Butyrate, given by oral administration or in drinking water, has been shown to improve experimental pulmonary fibrosis (PF) in mice despite of very low bioavailability. The pharmacokinetic-pharmacodynamics disconnection attracts us to explore its anti-PF mechanism in view of the intestinal expression of anti-PF factors. In bleomycin-induced PF in mice, rectal administration of butyrate (500 mg/kg) exhibited a significant anti-PF effect, with a maximum plasma concentration largely lower than the minimum effective concentration (1 mM) at which butyrate inhibited the expression of pro-inflammatory factors by lung epithelial cells and the production of extracellular matrix by lung fibroblasts. The rectal administration of butyrate significantly upregulated the mRNA expression of hepatocyte growth factor (HGF) in the colons of PF mice, but showed no significant effect on the mRNA expression of HGF in the small intestines, lungs and livers. In colon epithelial cells, the monocarboxylate transporter inhibitor α-cyano-4-hydroxycinnamic acid (CHC) abrogated butyrate-induced expression of HGF, indicating that butyrate functions through entering into cells. Butyrate showed no significant effect on the histone acetylation in the promoter region of HGF, suggesting that it promotes HGF expression not by directly affecting the histone deacetylation of HGF but by other pathways. GW9662, the inhibitor of PPARγ, significantly attenuated the effect of butyrate to promote the mRNA expression of HGF. Butyrate was able to enhance the acetylation of PPARγ, and a targeted mutation of lysine at the position 240 (K240) of PPARγ markedly diminished the induction of butyrate on HGF expression, suggesting that butyrate promoted HGF expression in colon epithelial cells by upregulating PPARγ K240 acetylation. In summary, rectal administration of butyrate promotes the expression of HGF in colonic epithelial cells through upregulating PPARγ acetylation via inhibition of HDAC activity. The findings of the present study provide a reasonable explanation for the anti-PF action mode of butyrate based on the 'lung-gut axis', and found that intestine-derived butyrate and HGF may be involved in the modulation of the occurrence and progression of PF.