Table 1.

Immunomodulatory effects of probiotic bacteria in respiratory virus infections in animal experiments

Probiotic strain/reference	Virus	Study design	Main findings
L. casei Shirota [16]	IFV A/PR/8/34 (H1N1)	BALB/c mice, intranasal administration 3× daily for 3 days before infection	Mice survival rate ↑ IL-12, IFN-γ, TNF-α in MLN cells ↑ Virus titers in nasal wash ↓
[17]		BALB/c mice, oral administration 5×/week for 3 weeks before infection	Mice survival rate ↑ Pulmonary NK cell activity ↑ IL-12 production by MLN cells ↑ Viral titers in nasal wash ↓
L. plantarum L-137 [18]	IFV A/FM1/47 (H1N1)	C57BL/6 mice, intragastric administration daily 7 days before and 6 days after infection	Viral titers in the lung ↓ IFN-β in sera ↑
L. plantarum 05AM2 L. plantarum 06TCa8 L. paracasei ssp. paracasei 06TCa19 L. paracasei ssp. paracasei 06TCa22 L. paracasei ssp. tolerans 06TCa39 L. plantarum 06TCa40 L. paracasei ssp. paracasei 06TCa43 L. plantarum 06CC2 L. delbrueckii ssp. lactis 06TC3 L. plantarum 06CC9 [19]	IFV A/PR/8/34 (H1N1)	BALB/c mice, oral administration 2× daily for 10 days starting 2 days before infection	Effects only with L. plantarum 06CC2: Body weight loss ↓ Virus yields in lungs ↓ Mice survival ↑ No. of macrophages and neutrophils in BALF ↓ TNF-α in BALF ↓ INF-α, IL-12, IFN-γ, NK cell activity ↑ mRNA IL-12 receptor, IFN-γ in Peyer’s patches ↑
L. plantarum DK119 [20]		BALB/c mice, oral administration daily for 10 days before infection and 14 days after infection + experiments with nasal administration	Both administration routes: Mice survival ↑ Lung viral loads ↓ BALF IL-12, IFN-γ ↑ BALF IL-4, IL-6, TNF-α ↓
L. gasseri TMC0356 L. rhamnosus GG [21]		BALB/c mice, oral administration daily for 1 day, infection on day 14	Effects with both bacteria: Clinical symptom scores ↓ Pulmonary virus titers ↓
[22]			Effects with L. gasseri: Peyer’s patches: mRNA IL-12, IL-15, IL-21 ↑ Lungs: mRNA IFN-γ, TNF, IL-12, perforin-1 ↑
[23]		BALB/c mice, intranasal administration 3× daily for 3 days before infection	L. gasseri TMC0356: Morbidity ↓ Mice survival ↑ mRNA IL-1β, TNF, IL-10, MCP-1 ↑
			L. rhamnosus GG: Accumulated symptoms ↓ Mice survival ↑ mRNA IL-1β, TNF, IL-10 + MCP-1↑
[24]
L. rhamnosus (strain not provided) [25]	IFV A/NWS/33 (H1N1)	BALB/c mice, sublingual administration for 10 days before infection	Mice mortality ↓ Lung lesion scores↓ Lung anti-IFV IgA ↑ Lung IL-12 ↑, IL-6+ TNF-α ↔ Lung CD4+, CD8+, CD25 expression ↑ Splenocyte NK cell activities ↑
L. fermentum-1 L. brevis-2 [26]		BALB/c mice, intranasal or oral administration for 21 days before infection	Mice survival ↑ Virus titer ↓ Lung IgA + IL-12 ↑ Lung TNF-α and IL-6 ↓ Lung IFN-γ ↔
L. fermentum CJL-112 [27]		BALB/c mice, intranasal administration for 21 days before infection	Effect in lungs: IL-2, IFN-γ, IL-1β ↑ IL-4, IL-5 ↔ IL-10 ↓ Anti-influenza IgA ↑
L. brevis KB290 [28]	IFV A/PR/8/34 (H1N1) IFV A/PR8/34 H1N1	BALB/c mice, oral administration 1× daily for 14 days before infection	Body weight loss ↓ Clinical symptom scores ↓ BALF IFV specific IgA ↑ Serum IFN-α ↑
L. pentosus S-PT84 [29]		BALB/c mice, intranasal administration 1× daily for 3 days before infection	Mice survival ↑ Virus titer in BALF ↓ IL-12, IFN-γ in MLN cells ↑ BALF IL-12, IFN-α ↑ NK cell activity ↑
L. pentosus b240 [30]		BALB/c mice, oral administration for 3 weeks by gavage before infection	Mice survival ↑ Virus titers 7 days after infection ↓ Anti-IFV IgA, IgG BALF + plasma on day 7 ↑
[31]	IFV A/California/04/2009 (H1N1)	BALB/c mice, oral administration daily for 5 weeks, IFV infection on day 21	Mice survival ↑ Virus proliferation ↔ Lung histopathology ↔ Cytokines/chemokines ↔ Differential regulation of antiviral gene expression
L. acidophilus L-92 [32]	IFV A/PR/8/34 (H1N1)	BALB/c mice, oral administration daily for 21 days, infection on day 16	Both bacteria: - Body weight ↔ - Fatality ↔ Viable probiotic: - Symptom score ↔ - Lung virus titers ↓ - Lung NK cell activity ↑ - Lung eotaxin, M-CSF, IL-1β, RANTES, IFN-α ↑ - Lung IgG ↓, IgA ↔ Nonviable probiotic: - Symptom score ↓ - Lung virus titers ↓ - Lung NK cell activity ↑
B. longum BB536 [33]		BALB/c mice, oral administration daily for 2 weeks before infection	Symptom score ↓ Loss of body weight ↓ Lung virus titers ↓ Lung IL-10, IL-12 ↔ Lung IL-6, IFN-γ (↓)
Bifidobacterium Lactobacillus Enterococcus (Bifico probiotic product) [34]	IFV A FM1 (H1N1)	BALB/c mice were subjected to 8 days of oral neomycin administration, then infected intranasally with virus. Probiotic administration by gavage for 4 days after infection	Lung IFN-γ, IL-17 ↑, IL-4, IL-10 ↓ Probiotic treatment significantly restored initial levels of upregulation of TLR7, MyD88, IRAK4, TRAF6, and NF-kB mRNA expression
L. plantarum NCIMB 8826 L. reuteri F275 [35]	Pneumonia virus of mice J3666	BALB/c and C57BL/6 mice, intranasal inoculation of 2 weekly doses 2 weeks before infection	Protection against virus infection ↑ Granulocyte recruitment ↓ CXCL10, CXCL1, CCL2,TNF↓ Virus recovery ↓
[36]			Live L. reuteri: Neutrophil recruitment ↑ CXCL1, CCL3, CCL2, CXCL10, TNF-α, IL-17A ↑ IFN-α, IFN-β, IFN-γ ↔
L. rhamnosus CRL1505 L. rhamnosus CRL1506 [37]	Viral pathogen molecular pattern poly(I:C) + RSV A2	BALB/c mice, nasal administration for 2 days before infection	BALF + serum IL-6, IFN-α,IFN-β, TNF-α, IL-10 ↑ Lung viral loads↓ Strains differentially modulated TLR3/RIG-I-triggered antiviral respiratory immune response

Abbreviations for columns:

Probiotic strain: L = Lactobacillus; B. = Bifidobacterium

Virus: IFV = influenza virus; RSV = respiratory syncytial virus

Main findings: IL = interleukin; IFN = interferon; TNF = tumor necrosis factor; MLN = mediastinal lymph node; NK = natural killer cell; BALF = bronchoalveolar lavage fluid

↑ = significant increase; ↓ = significant decrease; ↔ = no significant effect