The effect of TU-100 on hepatocarcinogenesis and colorectal liver metastasis in MASH model.

577 Background: TU-100 is most commonly used herbal medicine in clinical setting. We have already reported that TU-100 suppressed dysbiosis (J Med Invest, 2013), bacterial translocation (Surg Today, 2017) and hepatic fibrosis (Surgery, 2016). This time we investigate the effect of TU-100 on hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in MASH model. Methods: 1: Effect on HCC: Seven-week-old Tsumura Suzuki obese diabetes mice, a model that shows the spontaneous onset of MASH and HCC, were used. They were divided into a TU-100 treated group and a control group. Mice were sacrificed at 24 and 48 weeks to evaluate hepatic steatosis, fibrosis, carcinogenesis, cytokine expression, and microbiome abundance. 2: Effect on CRLM: Six-week-old male C57BL/6J mice were used. They were divided into the western diet (WD) group and the WD+TU-100 group. MC38 colon cancer cells were injected into the spleen at 16 weeks, and mice were killed at 2 weeks after injection to evaluate hepatic steatosis, fibrosis and mRNA expression in the liver. Results: 1: Effect on HCC: At 24 weeks, the TU-100 group showed significantly lower expression of IL6, IL1B, and ACTA2 mRNA in the liver (P<0.05). At 48 weeks, the TU-100 group showed a lower rate of MASH than the control group (28% vs 72%; P=0.1). Tumor diameter was significantly smaller in the TU-100 group compared with that in the control group (P<0.05). Regarding the intestinal microbiome, the genera Blautia and Ruminococcus were increased in the TU-100 group (P<0.05), whereas Dorea and Erysipelotrichaceae were decreased in the TU-100 group (P<0.05). 2: Effect on CRLM: Steatosis of the WD+TU-100 group was significantly suppressed compared with the WD group (p<0.05). The WD+TU-100 group showed significantly smaller tumor diameter than the WD group (p<0.05). In the WD+TU-100 group, expression of SAA1 and TIMP1 mRNA in the liver was significantly lower than in the WD group (p<0.05). Conclusions: TU-100 regulates the intestinal microbiome and may suppress hepatic steatosis and subsequent hepatocarcinogenesis in the MASH model. Furthermore, TU-100 may have effect on CRLM via suppression of SAA1/TIMP1.