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-11induced 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__norank_f__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.

Keywords: chemotherapy-induced colitis (CIC); colitis-associated colon cancer (CAC); cryptotanshinone; fecal microbiota; lipid metabolism.