TABLE 2.

Effects of gut microbiome metabolites in pulmonary fibrosis.

Metabolites	Variation trend	Effector	Effector mechanism	References
Glutamate	Increase	Collagen production	Glutamic–glutamine cycle involves in collagen production of myofibroblasts	Bernard et al., 2018; Hamanaka et al., 2019
		Fibroblasts apoptosis	Glutamine promotes anti-apoptosis of IPF fibroblasts through epigenetic regulation of apoptosis suppressor proteins	Bai et al., 2019
Arginine	Increase	Airway tension	NO produced by arginine metabolism is involved in regulating airway tension and affecting respiratory immune stress	Fu et al., 2020
		Collagen deposition	Proline from arginine metabolism is the rate-limiting substrate in collagen synthesis and is essential for collagen precipitation in pulmonary fibrosis	Niese et al., 2010; Roque and Romero, 2021
		Fibroblasts activation	Arginine depletion attenuates the proliferation, migration and invasion of fibroblasts, thereby slowing down pulmonary fibrosis	Li et al., 2021
		Immune imbalance	Arginine combined with norvaline can correct the imbalance of immune cells in BLM mice	Gao et al., 2019
		Macrophage activation	Arginine induces the increase of GSH and inhibits the release of various proinflammatory cytokines from the macrophage	Hnia et al., 2008
		Collagen degradation	Arginine inhibits the activation of NF-κB to reduce MMP-2 and MMP-9 activities	Wang et al., 2015
Tryptophan	Decrease	T cell immune response	Metabolic derivatives of tryptophan produced by IDO reduce T cell inflammation	Lou et al., 2019
		T cell differentiation	Tryptophan and its metabolites regulate the transcription of multiple genes to affect T cell differentiation	Rothhammer and Quintana, 2019; Takei et al., 2020
		Collagen generated	The metabolite 5-MTP reduces myofibroblasts aggregation, differentiation and collagen precipitation	Fang et al., 2020
Butyrate	-	Gene expression	Butyrate inhibits Thy-1 gene expression and pulmonary fibrosis by inhibiting HDAC activation	Zhu et al., 2016
		Fibroblasts activation	Butyrate inhibits histone 3 acetylation to affect fibroblasts activation and exert antifibrotic effect	Park et al., 2021
		TGF-β1 production	The combination of valproic acid and butyric acid reduces the amount of NF-κB entering the nucleus and the production of TGF-β1, thereby alleviating pulmonary fibrosis	Chen et al., 2006; Sakai and Tager, 2013
Bile acid	Increase	Collagen generated	Bile acid stimulates fibrotic mediators to activate TGF-β1/SMAD3 signaling pathway and bile acid receptor FXR or induce the activation of alveolar epithelial cells and lung fibroblasts	Chen et al., 2016, 2017
PSA	Increase	Inflammatory response	PSA through TLR2 induces Foxp3+ Treg to produce IL-10 and TGF-β2	Round and Mazmanian, 2010
Valproic	Decrease	Epithelial-to-mesenchymal transition	Valproic affects histone H3K27 acetylation to inhibit epithelial-mesenchymal transition	Noguchi et al., 2015

IPF, idiopathic pulmonary fibrosis; NO, nitric oxide; BLM, bleomycin; GSH, glutathione; NF-κB, B-cell nuclear factor κ; MMP, matrix metalloproteinase; IDO, indoleamine 2,3-dioxygenase-1; AhR, aryl hydrocarbon receptor; 5-MTP, 5-methoxytryptophan; HDAC, histone deacetylase; TGF-β, transforming growth factor-β; PSA, polysaccharide A; TLR2, Toll-like receptor 2; Treg, regulatory T cell; IL-10, interleukin-10.