Khandelwal S, Behroozikhah M, Claire A, Castillo V, Tindle C, Fuller M, Taheri S, Rogers TF, et al. AI-guided discovery of the invariant host response to viral pandemics. EBioMedicine. 2021;68(103390) doi: 10.1101/2020.09.21.305698.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅