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Gut probiotic Lactobacillus rhamnosus attenuates PDE4B-mediated interleukin-6 induced by SARS-CoV-2 membrane
Minh Tan Pham1, Albert Jackson Yang1, Ming-Shan Kao1
1Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, 32001, Taiwan.
Abstract:
Membrane glycoprotein is the most abundant protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but its role in coronavirus disease 2019 (COVID-19) has not been fully characterized. Mice intranasally inoculated with membrane glycoprotein substantially increased the interleukin (IL)-6, a hallmark of the cytokine storm, in bronchoalveolar lavage fluid (BALF), compared to mice inoculated with green fluorescent protein (GFP). The high level of IL-6 induced by membrane glycoprotein was significantly diminished in phosphodiesterase 4 (PDE4B) knockout mice, demonstrating the essential role of PDE4B in IL-6 signaling. Mycelium fermentation of Lactobacillus rhamnosus (L. rhamnosus) EH8 strain yielded butyric acid, which can down-regulate the PDE4B expression and IL-6 secretion in macrophages. Feeding mice with mycelia increased the relative abundance of commensal L. rhamnosus. Two-week supplementation of mice with L. rhamnosus plus mycelia considerably decreased membrane glycoprotein-induced PDE4B expression and IL-6 secretion. The probiotic activity of L. rhamnosus plus mycelia against membrane glycoprotein was abolished in mice treated with GLPG-0974, an antagonist of free fatty acid receptor 2 (Ffar2). Activation of Ffar2 in the gut-lung axis for down-regulation of the PDE4B-IL-6 signalling may provide targets for development of modalities including probiotics for treatment of the cytokine storm in COVID-19.
Insights
SARS-CoV-2 membrane glycoprotein elevates interleukin-6 (IL-6) via PDE4B. Lactobacillus rhamnosus plus mycelia reduces IL-6 by activating Ffar2, offering a probiotic strategy against COVID-19 cytokine storms.
Area of Science:
- Immunology
- Microbiology
- Virology
Background:
- The SARS-CoV-2 membrane glycoprotein's role in COVID-19 pathogenesis, particularly cytokine storm induction, requires further elucidation.
- Interleukin-6 (IL-6) is a key mediator of the cytokine storm observed in severe COVID-19.
- Phosphodiesterase 4B (PDE4B) has been implicated in IL-6 signaling pathways.
Purpose of the Study:
- To investigate the role of SARS-CoV-2 membrane glycoprotein in inducing IL-6 production.
- To explore the involvement of PDE4B in membrane glycoprotein-induced IL-6 signaling.
- To evaluate the potential of Lactobacillus rhamnosus (L. rhamnosus) and its fermentation products in mitigating the cytokine storm.
Main Methods:
- Mice were intranasally inoculated with SARS-CoV-2 membrane glycoprotein or green fluorescent protein (GFP).
- PDE4B knockout mice and wild-type mice were used to assess PDE4B's role in IL-6 signaling.
- Mice were supplemented with L. rhamnosus EH8 strain mycelia, and its effect on PDE4B and IL-6 was analyzed.
- The role of free fatty acid receptor 2 (Ffar2) was investigated using an Ffar2 antagonist (GLPG-0974).
Main Results:
- Intranasal inoculation with SARS-CoV-2 membrane glycoprotein significantly increased IL-6 levels in bronchoalveolar lavage fluid (BALF).
- This IL-6 increase was substantially reduced in PDE4B knockout mice, confirming PDE4B's essential role.
- L. rhamnosus mycelia fermentation produced butyric acid, which down-regulated PDE4B expression and IL-6 secretion in macrophages.
- Supplementation with L. rhamnosus plus mycelia decreased membrane glycoprotein-induced PDE4B expression and IL-6 secretion in mice.
- The probiotic effect was abolished by Ffar2 antagonism, indicating Ffar2's involvement in the gut-lung axis.
Conclusions:
- SARS-CoV-2 membrane glycoprotein induces IL-6 production through a PDE4B-dependent pathway.
- Lactobacillus rhamnosus, through its mycelia and butyric acid production, can down-regulate PDE4B and IL-6.
- Activation of Ffar2 in the gut-lung axis by L. rhamnosus offers a potential therapeutic strategy for managing COVID-19-associated cytokine storms.
