Bile acid distributions, sex-specificity, and prognosis in colorectal cancer

Cai, Yuping and Shen, Xinyi and Lu, Lingeng and Yan, Hong and Huang, Huang and Gaule, Patricia and Muca, Engjel and Theriot, Casey M. and Rattray, Zahra and Rattray, Nicholas J. W. and Lu, Jun and Ahuja, Nita and Zhang, Yawei and Paty, Philip B. and Khan, Sajid A. and Johnson, Caroline H. (2022) Bile acid distributions, sex-specificity, and prognosis in colorectal cancer. Biology of Sex Differences, 13 (1). 61. ISSN 2042-6410 (

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Background Bile acids are known to be genotoxic and contribute to colorectal cancer (CRC). However, the link between CRC tumor bile acids to tumor location, patient sex, microbiome, immune-regulatory cells, and prognosis is not clear. Methods We conducted bile acid analysis using targeted liquid chromatography–mass spectrometry (LC–MS) on tumor tissues from CRC patients (n = 228) with survival analysis. We performed quantitative immunofluorescence (QIF) on tumors to examine immune cells. Results Twelve of the bile acids were significantly higher in right-sided colon tumors compared to left-sided colon tumors. Furthermore, in male patients, right-sided colon tumors had elevated secondary bile acids (deoxycholic acid, lithocholic acid, ursodeoxycholic acid) compared to left-sided colon tumors, but this difference between tumors by location was not observed in females. A high ratio of glycoursodeoxycholic to ursodeoxycholic was associated with 5-year overall survival (HR = 3.76, 95% CI = 1.17 to 12.1, P = 0.026), and a high ratio of glycochenodeoxycholic acid to chenodeoxycholic acid was associated with 5-year recurrence-free survival (HR = 3.61, 95% CI = 1.10 to 11.84, P = 0.034). We also show correlation between these bile acids and FoxP3 + T regulatory cells. Conclusions This study revealed that the distribution of bile acid abundances in colon cancer patients is tumor location-, age- and sex-specific, and are linked to patient prognosis. This study provides new implications for targeting bile acid metabolism, microbiome, and immune responses for colon cancer patients by taking into account primary tumor location and sex.