Synbiotics Bifidobacterium infantis and milk oligosaccharides are effective in reversing cancer-prone non-alcoholic steatohepatitis using Western diet-fed FXR knockout mouse models

摘要

Prebiotic milk oligosaccharides (MO) are complex sugars that selectively enhance the growth of Bifidobacterium infantis (B. infantis). The current study examines the effects of bovine MO and B. infantis in preventing non-alcoholic steatohepatitis (NASH) in Western diet (WD)-fed bile acid (BA) receptor FXR (farnesoid × receptor) knockout (KO) mice. WD-fed FXR KO mice, which have cancer-prone NASH and reduced B. infantis, were supplemented with B. infantis, MO, and combination of both. Two months intervention by B. infantis and/or MO improved insulin sensitivity. In addition, all 3 treatments reduced expression of pro-inflammatory genes in the liver and ileum. Consistently, 7 months treatment reduced hepatic lymphocyte infiltration in WD-fed FXR KO mice. In addition, B. infantis, but not MO, decreased hepatic triglyceride and cholesterol. A combination of both further reduced hepatic cholesterol, the precursor of BAs, but not hepatic triglyceride. All three treatments modulated hepatic and serum BA profile by reducing deoxycholic acid, hyodeoxycholic acid and increasing chenodeoxycholic acid as well as ursodeoxycholic acid level. In addition, B. infantis and MO decreased hepatic CYP7A1 and increased the expression of Sult2a1, Sult2a2, and Sult2a3 suggesting decreased BA synthesis and increased detoxification. Furthermore, B. infantis and MO increased ileal BA membrane receptor TGR5 as well as Glp1r, PC1/3, and Nos3 suggesting increased TGR5-regulated signaling. Moreover, MO alone, but not B. infantis, could increase the abundance of butyrate-generating bacterium that has beneficial effect in NASH treatment. Together, B. infantis and MO have their unique and combined effects in reversing NASH in WD-fed FXR KO mice.