The Gut Microbiota and Respiratory Diseases: New Evidence

Table 1

The possible mechanisms underlying the effects of the gut microbiota on respiratory diseases.

Respiratory diseases	Alterations in the gut microbiota	Possible mechanisms	References
Asthma	Gut microbiota disrupted by antibiotics	Exacerbate Th2 responses by increasing the infiltration of inflammatory cells and the production of inflammatory cytokines (IL-4 and IL-13).	[117, 118]
		Reduce Treg abundance in the lung.	[119]
		Exaggerate Th1/Th17 adaptive immune responses in the lung.	[120]
	GF mice	Elevate the total number of eosinophils, number of CD4^+ T cells, and level of Th2 cytokines and alter the number and phenotype of conventional DCs in the airways.	[114]
		Increase CXCL16 expression and accumulate iNKT cells in the gut and lungs.	[121]
	Probiotics	Reverse the Th1/Th2 imbalance: increase the levels of the anti-inflammatory cytokine IL-10 while reduce the levels of proinflammatory cytokines such as IL-4, IL-5, and IL-13.	[122–125]
		Increase PPARγ expression of DCs in the lung.	[126]
		Increase lung CD4^+ T cell and CD4^+Foxp3^+ Treg abundance while decrease activated CD11b^+ DC abundance.	[37]
		Decrease MMP9 expression in the BALF and serum and inhibit inflammatory cell infiltration into the lung.	[36]
COPD	Cigarette smoke	Alter mucin gene expression and cytokine production in the gut; increase Muc2, Muc3, and Muc4 expression; and increase CXCL2 and IL-6 expression while decrease IFN-γ and TGF-β expression.	[54]
		Inhibit the NK-κB pathway by reducing p65 phosphorylation and IκBα in the gut.	[127]
	Probiotics	Suppress macrophage inflammation by inducing the expression of IL-1β, IL-6, IL-10, IL-23, TNF-α, CXCL-8, and HMGB1.	[58]
		Increase NK cell activity and the number of CD16^+ cells.	[128]
CF	Probiotics	Reduce IL-8 production by intestinal cells.	[129]
		Reduce the level of the gut inflammatory marker calprotectin.	[68]
	Antibiotic treatment	Augment the proportions of Th17, CD8^+ IL-17^+, and CD8^+ IFNγ^+ lymphocytes and IL-17-producing γδ T cells.	[130]
Lung cancer	Gut microbiota disrupted by antibiotics	Upregulate the expression of VEGFA and downregulate the expression of BAX and CDKN1B while reduce IFN-γ, GZMB, and PRF1 produced by CD8^+ T cells.	[131]
		Suppress CTX-induced Th17 responses and reduce the abundance of tumor-infiltrating CD3^+ T cells and Th1 cells.	[132]
	FMT	Accumulate CCR9^+CXCR3^+CD4^+ T cells into the tumor microenvironment.	[79]
	Probiotics	Upregulate the mRNA levels of IFN-γ, GZMB, and PRF1.	[131]
		Boost CTX-induced anticancer Th1 and Tc1 responses and promote the infiltration of IFN-γ^+γδT cells into cancer lesions.	[80]
Respiratory infection	Commensal gut microbiota	SFB promotes pulmonary Th17 immunity as demonstrated by increased IL-22 and IL-22^+ TCRβ^+ cell levels.	[133]
		Protect against Mtb infection by improving the activity of MAIT cells in the lungs.	[89]
		Regulate virus-specific CD4 and CD8 T cell and antibody responses.	[134]
		Contribute to the accumulation of IL-22-producing ILC3s in newborn lung.	[81]
		Induce NF-κB activation in the lung through TLR4.	[135, 136]
	Gut microbiota disrupted by antibiotics	Reduce pulmonary GM-CSF production through IL-17A signaling.	[115]
		Reduce MAIT cell and IL-17A levels.	[89]
		Reduce mincle expression on lung DCs.	[95]
		Decrease bacterial killing activity of alveolar macrophages while increase the levels of proinflammatory cytokines such as IL-6 and IL-1β in the lung.	[136]
	GF mice	Decrease proinflammatory cytokine (TNF-α and CXCL1) levels and neutrophil influx while produce large amounts of IL-10 in the lungs.	[137]
	FMT	Normalize the pulmonary TNF-α and IL-10 levels.	[82]
	Probiotics	Activate the TLR-signaling pathway through the protein Mal.	[85]
		Enhance the mRNA expression of IFN-γ, IL-12a, IL-2rb, IL-12rb1, PRF1, Klrk1, CD247, and TNF-α in the lung.	[138]
ALI	FMT	Reduce TNF-α, IL-1β, and IL-6 levels by downregulating the TGF-β1/Smads/ERK signaling pathway.	[102]

ALI: acute lung injury; BAX: Bcl-2 associated X; CDKN1B: cyclin-dependent kinase inhibitor 1B; CTX: cyclophosphamide; CXCL: C-X-C motif chemokine ligand; DCs: dendritic cells; ERK: extracellular signal-regulated kinase; FMT: fecal microbiota transplantation; GF mice: germ-free mice; GM-CSF: granulocyte-macrophage colony-stimulating factor; GZMB: granzyme B; HMGB1: high-mobility group box 1; IFN-γ: interferon-gamma; IκBα: inhibitor of NK-κB α; Klrk1: killer cell lectin-like receptor subfamily K, member 1; MAIT cells: mucosal-associated invariant T cells; Mal: MyD88 (myeloid differentiation primary response protein) adaptor protein; MMP9: matrix metalloproteinase 9; Muc: mucin; NF-κB: nuclear factor kappa-B; PPARγ: peroxisome proliferator-activated receptor gamma; PRF1: perforin; SFB: segmented filamentous bacteria; TLR: toll-like receptor; TNF-α: tumor necrosis factor alpha; Tregs: regulatory T cells; VEGFA: vascular endothelial growth factor A.