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Berberine has been demonstrated to alleviate renal interstitial, liver and myocardial fibrosis when administered orally despite its extremely low bioavailability. Here, we inspected effect of berberine on pulmonary fibrosis (PF) and explored underlying mechanisms on the basis of intestinal endocrine. The results showed that either oral or rectal administration of berberine exhibited marked alleviation of bleomycin-induced PF in mice. In contrast, anti-PF activity of berberine disappeared when given by an intravenous injection, implying that it functioned in a gut-dependent manner. Moreover, berberine promoted both mRNA and protein levels of HGF and PTEN in colons, but only their protein levels in lungs of PF mice. In addition, SU11274 but not BPV abolished the anti-PF effect of berberine. In vitro, berberine preferentially induced expression of HGF in fibroblast cells than epithelial, preadipocyte and endothelial cells. Similarly, rosiglitazone and 15dPGJ2 also enhanced expression of HGF in fibroblasts cells, and GW9662 and siPPAR-γ diminished induction of berberine on HGF expression. Berberine could enter into the cytoplasm, activate PPAR-γ directly and synergistically with 15dPGJ2, as shown by an up-regulation of CD36 and aP2 mRNA expression, nuclear translocation and DNA-binding activity of PPAR-γ both in vitro and in vivo. Additionally, GW9662 almost abolished anti-PF effect of berberine and induction of HGF expression in colons. In conclusion, oral administration of berberine displays anti-PF action probably in a colon-dependent manner, and mechanisms involve activation of PPAR-γ and resultant promotion of HGF expression in colonic fibroblasts. The up-regulated HGF arrives in lung tissues via blood circulation to palliate PF.Oral berberine could alleviate bleomycin-induced PF in mice in a colon-dependent manner.HGF but not PTEN was the key mediator for anti-PF effect of berberine.Berberine activated PPAR-γ and subsequently promoted HGF secretion in colons.Berberine had synergistic effect with 15dPGJ2 for PPAR-γ activation.PPAR-γ was the key mediator for berberine-mediated anti-PF effect.