Inflammation is a defense process of the body's system due to infections from bacteria and viruses and can also be caused by damage to body tissues1. Acute inflammation is the first line of defense due to infection. Coronavirus 2019 (COVID-19) is an acute inflammatory disease that can cause an impaired inflammatory immune response2. COVID-19 disease is a clinical syndrome caused by SARS-CoV-2. Originally discovered in China in December 2019, this disease has spread worldwide and was declared a pandemic by WHO on 11 March 2020. This disease causes human acute respiratory system like other betacoronavirus types such as human coronavirus 229E, NL63, OC43, HKU1, Middle-East respiratory syndrome (MERS), dan Severe Acute Respiratory Syndrome (SARS)3-5.

SARS-CoV-2 is transmissible through respiratory droplets, with a viral incubation period around 4-5 before initial symptoms emerge. About 97.5% of patients were reported to exhibit symptoms in 11.5 days6. The symptoms include fever, dry cough, breathing difficulty, muscle soreness, headache, and diarrhea. SARS-CoV-2 infections can turn into Acute Respiratory Distress Syndrome (ARDS) approximately 8-9 days after the first symptoms7. Severe ARDS in COVID-19 patients can be indicated by breathing difficulty and low blood oxygen level8. ARDS is known to cause respiratory failure leading to death in 70% of COVID-19 cases. Viral infection or secondary infection in patients is known to cause cytokine storm and sepsis symptoms, which result in death in 28% of the patients9. Uncontrolled inflammation in COVID-19 disease is reported to lead to multiorgan damage, eventually resulting in organ failure, especially heart, liver, and kidney failures10. However, this inflammation can be treated using probiotic bacteria.

Probiotic bacteria are the potential to treat diseases caused by inflammation and immune system responses11. Probiotic bacteria play roles in humoral immunity by interacting with intestinal epithelial cells and lamina propria-related cells through toll receptors. The probiotic bacteria are reported to lower cytokines that produce inflammatory cells and immune system decline through NF-KB transcription factor pathways12. Immune response and inflammation in the cell can be affected by NF-KB. In this regard, NF-KB has become the object of developing a treatment for diseases caused by inflammation13. Inflammatory response and immune system can be stimulated using Lactobacillus strain probiotic14.

Lactobacillus is a gram-positive, non-spore-forming, lactic acid bacteria. This bacterium generates lactic acid as its primary product through carbohydrate fermentation. Morphologically, Lactobacillus can be in the form of a non-shortening bar in the chain form. Lactobacillus is a part of microbiota colonizing the mouth and digestive tract15. Lactobacillus colony species commonly found in the digestive tract are Lactobacillus plantarum and L. fermentum16. Lactobacillus plantarum and L. fermentum exhibit high probiotic potentials and become potential anti-inflammatory and immune responses by modulating pro-inflammatory cytokines17. This paper reviews the anti-inflammatory and immunostimulant potentials of L. plantarum and L. fermentum reported in vitro, in vivo, and in clinical studies. This paper also provides information about the metabolite compounds of L. plantarum and L. fermentum as anti-inflammatory and immunostimulants in treating COVID-19.

The virus is attached to the host through a receptor. Angiotensin 2 (ACE2) and TMPRSS218 are known to be the host receptor used by SARS-CoV-2 to infect the cell. This target receptor can be found in the respiratory tract, such as epithelial cells, alveolar epithelial cells, vascular endothelial cells, and macrophages in the lungs19-21. Viral replication and release may cause pyroptosis in the host cell and damage the associated molecular pattern, including ATP, nucleic acid, and ASC oligomer. The virus is recognized by epithelial cells, endothelial cells, and alveolar macrophages, triggering the formation of pro-inflammatory cytokine and chemokine (including IL-6, IP-10, macrophage inflammatory protein 1α (MIP1α), MIP1β, and MCP1). This protein attracts monocyte, macrophage, and T cell to the infected area and promotes further inflammation by adding interferon-γ (IFN-γ) produced by T cells.

The damaged immune response can cause further accumulation of immune cells in the lungs, leading to excessive pro-inflammatory cytokines and eventually damaging the lungs. The produced cytokine storm circulates to other organs, causing multiorgan damage. Bronchoalveolar fluid (BALF) patients with COVID-19 symptoms are reported to contain Chemokine CCL2 and CCL7. Both chemokines are responsible for recruiting Cc-chemokine receptor 2-positive (CCR2+)22. Several cytokine and chemokine monocytes are reported to play roles in the inflammatory process in COVID-19 patients15,23-25. The inflammation severity is indicated by the increase in cytokine and chemokine levels. Macrophage activation due to the viral infection can cause increased cytokine IL-6, IL-7, TNF-α, and inflammatory chemokine, including Cc-chemokine 2 (CCL2), CCL3, CXC-chemokine 10 (CXCL10), and IL2. The irregularity of mononuclear phagocyte activation may cause hyperinflammation in COVID-19 patients. Some hypotheses exist on the mechanism contributing to monocyte hyperactivity due to macrophage in COVID-19 patients26,27.

The delayed type 1 interferon production leads to the increased cytopathic effect. The increased microbial threat may enhance the chemoattractant by alveolar epithelial cells, macrophages, and stromal cells, increasing the number of monocytes in the lungs. The monocytes then differentiate into pro-inflammatory macrophages through Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT). The T-cell will induce the monocyte-derived macrophages by producing granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, and IFNγ.

Oxidized phospholipids (OxPLs) deposit in the lungs' infected area and activate monocyte-macrophage through Toll-like receptors 4 (TLR4), TRAF6, and NF-κB. The virus infection can trigger the TLR7 activation through single-stranded RNA virus recognition. The virus enters the macrophage cytoplasm through the type-1 interferon receptor. The virus activates the NLRP3 inflammasome and causes mature IL-1β and IL-18 secretions. The IL-1β cytokine can increase macrophage activation in autocrine or paracrine. It can also decrease interferon type I production in the infected lungs. Macrophage-activated monocyte contributes to the formation of cytokine storm of COVID-19 by releasing many pro-inflammatory cytokines28.

SARS-CoV-2 hampers the body's normal immune response, causing immune system damage and uncontrolled inflammatory response in severe COVID-19 patients. COVID-19 patients are reported to exhibit lymphopenia, lymphocyte activation and dysfunction, granulocyte and monocyte disorder, high cytokine levels, increased immunoglobulin G (IgG), and a total of antibodies29. Immune response patterns in Covid-19 patients are depicted in Figure 1.

Lymphopenia is the primary marker of severe COVID-19 patients. Patients will likely exhibit declined CD4+ T, CD8+ T, and B cell levels30. T cell activation due to the virus infection may increase the IFN-γ, TNF-α, and IL-2 levels. In addition, lymphocytes are reported to release phenotypic programmed cell death protein-1 (PD1), T-cell immunoglobulin domain, mucin domain-3 (TIM3), and killer cell lectin-like receptor subfamily C member 1 (NKG2A). COVID-19 patients will likely exhibit increased neutrophil and decreased eosinophil, basophil, and monocyte. They also exhibit increased cytokine production, especially IL-1β, IL-6, dan IL-10. A higher IgG and total antibody titers are also observed in COVID-19 patients29.

Figure1. COVID-19 Immunopathological mechanism29.

Lactobacillus produces intracellular and extracellular metabolism. The produced metabolite can provide information regarding the potential of bacteria on nutrition and its toxicity effect on the disease. Some metabolites are reported to be defrosting agents, antioxidants, antimicrobial agents, natural diet additives, and anti-inflammatory agents31.

The fingerprint analysis of metabolite compounds can be performed using gas chromatography to determine Lactobacillus's intracellular and extracellular metabolite analysis32. Gas chromatography-Mass spectrometry (GC-MS) is a chromatography with high-resolution separation results and good sensitivity and specificity. This instrument can analyze metabolic products such as carbohydrates, fatty acids, organic acids, and amino acids33. The sample derivatization is necessary before performing GC-MS analysis34. Chaudary et al.35 identified 40 metabolites and five bacteria isolations, including L. plantarum DB-2, L. fermentum J-1, Pediococcus acidilactici M-3, L. plantarum SK- 3 dan P. pentosaceus SM-234. Metabolite compounds generated by Lactobacillus are presented in Table I.

TableI. Identification of metabolite compounds of L. plantarum and L. fermentum35

The identified metabolites, such as isopropyl alcohol, dodecane, hexadecane, tetradecane, hexahydro-3-(2-methyl propyl) pirolo[1,2-a], pyrazine-1,4-dion, 2,4-dimethyl benzaldehyde, isovaleric geraniol, phenol, 2,4 bis (1,1-dimethyl); 2,6,11,15-tetramethyl-hexadecanoic acid, (Z)-9-octadecenamide, are reported to be potential defrosting, antioxidant, antimicrobial, and anti-inflammatory agents31. In addition, short-chain fatty acids (SCFA) produced by probiotic bacteria, such as acetate, butyrate, and propionate, play roles in decreasing nitric oxide (NO)36,37. Inflammation causes an immune response to activating cytokine in producing NO, resulting in increased NO. SCFA produced by Lactobacillus can induce immune response through tolerogenic dendritic cells (Figure 2). Fatty acid compounds can have an inhibitory effect on inflammation, especially omega-6 fatty acids. However, the interaction mechanism of omega-6 fatty acids and their lipid mediators in inflammation is still not well understood38.

The tolerogenic process of dendritic cells makes the T-cell (CD4+) differentiate into T-cell regulators (Treg) and inhibits cytokine production by neutrophils and macrophages. Tolerogenic dendritic cells produce anti-inflammatory cytokines, interleukin-10 (IL-10), and transforming growth factor-β (TGF-β). A tolerogenic dendritic cell is a potential candidate for specific immunotherapy37.

Figure2. SCFA's work mechanism in decreasing inflammatory activities37.

Anti-inflammatory and immunostimulant activities of Lactobacillus have been widely studied through in vitro and in vivo research. Table II displays several studies on the anti-inflammatory and immunostimulant activities of L. plantarum with different strains. Lactobacillus’ immunostimulant activities can occur through the increase in cytokine IL-10 production in mononuclear cells (macrophage and T-cell) in the intestine39. A study shows that L. plantarum CM can inhibit the binding activity of NF-κB in response to TNF-α. This response weakens the release of monocyte chemotactic protein 1 (MCP-1), pro-inflammatory chemokine, and NF-κB gene and inhibits the proteasome functions. Lactobacillus plantarum CM inhibits the activation of NF-κB from TNF through MyD88-dependent and MyD88-independent pathways. Lactobacillus plantarum can also inhibit TNF-α-induced MCP-1 production in Caco-2 cells and lower NF-κB, mitogen protein kinase, and production of TNF-α or IL-1β40-42.

In vivo studies report that L. plantarum and L. fermentum possess inflammatory activities43,44. The effective dose of probiotic bacteria to treat inflammation is reported to be 1x108 – 109 CFU/mL44,45. Lactobacillus fermentum is reported to significantly lower malondialdehyde levels, TNF-α, IL-6, and resistin in mouse blood serum. Lactobacillus bacteria is also reported to increase catalase, superoxide dismutase, glutathione peroxidase, and adiponectin activities, suppressing the inflammation-inducing- oxidative stress. Most studies show that L. plantarum induces IL-10 secretion in splenocytes and mesenteric lymphocytes, blocking the expression of pro-inflammatory cytokines, IL-1β, IL-6, TNF-α, COX-2, forkhead box P3 (Foxp3), suppressor of cytokine signaling 3 (SOCS3). In vivo study shows a decline in mucose IL-12, IFN-γ, and immunoglobulin G2a in mice46. The treatment using L. plantarum Biocenol™ LP96 was reported to lower the expression of IL-1α, and IL-8 genes increase the IFN-γ and cytokine IL-10 secretion47. This paper reviewed in vitro and in vivo studies to show Lactobacillus’ metabolite product potential in inhibiting inflammatory activities.

TableII. Results of in vitro and in vivo studies on anti-inflammatory and immunostimulant activities of L. plantarum and L. fermentum.

Probiotics have an essential role in the eubiosis of the human microbiota68. Patients with COVID-19 symptoms had lower intestinal bacteria counts than normal patients69. These gut bacteria can enhance the immune response70. Probiotics and their metabolites can be used as a complementary strategy other than vaccines that can inhibit COVID-1971. Lactobacillus can inhibit the development of viruses through various mechanisms, direct interaction between probiotics and viruses; stimulation of the immune system; and virus-inhibiting metabolites72. The metabolites produced by lactic acid bacteria can inhibit the development of pathogenic bacteria and viruses73. These metabolites include amino acid derivatives (indolelactic acid, phenyllactic acid 2-hydroxy-4-,2-hydroxy-4-methylpentanoic acid, and 2-hydroxy-4-methylthio butanoic acid), fatty acids (3-hydroxy-5-cis-dodecanoic acid and 3-hydroxydodecanoic acid), organic compounds (acetic acid, lactic acid, propionic acid, succinic acid, and benzoate acid), cyclic peptides (cyclo(L-Phe-L-Pro) reutericyclin), and other groups of chemical compounds (δ-dodecalactone)74.

Clinical trials showed that 75.61% of patients treated with probiotic bacteria had a shorter treatment time than those not treated with probiotics. These bacteria can reduce secondary infections and moderate the patient's immune system based on the analytical parameters of IL-6, CRP, total T lymphocytes, NK cells, B lymphocytes, CD4 + T cells, CD8 + T cells, and CD4/CD8 ratio75. In another study, patients receiving probiotic bacteria L. plantarum (KABP022, KABP023, and KAPB033) with a combination of P. acidilactici KABP021 for 30 days showed inhibition against the COVID-19 virus76. In silico studies have also carried molecular docking on the metabolite L. plantarum Probio-88 to the SARS-CoV-2 helicase. The high binding affinity and hydrogen bonding suggests that the association of PlnE and PlnF on the helicase of SARS-COV-2 may inhibit virus replication77.

Indonesia abounds in biodiversity, including microorganisms. Lactobacillus plantarum and L. fermentum indigenous strains of Indonesian have potential as anti-inflammatory and immunostimulant. Our preliminary research showed that the superior candidate bacteria from the two strains had antibacterial activity and could withstand acidic conditions and high temperatures. Therefore, further study is needed to determine the anti-inflammatory and immunostimulant activities to be used as an immunomodulator for COVID-19.

Based on the results of experimental and clinical research data, L. plantarum and L. fermentum have activities as anti-inflammatory and immunostimulants in COVID-19 patients. Lactobacillus can reduce the activity of inflammatory cytokines IL-1β, IL-6, TNF-, COX-2, Foxp3, SOCS3 suppressor, and increase IL-10. Patients treated with probiotics had a faster recovery time than those not treated with Lactobacillus. Lactobacillus can reduce secondary infection and increase immune response in COVID-19 patients. Bioactive compounds from these bacteria can also cause anti-inflammatory and immunostimulant activities.

We would like to thank LPPM IPB University for supporting this research in the “Konektivitas Pembelajaran Mahasiswa Pascasarjana” Program.

All authors are the main contributors in carrying out the research and writing this review article.

None.

The authors have declared no conflict of interest.

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