Combined Inhibition of the TGF-β1/Smad Pathway by Prevotella copri and Lactobacillus murinus to Reduce Inflammation and Fibrosis in Primary Sclerosing Cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by inflammation and fibrosis of the bile ducts. Cholestasis may lead to hepatic inflammation and fibrosis, and amelioration of cholestasis may allow recovery from inflammatory and fibrotic pathological damage. Prevotella copri (P. copri) interventions have been reported to significantly improve cholestasis and liver fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced PSC mouse models. Even though P. copri treatment alone cannot bring about recovery from DDC-induced inflammation, it increases the abundance of Lactobacillus murinus (L. murinus) compared with DDC treatment, which has been reported to have anti-inflammatory effects. The abundance of L. murinus still not recovering to a normal level may underlie hepatic inflammation in P. copri + DDC mice. Separate or combined interventions of P. copri and L. murinus were used to investigate the molecular mechanism underlying the improvement in PSC inflammation and fibrosis. P. copri and L. murinus significantly reduced the hepatic inflammatory cell aggregation and inflammatory factor expression as well as the hepatic collagen content and fibrin factor expression in the PSC mice. Further analysis of phosphorylation and dephosphorylation levels revealed that treating the PSC mice with the P. copri and L. murinus combined intervention inhibited the activity of the DDC-activated TGF-β1/Smad pathway, thereby reducing liver inflammation and fibrosis. The combination of P. copri and L. murinus inhibits the TGF-β1/Smad pathway and reduces inflammation and fibrosis in PSC.

The effect of gut microbiome and plasma metabolome on systemic sclerosis: a bidirectional two-sample Mendelian randomization study

“…Tocilizumab, a drug that targets IL-6R, has shown beneficial improvements in skin and pulmonary fibrosis in SSc ( Denton et al, 2018 ). Previous studies shown that in other fibrotic diseases, Prevotella can inhibit the TGF-β/Smad signaling pathway and reduce the release of IL-6 to improve fibrosis ( Bertelsen et al, 2021 ; Shen et al, 2023 ). Therefore, it is important to investigate the protective mechanism of Prevotella in SSc for the prevention and treatment of SSc.…”

Bacterial diversity in cheese wastewater using Next-Generation Sequencing (NGS)

“…Jiang et al (2020) show that Lactobacillus mucosae can lower cholesterol. In the research of Shen et al (2023), Lactobacillus murinus is identified as having the ability to lower cholesterol levels.…”

Prevotella copri—a potential next‐generation probiotic

“…FXR can increase the absorption of BA in the intestine and regulate the balance of BA in the intestinal and hepatic circulation (Jiang, Yuan, et al, 2022). In addition, P. copri may reduce hepatic inflammation and fibrosis in mice with PSC through TGF-β1/Smad signal transduction, and the addition of Lactobacillus rhamnosus may promote the P. copri-induced improvement of inflammation in mice with PSC (Shen et al, 2023).…”

“…However, inflammation induced by P. copri only occurs when the intestinal mucosa is damaged (Shen et al, 2023). After antibiotic treatment, the abundance of all bacteria, including P. copri, is reduced, and carboplatin-induced intestinal mucosal inflammation is alleviated.…”