Cryptotanshinone alleviates chemotherapy-induced colitis in mice with colon cancer via regulating fecal-bacteria-related lipid metabolism

Patients with colorectal cancer treated with 5-fluorouracil (5-FU) and irinotecan (CPT-11) exhibit a risk for chemotherapy-induced colitis (CIC) that may lead to fatal consequences. Cryptotanshinone (CTS) is a natural compound extracted from the root of Salvia miltiorrhiza Bunge that shows potent antitumor activities. We previously reported CTS relieved 5-FU/CPT-11 induced colitis in tumor-free mice. In this study, we studied the effect of CTS on 5-FU/CPT-11 induced colitis in mice with colitis associated colon cancer (CAC). The effects of CTS on CIC were evaluated by disease activity index (DAI) and histological assessment via hematoxylin-and-eosin staining. Serum lipids and lipid-metabolic enzymes were detected by commercial kits. Fecal microbial diversity was detected by 16S ribosomal RNA gene sequencing. To find the role of fecal bacteria in CAC mice with 5-FU/CPT-11 induced colitis, pseudo-germ-free mice were established by intragastric administration of mixed antibiotics. Except for decreasing tumor number (3 +/- 1 vs 6 +/- 1, p < 0.05), CTS significantly alleviated DAI (1.9 +/- 0.6 vs 2.6 +/- 0.5, p < 0.05) and regulated serum lipids in CAC mice with 5-FU/CPT-11 induced colitis. Compared with model group, CTS significantly increased serum triglycerides (TG) (1.13 +/- 0.26 mM vs 0.79 +/- 0.03 mM, p < 0.05), high density lipoprotein (HDL) (3.88 +/- 0.1 mM vs 3.28 +/- 0.05 mM, p < 0.001) and oxidized low-density lipoprotein (oxLDL) (288.12 +/- 65.92 ng/mL vs 150.72 +/- 42.13 ng/mL, p < 0.05) level but decreased serum adiponectin level (1177.47 +/- 179.2 pg/mL vs 1523.43 +/- 91.8 pg/mL, p < 0.05). Among fecal bacteria significantly correlated with lipid metabolism, CTS significantly decreased the abundance of g norankj Muribaculaceae (21.15 % +/- 5.7 % vs 41.84 +/- 12.0 %, p < 0.01) but increased that of g Lactobacillus (11.13 % +/- 6.6 % vs 5.7 % +/- 4.6 %, p < 0.05), g Alistipes (3.66 % +/- 0.7 % vs 1.47 % 1,0%, p < 0.01) and g Odoribacter (1.31 % +/- 0.7 % vs 0.30 % +/- 0.2 %, p < 0.01). In addition, the development of CIC and abnormal lipid metabolism were significantly prevented in pseudo-germ-free mice. Therefore, we concluded CTS alleviated 5FU/CPT-11 induced colitis in CAC mice via regulating fecal flora associated lipid metabolism.

Automated summary

The study found that cryptotanshinone can significantly alleviate 5-FU/CPT-11 induced colitis in mice with colitis associated colon cancer by regulating lipid metabolism associated with fecal bacteria.