Obesity or high-fat diet enhances gut permeability and metabolic endotoxemia, which can trigger insulin resistance and NASH. However, there are few promising treatments targeting lipotoxicity-mediated endotoxemia in NASH. The Lactobacillus pentosus strain S-PT84 has immunomodulatory functions including Th1/Th2 balance modulatory effects and natural killer (NK)/NKT cell activation. In this study, we examined the effect of S-PT84 on diet-induced NASH. C57BL/6 mice were fed a high-cholesterol/high-fat diet (CL) alone or with 1×1010 S-PT84 (CL + S-PT) for 22 weeks. We quantified intrahepatic immune cells using a fluorescence-activated cell sorter (FACS). S-PT84 administration improved hepatic steatosis by decreasing TG and FFA levels by 34% and 37%, respectively. S-PT84 also inhibited the development of hepatic inflammation and fibrosis, lowering F4/80+ macrophage/Kupffer cell infiltration and the hydroxyproline content of the liver. S-PT84 administration in mice fed a CL diet led to improved hyperinsulinemia as well as enhanced hepatic insulin signal assessed by phospho-Akt. FACS analysis revealed that mice fed the CL+S-PT had 71% more CD11c-CD206+ M2 macrophages than mice fed the CL diet, resulting in a predominance of the M2 over the M1 macrophage population. S-PT84, however, showed little effect on NK/NKT cell and T regulatory cell populations in the liver. Furthermore, CL diet increased intestinal permeability as measured with the carboxyfluoresce assay and increased plasma lipopolysaccharide binding protein (LBP) levels. S-PT84 diminished increased intestinal permeability and plasma LBP levels. Additionally, S-PT84 reduced IL-17 producing T cells and increased ZO-1, occludin, and claudin proteins constituting tight junction in colon.
In conclusion, S-PT84 treatment attenuated lipotoxicity-induced insulin resistance and NASH by maintaining gut permeability and polarizing M2 liver macrophages.
Y. Sakai: None. M. Nagashimada: None. T. Ota: None.